Unfolding the pathogenesis of scleroderma through genomics and epigenomics

Publication date: Available online 16 May 2017
Source:Journal of Autoimmunity
Author(s): Pei-Suen Tsou, Amr H. Sawalha
With unknown etiology, scleroderma (SSc) is a multifaceted disease characterized by immune activation, vascular complications, and excessive fibrosis in internal organs. Genetic studies, including candidate gene association studies, genome-wide association studies, and whole-exome sequencing have supported the notion that while genetic susceptibility to SSc appears to be modest, SSc patients are genetically predisposed to this disease. The strongest genetic association for SSc lies within the MHC region, with loci in HLA-DRB1, HLA-DQB1, HLA-DPB1, and HLA-DOA1 being the most replicated. The non-HLA genes associated with SSc are involved in various functions, with the most robust associations including genes for B and T cell activation and innate immunity. Other pathways include genes involved in extracellular matrix deposition, cytokines, and autophagy. Among these genes, IRF5, STAT4, and CD247 were replicated most frequently while SNPs rs35677470 in DNASE1L3, rs5029939 in TNFAIP3, and rs7574685 in STAT4 have the strongest associations with SSc. In addition to genetic predisposition, it became clear that environmental factors and epigenetic influences also contribute to the development of SSc. Epigenetics, which refers to studies that focus on heritable phenotypes resulting from changes in chromatin structure without affecting the DNA sequence, is one of the most rapidly expanding fields in biomedical research. Indeed extensive epigenetic changes have been described in SSc. Alteration in enzymes and mediators involved in DNA methylation and histone modification, as well as dysregulated non-coding RNA levels all contribute to fibrosis, immune dysregulation, and impaired angiogenesis in this disease. Genes that are affected by epigenetic dysregulation include ones involved in autoimmunity, T cell function and regulation, TGFβ pathway, Wnt pathway, extracellular matrix, and transcription factors governing fibrosis and angiogenesis. In this review, we provide a comprehensive overview of the current findings of SSc genetic susceptibility, followed by an extensive description and a systematic review of epigenetic research that has been carried out to date in SSc. We also summarize the therapeutic potential of drugs that affect epigenetic mechanisms, and outline the future prospective of genomics and epigenomics research in SSc.



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Chronic Inflammatory Pain Impairs mGluR5-Mediated Depolarization-Induced Suppression of Excitation in the Anterior Cingulate Cortex

Abstract

The anterior cingulate cortex (ACC) is a critical hub for nociceptive perception and pain-related anxiety. Long-term synaptic plasticity in ACC was found to be important for chronic inflammatory pain and pain-related anxiety. As short-term synaptic plasticity, depolarization-induced suppression of excitation (DSE) is involved in several conditions, such as chronic stress, epilepsy, and autism. However, it is still unknown whether DSE in the ACC is involved in the central sensitization of pain and anxiety. Using a whole-cell patch clamp, calcium imaging, western blot, and behavioral testing, we found that DSE was induced by a 2 s depolarization in postsynaptic pyramidal cells in ACC. DSE was mediated by endocannabinoid signaling and modulated by metabotropic glutamate receptor 5 (mGluR5). DSE was impaired by decreasing expression and dysfunction of mGluR5 in a mouse model of inflammatory pain induced by complete Freund's adjuvant. CDPPB, an mGluR5-positive allosteric modulator, could rescue hypersensitivity and anxiety-like behavior in this pain model. Our results demonstrated that mGluR5-mediated short-term plasticity in ACC may be a critical mechanism for chronic pain, and mGluR5 may potentially serve as a target of pain therapy, including treatments for hyperalgesia and anxiety.

http://ift.tt/2rpm1ez

Atypical Endocannabinoid Signaling Initiates a New Form of Memory-Related Plasticity at a Cortical Input to Hippocampus

Abstract

Endocannabinoids (ECBs) depress transmitter release at sites throughout the brain. Here, we describe another form of ECB signaling that triggers a novel form of long-term potentiation (LTP) localized to the lateral perforant path (LPP) which conveys semantic information from cortex to hippocampus. Two cannabinoid CB₁ receptor (CB₁R) signaling cascades were identified in hippocampus. The first is pregnenolone sensitive, targets vesicular protein Munc18-1 and depresses transmitter release; this cascade is engaged by CB₁Rs in Schaffer–Commissural afferents to CA1 but not in the LPP, and it does not contribute to LTP. The second cascade is pregnenolone insensitive and LPP specific; it entails co-operative CB₁R/β1-integrin signaling to effect synaptic potentiation via stable enhancement of transmitter release. The latter cascade is engaged during LPP-dependent learning. These results link atypical ECB signaling to the encoding of a fundamental component of episodic memory and suggest a novel route whereby endogenous and exogenous cannabinoids affect cognition.

http://ift.tt/2qPYExz

Nanostructures based on protein self-assembly: From hierarchical construction to bioinspired materials

Publication date: Available online 16 May 2017
Source:Nano Today
Author(s): Hongcheng Sun, Quan Luo, Chunxi Hou, Junqiu Liu
Sophisticated protein self-assemblies have attracted great scientific interests in recent few decades due to their various potential applications in substance/signal transmission, biosensors, or disease diagnosis and treatment. The design and construction of proteins into hierarchical nanostructures via self-assembly strategies offer unique advantages in understanding the mechanism of naturally occurring protein assemblies and/or creating various functional biomaterials with advanced properties. This review covers the recent progress and trends in the self-assembled hierarchical protein structures and their bio-inspired applications. We initially discuss the design and development of sophisticated protein nanostructures through the preciously designed protein–protein interactions. Many intricate protein nanostructures from quasi-zero dimensional (0D) polyhedral cages, one-dimensional (1D) strings/rings/tubules, two-dimensional (2D) crystal sheets/cambered surfaces, and three-dimensional (3D) crystalline frameworks/hydrogels, have been constructed through self-assembly of rationally designed proteins. In addition, we also show the representative achievements in the study of the structure–function relationship for selected protein self-assemblies and highlight the latest research progress in developing artificial light harvesting systems, biological nanoenzyme mimics, intelligent protein nanocarriers, biomimetic protocells, and so on. As expected, protein self-assembly has become a powerful tool for development of multifarious bioinspired materials with advanced structures and properties.

Graphical abstract

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Synthesis and Pharmacological Evaluation of novel chromone derivatives as balanced multifunctional agents against Alzheimer's disease

Publication date: Available online 17 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Fan Li, Jia-Jia Wu, Jin Wang, Xue-Lian Yang, Pei Cai, Qiao-Hong Liu, Ling-Yi Kong, Xiao-Bing Wang
In a continuing effort to develop multitargeted compounds as potential treatment agents against Alzheimer's disease (AD), a series of chromone derivatives were designed, synthesized and evaluated. In vitro assay indicated that most of the target compounds have both MAOs inhibition activities, antioxidant activity and biometal chelating ability. Especially, compound s19 exhibits good inhibitory potency for inhibition of MAOs (IC50 value of 5.12 μM for hMAO-A and 0.816 μM for hMAO-B), moderate inhibition of Aβ aggregation (75.1% at 20 μM), metal chelation, control of ROS generation and antioxidant activity (ORAC = 3.62). In addition, s19 could reduce PC12 cells death induced by oxidative stress and penetrate the blood–brain barrier (BBB). Taken together, these results suggested that s19 might be a promising multitargeted compound for AD treatment.

Graphical abstract

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Increased oral inflammation, leukocytes, and leptin, and lower adiponectin in overweight or obesity

Objectives

The association between body mass index (BMI) and oral diseases was investigated, and levels of obesity-related inflammatory mediators were evaluated.

Subjects and Methods

Participants (n = 160) were clinically and radiographically examined for oral diseases. Blood profiles were recorded. Levels of adiponectin, leptin, and C-reactive protein (CRP) were measured.

Results

One hundred and thirteen (70.6%) participants had overweight or obese status (BMI ≥ 23.0 kg/m²). Sum of dental diseases and severe periodontitis were higher in overweight or obese individuals than in normal-weight participants (p = .037 and p = .002, respectively). A significant difference in oral mucosal disorders between normal weight and overweight or obesity was not found. Plasma leukocyte counts, liver enzymes, leptin, and CRP levels were increased while adiponectin levels were decreased in individuals with BMI≥23.0 kg/m² compared with normal-weight participants. After adjusting for age, sex, fasting plasma glucose level, smoking, and exercise, obesity was associated with sum of dental diseases (ß = 0.239, p = .013), severe periodontitis (OR=4.52; 95% CI 1.37, 14.95, p = .013), adiponectin (ß = –0.359, p < .001), leptin (ß = 0.630, p < .001), and CRP levels (OR=12.66; 95% CI 3.07, 52.21, p < .001).

Conclusion

Overweight or obese Thai people were related to an increase in inflammatory dental and periodontal diseases with an altered health profile and plasma inflammatory mediators.

http://ift.tt/2rp9LtS

Title Page/Sections Editors

Publication date: May 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 5





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Assessment of the efficacy and safety of a new complex skin cream in Asian women: A controlled clinical trial

Summary

Background

Medical products such as hydroquinone and tretinoin have been widely used to treat various types of skin hyperpigmentation. However, these products are limited in daily use given their adverse effects. Other alternative agents with fewer adverse side effects have been developed. However, single agents often do not produce satisfactory results.

Aims

To evaluate the efficacy and safety of a new brightening complex cream containing niacinamide, tranexamic acid, oxyresveratrol, glutathione disulfide, and linoleic acid.

Patients and Methods

A total of 26 Korean women seeking to lighten their skin were enrolled. The product was applied on the face two times per day for 12 weeks. Standardized photographs were taken at baseline, 4 weeks, 8 weeks, and 12 weeks. Efficacy was assessed using melanin index (MI), erythema index (EI), and chromatic aberration values (L*, a*, and b*). Improvement perceived by investigators and patients was measured as well.

Results

The L*-value was increased at 8 weeks (0.7±2.5, P<.05) and at 12 weeks (0.8±2.5, P<.05). The MI was significantly decreased at 8 weeks (−4.2±4.5, P<.05) and at 12 weeks (−3.8±4.8, P<.001). The EI was significantly improved at 12 weeks (−3.2±2.2, P<.001). More than 80% of patients were considered improved at 12 weeks based on the view of the investigators and patients.

Conclusions

The new brightening complex cream was proved to be effective and safe in Asian women.

http://ift.tt/2qPIeFz

Assessment of the efficacy and safety of a new complex skin cream in Asian women: A controlled clinical trial

Summary

Background

Medical products such as hydroquinone and tretinoin have been widely used to treat various types of skin hyperpigmentation. However, these products are limited in daily use given their adverse effects. Other alternative agents with fewer adverse side effects have been developed. However, single agents often do not produce satisfactory results.

Aims

To evaluate the efficacy and safety of a new brightening complex cream containing niacinamide, tranexamic acid, oxyresveratrol, glutathione disulfide, and linoleic acid.

Patients and Methods

A total of 26 Korean women seeking to lighten their skin were enrolled. The product was applied on the face two times per day for 12 weeks. Standardized photographs were taken at baseline, 4 weeks, 8 weeks, and 12 weeks. Efficacy was assessed using melanin index (MI), erythema index (EI), and chromatic aberration values (L*, a*, and b*). Improvement perceived by investigators and patients was measured as well.

Results

The L*-value was increased at 8 weeks (0.7±2.5, P<.05) and at 12 weeks (0.8±2.5, P<.05). The MI was significantly decreased at 8 weeks (−4.2±4.5, P<.05) and at 12 weeks (−3.8±4.8, P<.001). The EI was significantly improved at 12 weeks (−3.2±2.2, P<.001). More than 80% of patients were considered improved at 12 weeks based on the view of the investigators and patients.

Conclusions

The new brightening complex cream was proved to be effective and safe in Asian women.

http://ift.tt/2qPIeFz

Assessment of three-dimensional setup errors in image-guided pelvic radiotherapy for uterine and cervical cancer using kilovoltage cone-beam computed tomography and its effect on planning target volume margins

Nidhi Patni, Nagarjuna Burela, Rajesh Pasricha, Jaishree Goyal, Tej Prakash Soni, T Senthil Kumar, T Natarajan

Journal of Cancer Research and Therapeutics 2017 13(1):131-136

Purpose: To achieve the best possible therapeutic ratio using high-precision techniques (image-guided radiation therapy/volumetric modulated arc therapy [IGRT/VMAT]) of external beam radiation therapy in cases of carcinoma cervix using kilovoltage cone-beam computed tomography (kV-CBCT). Materials and Methods: One hundred and five patients of gynecological malignancies who were treated with IGRT (IGRT/VMAT) were included in the study. CBCT was done once a week for intensity-modulated radiation therapy and daily in IGRT/VMAT. These images were registered with the planning CT scan images and translational errors were applied and recorded. In all, 2078 CBCT images were studied. The margins of planning target volume were calculated from the variations in the setup. Results: The setup variation was 5.8, 10.3, and 5.6 mm in anteroposterior, superoinferior, and mediolateral direction. This allowed adequate dose delivery to the clinical target volume and the sparing of organ at risks. Conclusion: Daily kV-CBCT is a satisfactory method of accurate patient positioning in treating gynecological cancers with high-precision techniques. This resulted in avoiding geographic miss.

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Erratum: Effects of food insecurity on the women esophageal cancer in the Zanjan Province

Journal of Cancer Research and Therapeutics 2017 13(1):155-155



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ABCs of RhoGTPases indicating potential role as oncotargets

Indira Bora, Neeta Shrivastava

Journal of Cancer Research and Therapeutics 2017 13(1):2-8

RhoGTPases also known as molecular switches represent a family of GTP-binding proteins. They shuttle between "On" and "Off" states. In the "On" state, they activate plethora of molecules. These proteins perform a wide variety of functions involving cytoskeletal modeling, cell motility, migration, and mitosis. Members of this family are referred as master regulators of many cellular activities. Due to wide variety of portfolios attributed to RhoGTPases, their misbehavior leads to initiation and also progression of metastatic cancers. Many members of this family have been reported to be differentially regulated leading to spread of malignant cells from one site to other. These wandering cells find a comfortable site in accordance to Paget's soil and seed hypothesis and form secondary lesions. Out of multiple members of this family, RhoA and RhoC are important factors. RhoA is supposed to increase tumor proliferation when overexpressed while RhoC is responsible for tumor initiation. We searched publications on RhoGTPases, their functions and contribution in cancer development and metastasis on World Wide Web and PubMed. This review focuses on the role of Rac and Rho small GTPases in cell motility and granting the opportunistic motile behavior of aggressive cancer cells. To condense knowledge from existing literature about the roles played by these molecular switches, their structural and functional ramifications are introduced in the beginning followed by an account on their wrong behavior that leads to oncogenesis and oncoprogression. This piece of work highlights members of RhoGTPases as viable oncotargets.

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The association between rs1972820 and the risk of breast cancer in Isfahan population

Narges Zabihi, Samira Sadeghi, Hossein Tabatabaeian, Kamran Ghaedi, Mansoureh Azadeh, Mohammad Fazilati

Journal of Cancer Research and Therapeutics 2017 13(1):26-32

Context: A number of single nucleotide polymorphisms (SNPs) in ERBB4 gene have been linked to increase the risk of breast cancer. However, no study has been dedicated to analyze the significance of microRNA-related SNP rs1972820, located in ERBB4 3'-untranslated region (UTR), in breast tumors. Aims: Here, we investigated the frequency and association between rs1972820 and breast cancer. Subjects and Methods: The rs1972820 genotypes in 182 samples were collected from 96 healthy people, and 86 breast cancer patients were determined using tetra-primer amplification refractory mutation system-polymerase chain reaction. The frequency of genotypes was analyzed to find the association between rs1972820 and breast cancer risk. Statistical Analysis Used: Conditional logistic regression, odds ratios (ORs), the associated 95% confidence intervals (CIs), and Armitage's test were used in this study. Results: In silico analysis suggested that rs1972820 located in the 3'UTR of ERBB4 gene affects the binding affinity of miR-3144-3p a potential oncomiRNA. Statistical analysis showed a significant association between SNP rs1972820 G allele and reduced breast cancer risk, odds ratio = 0.443 (95% CI: 0.196–0.998). Conclusions: rs1972820 SNP allele is significantly associated with the reduced risk of breast cancer and could be considered as a potential marker for breast cancer predisposition in population of Isfahan.

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Multiple primary malignant neoplasms: A 10-year experience at a single institution from Turkey

Durmus Etiz, Evrim Metcalfe, Melek Akcay

Journal of Cancer Research and Therapeutics 2017 13(1):16-20

Purpose: The development of improved diagnostic techniques, increased survival, and life expectancy of cancer patients have all contributed to the higher frequency of multiple primary malignant neoplasms (MPMN). MPMN can be divided into two main categories: Synchronous MPMN (sMPMN) and metachronous MPMN (mMPMN). Materials and Methods: 122 patients with MPMN analyzed retrospectively who were admitted to the Radiation Oncology Department of Eskisehir Osmangazi University Medical Faculty from January 2004 to December 2013. The patient characteristics and relation with overall survival (OS) were examined. Results: The overall incidence of MPMN was found 1.2% in our institution. The median age was 59 (range: 29–80) years. Male:female ratio was 54.5:45.5%, and mMPMN:sMPMN ratio was 69.9:30.1%. The most common 3 cancers were head and neck (22%), breast (20%), and gastrointestinal (20%) for first primary; and gastrointestinal (22%), lung (19%), gynecologic tumors (15%) for second primary cancers, respectively. The median OS in patients with sMPMN and mMPMN were 30 (3–105) and 91 (4–493) months. 2, 3, and 5 years OS of patients with sMPMN were 86%, 75%, 63%, and with mMPMN were 92%, 88%, 80%, respectively (P < 0.005). Conclusion: OS was found longer in female patients with sMPMN (P < 0.05), and in all group with mMPMN (P < 0.005).

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Evaluation of the effect of temperature variation on response of PRESAGE® dosimeter

Bagher Farhood, Davood Khezerloo, Tohid Morteza Zadeh, Hassan Ali Nedaie, Daryoosh Hamrahi, Najimeh Khezerloo

Journal of Cancer Research and Therapeutics 2017 13(1):118-121

Introduction: Many factors, such as PRESAGE ® composition, dose rate, energy, and type of radiation, temperature, etc., may effect on PRESAGE ® dosimeter response. The aim of this study was investigating the effect of temperature variation on response of PRESAGE ® solid dosimeter. Materials and Methods: In this study, a PRESAGE ® solid detector was fabricated. Ninety-four percent weight polyurethane, 5% weight carbon tetrachloride, and 1% weight leucomalachite green were used. Radiological and physical characteristics of PRESAGEs ®, such as mass density, electron density, and effective number atomic were obtained and compared with water. Response of PRESAGE ® dosimeter in temperatures −4, 10, 25, 35, 45, 55, 65, 75, 85, and 90°C was evaluated. In addition, the absorption peak at various temperatures was investigated. Results: The results showed that the absorption peak at different temperatures was in the range of 630–635 nm. For temperatures below 75°C, the results indicated that temperature variation has no effect on the response of PRESAGE ® dosimeter whereas at the temperatures >75°C, temperature variation has an effect on PRESAGE ® dosimeter response. Conclusion: The finding showed that temperature changes have not impact on the absorption peak. In addition, the results related to the effect of temperature variation on the response of PRESAGE ® dosimeter showed that in the range of clinical applications (temperatures below 75°C), temperature variation has no effect on PRESAGE ® dosimeter response.

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Comparison of beam hardening effect of physical and enhanced dynamic wedges at bladder inhomogeneity using EBT3 film dosimeter

Ghazale Geraily, Nooshin Sharafi, Alireza Shirazi, Mahbod Esfehani, Maryam Masoudifar, Blookat Eftekhar Rajab

Journal of Cancer Research and Therapeutics 2017 13(1):97-101

Introduction: Using physical wedges (PWs) to modify dose distribution and more homogeneous target coverage is a well-established technique. However, there are many problems with PWs known as beam hardening, which made them problematic. This can be overcome by dynamic wedges which do not filter beam. Comparison of physical properties of physical and enhanced dynamic wedges (EDWs) restricted to homogeneous medium. Hence, the main aim of this study is to compare dosimetric properties of physical and EDWs at bladder inhomogeneous phantom as a most common case implementing wedges. Materials and Methods: An inhomogeneous pelvic phantom with homogeneities of uterus, femur, soft tissue, rectum, and bladder was designed. Eclipse treatment planning system with the aim of bladder target was used for calculations. All dose distributions were measured with EBT3 films. Results: Comparison between beam profiles of physical and EDWs at wedged and nonwedged directions shows a greater difference at near inhomogeneous soft tissue interface and also at heel side of wedges. Conclusion: Little difference observed between dose distribution of physical and EDWs shows neglectable effect of beam hardening produced by PW compared to EDW at inhomogeneous medium. Furthermore, EBT3 films present good feature to measure dose distributions at EDW fields.

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Morbidity of central compartment clearance: Comparison of lesser versus complete clearance in patients with thyroid cancer

Gouri Pantvaidya, Rakesh Katna, Anuja Deshmukh, Deepa Nair, Anil D'Cruz

Journal of Cancer Research and Therapeutics 2017 13(1):102-106

Background: Extent of central compartment neck dissection (CCND) in thyroid cancers has been a debate because of associated morbidity. There have been attempts to reduce the extent of surgery in an attempt to decrease morbidity. Patients and Methods: We analyzed the morbidity of CCND from our prospectively maintained surgical morbidity database. CCND was divided into bilateral complete clearance (BCC) and less than complete clearance (LCC). LCC was performed for clinicoradiologically node negative patients. Rates of hypocalcemia and recurrent laryngeal nerve (RLN) palsy rates were compared for LCC versus BCC. We also classified procedures performed in the central neck according to the extent of dissection. Results: Of 153 evaluable patients, BCC was performed in 43.8% and LCC in 56.2%. Rate of postoperative hypocalcemia was 40.2% in BCC group versus 17.4% in LCC group. We had an overall RLN palsy rate of 7.4%. There was no significant difference in RLN palsy rates between the groups. Conclusion: Lesser extent of dissection in central compartment reduces postoperative hypocalcemia but has no influence on RLN palsy rates.

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A3 adenosine receptor agonist induce G1 cell cycle arrest via Cyclin D and cyclin-dependent kinase 4 pathways in OVCAR-3 and Caov-4 cell lines

Hamid Reza Joshaghani, Seyyed Mehdi Jafari, Mahmoud Aghaei, Mojtaba Panjehpour, Hamideh Abedi

Journal of Cancer Research and Therapeutics 2017 13(1):107-112

Aim of the Study: The cell cycle, a vital process that involves in cells' growth and division, lies at the heart of cancer. It has been shown that IB-MECA, an A3 adenosine receptor agonist inhibits the proliferation of cancer cells by inducing cell cycle arrest in several tumors. In this study, we evaluated the role of IB-MECA inhibition in cell cycle progression in ovarian cancer cells. Materials and Methods: Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in Caov-4 and OVCAR-3. Analysis of cell cycle distribution was carried out by flow cytometry. To determine the mechanisms of IB-MECA-mediated induction of cell cycle arrest, the expression of cell cycle regulatory proteins Cyclin D1 and cyclin-dependent kinase 4 (CDK4) was evaluated. Results: Our results showed that IB-MECA significantly reduced cell viability in a dose-dependent manner. Moreover, our results indicated that a low concentration of IB-MECA induced G1 cell cycle arrest. Reduction of Cyclin D1 and CDK4 protein levels was also observed after treating cancer cells with IB-MECA. Conclusion: This study demonstrated that IB-MECA induces G1 phase cell cycle arrest through Cyclin D1/CDK4-mediated pathway in ovarian cancer cells.

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Genomic aberrations in non- small cell lung cancer and their impact on treatment outcome

Amrallah A Mohammed, Hani El-Tanni, Mohammed A Alsakkaf, Ahmad A Mirza, Tariq Al-Malki Atiah, Arwa Al-Malki Atiah

Journal of Cancer Research and Therapeutics 2017 13(1):9-15

The therapeutic options of nonsmall cell lung cancer (NSCLC) therapy has been changed since the first discovery of activating epidermal growth factor receptor (EGFR) mutations and the development of specific EGFR tyrosine kinase inhibitors, which resulted in the evolution of "personalized medicine." There are a considerable number of genomic aberrations in NSCLC serving as potential predictive biomarkers and drug targets and still more. We summarized the molecular pathways, potential targets, and possible impact on disease outcome in NSCLC.

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Anaplastic hemangiopericytoma of eyelid: An unusual location

Pradeep Ventrapati, Sushmita Pathy, Ajeet Kumar Gandhi, Seema Kashyap

Journal of Cancer Research and Therapeutics 2017 13(1):145-147

Hemangiopericytomas (HPCs) are rare soft tissue tumors. The eyelid is a very uncommon site for these tumors, and an anaplastic variant of HPC in the eyelid has not been reported before. A 44-year-old male presented with complaints of slowly progressive, painless swelling on the inner aspect of the left upper eyelid for 9 months. He underwent local excision of the swelling and histopathology revealed a WHO Grade III anaplastic HPC. Whole body 18 F-fluorodeoxyglucose positron emission tomography-computed tomography done postoperatively did not show any evidence of local or distant disease. The patient was planned for adjuvant radiotherapy of 60 Gy in 30 fractions over 6 weeks in view of high grade of histopathology and doubtful margins. He is disease free at the time of the last follow-up. To the best of our knowledge, this is the first case of anaplastic HPC of eyelid being reported in English literature.

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Evaluation of role of alpha-methyl acyl-coenzyme A racemase/P504S and high molecular weight cytokeratin in diagnosing prostatic lesions

Deepika Jain, Sumiti Gupta, Nisha Marwah, Rajnish Kalra, Veena Gupta, Meenu Gill, Nikita Jain, Shubha Lal, Rajeev Sen

Journal of Cancer Research and Therapeutics 2017 13(1):21-25

Background: In recent years basal cell markers (high molecular weight cytokeratin [HMWCK]) and prostate biomarker alpha-methyl acyl-coenzyme A racemase (AMACR) have been used as adjuvant to morphology in diagnostically challenging cases with a very high sensitivity and specificity. This has increased the diagnostic accuracy of prostate cancer worldwide. Materials and Methods: In this prospective study, total of 50 cases including 37 cases of malignant lesions and 13 cases of benign lesions of the prostate were taken. Tumor grade was determined according to Gleason's grading system. AMACR and HMWCK expressions were determined by immunohistochemical staining. The obtained results were analyzed and evaluated using Chi-square statistical test (SPSS version 20). Results: AMACR was not expressed in any of the 13 cases of benign lesions of the prostate while in malignant lesions of prostate it was expressed in 33 of 37 (89.18%) cases. All 4 (100%) cases of well-differentiated carcinoma were positive for AMACR expression. 21 of 25 (84%) moderately differentiated and all 10 (100%) cases of poorly differentiated tumors were positive for AMACR. There was statistically significant difference in expression of AMACR between benign and malignant lesions of the prostate, indicated byP = 0.001. In benign lesions, HMWCK was expressed in all the 13 (100%) cases while in malignant lesions of prostate it was not expressed in any of the (0%) case. All 13 benign lesions were positive for HMWCK only. AMACR expression was not seen in any of the benign lesion. Out of 37 malignant cases, 4 cases were negative for both, 33 cases were positive only for AMACR, but no case was positive only for HMWCK. Conclusions: As an adjunct to biopsy, AMACR and HMWCK have value for resolving diagnostically challenging cases.

http://ift.tt/2pV4ngH

Recurrent osteosarcoma with calcified liver metastases: Uncommon development of a common disease

Shikha Goyal, Pramod K Julka

Journal of Cancer Research and Therapeutics 2017 13(1):139-141

Osteosarcoma is the commonest primary malignant bone tumor. Since bones lack a lymphatic system, metastatic spread in these tumors is exclusively hematogenous, the commonest sites being lungs and bone. We report a case of osteosarcoma humerus which recurred locally after primary therapy consisting of neoadjuvant chemotherapy and limb salvage surgery, who developed calcified liver metastases in addition to local and pulmonary relapse. Liver, though a common site of hematogenous spread in most solid tumors, has rarely been reported to be involved in metastatic osteosarcomas.

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Dosimetric verification of dose calculation algorithm in the lung during total marrow irradiation using helical tomotherapy

Ewelina Konstanty, Julian Malicki, Katarzyna Łagodowska, Anna Kowalik

Journal of Cancer Research and Therapeutics 2017 13(1):33-37

Introduction: Treatment of proliferative diseases of the hematopoietic system involves, in most cases, chemotherapy combined with radiation therapy, which is intended to provide adequate immunosuppressant. Conventionally, total body irradiation (TBI) was used; however, total marrow irradiation (TMI) performed with helical tomotherapy (HT) has been proposed as an alternative, with the aim of delivering the highest dose in the target area (skeleton bone). Purpose: The purpose of this study is to evaluate the accuracy of the dose calculation algorithm for the lung in TMI delivered with HT. Methods: Thermoluminescent detectors (TLD-100 Harshaw) were used to measure delivered doses. Doses were calculated for 95 selected points in the central lung (53 TLDs) and near the rib bones (42 TLDs) in the anthropomorphic phantom. A total of 12 Gy were delivered (6 fractions of 2 Gy/fraction). Results: HT-TMI technique reduces the dose delivered to the lungs in a phantom model to levels that are much lower than those reported for TBI delivered by a conventional linear accelerator. The mean calculated lung dose was 5.6 Gy versus a mean measured dose of 5.7 ± 2.4 Gy. The maximum and minimum measured doses were, respectively, 11.3 Gy (chest wall) and 2.8 Gy (central lung). At most of the 95 points, the measured dose was lower than the calculated dose, with the largest differences observed in the region located between the target volume and the adjacent lung tissue. The mean measured dose was lower than the calculated dose in both primary locations: −3.7% in the 42 rib-adjacent detectors and −3.0% in the 53 central lung TLDs. Conclusion: Our study has shown that the measured doses may be lower than those calculated by the HT-TMI calculation algorithm. Although these differences between calculated and measured doses are not clinically relevant, this finding merits further investigation.

http://ift.tt/2rdMmyN

Transcoelomic spread and ovarian seeding during ovulation: A possible pathogenesis of Krukenberg tumor

Bikash Shah, Wen-Hao Tang, Shammi Karn

Journal of Cancer Research and Therapeutics 2017 13(1):152-153



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Dual phase cone-beam computed tomography in detecting <3 cm hepatocellular carcinomas during transarterial chemoembolization

Xiaodong Wang, Hooman Yarmohammadi, Guang Cao, Xinqiang Ji, Jungang Hu, Hirad Yarmohammadi, Hui Chen, Xu Zhu, Renjie Yang, Stephen B Solomon

Journal of Cancer Research and Therapeutics 2017 13(1):38-43

Objective: The objective of this study was to evaluate the sensitivity of dual phase cone-beam computed tomography (CBCT) in detecting small (<3 cm in diameter) hepatocellular carcinoma (HCC) tumors during transarterial chemoembolization (TACE). Materials and Methods: Twenty-two consecutive patients with unresectable small HCCs in whom TACE was performed were retrospectively evaluated. Contrast CT or contrast magnetic resonance imaging (MRI) was performed in all patients within 1 month prior to the procedure. Dual phase CBCT was performed prior to TACE and lipiodol-CBCT was performed after treatment. The sensitivity of dual phase CBCT in detecting small HCCs was compared to hepatic angiography, contrast enhanced CT and MRI. Results: Seventy HCC tumors with sizes of

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From the editor

Kishore Singh

Journal of Cancer Research and Therapeutics 2017 13(1):1-1



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Disease characteristics and treatment attributes of patients admitted to the oncology ward of a tertiary care government hospital

Virender Suhag, BS Sunita, Pankaj Vats, Arti Sarin, AK Singh, Mayuri Jain

Journal of Cancer Research and Therapeutics 2017 13(1):44-50

Background: The burden of oncology patients in the most developing countries including India has witnessed a steady, progressive, and significant upward trend attributed mainly to increased life span, availability of better imaging modalities, increased awareness, and lifestyle and environmental changes. The management of such patients in government setup often presents lots of challenges such as advanced stage of presentation, existence of medical comorbid conditions, scarcity of beds, and long multimodal treatment often complicated with therapy-induced toxicities. Materials and Methods: A prospective study was undertaken in a Radiation Oncology ward catering to male patients over 6-month duration in a superspecialty hospital of defense services. The clinical, pathological, and treatment-related attributes were recorded. Wherever possible, the clinical course of stay, complications during admission, and the response to primary management were studied. Results: A total of 570 patients were admitted for 6-month duration. Of these patients, 240 were transferred in from other peripheral service hospitals while the remaining were admitted directly from this hospital or transferred from various wards of this hospital. The mean age of the patients was 46.5 years. Most common histology was squamous cell carcinoma. The most common site of primary was head and neck, followed closely by central nervous system tumors and gastrointestinal tract. A total of 185 patients were fresh cases admitted for workup and complete duration of definitive management (of which 82 received concurrent chemoradiation), 280 patients were for follow-up, 70 patients were admitted briefly for supportive care during a while on chemoradiation, and 15 patients were admitted for administrative reasons. Fifty-eight patients developed Grade II and onward therapy-induced hematological, gastrointestinal, cutaneous complications, and 14 patients suffered from febrile neutropenia. Thirty patients developed other significant complications warranting cross-referrals to other specialists. One hundred and thirty patients underwent more than one imaging modalities (contrast-enhanced computed tomography, magnetic resonance imaging, bone scan, and positron emission tomography-computed tomography). The duration of stay varied from 3 to 64 days, with an average duration of 38 days. There were 18 deaths during the study period. Conclusion: The course of hospitalization for oncology cases is often prolonged and complicated by significant complications, warranting aggressive supportive care by various concerned specialists. These patients often require multiple imaging for primary and metastatic workup. There is a need for judicious selection of patients meriting admission for optimum utilization of existing resources.

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Radiation-induced non-targeted effect in vivo: Evaluation of cyclooygenase-2 and endothelin-1 gene expression in rat heart tissues

Reza Fardid, Masoud Najafi, Ashkan Salajegheh, Elahe Kazemi, Abolhasan Rezaeyan

Journal of Cancer Research and Therapeutics 2017 13(1):51-55

Aim: In this study, we investigated expression levels of cyclooxygenase-2 (COX-2) and endothelin-1 (ET-1) genes after pelvis and heart irradiation in a rat model. These factors are involved in heart diseases (HDs). Materials and Methods: We used seven groups, including two groups of pelvic irradiation, two groups of whole body irradiation, two groups of heart irradiation, and one control nonirradiated group. Pelvis irradiations were conducted at a 2 cm × 2 cm in the pelvis area. Irradiation condition conducted using 1.25 MeV cobalt-60 gamma-rays (30 cGy/min). The changes at ET-1 and COX-2 gene expressions in heart tissue after pelvis and heart irradiation were measured and compared to the control and whole body irradiation groups at 24 h and 72 h after the exposure. Results: In heart irradiation groups, 3-fold up-regulation of both ET-1 and COX-2 was observed. In pelvis irradiation groups, 3-fold up-regulation of ET-1 was seen, but not significant changes in COX-2 gene expression have observed at distant heart tissues after pelvis irradiation. Conclusion: This study reveals that nontargeted effect induced by radiation may be considered as an important phenomenon for induction of HD after radiotherapy.

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Acoustic analysis of voice in nonlaryngeal head and neck cancer patients post chemoradiotherapy

Nikhila Radhakrishna, BK Yamini, Amrut Sadashiv Kadam, N Shivashankar, Chendil Vishwanathan, Rajesh Javarappa

Journal of Cancer Research and Therapeutics 2017 13(1):113-117

Background: Concurrent chemoradiotherapy (CCRT) used for definitive management of locally advanced head and neck squamous cell carcinoma (HNSCC) allows organ preservation at the cost of preservation of function. Vocal cords, being within the field of irradiation, undergo acute and chronic changes which adversely impacts the patients' voice. Aims: To assess the acute changes in the acoustic characteristics of voice post-CCRT in patients with nonlaryngeal HNSCC. Materials and Methods: Thirty patients with HNSCC treated with CCRT, a total dose of 66–70 Gy/33–35 fractions at five fractions/week, with weekly cisplatin. Acoustic analysis (AA) and laryngoscopic examination performed at baseline, 6 weeks, and 3 months post-CCRT. Statistical analysis of the parameters using ANOVA and Student's t-test was performed. Results: Of the thirty patients, 26 patients completed CCRT. At 6 weeks post-CCRT, among 14/26 patients, most (11/14 [78.57%]) developed Grade III toxicity. On AA, both increase and decrease in mean F0 from baseline was observed. An increase (P < 0.05) in each, i.e., jitter, shimmer, and noise to harmonics ratio (NHR) were recorded. At 3 months post-CCRT, among 8/14 available, most (6/8 [75%]) showed Grade II toxicity. The mean F0 reduced for both genders; jitter and shimmer, and NHR values maintained an increase (P > 0.05). Conclusions: Periodic AA allows quantification of voice changes and mapping of vocal toxicity induced by CCRT.

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Treatment of red tattoo reaction using CO 2 laser

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Variability of high-dose melphalan exposure on oral mucositis in patients undergoing prophylactic low-level laser therapy

Abstract

The present study outlines the clinical impact and risk factors of oral mucositis in 79 patients with multiple myeloma following high-dose melphalan for autologous transplant. All patients underwent daily prophylactic low-level indium gallium aluminum phosphate diode laser therapy (660 nm, 15 mW, 3.75 J/cm², 10 s per point) from the beginning of the conditioning regimen up to day +2. Oral mucositis assessments were made daily until hospital discharge. For analysis, oral mucositis was divided into two groups according to severity: group 1, patients with oral mucositis grade <III (n = 71) and group 2, patients with oral mucositis grade ≥III (n = 8). Univariate logistic models were used to determine the risk factors. Patients in group 1 were found to have statistically fewer days of oral pain than those in group 2 (3.94 and 6.25 days, respectively, p = 0.014). Morphine was required in 75% of patients in group 2, versus 42.25% in group 1 (p = 0.06). Risk of severe oral mucositis was associated with higher serum creatinine levels (OR = 6.10; 95% CI 1.25–31.60; p = 0.02) and older age (OR = 1.21; 95% CI 1.05–1.47; p = 0.027). Severe oral mucositis was associated with worse clinical outcomes. Older patients and those with renal dysfunction previous autologous transplant had the greatest risk for severe oral mucositis despite prophylactic laser treatment. Our results highlight the importance of further research to define the dose, application time, and number of prophylactic laser sessions in those patients with the greatest risk for severe oral mucositis.

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Endocrine actions of vitamin D in skin: Relevance for photocarcinogenesis of non-melanoma skin cancer, and beyond

Publication date: Available online 16 May 2017
Source:Molecular and Cellular Endocrinology
Author(s): Jörg Reichrath, Roman Saternus, Thomas Vogt
The skin represents a pivotal organ for the human body's vitamin D endocrine system, being both the site of ultraviolet (UV)-B-induced vitamin D synthesis and a target tissue for the pluripotent effects of 1,25(OH)2D3 and other biologically active vitamin D metabolites. As many other steroid hormones, 1,25(OH)2D3 exerts its effects via two independent signal transduction pathways: the classical genomic and the non-genomic pathway. While non-genomic effects of 1,25(OH)2D3 are in part exerted via effects on intracellular calcium, genomic effects are mediated by the vitamin D receptor (VDR). Recent findings convincingly support the concept of a new function of the VDR as a tumor suppressor in skin, with key components of the vitamin D endocrine system, including VDR, CYP24A1, CYP27A1, and CYP27B1 being strongly expressed in non-melanoma skin cancer (NMSC). It has now been shown that anti-tumor effects of VDR, that include some of its ligand-induced growth-regulatory effects, are at least in part mediated by interacting in a highly coordinated manner with the p53 family (p53/p63/p73) in response to a large number of alterations in cell homeostasis, including UV-induced DNA damage, a hallmark for skin photocarcinogenesis. Considering the relevance of the vitamin D endocrine system for carcinogenesis of skin cancer, it is not surprising that low 25(OH)D serum concentrations and genetic variants (SNPs) of the vitamin D endocrine system have been identified as potential risk factors for occurrence and prognosis of skin malignancies. In conclusion, an increasing body of evidence now convincingly supports the concept that the vitamin D endocrine system is of relevance for photocarcinogenesis and progression of NMSC and that its pharmacologic modulation by vitamin D, 1,25(OH)2D3, and analogs represents a promising new strategy for prevention and/or treatment of these malignancies.



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Test-Retest Reliability of the Dual-Microphone Voice Range Profile

The voice range profile (VRP) measures vocal intensity and fundamental frequency. Phonosurgical and logopedic treatment outcome studies using the VRP report voice improvements of 3–6 semitones (ST) in ST range and 4–7 decibels (dB) in sound pressure level range after treatment. These small improvements stress the importance of reliable measurements. The aim was to evaluate the test-retest reliability of the dual-microphone computerized VRP on participants with healthy voices.

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Tumescent anaesthesia: its applications and well tolerated use in the out-of-operating room setting.

Purpose of review: Tumescent anaesthesia is a method of administering dilute local anaesthetic into the subcutaneous tissue. Many anaesthesiologists are unfamiliar with the technique, its applications and potential risks. Recent findings: The maximum safe dose of lidocaine with epinephrine in tumescent anaesthesia for liposuction is probably between 35 and 55 mg/kg. Without liposuction, the maximum dose of lidocaine with epinephrine should be no more than 28 mg/kg. After tumescent infiltration for liposuction, serum lidocaine concentrations peak between 12 and 16 h after injection. When tumescent lidocaine without epinephrine is used for endovenous laser therapy, peak serum lidocaine concentrations are observed much earlier, between 1 and 2 h after injection. Slow administration of more dilute concentrations of local anaesthetic decreases the risk of local anaesthetic systemic toxicity. Summary: Although appealing because of its ability to provide prolonged analgesia, high doses of local anaesthetic are frequently administered using the tumescent technique, and absorption of local anaesthetic from the subcutaneous tissue is variable. When caring for patients having procedures in which tumescent anaesthesia is used, the risk of local anaesthetic toxicity should be acknowledged and lipid emulsion should be available for prompt treatment if needed. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Sedation for advanced procedures in the bronchoscopy suite: proceduralist or anesthesiologist?.

Purpose of review: This article focuses on the issue of sedation provided either by proceduralists or anesthesiologists for advanced bronchoscopy procedures. The relative merits of both approaches are presented. Current evidence from the literature and guideline recommendations relevant to this topic are reviewed. Recent findings: In general, patient and proceduralist satisfaction as well as patient safety are increased when intravenous sedation is provided for advanced bronchoscopic procedures. However, guidelines by various societies remain vague on defining the appropriate level of care required when providing sedation for these procedures. In addition, targeted depth of sedation varies considerably among practitioners. While in some settings, nonanesthesiologist-administered propofol sedation has been proven safe; nevertheless, its use is controversial, especially in the bronchoscopy suite. Summary: The role of the anesthesiologist in sedation for advanced bronchoscopy remains undefined. When deep sedation for prolonged interventional procedures is needed or when dealing with patients who have multiple comorbidities, an anesthesiologist should be involved. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Safety of deep sedation in the endoscopy suite.

Purpose of review: As the complexity of endoscopic procedures increases, the use of propofol and the desire for deep sedation are becoming more common in the endoscopy suite. This review explores sedation depth, agents used for sedation, recommended monitoring, and adverse event risks that occur during sedation for endoscopy. Recent findings: The sedation provider for endoscopy varies by practice location and with regulatory requirements. As increasingly deep levels of sedation are used in this setting, the need for all providers to have training in the ability to rescue patients from sedation-related side effects is paramount. Propofol has an important role for prolonged and uncomfortable endoscopic interventions and has a strong safety record in the endoscopy suite. Vital signs monitoring is recommended during all endoscopy sedation, and there is emerging interest in advanced monitoring (e.g., capnography, processed electroencephalogram, respiratory monitoring) in this setting. The reported rate of adverse events during endoscopy sedation varies widely; however, advanced age and increasing American Society of Anesthesiologists physical status score are consistently associated with increased risk. Whether anesthesiologist-administered sedation is safer than non-anesthesiologist-administered sedation remains controversial. Summary: This review provides some guidance to providers who administer sedation in the endoscopy suite and is intended to improve the safety of patients. The recommendations are based on best available evidence and expert opinion. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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The role of the anaesthesiologist in air ambulance medicine.

Purpose of review: The care administered on air ambulances has become increasing complex. This has led to a discussion among experts as to whether air ambulance travel should be manned by physicians. This review provides evidence in support of anaesthesiologists being the physician-leaders in air ambulance medicine, because of their training in advanced airway management, critical care, and resuscitation. Recent findings: Successful prehospital care requires the ability to perform a complex set of advanced diagnostics and interventions. These include airway management, haemorrhage control, pain management, point-of-care diagnostics, complex interfacility transport, and advanced interventions. This skill set closely mirrors the training and expertise of anaesthesiologists. Summary: There are few studies investigating the specific benefit of anaesthesiologists in air ambulance medicine. However, current evidence indicates that their presence does improve patient care and safety. Future studies on this topic should use evidence-based quality indicators and standardized data sets to seek answers to optimal staffing of air ambulance teams. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Perioperative management of antithrombotic therapies.

Purpose of review: Perioperative coagulation management is becoming increasingly frequent in the daily routine of the anesthesiologist and with the plethora of new substances on the market also increasingly complex. The perioperative setting poses unique challenges requiring an individualized evaluation and management of antithrombotic therapy. This review shall summarize the newest developments in this domain. Recent findings: New data in patients with atrial fibrillation have led to a paradigm change in the perioperative management of antithrombotics. The role of bridging therapy has been downgraded in the guidelines, which only foresee bridging in patients with high thromboembolic risk. Furthermore, direct oral anticoagulants are now a cornerstone in antithrombotic therapy, calling for specific perioperative management. The new reversal agents idarucizumab, and potentially in the future andexanet alfa and ciraparantag, will play an increasingly important role in the treatment of major bleeding in this group of patients. Summary: With the new evidence and treatment options available, perioperative coagulation management is experiencing a Renaissance, opening many interesting new doors, but also presenting the clinician with new challenges. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Self-extubation Laryngeal Injuries at an Academic Tertiary Care Center: A Retrospective Pilot Study.

Related Articles

Self-extubation Laryngeal Injuries at an Academic Tertiary Care Center: A Retrospective Pilot Study.

Ann Otol Rhinol Laryngol. 2017 May 01;:3489417709795

Authors: Cohn JE, Touati A, Lentner M, Weitzel M, Fisher C, Sataloff RT

Abstract
OBJECTIVES: The purpose of this study is to identify laryngeal symptoms and injuries in self-extubated patients.
METHODS: A retrospective chart review was conducted to identify symptoms and clinical findings associated with self-extubation. A novel scoring system was developed and used to quantify these findings. Symptom score included all symptoms that patients reported after self-extubation. Clinical score consisted of laryngeal findings visualized on nasopharyngeal laryngoscopy. Finally, a total self-extubation score was calculated as the sum of the symptom and clinical scores. Additionally, duration of intubation and endotracheal tube size were correlated with these scores.
RESULTS: Sixty (n = 60) patients who self-extubated in our institution's intensive care unit were identified. Average calculated symptom, clinical, and total self-extubation scores were 0.92, 1.43, and 2.35, respectively. The most common symptom observed was hoarseness (62%), while the most common clinical finding was posterior laryngeal edema (58%). A significant positive correlation was found between duration of intubation and both symptom score and total self-extubation score (r = 0.314, P = .008 and r = 0.223, P = .05, respectively). Symptom score predicted clinical score with a significant positive correlation present (r = 0.278, P = .02).
CONCLUSIONS: This study demonstrates that the majority of self-extubated patients have laryngeal symptoms and clinical findings. A comprehensive, multidisciplinary evaluation is warranted for self-extubations.

PMID: 28503976 [PubMed - as supplied by publisher]

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Importance of Group Therapeutic Support for Family Members of Children with Alopecia Areata: A Cross-Sectional Survey Study

Abstract

Background/Objectives

The psychological effect of alopecia areata (AA) is well documented, but group interaction may help lessen this burden. We aimed to determine factors that draw patients with AA and their families to group events.

Methods

Surveys were administered at the annual alopecia areata bowling social in 2015 and 2016. This event is a unique opportunity for children with AA and their families to meet others with the disease and connect with local support group resources from the Minnesota branch of the National Alopecia Areata Foundation. Data from 2015 and 2016 were combined. Comparisons of subgroups were performed using Fisher exact tests for response frequencies and percentages and two-sample t tests for mean values.

Results

An equal number of men and women participated in the study (n = 13 each). The average age was 41.1 years. There were no significant differences (p > 0.05) in survey responses based on respondent age or sex. Twenty-three (88.5%) attendees sought to connect with others with AA and met three or more people during the event. Seventeen (65.4%) also attended other support group events. Twelve respondents (46.2%) came to support a friend or family member. One hundred percent of attendees identified socializing with others with AA as important.

Conclusions

Group interaction is an important source of therapeutic support for people with AA and their families.

http://ift.tt/2roRpdf

Hypoxic Pathobiology of Breast Cancer Metastasis

Publication date: Available online 16 May 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Luana Schito, Sergio Rey
Dissemination of breast cancer cells (BCCs) to distant sites (metastasis) is the ultimate cause of mortality in patient with breast cancer. Hypoxia (low O2) is a microenvironmental hallmark of most solid cancers arising as a mismatch between cellular O2 consumption and supply. Hypoxic selection of BCCs triggers molecular and cellular adaptations dependent upon hypoxia-inducible factors (HIFs), a family of evolutionarily conserved transcriptional activators that coordinate the expression of numerous genes controlling each step of the metastatic process. In this review, we summarize current advances in the understanding of HIF-driven molecular mechanisms that promote BCC metastatic dissemination and patient mortality. In addition, we discuss the clinical and therapeutic implications of HIF targeting in breast cancers.



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Acceptability, Feasibility, and Effectiveness of Interdisciplinary Group Education Sessions for Women Veterans with a History of Sexual Trauma

Violence and Gender , Vol. 0, No. 0.


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Thymidine Catabolism as a Metabolic Strategy for Cancer Survival

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Sho Tabata, Masatatsu Yamamoto, Hisatsugu Goto, Akiyoshi Hirayama, Maki Ohishi, Takuya Kuramoto, Atsushi Mitsuhashi, Ryuji Ikeda, Misako Haraguchi, Kohichi Kawahara, Yoshinari Shinsato, Kentaro Minami, Atsuro Saijo, Masaki Hanibuchi, Yasuhiko Nishioka, Saburo Sone, Hiroyasu Esumi, Masaru Tomita, Tomoyoshi Soga, Tatsuhiko Furukawa, Shin-ichi Akiyama
Thymidine phosphorylase (TP), a rate-limiting enzyme in thymidine catabolism, plays a pivotal role in tumor progression; however, the mechanisms underlying this role are not fully understood. Here, we found that TP-mediated thymidine catabolism could supply the carbon source in the glycolytic pathway and thus contribute to cell survival under conditions of nutrient deprivation. In TP-expressing cells, thymidine was converted to metabolites, including glucose 6-phosphate, lactate, 5-phospho-α-D-ribose 1-diphosphate, and serine, via the glycolytic pathway both in vitro and in vivo. These thymidine-derived metabolites were required for the survival of cells under low-glucose conditions. Furthermore, activation of thymidine catabolism was observed in human gastric cancer. These findings demonstrate that thymidine can serve as a glycolytic pathway substrate in human cancer cells.

Graphical abstract

Teaser

Tabata et al. find that thymidine phosphorylase (TP)-mediated thymidine catabolism can supply carbon to the glycolytic pathway in mammalian cells. In TP-expressing cancer cells, thymidine contributes to cell survival under nutrient starvation.


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The INO80 Complex Removes H2A.Z to Promote Presynaptic Filament Formation during Homologous Recombination

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Claudio A. Lademann, Jörg Renkawitz, Boris Pfander, Stefan Jentsch
The INO80 complex (INO80-C) is an evolutionarily conserved nucleosome remodeler that acts in transcription, replication, and genome stability. It is required for resistance against genotoxic agents and is involved in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR). However, the causes of the HR defect in INO80-C mutant cells are controversial. Here, we unite previous findings using a system to study HR with high spatial resolution in budding yeast. We find that INO80-C has at least two distinct functions during HR—DNA end resection and presynaptic filament formation. Importantly, the second function is linked to the histone variant H2A.Z. In the absence of H2A.Z, presynaptic filament formation and HR are restored in INO80-C-deficient mutants, suggesting that presynaptic filament formation is the crucial INO80-C function during HR.

Graphical abstract

Teaser

The chromatin remodeler INO80-C is required for efficient DSB repair. Lademann et al. find that INO80-C has a dual role in homologous recombination, functioning during DNA end resection and Rad51 filament formation. Specifically, the second function is critical for DNA repair and is mechanistically promoted by a turnover of the histone variant H2A.Z.


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Modeling Genomic Instability and Selection Pressure in a Mouse Model of Melanoma

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Lawrence N. Kwong, Lihua Zou, Sharmeen Chagani, Chandra Sekhar Pedamallu, Mingguang Liu, Shan Jiang, Alexei Protopopov, Jianhua Zhang, Gad Getz, Lynda Chin
Tumor evolution is an iterative process of selection for pro-oncogenic aberrations. This process can be accelerated by genomic instability, but how it interacts with different selection bottlenecks to shape the evolving genomic landscape remains understudied. Here, we assessed tumor initiation and therapy resistance bottlenecks in mouse models of melanoma, with or without genomic instability. At the initiation bottleneck, whole-exome sequencing revealed that drug-naive tumors were genomically silent, and this was surprisingly unaffected when genomic instability was introduced via telomerase inactivation. We hypothesize that the strong engineered alleles created low selection pressure. At the therapy resistance bottleneck, strong selective pressure was applied using a BRAF inhibitor. In the absence of genomic instability, tumors acquired a non-genomic drug resistance mechanism. By contrast, telomerase-deficient, drug-resistant melanomas acquired highly recurrent copy number gains. These proof-of-principle experiments demonstrate how different selection pressures can interact with genomic instability to impact tumor evolution.

Graphical abstract

Teaser

In this study, Kwong et al. use genetically engineered mouse models of melanoma, whole-exome sequencing, telomere dysfunction, and targeted therapy to study how genomic instability and selection pressures interact to shape tumor evolution. They find that genomic instability manifests itself differentially under conditions of low and high selective pressure.


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The Presence of Interleukin-13 at Pancreatic ADM/PanIN Lesions Alters Macrophage Populations and Mediates Pancreatic Tumorigenesis

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Geou-Yarh Liou, Ligia Bastea, Alicia Fleming, Heike Döppler, Brandy H. Edenfield, David W. Dawson, Lizhi Zhang, Nabeel Bardeesy, Peter Storz
The contributions of the innate immune system to the development of pancreatic cancer are still ill defined. Inflammatory macrophages can initiate metaplasia of pancreatic acinar cells to a duct-like phenotype (acinar-to-ductal metaplasia [ADM]), which then gives rise to pancreatic intraepithelial neoplasia (PanIN) when oncogenic KRas is present. However, it remains unclear when and how this inflammatory macrophage population is replaced by tumor-promoting macrophages. Here, we demonstrate the presence of interleukin-13 (IL-13), which can convert inflammatory into Ym1+ alternatively activated macrophages, at ADM/PanIN lesions. We further show that Ym1+ macrophages release factors, such as IL-1ra and CCL2, to drive pancreatic fibrogenesis and tumorigenesis. Treatment of mice expressing oncogenic KRas under an acinar cell-specific promoter with a neutralizing antibody for IL-13 significantly decreased the accumulation of alternatively activated macrophages at these lesions, resulting in decreased fibrosis and lesion growth.

Graphical abstract

Teaser

Liou et al. show that PanIN and Tuft cells produce IL-13 and that the presence of IL-13 at early pancreatic lesions leads to the accumulation of alternatively activated macrophages. Alternatively activated macrophages release factors, such as IL-1ra and CCL2, to drive pancreatic fibrosis and lesion growth.


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Inhibitory Control of Feature Selectivity in an Object Motion Sensitive Circuit of the Retina

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Tahnbee Kim, Daniel Kerschensteiner
Object motion sensitive (OMS) W3-retinal ganglion cells (W3-RGCs) in mice respond to local movements in a visual scene but remain silent during self-generated global image motion. The excitatory inputs that drive responses of W3-RGCs to local motion were recently characterized, but which inhibitory neurons suppress W3-RGCs' responses to global motion, how these neurons encode motion information, and how their connections are organized along the excitatory circuit axis remains unknown. Here, we find that a genetically identified amacrine cell (AC) type, TH2-AC, exhibits fast responses to global motion and slow responses to local motion. Optogenetic stimulation shows that TH2-ACs provide strong GABAA receptor-mediated input to W3-RGCs but only weak input to upstream excitatory neurons. Cell-type-specific silencing reveals that temporally coded inhibition from TH2-ACs cancels W3-RGC spike responses to global but not local motion stimuli and, thus, controls the feature selectivity of OMS signals sent to the brain.

Graphical abstract

Teaser

Kim and Kerschensteiner report that a specific amacrine cell type (TH2-AC) distinguishes local and global motion in the kinetics of its responses. Optogenetic activation and cell-type-specific silencing show that TH2-ACs provide strong inhibitory input to object motion sensitive retinal ganglion cells (W3-RGCs) and that this input suppresses W3-RGC responses to global motion stimuli.


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Crystal Structure of Tetrameric Arabidopsis MYC2 Reveals the Mechanism of Enhanced Interaction with DNA

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Teng-fei Lian, Yong-ping Xu, Lan-fen Li, Xiao-Dong Su
Jasmonates (JAs) are essential plant hormones that play important roles in the regulation of plant growth and the response to environmental stress. In the JA signaling pathway, the core transcription factors are a class of basic helix-loop-helix (bHLH) proteins, including MYC2, MYC3, and MYC4, that have different regulatory capacities. Here, we report the 2.7 Å crystal structure of the MYC2 bHLH domain complexed with G-box DNA, showing a cis-tetrameric structure. Biochemical assays confirmed that full-length MYC2 forms a stable homo-tetramer both in solution and in DNA-bound states, whereas MYC3 forms only a homodimer. Isothermal titration calorimetry (ITC) assays demonstrated that tetramerization enhanced DNA binding affinity, and fluorescence resonance energy transfer (FRET) assay indicated DNA looping potential of tetrameric MYC2. Luciferase assay further confirmed the importance of tetramerization in transcriptional regulation. Our studies provide a mechanistic explanation for the regulatory differences of MYC transcription factors.

Graphical abstract

Teaser

Lian et al. solved the crystal structure of the Arabidopsis transcription factor MYC2-DNA complex and showed that MYC2 and MYC3 exist as homotetramer and homodimer in solution, respectively, explaining the different regulatory capacities of these bHLH transcription factors.


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Widespread Mitotic Bookmarking by Histone Marks and Transcription Factors in Pluripotent Stem Cells

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Yiyuan Liu, Bobbie Pelham-Webb, Dafne Campigli Di Giammartino, Jiexi Li, Daleum Kim, Katsuhiro Kita, Nestor Saiz, Vidur Garg, Ashley Doane, Paraskevi Giannakakou, Anna-Katerina Hadjantonakis, Olivier Elemento, Effie Apostolou
During mitosis, transcription is halted and many chromatin features are lost, posing a challenge for the continuity of cell identity, particularly in fast cycling stem cells, which constantly balance self-renewal with differentiation. Here we show that, in pluripotent stem cells, certain histone marks and stem cell regulators remain associated with specific genomic regions of mitotic chromatin, a phenomenon known as mitotic bookmarking. Enhancers of stem cell-related genes are bookmarked by both H3K27ac and the master regulators OCT4, SOX2, and KLF4, while promoters of housekeeping genes retain high levels of mitotic H3K27ac in a cell-type invariant manner. Temporal degradation of OCT4 during mitotic exit compromises its ability both to maintain and induce pluripotency, suggesting that its regulatory function partly depends on its bookmarking activity. Together, our data document a widespread yet specific bookmarking by histone modifications and transcription factors promoting faithful and efficient propagation of stemness after cell division.

Graphical abstract

Teaser

During mitosis, cell identity is temporarily challenged. Liu et al. reveal that maintenance and acquisition of stem cell identity rely on persistent binding of key histone modifications and transcription factors on specific sites of mitotic chromatin.


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Endogenous Replication Stress in Mother Cells Leads to Quiescence of Daughter Cells

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Mansi Arora, Justin Moser, Harsha Phadke, Ashik Akbar Basha, Sabrina L. Spencer
Mammalian cells have two fundamentally different states, proliferative and quiescent, but our understanding of how and why cells switch between these states is limited. We previously showed that actively proliferating populations contain a subpopulation that enters quiescence (G0) in an apparently stochastic manner. Using single-cell time-lapse imaging of CDK2 activity and DNA damage, we now show that unresolved endogenous replication stress in the previous (mother) cell cycle prompts p21-dependent entry of daughter cells into quiescence immediately after mitosis. Furthermore, the amount of time daughter cells spend in quiescence is correlated with the extent of inherited damage. Our study thus links replication errors in one cell cycle to the fate of daughter cells in the subsequent cell cycle. More broadly, this work reveals that entry into quiescence is not purely stochastic but has a strong deterministic component arising from a memory of events that occurred in the previous generation(s).

Graphical abstract

Teaser

Arora et al. find that unresolved DNA replication errors in mother cells are passed on to daughter cells, prompting entry of daughter cells into a temporary quiescence whose duration is correlated with the extent of inherited damage. The authors thereby uncover a key source of heterogeneity in cell-cycle duration.


http://ift.tt/2roTrZT

Huntington’s Disease iPSC-Derived Brain Microvascular Endothelial Cells Reveal WNT-Mediated Angiogenic and Blood-Brain Barrier Deficits

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Ryan G. Lim, Chris Quan, Andrea M. Reyes-Ortiz, Sarah E. Lutz, Amanda J. Kedaigle, Theresa A. Gipson, Jie Wu, Gad D. Vatine, Jennifer Stocksdale, Malcolm S. Casale, Clive N. Svendsen, Ernest Fraenkel, David E. Housman, Dritan Agalliu, Leslie M. Thompson
Brain microvascular endothelial cells (BMECs) are an essential component of the blood-brain barrier (BBB) that shields the brain against toxins and immune cells. While BBB dysfunction exists in neurological disorders, including Huntington's disease (HD), it is not known if BMECs themselves are functionally compromised to promote BBB dysfunction. Further, the underlying mechanisms of BBB dysfunction remain elusive given limitations with mouse models and post-mortem tissue to identify primary deficits. We undertook a transcriptome and functional analysis of human induced pluripotent stem cell (iPSC)-derived BMECs (iBMEC) from HD patients or unaffected controls. We demonstrate that HD iBMECs have intrinsic abnormalities in angiogenesis and barrier properties, as well as in signaling pathways governing these processes. Thus, our findings provide an iPSC-derived BBB model for a neurodegenerative disease and demonstrate autonomous neurovascular deficits that may underlie HD pathology with implications for therapeutics and drug delivery.

Graphical abstract

Teaser

Lim et al. show that HD iPSCs-derived brain microvascular endothelial cells have impaired angiogenic and barrier properties. Transcriptomic analysis provides mechanistic insights into pathways that underlie dysfunction, and WNT inhibition prevents angiogenic deficits. This system also suggests strategies to reduce disease burden and assess BBB penetration of drugs for HD.


http://ift.tt/2roDW4c

CNS Macrophages Control Neurovascular Development via CD95L

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Si Chen, Nathalie Tisch, Marcel Kegel, Rosario Yerbes, Robert Hermann, Hannes Hudalla, Cecilia Zuliani, Gülce Sila Gülcüler, Klara Zwadlo, Jakob von Engelhardt, Carmen Ruiz de Almodóvar, Ana Martin-Villalba
The development of neurons and vessels shares striking anatomical and molecular features, and it is presumably orchestrated by an overlapping repertoire of extracellular signals. CNS macrophages have been implicated in various developmental functions, including the morphogenesis of neurons and vessels. However, whether CNS macrophages can coordinately influence neurovascular development and the identity of the signals involved therein is unclear. Here, we demonstrate that activity of the cell surface receptor CD95 regulates neuronal and vascular morphogenesis in the post-natal brain and retina. Furthermore, we identify CNS macrophages as the main source of CD95L, and macrophage-specific deletion thereof reduces both neurovascular complexity and synaptic activity in the brain. CD95L-induced neuronal and vascular growth is mediated through src-family kinase (SFK) and PI3K signaling. Together, our study highlights a coordinated neurovascular development instructed by CNS macrophage-derived CD95L, and it underlines the importance of macrophages for the establishment of the neurovascular network during CNS development.

Graphical abstract

Teaser

Chen et al. identify CNS macrophages as regulators of neurovascular remodeling. Using cell-specific knockout models, they demonstrate that CNS macrophage-derived CD95L binds to the CD95 receptor on neurons and endothelial cells to promote neurovascular development through SFK and PI3K signaling. Furthermore, neuronal function is impaired long term in the absence of CD95L.


http://ift.tt/2roNJY2

The Intergenic Recombinant HLA-B∗46:01 Has a Distinctive Peptidome that Includes KIR2DL3 Ligands

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Hugo G. Hilton, Curtis P. McMurtrey, Alex S. Han, Zakia Djaoud, Lisbeth A. Guethlein, Jeroen H. Blokhuis, Jason L. Pugh, Ana Goyos, Amir Horowitz, Rico Buchli, Ken W. Jackson, Wilfred Bardet, David A. Bushnell, Philip J. Robinson, Juan L. Mendoza, Michael E. Birnbaum, Morten Nielsen, K. Christopher Garcia, William H. Hildebrand, Peter Parham
HLA-B^∗46:01 was formed by an intergenic mini-conversion, between HLA-B^∗15:01 and HLA-C^∗01:02, in Southeast Asia during the last 50,000 years, and it has since become the most common HLA-B allele in the region. A functional effect of the mini-conversion was introduction of the C1 epitope into HLA-B^∗46:01, making it an exceptional HLA-B allotype that is recognized by the C1-specific natural killer (NK) cell receptor KIR2DL3. High-resolution mass spectrometry showed that HLA-B^∗46:01 has a low-diversity peptidome that is distinct from those of its parents. A minority (21%) of HLA-B^∗46:01 peptides, with common C-terminal characteristics, form ligands for KIR2DL3. The HLA-B^∗46:01 peptidome is predicted to be enriched for peptide antigens derived from Mycobacterium leprae. Overall, the results indicate that the distinctive peptidome and functions of HLA-B^∗46:01 provide carriers with resistance to leprosy, which drove its rapid rise in frequency in Southeast Asia.

Graphical abstract

Teaser

Hilton et al. show how the recombination that formed HLA-B∗46:01 endowed it with a distinctive peptidome and unique functional properties. These properties likely protect carriers from severe infection with Mycobacterium leprae, the cause of leprosy, and they may account for the high frequency of HLA-B∗46:01 in Southeast Asia.


http://ift.tt/2roTuVz

Absence of Specific Chlamydia trachomatis Inclusion Membrane Proteins Triggers Premature Inclusion Membrane Lysis and Host Cell Death

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Mary M. Weber, Jennifer L. Lam, Cheryl A. Dooley, Nicholas F. Noriea, Bryan T. Hansen, Forrest H. Hoyt, Aaron B. Carmody, Gail L. Sturdevant, Ted Hackstadt
Chlamydia trachomatis is a human pathogen associated with significant morbidity worldwide. As obligate intracellular parasites, chlamydiae must survive within eukaryotic cells for sufficient time to complete their developmental cycle. To promote host cell survival, chlamydiae express poorly understood anti-apoptotic factors. Using recently developed genetic tools, we show that three inclusion membrane proteins (Incs) out of eleven examined are required for inclusion membrane stability and avoidance of host cell death pathways. In the absence of specific Incs, premature inclusion lysis results in recognition by autophagolysosomes, activation of intrinsic apoptosis, and premature termination of the chlamydial developmental cycle. Inhibition of autophagy or knockdown of STING prevented host cell death and activation of intrinsic apoptosis. Significantly, these findings emphasize the importance of Incs in the establishment of a replicative compartment that sequesters the pathogen from host surveillance systems.

Graphical abstract

Teaser

Weber el al use genetic means to disrupt Chlamydia trachomatis proteins essential for parasitophorous vacuole (inclusion) membrane stability. Premature inclusion lysis exposes chlamydiae to the cytosol to induce autophagic and apoptotic pathways. Understanding how normally anti-apoptotic chlamydiae induce apoptosis will help define mechanisms of chlamydial intracellular survival.


http://ift.tt/2roLWCa

Innate Recognition of Intracellular Bacterial Growth Is Driven by the TIFA-Dependent Cytosolic Surveillance Pathway

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Ryan G. Gaudet, Cynthia X. Guo, Raphael Molinaro, Haila Kottwitz, John R. Rohde, Anne-Sophie Dangeard, Cécile Arrieumerlou, Stephen E. Girardin, Scott D. Gray-Owen
Intestinal epithelial cells (IECs) act as sentinels for incoming pathogens. Cytosol-invasive bacteria, such as Shigella flexneri, trigger a robust pro-inflammatory nuclear factor κB (NF-κB) response from IECs that is believed to depend entirely on the peptidoglycan sensor NOD1. We found that, during Shigella infection, the TRAF-interacting forkhead-associated protein A (TIFA)-dependent cytosolic surveillance pathway, which senses the bacterial metabolite heptose-1,7-bisphosphate (HBP), functions after NOD1 to detect bacteria replicating free in the host cytosol. Whereas NOD1 mediated a transient burst of NF-κB activation during bacterial entry, TIFA sensed HBP released during bacterial replication, assembling into large signaling complexes to drive a dynamic inflammatory response that reflected the rate of intracellular bacterial proliferation. Strikingly, IECs lacking TIFA were unable to discriminate between proliferating and stagnant intracellular bacteria, despite the NOD1/2 pathways being intact. Our results define TIFA as a rheostat for intracellular bacterial replication, escalating the immune response to invasive Gram-negative bacteria that exploit the host cytosol for growth.

Graphical abstract

Teaser

Gaudet et al. describe an innate immune pathway that confers the ability to detect replicating bacteria free in the host cytosol. This pathway, mediated by the protein TIFA, informs the host to the magnitude of intracellular bacterial proliferation, providing the contextual signal to dramatically amplify the inflammatory response to virulent pathogens.


http://ift.tt/2roWzoQ

A Murine Intestinal Intraepithelial NKp46-Negative Innate Lymphoid Cell Population Characterized by Group 1 Properties

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Aline Van Acker, Konrad Gronke, Aindrila Biswas, Liesbet Martens, Yvan Saeys, Jessica Filtjens, Sylvie Taveirne, Els Van Ammel, Tessa Kerre, Patrick Matthys, Tom Taghon, Bart Vandekerckhove, Jean Plum, Ildiko Rita Dunay, Andreas Diefenbach, Georges Leclercq
The Ly49E receptor is preferentially expressed on murine innate-like lymphocytes, such as epidermal Vγ3 T cells, intestinal intraepithelial CD8αα⁺ T lymphocytes, and CD49a⁺ liver natural killer (NK) cells. As the latter have recently been shown to be distinct from conventional NK cells and have innate lymphoid cell type 1 (ILC1) properties, we investigated Ly49E expression on intestinal ILC populations. Here, we show that Ly49E expression is very low on known ILC populations, but it can be used to define a previously unrecognized intraepithelial innate lymphoid population. This Ly49E-positive population is negative for NKp46 and CD8αα, expresses CD49a and CD103, and requires T-bet expression and IL-15 signaling for differentiation and/or survival. Transcriptome analysis reveals a group 1 ILC gene profile, different from NK cells, iCD8α cells, and intraepithelial ILC1. Importantly, NKp46⁻CD8αα⁻Ly49E⁺ cells produce interferon (IFN)-γ, suggesting that this previously unrecognized population may contribute to Th1-mediated immunity.

Graphical abstract

Teaser

Van Acker et al. define an intestinal intraepithelial innate lymphoid cell population that is dependent on T-bet and IL-15 and displays a group 1 ILC gene profile uniquely different from NK cells, iCD8α cells, and previously described ILC1 cells. Upon stimulation, these cells produce the Th1-related cytokine IFN-γ.


http://ift.tt/2roFefN

Fatty Acid Oxidation in Zebrafish Adipose Tissue Is Promoted by 1α,25(OH)2D3

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Xuyan Peng, Guohui Shang, Wenqing Wang, Xiaowen Chen, Qiyong Lou, Gang Zhai, Dongliang Li, Zhenyu Du, Yali Ye, Xia Jin, Jiangyan He, Yi Zhang, Zhan Yin
1α,25(OH)2D3 (vitamin D3) is crucial for mineral homeostasis in mammals, but the precise effects of 1α,25(OH)2D3 in adipose tissue remain to be clarified in vivo. The initial 25-hydroxylation is catalyzed by liver microsomal cytochrome P450 2R1 (CYP2R1), which is conserved in vertebrates. To probe the physiological function(s) of 1α,25(OH)2D3 in teleosts, we generated two independent cyp2r1-deficient zebrafish lines. These mutants exhibit retarded growth and increased obesity, especially in the visceral adipose tissue (VAT). These defects could be rescued with 25(OH)D3 treatments. ChIP-PCR analyses demonstrated that pgc1a is the target of the vitamin D receptor in the liver and VAT of zebrafish. Significantly decreased protein levels of Pgc1a, impaired mitochondrial biogenesis, and free fatty acid oxidation are also observed in the cyp2r1 mutant VAT. Our results demonstrate that regulation of 1α,25(OH)2D3 during lipid metabolism occurs through the regulation of Pgc1a for mitochondrial biogenesis and oxidative metabolism within zebrafish VAT.

Graphical abstract

Teaser

Peng et al. find that Cyp2r1 depletion results in 1,25(OH)2D3 deficiency, retarded growth, and excessive visceral adipose tissue (VAT) in zebrafish. 1,25(OH)2D3 regulates lipid metabolism through the regulation of Pgc1a, controlling mitochondrial biogenesis and oxidative metabolism in zebrafish VAT.


http://ift.tt/2roRWe7

Lack of MTTP Activity in Pluripotent Stem Cell-Derived Hepatocytes and Cardiomyocytes Abolishes apoB Secretion and Increases Cell Stress

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Ying Liu, Donna M. Conlon, Xin Bi, Katherine J. Slovik, Jianting Shi, Hailey I. Edelstein, John S. Millar, Ali Javaheri, Marina Cuchel, Evanthia E. Pashos, Jahangir Iqbal, M. Mahmood Hussain, Robert A. Hegele, Wenli Yang, Stephen A. Duncan, Daniel J. Rader, Edward E. Morrisey
Abetalipoproteinemia (ABL) is an inherited disorder of lipoprotein metabolism resulting from mutations in microsomal triglyceride transfer protein (MTTP). In addition to expression in the liver and intestine, MTTP is expressed in cardiomyocytes, and cardiomyopathy has been reported in several ABL cases. Using induced pluripotent stem cells (iPSCs) generated from an ABL patient homozygous for a missense mutation (MTTP^R46G), we show that human hepatocytes and cardiomyocytes exhibit defects associated with ABL disease, including loss of apolipoprotein B (apoB) secretion and intracellular accumulation of lipids. MTTP^R46G iPSC-derived cardiomyocytes failed to secrete apoB, accumulated intracellular lipids, and displayed increased cell death, suggesting intrinsic defects in lipid metabolism due to loss of MTTP function. Importantly, these phenotypes were reversed after the correction of the MTTP^R46G mutation by CRISPR/Cas9 gene editing. Together, these data reveal clear cellular defects in iPSC-derived hepatocytes and cardiomyocytes lacking MTTP activity, including a cardiomyocyte-specific regulated stress response to elevated lipids.

Graphical abstract

Teaser

Liu et al. use patient-specific iPSCs and CRISPR/Cas9 genome editing to uncover the functional consequences of MTTP mutations in human hepatocytes and cardiomyocytes. They find that MTTP is required for apoB secretion and that its absence results in increased cell stress in cardiomyocytes.


http://ift.tt/2roLV14

Systems Analysis Reveals High Genetic and Antigen-Driven Predetermination of Antibody Repertoires throughout B Cell Development

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Victor Greiff, Ulrike Menzel, Enkelejda Miho, Cédric Weber, René Riedel, Skylar Cook, Atijeh Valai, Telma Lopes, Andreas Radbruch, Thomas H. Winkler, Sai T. Reddy
Antibody repertoire diversity and plasticity is crucial for broad protective immunity. Repertoires change in size and diversity across multiple B cell developmental stages and in response to antigen exposure. However, we still lack fundamental quantitative understanding of the extent to which repertoire diversity is predetermined. Therefore, we implemented a systems immunology framework for quantifying repertoire predetermination on three distinct levels: (1) B cell development (pre-B cell, naive B cell, plasma cell), (2) antigen exposure (three structurally different proteins), and (3) four antibody repertoire components (V-gene usage, clonal expansion, clonal diversity, repertoire size) extracted from antibody repertoire sequencing data (400 million reads). Across all three levels, we detected a dynamic balance of high genetic (e.g., >90% for V-gene usage and clonal expansion in naive B cells) and antigen-driven (e.g., 40% for clonal diversity in plasma cells) predetermination and stochastic variation. Our study has implications for the prediction and manipulation of humoral immunity.

Graphical abstract

Teaser

Greiff et al. develop an integrated systems immunology approach for quantifying the extent of antibody repertoire predetermination. They find a dynamic balance of both high genetic (maximum: 99%) and antigen-driven (maximum: 40%) repertoire predetermination. The authors also uncover stochastic variation across B cell development, antigen exposure, and repertoire components (germline gene usage, clonal expansion, clonal diversity, repertoire size), which has implications for the prediction and manipulation of humoral immunity.


http://ift.tt/2roLTGu

A Temporal Proteomic Map of Epstein-Barr Virus Lytic Replication in B Cells

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Ina Ersing, Luis Nobre, Liang Wei Wang, Lior Soday, Yijie Ma, Joao A. Paulo, Yohei Narita, Camille W. Ashbaugh, Chang Jiang, Nicholas E. Grayson, Elliott Kieff, Steven P. Gygi, Michael P. Weekes, Benjamin E. Gewurz
Epstein-Barr virus (EBV) replication contributes to multiple human diseases, including infectious mononucleosis, nasopharyngeal carcinoma, B cell lymphomas, and oral hairy leukoplakia. We performed systematic quantitative analyses of temporal changes in host and EBV proteins during lytic replication to gain insights into virus-host interactions, using conditional Burkitt lymphoma models of type I and II EBV infection. We quantified profiles of >8,000 cellular and 69 EBV proteins, including >500 plasma membrane proteins, providing temporal views of the lytic B cell proteome and EBV virome. Our approach revealed EBV-induced remodeling of cell cycle, innate and adaptive immune pathways, including upregulation of the complement cascade and proteasomal degradation of the B cell receptor complex, conserved between EBV types I and II. Cross-comparison with proteomic analyses of human cytomegalovirus infection and of a Kaposi-sarcoma-associated herpesvirus immunoevasin identified host factors targeted by multiple herpesviruses. Our results provide an important resource for studies of EBV replication.

Graphical abstract

Teaser

Ersing et al. present a temporal proteomic map of EBV B cell lytic replication. Tandem-mass-tag-based proteomics uncover extensive remodeling of the human proteome by EBV, conserved across the two major EBV strains. Cell-cycle, innate, and adaptive immune pathways are modulated, complement is upregulated, and the B cell receptor is degraded by infection.


http://ift.tt/2rowhCX

A Design Principle for an Autonomous Post-translational Pattern Formation

Publication date: 16 May 2017
Source:Cell Reports, Volume 19, Issue 7
Author(s): Shuhei S. Sugai, Koji L. Ode, Hiroki R. Ueda




http://ift.tt/2roNLPE

In response to “Otolaryngology workforce analysis”

http://ift.tt/2rowO7W

Intervention for elevated intracranial pressure improves success rate after repair of spontaneous cerebrospinal fluid leaks

Objectives/Hypothesis

Spontaneous cerebrospinal fluid (CSF) leaks are associated with increased intracranial pressure (ICP) and considered a manifestation of idiopathic intracranial hypertension. Although postoperative acetazolamide and placement of CSF shunt systems are considered valuable interventions for elevated ICP, the impact on recurrence rate remains unclear. The objective of this study was to systematically review evidence from reported literature to evaluate whether postoperative ICP management reduces recurrence rates after primary endoscopic repair.

Study Design

Prospective case series and systematic review.

Methods

Demographics, defect location, success rates, and ICP management in spontaneous CSF leak patients were prospectively collected over 8 years. A search was also conducted in PubMed to identify studies reporting cases of spontaneous CSF rhinorrhea.

Results

Fifty-six articles with nonduplicated data were identified and combined with a prospective series of 108 patients for a total of 679 patients treated for spontaneous CSF rhinorrhea. Average age was 50.4 years with 77% female. Average body mass index was 35.8 kg/m². Defects were most commonly located in the sphenoid sinus (n = 334) followed by the ethmoid (n = 318) and the frontal sinus (n = 46). Successful primary repair was 92.82% in patient cohorts where ICP evaluation and intervention with acetazolamide or CSF shunt systems was performed, but was significantly decreased to 81.87% in series with no active management of elevated ICP (P < .001).

Conclusions

Evaluation and intervention for elevated ICP in spontaneous CSF leaks is associated with significantly improved success rates following primary endoscopic repair.

Level of Evidence

4. Laryngoscope, 2017

http://ift.tt/2roFsU5

Early neurocognitive improvements following parathyroidectomy for primary hyperparathyroidism

Objectives

To establish a time frame for postoperative improvements in neurocognitive function in patients who undergo parathyroidectomy for primary hyperparathyroidism by utilizing repeat neuropsychological assessment at multiple time points before and after surgery.

Study Design

Prospective cohort study.

Methods

A prospective study was conducted at a tertiary academic medical center between August 2014 and December 2015, including 50 patients with primary hyperparathyroidism who underwent parathyroidectomy. A panel of neurocognitive tests was administered at two separate time points: preoperative and 1-week postoperative. Validated neuropsychological assessment tools were utilized, including Rey Auditory-Verbal Learning Test, Trail Making Test A and B, Benton Controlled Oral Word Association, WAIS-IV Digit Span, Hospital Anxiety and Depression Scale, Positive and Negative Affect Schedule, and Insomnia Severity Index. Barona Information Sheet was used to collect demographic data. Paired t tests were to compare pre- and postoperative scores.

Results

Thirty-five patients completed the preoperative and 1-week postoperative testing. In cognitive testing, significant improvement was noted in immediate recall (P < 0.001), working memory (P = 0.011), and attention (P = 0.008) at 1-week postoperative. In mood testing, depression (P < 0.001), anxiety (P < 0.001), and negative affect (P = 0.001) scores were significantly improved at 1-week postoperative. Insomnia scores also were significantly improved at 1 week (P < 0.001).

Conclusion

Objective improvements in neurocognitive function following parathyroidectomy for primary hyperparathyroidism were noted as early as 1 week after surgery, which is earlier than previously reported.

Level of Evidence

2b. Laryngoscope, 2017

http://ift.tt/2qqjNxu

Evaluation of leg wrapping for the prevention of postspinal hypotension in cesarean section under spinal anesthesia

Aparna Abhijit Bagle, Adithya Vishnu, Anil Kumar, Amit Malik, Vinit Garg, Gayatri Khanvilkar

Anesthesia: Essays and Researches 2017 11(2):439-443

Background: Spinal blockade provides excellent anesthesia for patients undergoing cesarean section. However, hypotension after spinal anesthesia is a common adverse effect that is commonly experienced in patients undergoing cesarean section. The aim of our study was to analyze if a simple technique like leg wrapping with elastic crepe bandage would be effective in controlling postspinal hypotension. Materials and Methods: Sixty full-term pregnant patients who were posted for cesarean section belonging to American Society of Anesthesiologists I and II were divided into two groups. Patients in Group W had their legs wrapped with elastic crepe bandage and in the other Group N, leg wrapping was not done. All the patients were preloaded with Ringer lactate at 10 ml/kg before the spinal anesthesia. The hemodynamic parameters were monitored every 3 min until the delivery of the baby and every 5 min until the end of surgery. If hypotension occurred, then along with crystalloid loading a bolus dose of mephentermine 6 mg was given intravenously. Statistical Analysis: Statistical software "Numbers version 3.6.1 (2566)" was used for statistical calculations. Results: Frequency of hypotension in Group W (10%) was significantly less compared to Group N (60%). Vasopressor requirement was significantly less in Group W (P = 0.009), which was highly significant. Conclusion: Wrapping of lower extremities was a simple, easy, and an effective method of decreasing episodes of hypotension and vasopressor requirement after spinal anesthesia in cesarean patients and needs to be practiced routinely.

http://ift.tt/2qpPTsC

Effect of single compared to repeated doses of intravenous S(+) ketamine on the release of pro-inflammatory cytokines in patients undergoing radical prostatectomy

Hassan Mohamed Ali, Ali M Mokhtar

Anesthesia: Essays and Researches 2017 11(2):282-286

Background: Radical prostatectomy is a major surgical procedure that is associated with marked inflammatory response and impairment of the immune system which may affect the postoperative outcome. The aim of this study was to evaluate the effect of preincision single or multiple doses of S(+) ketamine on the pro-inflammatory cytokines, namely tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Patients and Methods: This is a randomized controlled trial including 60 American Society of Anesthesiologists Physical Status I and II patients scheduled for radical prostatectomy under combined general-epidural anesthesia in Cairo university Teaching Hospital. Patients were randomly divided into three groups each of twenty patients: Group I received no S(+) ketamine (control group), Group II received S(+) ketamine as a single preincision dose, and Group III received preincision and repeated doses of S(+) ketamine. S(+) ketamine was injected as a single intravenous dose of 0.5 mg/kg in Group II and III, repeated as 0.2 mg/kg at 20 min interval until 30 min before the end of surgery. Results: The three groups were comparable in age, weight, and duration of the operation. The study also revealed that a single preincision dose of S(+) ketamine decreased TNF-α to reach 1027.04 ± 50.13 μ/ml and IL-6 to reach 506.89 ± 25.35 pg/ml whereas the repeated doses of S(+) ketamine decreased TNF-α to reach 905.64 ± 35065 μ/ml and IL-6 to reach 412.79 ± 16.5 pg/ml (P < 0.05). Conclusion: S(+) ketamine suppresses pro-inflammatory cytokine production, especially when given in repeated doses.

http://ift.tt/2pUMSx8

Anesthetic management of a parturient with severe pulmonary restenosis posted for cesarean section

Rajkiran Babubhai Shah, Beena P Butala, Geeta P Parikh

Anesthesia: Essays and Researches 2017 11(2):517-519

Adults with congenital heart disease are increasing due to improvement in infant heart surgery and availability of better cardiac care. Pregnancy in these patients requires multidisciplinary team approach due to circulatory changes. We describe an anesthetic management of the parturient undergoing cesarean section having severe pulmonary restenosis.

http://ift.tt/2qpYqvK

Comparison of usefulness of ketamine and magnesium sulfate nebulizations for attenuating postoperative sore throat, hoarseness of voice, and cough

Sunil Rajan, George Jacob Malayil, Rekha Varghese, Lakshmi Kumar

Anesthesia: Essays and Researches 2017 11(2):287-293

Context: Postoperative sore throat (POST) is a complication that is unresolved in patients undergoing endotracheal intubation. Aim: To compare the effects of ketamine and magnesium sulfate nebulizations in two strengths, on the incidence and severity of POST, hoarseness, and cough. Settings and Design: Sixty surgical patients undergoing elective abdominal and lower limb surgeries under combined epidural and general anesthesia were included in this prospective, randomized, double-blinded study. Subjects and Methods: Patients in each group were nebulized with the respective study drug 15 min prior to the surgery, i.e., ketamine in Group K, magnesium sulfate 250 mg, and 500 mg in Group M1 and Group M2, respectively, and normal saline as control in Group C. A standardized anesthesia protocol was followed for all patients. After extubation, the patients were asked to grade POST, hoarseness, and cough at 0, 2, 4, 12, and 24 h. Statistical Analysis Used: One-way analysis of variance, Chi-square test, Fisher's exact test, paired t-tests, and Wilcoxon's signed-rank test as applicable. Results: Ketamine and magnesium sulfate 500 mg demonstrated a statistically significant decrease in POST at 0, 2, and 4 h, and postoperative hoarseness at 0 h. There was decrease in the incidence and severity of sore throat, hoarseness, and cough at all periods in the study groups as compared with control. Conclusion: Nebulization with ketamine 50 mg and magnesium sulfate 500 mg, 15 min before induction of general anesthesia and intubation, reduce the incidence and severity of POST and hoarseness of voice.

http://ift.tt/2pUKshR