Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14 C-microtracer and therapeutic dose in cancer patients

Abstract

Introduction

Niraparib (Zejula™) is a poly(ADP-ribose) polymerase inhibitor recently approved by the US Food and Drug Administration for the maintenance treatment of patients with recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. The pivotal phase III clinical trial has shown improved progression-free survival in patients receiving niraparib compared with those receiving placebo.

Purpose

Since niraparib is administered orally, it is of interest to investigate the oral bioavailability (F _po) of this novel compound, which is the aim of this study.

Methods

Six patients received an oral therapeutic dose of 300 mg niraparib, followed by a 15-min intravenous infusion of 100 µg ¹⁴C-niraparib with a radioactivity of approximately 100 nCi. The niraparib therapeutic dose was measured in plasma using a validated liquid chromatography–tandem mass spectrometry method, whereas the total ¹⁴C-radioactivity and ¹⁴C-niraparib plasma levels were measured by accelerator mass spectrometry and a validated high performance liquid chromatography assay with AMS.

Results

The F _po of niraparib was determined to be 72.7% in humans.

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Population pharmacokinetics of trastuzumab emtansine in previously treated patients with HER2-positive advanced gastric cancer (AGC)

Abstract

Purpose

Ado-trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising trastuzumab conjugated via a stable thioether linker to DM1, a highly potent cytotoxic agent. A population pharmacokinetics (PK) analysis was performed to characterize T-DM1 PK and evaluate the impact of patient characteristics on T-DM1 PK in previously treated patients with HER2-positive advanced gastric cancer (AGC).

Methods

Following T-DM1 weekly or every three weeks dosing, T-DM1 concentration measurements (n = 780) were collected from 136 patients in the GATSBY (NCT01641939) study and analyzed using nonlinear mixed effects modeling. The influence of demographic, baseline laboratory, and disease characteristics on T-DM1 PK was examined.

Results

T-DM1 PK was best described by a two-compartment model with parallel linear and nonlinear (Michaelis–Menten) elimination from the central compartment. The final population model estimated linear clearance (CL) of 0.79 L/day, volume of distribution in the central compartment (V _c) of 4.48 L, distribution clearance (Q) of 0.62 L/day, volume of distribution in the peripheral compartment (V _p) of 1.49 L, nonlinear CL of 2.06 L/day, and KM of 1.63 μg/mL. Parameter uncertainty was low to moderate for fixed effects, except KM (estimated with poor precision). Patients with high body weight and low baseline trastuzumab concentrations had significantly faster linear CL; those with higher body weight had significantly larger V _c.

Conclusions

In a HER2-positive AGC population, T-DM1 PK was best described by a two-compartment model with parallel linear and nonlinear elimination. Baseline body weight and trastuzumab concentration were identified as significant covariates for T-DM1 PK in a HER2-positive AGC population.

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Cholecystokinin receptor antagonist alters pancreatic cancer microenvironment and increases efficacy of immune checkpoint antibody therapy in mice

Abstract

Advanced pancreatic ductal adenocarcinoma (PDAC) has typically been resistant to chemotherapy and immunotherapy; therefore, novel strategies are needed to enhance therapeutic response. Cholecystokinin (CCK) has been shown to stimulate growth of pancreatic cancer. CCK receptors (CCKRs) are present on pancreatic cancer cells, fibroblasts, and lymphocytes. We hypothesized that CCKR blockade would improve response to immune checkpoint antibodies by promoting influx of tumor-infiltrating lymphocytes (TILs) and reducing fibrosis. We examined the effects of CCKR antagonists or immune checkpoint blockade antibodies alone or in combination in murine models of PDAC. Monotherapy with CCKR blockade significantly decreased tumor size and metastases in SCID mice with orthotopic PDAC, and in C57BL/6 mice, it reduced fibrosis and induced the influx of TILs. Immune-competent mice bearing syngeneic pancreatic cancer (Panc02 and mT3-2D) that were treated with the combination of CCK receptor antagonists and immune checkpoint blockade antibodies survived significantly longer with smaller tumors. Tumor immunohistochemical staining and flow cytometry demonstrated that the tumors of mice treated with the combination regimen had a significant reduction in Foxp3+ T-regulatory cells and an increase in CD4+ and CD8+ lymphocytes. Masson's trichrome stain analysis revealed 50% less fibrosis in the tumors of mice treated with CCKR antagonist compared to controls and compared to checkpoint antibody therapy. CCKR antagonists given with immune checkpoint antibody therapy represent a novel approach for improving survival of PDAC. The mechanism by which this combination therapy improves the survival of PDAC may be related to the decreased fibrosis and immune cells of the tumor microenvironment.

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Hereditary persistence of hemoglobin F is protective against red cell sickling. A case report and brief review

Publication date: Available online 16 October 2017
Source:Hematology/Oncology and Stem Cell Therapy
Author(s): Alexandra Sokolova, Anton Mararenko, Alexander Rozin, Alida Podrumar, Vladimir Gotlieb
Fetal hemoglobin (HbF) is a physiologic protein tetramer that is crucial for a developing fetus to survive in utero. Maternal hemoglobin has a relatively lower affinity for oxygen, and thus allows for an efficient transfer of oxygen from maternal to fetal blood. In addition to fulfilling a critical physiologic role, HbF is also known to alleviate symptoms of sickle-cell disease (SCD). The concentration of HbF depends on several factors. HbF is elevated in inherited conditions, such as hereditary persistence of HbF, hereditary spherocytosis, and thalassemia. The level of HbF is also increased in acquired states, such as pregnancy, aplastic anemia, thyrotoxicosis, hepatoma, myeloproliferative disorders, or hypoplastic myelodysplastic syndrome. It has been identified that some genetic loci have significant influence on HbF levels. The XmnI polymorphism, the HMIP locus, and the BCL11A gene are responsible for 45% of variations in HbF levels. Although SCD has been well described in the subpopulations of Africa, it is less common in the subpopulations of India. We describe a case of SCD, in which a patient with high HbF level presented at a very late age (27 years old). We presume the patient's inherently elevated HbF levels were able to compensate for the hypoxic episodes associated with SCD. The onset of symptoms was delayed as a result of elevated HbF levels.



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Anemia in Patient with Primary Hyperoxaluria and Bone Marrow Involvement by Oxalate Crystals

Publication date: Available online 16 October 2017
Source:Hematology/Oncology and Stem Cell Therapy
Author(s): Vitaliy Mykytiv, Fiz Campoy Garcia
We present a rare case of anaemia secondary to bone marrow infiltration by oxalate crystals and renal failure in a patient diagnosed with primary hyperoxaluria. In our case, the anaemia was recovered after the double liver and kidney transplantation, the latter was performed on two occasions after the failure of the first graft.



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Correction to: Breast cancer metastases to the thyroid gland - An uncommon sentinel for diffuse metastatic disease: A case report and literature review

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Unexpected hypotension in catecholamine reversal: a case report

Catecholamine agents are commonly used to support circulation; however, they may cause unexpected hypotension in a special situation. Here we describe the first unexpected case of hypotension in response to ca...

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Pseudoangiomatous stromal hyperplasia – a benign and rare tumor of the breast in an adolescent: a case report

Pseudoangiomatous stromal hyperplasia is an uncommon mesenchymal breast neoplasm.

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Erratum to: How to choose the best journal for your case report

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Osteitis of the radius following Bacillus Calmette–Guérin vaccination at birth: a case report

The Bacillus Calmette–Guérin vaccine, which is used for the prevention of tuberculosis, is considered protective against the severe forms of childhood tuberculosis. However, some serious adverse reactions incl...

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European Respiratory Society guidelines for the management of adult bronchiectasis.

Related Articles

European Respiratory Society guidelines for the management of adult bronchiectasis.

Eur Respir J. 2017 Sep;50(3):

Authors: Polverino E, Goeminne PC, McDonnell MJ, Aliberti S, Marshall SE, Loebinger MR, Murris M, Cantón R, Torres A, Dimakou K, De Soyza A, Hill AT, Haworth CS, Vendrell M, Ringshausen FC, Subotic D, Wilson R, Vilaró J, Stallberg B, Welte T, Rohde G, Blasi F, Elborn S, Almagro M, Timothy A, Ruddy T, Tonia T, Rigau D, Chalmers JD

Abstract
Bronchiectasis in adults is a chronic disorder associated with poor quality of life and frequent exacerbations in many patients. There have been no previous international guidelines.The European Respiratory Society guidelines for the management of adult bronchiectasis describe the appropriate investigation and treatment strategies determined by a systematic review of the literature.A multidisciplinary group representing respiratory medicine, microbiology, physiotherapy, thoracic surgery, primary care, methodology and patients considered the most relevant clinical questions (for both clinicians and patients) related to management of bronchiectasis. Nine key clinical questions were generated and a systematic review was conducted to identify published systematic reviews, randomised clinical trials and observational studies that answered these questions. We used the GRADE approach to define the quality of the evidence and the level of recommendations. The resulting guideline addresses the investigation of underlying causes of bronchiectasis, treatment of exacerbations, pathogen eradication, long term antibiotic treatment, anti-inflammatories, mucoactive drugs, bronchodilators, surgical treatment and respiratory physiotherapy.These recommendations can be used to benchmark quality of care for people with bronchiectasis across Europe and to improve outcomes.

PMID: 28889110 [PubMed - in process]

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Anticancer Agents; +184 new citations

184 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

Anticancer Agents

These pubmed results were generated on 2017/10/15

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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[Endovascular Treatment for Carotid Blowout Syndrome after Radiation for Esophageal Cancer:A Case Report].

Related Articles

[Endovascular Treatment for Carotid Blowout Syndrome after Radiation for Esophageal Cancer:A Case Report].

No Shinkei Geka. 2017 Sep;45(9):791-798

Authors: Takahashi S, Kawaguchi T, Niizuma K, Nakagawa A, Fujimura M, Ogawa T, Katori Y, Tominaga T

Abstract
Here, we discuss a case of carotid blowout syndrome successfully treated with endovascular parent artery occlusion. A 71-year-old woman underwent treatment for esophageal cancer resection, followed by 50-Gy radiotherapy, 19 years prior. Due to local recurrence, she underwent 66- and 72-Gy radiation treatments at 2 and 4 years after the initial treatment, respectively. Afterward, tracheostomy and enterostomy were performed. This time, she was transported to our emergency department because of acute eruptive bleeding from the tracheal tube. As her vitals indicated shock, emergency endovascular treatment was performed. Digital subtraction angiography revealed that the common carotid artery in the left-sided of the neck had a pseudoaneurysm extruding to the pharyngeal cavity, which was considered to be the lesion responsible for the acute rupture. She was diagnosed as having carotid blowout syndrome. Balloon test occlusion showed that the cross flow via the anterior and posterior communicating arteries was sufficient, so parent artery occlusion was chosen for bleeding control. Carotid bifurcation was preserved to keep the collateral circulation via the external carotid artery. The patient was discharged 22 days after treatment, without any neurological deficits. Although injured vessel removal with high-flow bypass was an ideal treatment to achieve bleeding control without ischemic complication, endovascular treatment can be an efficient second-best treatment. To minimize the risk of late ischemic complications, flow preservation via carotid bifurcation might be important.

PMID: 28924068 [PubMed - in process]

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Ethnic Variation in Satisfaction and Appearance Concerns in Adolescents With Idiopathic Scoliosis Undergoing Posterior Spinal Fusion With Instrumentation

Publication date: Available online 16 October 2017
Source:Spine Deformity
Author(s): Alexander A. Theologis, Matthew Crawford, Mohammad Diab
Study DesignCohort analysis.ObjectiveDocument satisfaction with management and appearance concerns in children of different ethnicity who underwent spinal fusion/instrumentation for adolescent idiopathic scoliosis (AIS).Summary of Background DataScoliosis Research Society Questionnaire (SRS-30) outcomes in AIS indicate a link between appearance and satisfaction as well as ethnic variation in appearance domain. Exploration of these findings in the Scoliosis Appearance Questionnaire (SAQ) will allow better understanding of ethnic variation in appearance concerns.MethodsChildren with AIS who underwent posterior-only operations and completed the SAQ's question 31 were identified. Univariate logistic regression of SAQ questions 12-30 was used to assess relationships with ethnicity.Results1,977 children [boys: 281, girls: 1,290, unspecified: 406; average age 15.1 ± 2.0 years preoperatively and 817 children (boys: 113, girls: 569, unspecified: 135; average age 15.1 ± 2.0 years) at 2 years' follow-up met inclusion criteria. The majority were Caucasian (57.3%). Few were Hispanic (3.4%). Preoperatively, the largest percentage of patients in each ethnic group answered "very true" to "wanting to be more even." Preoperatively, Asians were least likely to be concerned about evenness of shoulders, hips, waist, ribs, and chest in back (p < .05); however, they expressed greatest concern about height (p < .05). African Americans and Hispanics were more likely to be concerned about breast evenness and anterior chest and looking better in clothes (p < .05). African Americans were most concerned about overall evenness and evenness of shoulders, hips, waist, ribs, posterior chest, leg length, and looking more attractive (p < .05). Surgical scar was most important postoperatively for all ethnicities. African Americans and Hispanics were more self-conscious about scar (p < .05). African Americans were most likely to want to be more even and have more even shoulders, hips, waist, leg lengths, ribs, breasts, and chest postoperatively.ConclusionsEthnicity influenced appearance concerns in pre- and postoperative SAQ evaluation. Ethnic variation in appearance concerns should be taken into account and differentiated when counseling patients about AIS and surgical correction.Level of EvidenceLevel III.



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Current Evidence Regarding the Diagnostic Methods for Pediatric Lumbar Spondylolisthesis: A Report From the Scoliosis Research Society Evidence Based Medicine Committee

Publication date: Available online 16 October 2017
Source:Spine Deformity
Author(s): Han Jo Kim, Charles H. Crawford, Charles Ledonio, Shay Bess, A. Noelle Larson, Marilyn Gates, Matthew Oetgen, James O. Sanders, Douglas Burton
Study DesignStructured literature review.ObjectivesThe Scoliosis Research Society (SRS) requested an assessment of the current state of peer-reviewed evidence regarding pediatric lumbar spondylolisthesis with the goal of identifying what is known and what gaps remain in further understanding the diagnostic methods for pediatric spondylolisthesis.Summary of Background DataSpondylolisthesis in the lumbar spine is common among children and adolescents and no formal synthesis of the published literature regarding diagnostic methods has been previously performed.MethodsA comprehensive literature search was performed. Abstracts were reviewed and data from included studies were analyzed by the committee. From 6600 initial citations with abstract, 663 articles underwent full-text review. The best available evidence for the clinical questions regarding diagnostic methods was provided by 26 included studies. Six of the studies were graded as Level III (retrospective comparative), and represent the current best available evidence whereas 20 of the studies were graded as Level IV (retrospective case series) evidence. No Level V (expert opinion) studies were included in the final list. None of the studies were graded as Level I or Level II.ResultsPlain radiography is the workhorse imaging modality for diagnosing spondylolisthesis. No association between radiologic grade of spondylolisthesis and clinical presentation were noted; however, grade III and IV slips more often required surgery, and increasing slip angles were associated with worse baseline outcome scores.There is Level III evidence that the Meyerding grade appears to be more accurate for measuring slip percentage whereas the Lonstein Slip angle and Dubousset Lumbosacral Kyphosis angles are the best for measuring lumbosacral kyphosis in spondylolisthesis. In addition, higher sacral table index, pelvic incidence, sacral slope, and lower sacral table angle were associated with spondylolisthesis. True incidence could not be determined by the current literature available. However, studies in adolescent athletes demonstrated an incidence of 6% to 7% across studies.ConclusionsThe current "best available" evidence to guide the diagnosis and characterization of pediatric spondylolisthesis is presented. Future studies are needed to provide more high-quality evidence to answer these clinically relevant questions.Level of EvidenceLevel III, review of Level III studies.



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Determinants Associated With Unmet Need for Family Planning in Pakistan

The recent data in the Pakistan Demographic and Health Survey 2012-2013 shows a high unmet need for contraceptives, although family planning programs have been in place in Pakistan since the late 1950s. The phenomenon presents ...

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What’s in a Cigarette? The Personal, Social and Environmental Cost of Cigarette Smoking Today

"Smoking is injurious to health!" – a statement we are all familiar with. However, individuals who continue to smoke in spite of this awareness, do so for one reason or another. According to World Health ...

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Drug-induced Osteoporosis and the Local Pharmacy: An Ideal Setting for Effective Intervention to Identify and Inform High-risk Patients

Osteoporosis is a disease characterized by low bone mineral density and deterioration of the bone architecture leading to increased fragility and fractures. Primary osteoporosis indicates loss of bone mass due to aging and menopause. Secondary ...

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Level Specific CE-Chirp® BAEP's: A new faster technique in neuromonitoring cochlear nerve during cerebello-pontine angle tumor surgery

Publication date: Available online 3 October 2017
Source:Interdisciplinary Neurosurgery
Author(s): Ettore Di Scipio, Luciano Mastronardi
BackgroundLevel Specific (LS) CE-Chirp® Brainstem Auditory Evoked Potentials (BAEP's) are the most recent evolution of classical Click BAEP's, performed both in clinical studies and in intraoperative neuromonitoring (IONM) of acoustic pathways during several neurosurgical procedures. LS CE-Chirp® is a new group of acoustic stimuli, latter evolution of Broadband CE-Chirp®, designed by Claus Elberling to provide faster recording of larger amplitude BAEP's V waves in infants. While the original Broadband CE-Chirp® was conceived for optimal response amplitude of V wave at low and medium stimulation intensities, the LS CE-Chirp® provides clearer I–III–V waves at high intensities.Material and methodWe report a consecutive series of 31 cases in which the new LS CE-Chirp® BAEP's were performed during different skull base surgery procedures during the last 24months: 25 vestibular schwannomas, 3 cerebello-pontine angle (CPA) meningiomas and 3 CPA epidermoid tumors.ResultsUsing LS-CE-Chirp® BAEP's monitoring, neurosurgeon was alerted in 10–15s about variation of conduction parameters of acoustic pathways. At the end of surgery, BAEP's were normal in 11 patients, showed deconstructed waves in 14, and elongated waves in 6. At a minimum clinical and BAEP's follow-up of 6months, hearing function was preserved in 19 cases (61,3%).ConclusionsWe herein confirm that LS CE-Chirp® BAEP's provide a fast feedback to surgeons regarding acoustic pathways function, helping them during skull base tumor removal in the attempt to hearing preservation when it is socially useful in the preoperative evaluation.



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Deep brain stimulation lead migration in a child secondary to osteogenesis at the burr hole site

Publication date: Available online 27 September 2017
Source:Interdisciplinary Neurosurgery
Author(s): Cameron Brimley, Amir Kershenovich
The frequency of deep brain stimulation (DBS) complications is low; however, lead migration is a common way DBS therapy can become ineffective. We present a case of a nine-year-old male with generalized dystonia who underwent bilateral GPi DBS lead placement. The efficacy of the DBS system was diminished over two years and one of the leads was noted to be displaced on skull X-rays and confirmed with a head CT. During surgery to replace it, bone growth within the burr hole site was noted to have occurred and determined to be the cause for the lead migration. This is the first known case reporting osteogenesis at the burr hole site as a cause of lead migration. This complication should be kept in mind when performing DBS in children to refine a surgical technique that could prevent osteogenesis at the burr hole.



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Re-evaluation of foramen magnum decompression with dura left open for Chiari I malformation

Publication date: Available online 2 October 2017
Source:Interdisciplinary Neurosurgery
Author(s): Tetsuryu Mitsuyama, Yasuo Aihara, Takaomi Taira, Seiichiro Eguchi, Kentaro Chiba, Yoshikazu Okada, Takakazu Kawamata
ObjectiveOne of the controversies in foramen magnum decompression (FMD) is the management of dura. Graft adhesion is the most common finding in revisions after FMD with duraplasty. Furthermore, certain number of patients after FMD without dural opening required revision surgery. The most common cause is excessive fibrosis over the preserved dura. On the other hand, FMD with dura left open could reduce the risk for symptomatic recurrence, although it was generally abandoned because of the higher risk of postoperative CSF leakage or meningitis. Purpose of this study was to re-evaluate FMD with dura left open after the application of tight fascial closures in order to reduce the risk of cerebrospinal fluid (CSF) leakage. We compared CSF-related complications of this surgery with other FMD techniques based on literature review.Patients and methodsOur retrospective study included 13 patients who underwent FMD with dura left open. We paid particular attention to prevent CSF leak by the tight suturing of fascial layers especially at both ends of each layer and keeping muscle attachments to inion intact.ResultsCSF-related complications and symptomatic recurrence were not observed. The postoperative CSF collection contained within the tightly closed fasciae became of limited size over several months.ConclusionFMD with dura left open did not show higher rate of CSF leakage as compared to other FMD techniques. The tight closure of fascial layers is essential to minimalize CSF leakage in this surgery. Moreover, it has the advantage of reducing symptomatic recurrence over other FMD techniques.



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Characteristics and surgical outcomes of tuberculous meningitis and of tuberculous spondylitis in pediatric patients at Dr. Hasan Sadikin Hospital, Bandung: A single center experience

Publication date: Available online 2 October 2017
Source:Interdisciplinary Neurosurgery
Author(s): Ahmad Faried, Ahmad Ramdan, Muhammad Z. Arifin, Heda M. Nataprawira
IntroductionTuberculous meningitis (TBM) and tuberculous spondylitis (TBS) are the form of extra-pulmonary tuberculosis.Material and methodA retrospective cohort study was conducted among children with TBM (2009–2014) and TBS (2004–2014) who were treated in our center; Department of Child Health, Department Neurosurgery and Department Orthopedics.ResultsOf 123 children diagnosed with TBM (53) and TBS (70); based on modified British Medical Research Council: Stage I (3 cases), Stage IIa (3 cases), Stage IIb (23 cases), Stage III (24 cases). TBM developed hydrocephalus: 36 cases performed ventriculoperitoneal shunt and 17 cases external ventricular drainage. In TBM: 9.4% (5/53) had vegetative state and mortality rate was 20.8% (11/53). TBM Hospital discharge correlated with Glasgow coma scale preoperation (p<0.001). In TBS: Thoracic spine was involved in 67.1% cases, Lumbar in 28.6% and Cervical in 4.3%. Of 70 cases: 45 cases with neurological deficit and 25 cases without one. Of 24 cases underwent spine surgery: 6 cases performed anterior decompression spinal fusion and 18 cases performed posterior debridement with stabilization. In TBS patients, mortality rate was 1.4% (1/70).ConclusionsThe surgical outcomes of both TBM and TBS still poor in many ways. Improving TB outcomes as implementation of the End TB Strategy program at 2030 remain our homework.



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Unruptured medial paraclinoid internal carotid artery aneurysm embedded within symptomatic nonfunctioning pituitary giant adenoma: A high-risk comorbid pathology in transsphenoidal surgery and its countermeasures

Publication date: December 2017
Source:Interdisciplinary Neurosurgery, Volume 10
Author(s): Taiki Saito, Yuichiro Yoneoka, Jun Watanabe, Bumpei Kikuchi, Hitoshi Hasegawa, Yukihiko Fujii
BackgroundInjury of the internal carotid artery (ICA) in the cavernous portion is one of the most critical complications of transsphenoidal surgery (TSS), especially in cases of coexistence with a pituitary adenoma (PA) and ICA aneurysm.Case descriptionWe present a rare case of unruptured medial paraclinoid ICA aneurysm (ICA-An) associated with symptomatic nonfunctioning giant PA. After endovascular coil embolization of the unruptured 4-mm saccular medial paraclinoid ICA-An, the patient underwent adenomectomy through an endoscopic endonasal TSS. During the bone resection over the right sellar floor near the right cavernous sinus, a tangle of packed coils in the treated medial paraclinoid ICA-An was observed immediately after a bite of a Kerrison rongeur. The dural layer over the coiled aneurysm had become thin to the point of transparency or complete absence. Careful inspection revealed that the bone hillock was formed by the medial paraclinoid ICA-An. Gross total resection of the adenoma was achieved without vascular injuries related to the coiled aneurysm despite postoperative transient right oculomotor paresis.ConclusionsThis case conveys three important lessons about TSS: 1) coil embolization will manage a medial paraclinoid ICA-An as a sufficient preoperative procedure for TSS; 2) a medial paraclinoid ICA-An can appear directly under the sellar floor as an apparent extradural aneurysm; and; 3) surgeons should take great care in procedures near a coil-embolized medial paraclinoid ICA-An because the aneurysmal wall can be thin to the point of transparency.



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Demographic and angioarchitectural features associated with seizures presentation in patients with brain arteriovenous malformations in Durban, KwaZulu-Natal, South Africa

Publication date: Available online 28 September 2017
Source:Interdisciplinary Neurosurgery
Author(s): Mogwale Samson Motebejane, Duncan Royston, Gaëtan Kabera, Rohen Harrichandparsad, Ian Kaminsky, In Sup Choi
BackgroundBrain arteriovenous malformations (AVMs) often present with epileptic seizures which carry standard mortality rate two to three folds higher than in the general population, yet preventative eradication of these lesions remains controversial. The aim of this study was to determine the demographic and angioarchitectural features associated with clinical presentation of seizures in patients with brain AVMs.MethodsWe conducted a retrospective chart review of all consecutive patients who presented to three interventional neuroradiology hospitals, with brain AVMs in Kwazulu-Natal, South Africa, over a period of 10years. The demographic and clinical presentations were derived from patient's electronic medical records. Radiological features were determined using axial Computerized Topography (CT) or Magnetic Resonance Imaging (MRI) Scan. Angioarchitectural features were determined from Digital Subtraction Angiography (DSA). Simple and multiple logistic regression models were used to identify factors associated with the risk of seizure as initial presentation in brain AVMs.ResultsThe analysis identified race/ethnicity, nidus size and location as the predictors of seizure presentation. By multiple logistic regression analysis, African-black race (OR=4.7; 95%CI: 1.15–19.60), brain AVM nidus >3cm in diameter, (OR=4.4; 95%CI: 1.7−11.42) and cortical lobar location (OR=13.6; 95%CI: 2.80−65.14) were found to be significant predictors of brain AVM-associated seizures.ConclusionImproved knowledge of specific morphological factors associated with brain AVM epilepsy could aid in the formulation of appropriate therapeutic strategies for control and/or cure of these brain AVM-associated seizures.



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Beyond Patents: Assessing the Value and Impact of Research Investments: Proceedings of a Workshop–in Brief.

Companies know exactly what they spend on research, but knowing exactly what they get for their money is a more difficult question to answer. Without a good way to measure value, research can be viewed as a cost that can be cut to boost near-term earnings. The number of patents is one metric for measuring the value of research, but that information is not necessarily useful without knowing the business value of those patents in the marketplace. What other metrics serve to highlight the value of research and innovation? On June 27 and 28, 2017, the Government-University-Industry Research Roundtable held a meeting to explore these issues. This publication briefly summarizes the presentations and discussions from the meeting.

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Sporadic NF2 Mosaic: Multiple spinal schwannomas presenting with severe, intractable pain following pregnancy

Publication date: December 2017
Source:Interdisciplinary Neurosurgery, Volume 10
Author(s): Jeffrey H. Zimering, Bryan D. Choi, Matthew J. Koch, John C. Dewitt, Anat Stemmer-Rachamimov, John H. Shin
The aim of the present paper is to report undiagnosed sporadic neurofibromatosis type 2 presenting with symptomatic compressive spinal tumors following pregnancy. A 36-year-old woman experienced progressive, severe lumbar radicular pain in the second trimester of pregnancy which became intractable soon after delivery. Magnetic resonance imaging revealed a complex heterogeneous hypointense mass lesion around the conus. There were two small punctate lesions in the cauda equina suggestive of myxopapillary ependymoma with 'drop metastases.' The patient underwent surgical resection of two cystic compressive conus masses. Her low back pain improved after surgery. The masses were consistent with cystic/cellular schwannomas. An incidental finding was of a small, low-grade spinal ependymoma which lacked the characteristic histologic features of myxopapillary ependymoma. Multiple, large cystic schwannomas are not uncommon in schwannomatosis, however, the co-occurrence of low-grade ependymoma strongly suggests a clinical diagnosis of new, sporadic neurofibromatosis type 2. Although cranial nerve schwannomas (orbital, auditory) have been reported to enlarge during pregnancy, to our knowledge, this is the first report of multiple cystic/cellular schwannomas causing severe pain (due to conus compression) during and immediately after pregnancy.



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Evaluation of Health in Pregnancy grants in Scotland: a natural experiment using routine data.

'Health in Pregnancy' grants were not associated with higher birthweight but seem to have influenced maternal health-seeking behaviour.

http://ift.tt/2zw5RnM

Pain Management and the Opioid Epidemic: Balancing Societal and Individual Benefits and Risks of Prescription Opioid Use.

Drug overdose, driven largely by overdose related to the use of opioids, is now the leading cause of unintentional injury death in the United States. The ongoing opioid crisis lies at the intersection of two public health challenges: reducing the burden of suffering from pain and containing the rising toll of the harms that can arise from the use of opioid medications. Chronic pain and opioid use disorder both represent complex human conditions affecting millions of Americans and causing untold disability and loss of function. In the context of the growing opioid problem, the U.S. Food and Drug Administration (FDA) launched an Opioids Action Plan in early 2016. As part of this plan, the FDA asked the National Academies of Sciences, Engineering, and Medicine to convene a committee to update the state of the science on pain research, care, and education and to identify actions the FDA and others can take to respond to the opioid epidemic, with a particular focus on informing FDA's development of a formal method for incorporating individual and societal considerations into its risk-benefit framework for opioid approval and monitoring.

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Opportunities for Organ Donor Intervention Research: Saving Lives by Improving the Quality and Quantity of Organs for Transplantation [Prepublication Draft].

The organ donation and transplantation system strives to honor the gift of donated organs by fully using those organs to save and improve the quality of the lives of their recipients. However, there are not enough donated organs to meet the demand and some donated organs may not be recovered, some recovered organs may not be transplanted, and some transplanted organs may not function adequately.

http://ift.tt/2ztR7pi

The Asymptomatic Carotid Surgery Trial-2 (ACST-2): an ongoing randomised controlled trial comparing carotid endarterectomy with carotid artery stenting to prevent stroke.

This ongoing trial, comparing the long-term benefits of carotid surgery with carotid stenting, had recruited over 2000 patients by March 2016, will complete recruitment of 3600 by 2020 and report initial results in 2021.

http://ift.tt/2zdSGXG

Assessing chronic disease management in European health systems: Concepts and approaches [Internet].

The rising burden of chronic illness, in particular the rapid increase in the number of people with multiple health problems, is a challenge to health systems globally. Associated premature mortality and reduced physical functioning, along with higher use of health services and related costs, are among the key concerns faced by policy-makers and practitioners.

http://ift.tt/2zttaOW

Dual Use Research of Concern in the Life Sciences: Current Issues and Controversies.

There is a growing tension between a scientific culture based on transparency and the need for secrecy to protect national security. While most scientists would argue that the openness that characterizes much of the scientific research enterprise is the source of the extraordinary gains in scientific knowledge that have enriched us materially and intellectually, the ideal of a scientific culture based on principles of openness and transparency faces continuing challenges.

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Global Health and the Future Role of the United States.

While much progress has been made on achieving the Millenium Development Goals over the last decade, the number and complexity of global health challenges has persisted. Growing forces for globalization have increased the interconnectedness of the world and our interdependency on other countries, economies, and cultures. Monumental growth in international travel and trade have brought improved access to goods and services for many, but also carry ongoing and ever-present threats of zoonotic spillover and infectious disease outbreaks that threaten all.

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Factors affecting seeking health-related information through the internet among patients in Kuwait

Publication date: Available online 14 October 2017
Source:Alexandria Journal of Medicine
Author(s): Haya M. Alkhatlan, Khan F. Rahman, Badriyah H. Aljazzaf
BackgroundThe internet is a powerful worldwide communication medium that provides its users with immediate information irrespective of their location, culture, language and time. E-health service will have a great impact in reducing the costs of health care, increasing satisfaction of patients and health professionals, and minimizing the burden on health facilities.ObjectiveThis study aims to determine the proportion of patients who obtain health-related information through the internet as well as factors that could affect using the internet for seeking health information.Subjects and methodsThis study was conducted in six general hospitals in Kuwait. A cross-sectional study was adopted to determine the proportion of patients who obtain health-related information through the internet. It was followed by a case-control study to determine factors that could be associated with on-line search of health information. A questionnaire was used which included data related to socio-demographic characteristics, clinical history and computer experience. The final analysis included 220 participants.ResultsThe majority of participants (93.2%) mentioned that they have used the internet for one or more purposes. Only 129 participants (62.9%) used the internet for obtaining health related information. All studied socio-demographic factors, except age and marital state, and computer skills variables had significant effect on on-line search for health information. After adjustment for confounding, only gender, nationality, level of education, and using computer at work were proved to be significant determinants of the outcome of interest.ConclusionIt is important to close the gap in health literacy and increase the use of health information technology to support patient self-management. The creation of an eHealth-literate population should be a priority in Kuwaiti public health policy.



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Adjustment disorder after botulinum toxin injection in an adolescent palatal myoclonus case: The importance of informed consent in the treatment of neuropsychiatric disorders in children and adolescents

Publication date: Available online 12 October 2017
Source:Alexandria Journal of Medicine
Author(s): Yusuf Öztürk, Zehra Topal, Nuran Demir, Ali Evren Tufan




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Hepatitis E virus isolated from chronic hepatitis B patients in Malaysia: Sequences analysis and genetic diversity suggest zoonotic origin

Publication date: Available online 9 October 2017
Source:Alexandria Journal of Medicine
Author(s): Shuaibu Abdullahi Hudu, Mohd Taib Niazlin, Syafinaz Amin Nordin, Nabil Saad Harmal, Soek Siam Tan, Haniza Omar, Hamiza Shahar, Noor Aliza Mutalib, Zamberi Sekawi
Background: Zoonotically acquired HEV has been described as one of the most successful zoonotic viral infections in human history.Aim: In this study we characterized HEV comparative genomic analysis as it relates to swine HEV.Materials and methods: A total of 82 chronic hepatitis B patients were recruited from May 2015 to May 2016 for this study. We conducted a serological and molecular investigation of HEV among these patients. The detected HEV were sequenced and the genomes and deduced amino acids were characterized using molecular evolutionary genetic analysis software version 7.Results: Of the 82 chronic hepatitis B patients that were tested, 9.8% (8/82) were found to be HEV positive. Phylogenetic analysis of the HEV RNA sequences showed they are of genotype 4 and demonstrated high sequence identity with a swine isolate from China, with variation in amino acids at position 22, where leucine was present in the Malaysian human isolate while phenylalanine was present in the China swine isolate.Conclusion: Comparative analysis of the human HEV ORF-2 nucleotide sequence suggest zoonotic origin.



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Utility of diffusion weighted imaging (DWI) in assessment of liver fibrosis

Publication date: Available online 9 October 2017
Source:Alexandria Journal of Medicine
Author(s): Doaa M. Emara, Marwa M. Reda, Doaa A. Elwazzan
Objectives: hepatic fibrosis occurs due to chronic liver injury. Early fibrosis can be reversed by treatment with specific antifibrotic therapy in addition to removal of the cause if possible, that is why, identification of the early liver fibrosis is important. MRI DWI is a non-invasive non-contrast imaging technique which help in diagnosis of different stages of hepatic fibrosis. Aim of the work: was to study the predictive value of diffusion weighted MRI for assessing liver fibrosis in comparison to liver biopsy in chronic hepatitis C virus patients. Methods: all the studied cases were subjected to the followings: (1) History and laboratory examination (PCR for HCV and liver function tests). (2) MRI DWI and post processing ADC map. (3) Percutaneous liver biopsy in cases with HCV for histopathological examination to assess the stage of fibrosis. Results: this study was carried out on 75 subjects, divided into two group, 50 cases and 25 controls, the mean age in the two studied groups was 36.5±9.32 and 35.8±6.75 respectively in patients and control. ADC of both liver and spleen showed a highly significant increase in the control than in the cases with mean liver ADC in the control group=2.3±0.25. There was a significant negative correlation between the mean ADC of the liver, spleen and the stage of liver fibrosis.



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Additive manufacturing applications in medical cases: A literature based review

Publication date: Available online 6 October 2017
Source:Alexandria Journal of Medicine
Author(s): Mohd. Javaid, Abid Haleem
BackgroundA significant number of the research paper on Medical cases using Additive manufacturing studied. Different applications of additive manufacturing technologies in the medical area analysed for providing the state of the art and direction of the development.The aim of workTo illustrate the Additive Manufacturing technology as being used in medical and its benefits along-with contemporary and future applications.Materials and methodsLiterature Review based study on Additive Manufacturing that are helpful in various ways to address medical problems along with bibliometric analysis been done.ResultBriefly described the review of forty primary applications of AM as used for medical purposes along with their significant achievement. Process chain development in the application of AM is identified and tabulated for every process chain member, its achievement and limitations for various references.There are five criteria which one can achieve through medical model when made through AM technology. To support the achievements and limitations of every criterion proper references are provided. The ongoing research is also classified according to the application of AM in medical with criteria, achievement and references. Eight major medical areas where AM is implemented have been identified along with primary references, objectives and advantages.ConclusionPaper deals with the literature review of the Medical application of Additive Manufacturing and its future. Medical models which are customised and sourced from data of an individual patient, which vary from patient to patient can well be modified and printed. Medical AM involves resources of human from the field of reverse engineering, medicine and biomaterial, design and manufacturing of bones, implants, etc. Additive Manufacturing can help solve medical problems with extensive benefit to humanity.



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Traditional practices and childhood cryptosporidiosis in Nigeria: A review

Publication date: Available online 16 October 2017
Source:Alexandria Journal of Medicine
Author(s): Adekunle B. Ayinmode, Oluwasola O. Obebe
Cryptosporidium infection is known worldwide as an important aetiology of chronic diarrhoea that can become fatal in children (below 5years of age) and immunocompromised individuals. This review was aimed at identifying some traditional practices that may be risk factors for childhood diseases like cryptosporidiosis in a country like Nigeria with different tribes and cultures. Information gathered from literature search and informal sources identified some indigenous practices like birth rituals, special childhood menus, traditional nanny practice, local management of childhood diarrhoea and some myths among others, as factors that may negatively impact childhood health in a multi-cultural population like Nigeria. A proper understanding of these traditional practices will enable the prevention and control of childhood disease like cryptosporidiosis in a multi-ethnic setting.



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Role of magnetic resonance imaging in the evaluation of the popliteus musclotendinous injuries as a part of the posterolateral corner injuries of the knee

Publication date: Available online 30 September 2017
Source:Alexandria Journal of Medicine
Author(s): Aly A. Abdel-Kerim Farahat, Abd ElAziz Elnekeidy, Mohamed Abdel Motaleb Abdelgelil
IntroductionThe popliteus musclotendinous complex is considered to be one of the main stabilizers of the posterolateral corner of the knee having different attachments and variable sites of injuries, the use of MRI helps the radiologists to depict such injuries consistently.Purpose of the studyTo study the role of MRI in evaluating the popliteus musclotendinous injuries as a part of the PLCof the knee.Patients and methodsOur study included 15 patients with trauma to the knee undergoing MRI using 1.5T magnet using the following sequence: Axial, Coronal, sagittal proton density fat sat, T1, T2 and T2 gradient and conventional X-ray/CT [All patients did conventional X-ray Knee (AP and Lateral views), two patients did CT study of the knee].ResultsOut of 15 studied patients with PLC injuries, eight (53.33%) patients had popliteus complex injuries, 7 (87.5%) patients showed combined injuries with other posterolateral structures while one (12.5) patient had isolated popliteus musclotendinous complex injury.ConclusionMRI imaging is crucial in the evaluation of the different sites and patterns of injuries of the popliteus musclotendinous complex when suspecting PLC injury.



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Association of IL-23R gene single nucleotide polymorphism; rs 11209026 with incidence and severity of ankylosing spondylitis in a cohort of Egyptian patients

Publication date: Available online 15 September 2017
Source:Alexandria Journal of Medicine
Author(s): Mohamed I. Sayed, Doaa I. Hashad, Eman A. Soliman, Maha M. Talaaba
The aim of the present study was to investigate the possible association between incidence and severity of ankylosing spondylitis (AS) in a cohort of Egyptians and Interleukin-23Receptor (IL23R) genesingle nucleotide polymorphism(rs11209026). Methods:The study included thirty-two AS patients and forty volunteers who serves asa control group. The studied polymorphismwas genotyped using 5′ Nuclease assay. Results: A statistically significant difference was detected between both studied groups as regards different IL23R genesingle nucleotide polymorphism(rs11209026) genotypes. Heterozygous genotype was the most prevailing among both cases and controls. At a cutoff level of 110pg/mL, a statically significant difference was observed between cases and controls as regards serum IL23 level. Conclusions:In Egyptians, IL-23R single nucleotide polymorphism (rs11209026) appears to be associated with ankylosing spondylitis occurrence not severity, while higher levels of IL-23 might be associated with disease severity.



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Serum cobalamin and red cell folate levels of anti-psychotic treatment and treatment naïve psychiatic patients in a tertiary hospital in Nigeria

Publication date: Available online 14 September 2017
Source:Alexandria Journal of Medicine
Author(s): AO Shittu, AO Adewoye, HO Olawumi
BackgroundPsychiatric disorders contribute significantly to the global burden of diseases. There is an urgent need to curtail the morbidity and mortality associated with psychiatric disorders. Deficiencies of cobalamin and folate have been linked with psychiatric disorders.Materials and methodSixty-six each of antipsychotic treatment, treatment naïve psychiatric patients and control were recruited for the study. Red cell folate and serum cobalamin were determined with Enzyme Linked Immunosorbent Assay kits and the haemogram using Sysmex XT2000i.ResultFolate deficiency was present in 13.6% of newly diagnosed anti-psychotic naive psychiatric patients with few of them having neutrophil hypersegmentation (7.6%) and macrocytosis (4.5%). Mean red cell folate levels for anti-psychotic naïve, patients on anti-psychotic and controls were 350.23±0.54nmol/l, 370±0.70nmol/l and 370±0.51nmol/l respectively, with p-values of 0.0001 and 0.3500 respectively when compared with control, while serum cobalamin levels were within the normal reference range in all patients and controls.Reticulocyte count had 8 times and 3 times likelihood of influencing low serum folate and low serum cobalamin respectively.ConclusionAll patients had Serum cobalamin levels within the reference interval, the same can be said of the RBC folate levels of the greater percentage (95.5%) of psychiatric patients on psychotropic drugs.



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Endoscopy audit over 10years in a community hospital in Egypt

Publication date: Available online 12 September 2017
Source:Alexandria Journal of Medicine
Author(s): Ahmed Gado, Basel Ebeid, Aida Abdelmohsen, Tarek Gado, Anthony Axon
BackgroundPractice variation is likely to have an important impact on the effectiveness of endoscopy. Performing regular quality audits allows identification of potential underperformance and consequently can result in significant improvement in endoscopy quality. An annual audit was conducted in a community hospital in Egypt.AimThe aim of the study was to determine if practice and performance of endoscopy is influenced by a consistent audit process by looking for improvement in completeness of procedures over a 10-year period.Patients and methodsA total of 3736 consecutive procedures were prospectively assessed between years 2004 and 2014.ResultsThe completion rates improved consistently. Esophagogastroduodenoscopy (EGD) completion rate was 99.9% in 2004–2008 and 99% in 2009–2013 (P=0.5). Initial hemostasis of EGD-gastrointestinal bleed increased from 82% in 2004–2008 to 86% in 2009–2013 (P=0.04). Adequate bowel cleansing increased from 60% in 2004–2008 to 67% in 2009–2013 (P=0.13). Crude completion rates increased from 66% in 2004–2008 to 79% in 2009–2013 (P=0.007). Adjusted completion rates increased from 80% in 2004–2008 to 95% in 2009–2013 (P=0.0001). Ileoscopy rates in patients with chronic diarrhea increased from 79% in 2004–2008 to 97% in 2009–2013 (P=0.01). Endoscopic polypectomy rates increased from 65% in 2004–2008 to 94% in 2009–2013 (P=0.0004). Complete polyp removal rates increased from 77% in 2004–2008 to 87% in 2009–2013 (P=0.19). Complete polyp retrieval rates increased from 85% in 2004–2008 to 89% in 2009–2013 (P=0.34).ConclusionContinuous audit over 10years can enhance endoscopy performance, improve the quality of endoscopic procedures and lead to better outcomes.



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A Community-Based Study of Staphylococcus aureus Nasal Colonization and Molecular Characterization Among Men Who Have Sex with Men.

Related Articles

A Community-Based Study of Staphylococcus aureus Nasal Colonization and Molecular Characterization Among Men Who Have Sex with Men.

LGBT Health. 2017 Oct;4(5):345-351

Authors: Leung NS, Vidoni ML, Robinson DA, Padgett P, Brown EL

Abstract
PURPOSE: The aims of this cross-sectional study were to determine the prevalence of Staphylococcus aureus nasal colonization, evaluate community-related behavioral risk factors, and utilize staphylococcal protein A (spa) typing for epidemiological surveillance among community-based men who have sex with men from the National HIV Behavioral Surveillance System in Houston, Texas.
METHODS: Descriptive methods and logistic analyses were used to determine associations with nasal colonization.
RESULTS: The prevalence of S. aureus colonization was 29.7%; of these, 3.0% were colonized with methicillin-resistant S. aureus. Logistic analyses revealed that anal intercourse practices were associated with colonization (P < 0.05). A diverse population of 38 spa types was identified.
CONCLUSION: Our findings suggest that an association among preferential sex practices, condom use, and S. aureus colonization exists and should be investigated further.

PMID: 29022859 [PubMed - in process]

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The commensal lifestyle of Staphylococcus aureus and its interactions with the nasal microbiota.

Related Articles

The commensal lifestyle of Staphylococcus aureus and its interactions with the nasal microbiota.

Nat Rev Microbiol. 2017 Oct 12;15(11):675-687

Authors: Krismer B, Weidenmaier C, Zipperer A, Peschel A

Abstract
Although human colonization by facultative bacterial pathogens, such as Staphylococcus aureus, represents a major risk factor for invasive infections, the commensal lifestyle of such pathogens has remained a neglected area of research. S. aureus colonizes the nares of approximately 30% of the human population and recent studies suggest that the composition of highly variable nasal microbiota has a major role in promoting or inhibiting S. aureus colonization. Competition for epithelial attachment sites or limited nutrients, different susceptibilities to host defence molecules and the production of antimicrobial molecules may determine whether nasal bacteria outcompete each other. In this Review, we discuss recent insights into mechanisms that are used by S. aureus to prevail in the human nose and the counter-strategies that are used by other nasal bacteria to interfere with its colonization. Understanding such mechanisms will be crucial for the development of new strategies for the eradication of endogenous facultative pathogens.

PMID: 29021598 [PubMed - in process]

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The epidemiology and transmission of methicillin-resistant Staphylococcus aureus in the community in Singapore: study protocol for a longitudinal household study.

Related Articles

The epidemiology and transmission of methicillin-resistant Staphylococcus aureus in the community in Singapore: study protocol for a longitudinal household study.

BMC Infect Dis. 2017 Oct 11;17(1):678

Authors: Shankar N, Chow ALP, Oon J, Hsu LY, Ang B, Pang J, De Sessions PF, Periaswamy B, Tambyah PA, Teo DB, Tam CC

Abstract
BACKGROUND/AIM: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common multidrug-resistant organisms in healthcare settings worldwide, but little is known about MRSA transmission outside of acute healthcare settings especially in Asia. We describe the methods for a prospective longitudinal study of MRSA prevalence and transmission.
METHODS: MRSA-colonized individuals were identified from MRSA admission screening at two tertiary hospitals and recruited together with their household contacts. Participants submitted self-collected nasal, axilla and groin (NAG) swabs by mail for MRSA culture at baseline and monthly thereafter for 6 months. A comparison group of households of MRSA-negative patients provided swab samples at one time point. In a validation sub-study, separate swabs from each site were collected from randomly selected individuals, to compare MRSA detection rates between swab sites, and between samples collected by participants versus those collected by trained research staff. Information on each participant's demographic information, medical status and medical history, past healthcare facilities usage and contacts, and personal interactions with others were collected using a self-administered questionnaire.
DISCUSSION/CONCLUSION: Understanding the dynamics of MRSA persistence and transmission in the community is crucial to devising and evaluating successful MRSA control strategies. Close contact with MRSA colonized patients may to be important for MRSA persistence in the community; evidence from this study on the extent of community MRSA could inform the development of household- or community-based interventions to reduce MRSA colonization of close contacts and subsequent re-introduction of MRSA into healthcare settings. Analysis of longitudinal data using whole-genome sequencing will yield further information regarding MRSA transmission within households, with significant implications for MRSA infection control outside acute hospital settings.

PMID: 29020940 [PubMed - in process]

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DNMT1, DNMT3A and DNMT3B proteins are differently expressed in mouse oocytes and early embryos

Abstract

DNA methylation is one of the epigenetic mechanisms and plays important roles during oogenesis and early embryo development in mammals. DNA methylation is basically known as adding a methyl group to the fifth carbon atom of cytosine residues within cytosine–phosphate–guanine (CpG) and non-CpG dinucleotide sites. This mechanism is composed of two main processes: de novo methylation and maintenance methylation, both of which are catalyzed by specific DNA methyltransferase (DNMT) enzymes. To date, six different DNMTs have been characterized in mammals defined as DNMT1, DNMT2, DNMT3A, DNMT3B, DNMT3C, and DNMT3L. While DNMT1 primarily functions in maintenance methylation, both DNMT3A and DNMT3B are essentially responsible for de novo methylation. As is known, either maintenance or de novo methylation processes appears during oocyte and early embryo development terms. The aim of the present study is to investigate spatial and temporal expression levels and subcellular localizations of the DNMT1, DNMT3A, and DNMT3B proteins in the mouse germinal vesicle (GV) and metaphase II (MII) oocytes, and early embryos from 1-cell to blastocyst stages. We found that there are remarkable differences in the expressional levels and subcellular localizations of the DNMT1, DNMT3A and DNMT3B proteins in the GV and MII oocytes, and 1-cell, 2-cell, 4-cell, 8-cell, morula, and blastocyst stage embryos. The fluctuations in the expression of DNMT proteins in the analyzed oocytes and early embryos are largely compatible with DNA methylation changes and genomic imprintestablishment appearing during oogenesis and early embryo development. To understand precisemolecular biological meaning of differently expressing DNMTs in the early developmental periods, further studies are required.

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The prostate response to prolactin modulation in adult castrated rats subjected to testosterone replacement

Abstract

Despite the androgenic dependence, other hormones, growth factors, and cytokines are necessary to support prostatic growth and maintain the glandular structure; among them, prolactin is a non-steroidal hormone secreted mainly by the pituitary gland. However, extra-pituitary expression of prolactin, such as in the prostate, has also been demonstrated, highlighting the paracrine and autocrine actions of prolactin within the prostate. Here, we investigated whether prolactin modulation alters ventral prostate (VP) morphophysiology in adult castrated rats. Sprague Dawley rats were castrated and after 21 days, divided into ten experimental groups (n = 6/group): castrated control: castrated animals that did not receive treatment; castrated+testosterone: castrated animals that received T (4 mg/kg/day); castrated+PRL (PRL): castrated animals receiving prolactin (0.3 mg/kg/day); castrated+T+PRL: castrated animals that received a combination of testosterone and prolactin; and castrated+bromocriptine (BR): castrated animals that received bromocriptine (0.4 mg/kg/day). The control group included intact animals. The animals were treated for 3 or 10 consecutive days. At the end of experimental period, the animals were euthanized, and the blood and VP lobes were collected and analyzed by different methods. The main findings were that the administration of prolactin to castrated rats did not exert anabolic effects on the VP. Although we observed activation of downstream prolactin signaling after prolactin administration, this was not enough to overcome the prostatic androgen deficiency. Likewise, there was no additional glandular involution in the castrated group treated with bromocriptine. We concluded that despite stimulating the downstream signaling pathway, exogenous prolactin does not act on VP in the absence or presence of high levels of testosterone.

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Blockade of LGR4 inhibits proliferation and odonto/osteogenic differentiation of stem cells from apical papillae

Abstract

During tooth root development, stem cells from apical papillae (SCAPs) are indispensable, and their abilities of proliferation, migration and odontoblast differentiation are linked to root formation. Leucine-rich repeat-containing GPCR 4 (LGR4) modulates the biological processes of proliferation and differentiation in multiple stem cells. In this study, we showed that LGR4 is expressed in all odontoblast cell lineage cells and Hertwig's epithelial root sheath (HERS) during the mouse root formation in vivo. In vitro we determined that LGR4 is involved in the Wnt/β-catenin signaling pathway regulating proliferation and odonto/osteogenic differentiation of SCAPs. Quantitative reverse-transcription PCR (qRT-PCR) confirmed that LGR4 is expressed during odontogenic differentiation of SCAPs. CCK8 assays and in vitro scratch tests, together with cell cycle flow cytometric analysis, demonstrated that downregulation of LGR4 inhibited SCAPs proliferation, delayed migration and arrested cell cycle progression at the S and G2/M phases. ALP staining revealed that blockade of LGR4 decreased ALP activity. QRT-PCR and Western blot analysis demonstrated that LGR4 silencing reduced the expression of odonto/osteogenic markers (RUNX2, OSX, OPN, OCN and DSPP). Further Western blot and immunofluorescence studies clarified that inhibition of LGR4 disrupted β-catenin stabilization. Taken together, downregulation of LGR4 gene expression inhibited SCAPs proliferation, migration and odonto/osteogenic differentiation by blocking the Wnt/β-catenin signaling pathway. These results indicate that LGR4 might play a vital role in SCAPs proliferation and odontoblastic differentiation.

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Spatiotemporal expression of proprotein convertase subtilisin/kexin type 5 in the development of anorectal malformations in fetal rats

Abstract

This study examined the expression patterns of proprotein convertase subtilisin/kexin type 5 (Pcsk5) during anorectal development in normal and anorectal malformations (ARM) rat embryos, determine the possible role of Pcsk5 in the pathogenesis of ARM. An ARM rat model was developed by the administration of ethylenethiourea gestational day 10 (GD10). Embryos were harvested by surgical excision from GD13 to GD16, and the spatiotemporal expression of Pcsk5 was evaluated, using immunohistochemistry staining, Western blotting and real time RT-PCR. Immunohistochemistry staining in normal embryos revealed that Pcsk5 was abundantly expressed on the epithelium of the cloaca (CL) on GD13. On GD14 and GD15, positive cells were noted on the urorectal septum and the thin anal membrane. However, the epithelium of the CL of ARM embryos only faintly expressed Pcsk5 from GD13 to GD15. Western blotting and real time RT-PCR showed time-dependent increase of Pcsk5 expression in the developing hindgut. Pcsk5 expression levels were lower in the ARM group from GD14 to GD16 (p ≤ 0.05). These results indicate that downregulation of Pcsk5 during cloaca development into the rectum and urethra might be related to the formation of ARMs.

http://ift.tt/2yNbd0S

Expression and distribution of three transient receptor potential vanilloid(TRPV) channel proteins in human odontoblast-like cells

Abstract

Odontoblasts have been suggested to contribute to nociceptive sensation in the tooth via expression of the transient receptor potential (TRP) channels. The TRP channels as a family of nonselective cation permeable channels play an important role in sensory transduction of human. In this study, we examined the expression of transient receptor potential vanilloid-1 (TRPV1), transient receptor potential vanilloid-2 (TRPV2) and transient receptor potential vanilloid-3 (TRPV3) channels in native human odontoblasts (HODs) and long-term cultured human dental pulp cells with odontoblast phenotyoe (LHOPs) obtained from healthy wisdom teeth with the use of immunohistochemistry (IHC), immunofluorescence (IF), quantitative real-time polymerase chain reaction (qRT-PCR),western blotting (WB) and immunoelectron microscopy (IEM) assay. LHOPs samples were made into ultrathin sections, mounted on nickel grids, floated of three TRPV antibodies conjugated with 10 nm colloidal gold particles and observed under IEM at 60,000 magnifications. The relative intracellular distributions of these three channels were analyzed quantitatively on IEM images using a robust sampling, stereological estimation and statistical evaluation method. The results of IHC and IF convinced that TRPV1, TRPV2 and TRPV3 channels were expressed in native HODs and (LHOPs). The result of qRT-PCR and WB confirmed that the gene and protein expression of TRPV1, TRPV2, and TRPV3 channels and TRPV1 mRNA are more abundantly expressed than TRPV2 and TRPV3 in HODs (P < 0.05). Quantitative analysis of IEM images showed that the relative intracellular distributions of these three channels are similar, and TRPV1, TRPV2 and TRPV3 proteins were preferential labeled in human odontoblast processes, mitochondria, and endoplasmic reticulum. Thus, HODs could play an important role in mediating pulp thermo-sensation due to the expression of these three TRPV channels. The difference of relative intracellular distributions of three channels suggests that special structures such as processes may have an important role to sensing of the outer stimuli first.

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Comparative Safety of Targeted Therapies for Metastatic Colorectal Cancer between Elderly and Younger Patients: a Study Using the International Pharmacovigilance Database

Abstract

Background

Metastatic colorectal cancer (mCRC) is increasingly treated using targeted therapies. Post-marketing safety of these agents is understudied, especially in the elderly.

Objective

This study aimed to compare, according to age, the adverse drug reactions (ADRs) of targeted therapies used for mCRC in real life.

Patients and Methods

An extraction of VigiBase, which contains World Health Organization individual case safety reports (ICSRs), was performed. All ADR reports with aflibercept, bevacizumab, cetuximab, panitumumab, or regorafenib used in CRC were considered. For all drugs, chi-square tests were used to compare frequencies of serious ADRs between patients aged ≥75 and <75 years. For selected ADRs and each drug, the drug-ADR association compared to other anticancer drugs was estimated through the proportional reporting ratio (PRR) in both age groups.

Results

There were 21,565 ICSRs included, among which 74% were serious and 11% were fatal. Median age was 64 years (Inter Quartile Range = 56–71) and 15% of patients were aged ≥75; 57% were male. Serious ICSRs accounted for 47,292 ADRs. Neutropenia was not more reported in elderly for all drugs while diarrhea was more reported in elderly for panitumumab. Cardiac disorders were more reported in elderly patients, in particular heart failure, especially for bevacizumab, cetuximab, and regorafenib, as were respiratory, thoracic, and mediastinal disorders. Most of PRR were not different between the two groups, except encephalopathies, which were significantly associated with bevacizumab in the elderly only.

Conclusions

ADRs related to targeted therapies used for mCRC treatment were different across age groups; yet, not systematically more reported or worse in elderly patients. Selected elderly patients could, therefore, be treated with these targeted therapies.

http://ift.tt/2zhzqcz

Metabolic iodine and tumours

Abstract

Purpose

Purpose of the work is to highlight a possible connection between metabolic iodine and natural tumour control.

Method

Method adopted is to use information available in the literature.

Result

Result indicated a means of the purpose being attained.

Conclusion

Conclusion drawn is that a tumour control method derives from the relationship studied.

http://ift.tt/2gJyJAW

Lithocholic bile acid inhibits lipogenesis and induces apoptosis in breast cancer cells

Abstract

Background

It has amply been documented that mammary tumor cells may exhibit an increased lipogenesis. Biliary acids are currently recognized as signaling molecules in the intestine, in addition to their classical roles in the digestion and absorption of lipids. The aim of our study was to evaluate the impact of lithocholic acid (LCA) on the lipogenesis of breast cancer cells. The putative cytotoxic effects of LCA on these cells were also examined.

Methods

The effects of LCA on breast cancer-derived MCF-7 and MDA-MB-231 cells were studied using MTT viability assays, Annexin-FITC and Akt phosphorylation assays to evaluate anti-proliferative and pro-apoptotic properties, qRT-PCR and Western blotting assays to assess the expression of the bile acid receptor TGR5 and the estrogen receptor ERα, and genes and proteins involved in apoptosis (Bax, Bcl-2, p53) and lipogenesis (SREBP-1c, FASN, ACACA). Intracellular lipid droplets were visualized using Oil Red O staining.

Results

We found that LCA induces TGR5 expression and exhibits anti-proliferative and pro-apoptotic effects in MCF-7 and MDA-MB-231 cells. Also, an increase in pro-apoptotic p53 protein expression and a decrease in anti-apoptotic Bcl-2 protein expression were observed after LCA treatment of MCF-7 cells. In addition, we found that LCA reduced Akt phosphorylation in MCF-7 cells, but not in MDA-MB-231 cells. We also noted that LCA reduced the expression of SREBP-1c, FASN and ACACA in both breast cancer-derived cell lines and that cells treated with LCA contained low numbers of lipid droplets compared to untreated control cells. Finally, a decrease in ERα expression was observed in MCF-7 cells treated with LCA.

Conclusions

Our data suggest a potential therapeutic role of lithocholic acid in breast cancer cells through a reversion of lipid metabolism deregulation.

http://ift.tt/2ztQNqA

Memory CD4 + T cell subsets in tumor draining lymph nodes of breast cancer patients: A focus on T stem cell memory cells

Abstract

Background

The compartments of memory T cells play a fundamental role in the immune system by substantiating specific and acquired immunity. A new subset of memory cells, T stem cell memory (T_SCM) cells, with stem cell-like properties, a high capacity to proliferate, a long survival, and an ability to differentiate into all effector and memory cells has recently been introduced. In the present study, we aimed to determine the frequency of CD4⁺ T_SCM and other T memory cell subsets in tumor draining lymph nodes of breast cancer patients.

Materials and methods

Mononuclear cells were obtained from axillary lymph nodes of 52 untreated patients with breast cancer (BC) and stained with fluorochrome conjugated anti-CD4, −CCR7, −CD45RO and -CD95 antibodies to detect different subtypes of memory cells in CD4⁺ lymphocyte populations. Data were acquired using a four-color FACSCalibur flow cytometer and analyzed using CellQuest Pro software.

Results

We found that >70% of CD4⁺ lymphocytes in draining lymph nodes of BC patients exhibited a memory phenotype of which 7.04 ± 1.04% had a T_SCM phenotype (CD4⁺CCR7⁺CD45RO⁻CD95⁺). The frequency of T_SCM cells was significantly higher in tumor positive lymph nodes compared to tumor negative lymph nodes (p = 0.026) as well as among those patients who had at least one affected lymph node (p = 0.012). Moreover, we found that the total frequency of central memory T cells (T_CM) with a low expression of CD45RO was significantly higher among these patients. The percentage of CD45RO^Low T_CM cells was also found to increase with tumor progression from stage I to stage III (p = 0.020). On the other hand, we found that the percentage of CD95^Hi effector memory T cells (T_EM) was significantly decreased in involved lymph nodes (p = 0.009).

Conclusion

Our data suggest that following long-term exposure to putative tumor antigens, T_SCM cells proliferate to generate a pool of committed memory and effector T cells. As the tumor progresses, the immunosuppressive milieu induced by tumor cells may slow down the differentiation of CD45RO^Low T_CM cells to more functional sub-populations.

http://ift.tt/2zegHxy

Implications of FGF19 on sorafenib-mediated nitric oxide production in hepatocellular carcinoma cells - a short report

Abstract

Background

Hepatocellular carcinoma (HCC), a primary neoplasm derived from hepatocytes, is the second leading cause of cancer mortality worldwide. Previous work has shown that fibroblast growth factor 19 (FGF19), an oncogenic driver, acts as a negative regulator of the therapeutic efficacy of the tyrosine kinase inhibitor sorafenib in HCC cells. The FGF19-mediated mechanism affecting sorafenib treatment, however, still remains to be resolved. Here, we hypothesize that the FGF19-FGFR4 axis may affect the effectiveness of sorafenib in the treatment of HCC.

Methods

FGF19 and FGFR4 cDNAs were cloned into a pcDNA3.1 vector and subsequently used for exogenous over-expression analyses. FGF19 knockdown cells were generated using a lentiviral-mediated short hairpin RNA (shRNA) methodology and FGFR4 knockout cells were generated using a CRISPR-Cas9 methodology. FGFR4 activation in HCC cells was inhibited by BLU9931. The effects of exogenous gene over-expression, expression knockdown and knockout, as well as drug efficacies in HCC cells, were validated using Western blotting. HCC cell proliferation was assessed using a CellTiter 96^® AQueous One Solution Cell Proliferation Assay, whereas NO levels were assessed using DAF-FM DA staining in conjunction with electrochemical biosensors.

Results

We found that FGF19, when exogenously overexpressed, results in a reduced sorafenib-induced NO generation and a decreased proliferation of HCC cells. In contrast, we found that either FGF19 silencing or knockout of its receptor FGFR4 sensitized HCC cells to sorafenib through the induction of NO generation. Concordantly, we found that inactivation of FGFR4 by BLU9931 enhanced the sensitivity of HCC cells to sorafenib.

Conclusion

From our data we conclude that the FGF19-FGFR4 axis may play a critical role in the effects elicited by sorafenib in HCC cells. Blocking the FGF19-FGFR4 axis may provide novel opportunities to improve the efficacy of sorafenib in the treatment of patients with HCC.

http://ift.tt/2zuAM3Z

Lung cancer-associated brain metastasis: Molecular mechanisms and therapeutic options

Abstract

Background

Lung cancer is the most common cause of cancer-related mortality in humans. There are several reasons for this high rate of mortality, including metastasis to several organs, especially the brain. In fact, lung cancer is responsible for approximately 50% of all brain metastases, which are very difficult to manage. Understanding the cellular and molecular mechanisms underlying lung cancer-associated brain metastasis brings up novel therapeutic promises with the hope to ameliorate the severity of the disease. Here, we provide an overview of the molecular mechanisms underlying the pathogenesis of lung cancer dissemination and metastasis to the brain, as well as promising horizons for impeding lung cancer brain metastasis, including the role of cancer stem cells, the blood-brain barrier, interactions of lung cancer cells with the brain microenvironment and lung cancer-driven systemic processes, as well as the role of growth factor/receptor tyrosine kinases, cell adhesion molecules and non-coding RNAs. In addition, we provide an overview of current and novel therapeutic approaches, including radiotherapy, surgery and stereotactic radiosurgery, chemotherapy, as also targeted cancer stem cell and epithelial-mesenchymal transition (EMT)-based therapies, micro-RNA-based therapies and other small molecule or antibody-based therapies. We will also discuss the daunting potential of some combined therapies.

Conclusions

The identification of molecular mechanisms underlying lung cancer metastasis has opened up new avenues towards their eradication and provides interesting opportunities for future research aimed at the development of novel targeted therapies.

http://ift.tt/2zfT3kj

TRAIL enhances quinacrine-mediated apoptosis in breast cancer cells through induction of autophagy via modulation of p21 and DR5 interactions

Abstract

Purpose

Previously, we reported that quinacrine (QC) may cause apoptosis in breast and colon cancer cells by activating the death receptor 5 (DR5), resulting in autophagic cell death through p21 modulation. Here, we systematically evaluated the combined role of p21 and DR5 and their crosstalk in QC-mediated autophagy and apoptosis in breast cancer cells using in vitro and in vivo models.

Methods

Multiple breast cancer-derived cell lines (MCF-7, ZR-75-1, T47D, MDA-MB-231 and MCF-10A-Tr) and a mouse xenograft model were used. Also, multiple assays, including Western blotting, immunoprecipitation, staining for autophagy and apoptosis, gene silencing, hematoxylin and eosin staining, immunohistochemistry, cell viability assessment, fluorescence imaging and cell sorting were used.

Results

We found that QC activates p21 and DR5 in combination with the apoptosis inducer TRAIL in the breast cancer-derived cells tested. Combined TRAIL and QC treatment increased autophagy and apoptosis by increasing the interaction between, and co-localization of, p21 and DR5 in the death-inducing signaling complex (DISC). We found that this combination also inhibited the mTOR/PI3K/AKT signaling cascade and modulated reactive oxygen species (ROS) and nitric oxide (NO) production. Reductions in autophagy and apoptosis in DR5-knockout cells and a lack of change in p21-DR5-silenced cells were noted after TRAIL + QC treatment. This result explains dependence of the death (autophagy and apoptosis) cascade on these two key regulatory proteins. In addition, we found in an in vivo mouse xenograft model that increased expression and enhanced co-localization of p21 and DR5 after TRAIL + QC treatment supported a joint regulatory role of these proteins in the co-prevalence of autophagy and apoptosis.

Conclusion

Our data suggest that a combined treatment of TRAIL and QC causes cell death in breast cancer-derived cells via autophagy and apoptosis by increasing the interaction of p21 and DR5, as indicated by both in vitro and in vivo studies.

http://ift.tt/2zu9nyM

Phosphorylated CXCR4 expression has a positive prognostic impact in colorectal cancer

Abstract

Background

The CXCL12-CXCR4 chemokine axis plays an important role in cell trafficking as well as in tumor progression. In colorectal cancer (CRC), the chemokine receptor CXCR4 has been shown to be an unfavorable prognostic factor in some studies, however, the role of its activated (phosphorylated) form, pCXCR4, has not yet been evaluated. Here, we aimed to investigate the prognostic value of CXCR4 and pCXCR4 in a large cohort of CRC patients.

Patients and methods

A tissue microarray (TMA) of 684 patient specimens of primary CRCs was analyzed by immunohistochemistry (IHC) for the expression of CXCR4 and pCXCR4 by tumor cells and tumor-infiltrating immune cells (TICs).

Results

The combined high expression of CXCR4 and pCXCR4 showed a favorable 5-year overall survival rate (68%; 95%CI = 59–76%) compared to tumors showing a high expression of CXCR4 only (48%; 95%CI = 41–54%). High expression of pCXCR4 was significantly associated with a favorable prognosis in a test and validation group (p = 0.015 and p = 0.0001). Moreover, we found that CRCs with a high density of pCXCR4+ tumor-infiltrating immune cells (TICs) also showed a favorable prognosis in a test and validation group (p = 0.054 and p = 0.004). Univariate Cox regression analysis for TICs revealed that a high density of pCXCR4+ TICs was a favorable prognostic marker for overall survival (HR = 0.97,95%CI = 0.96–1.00; p = 0.01). In multivariate Cox regression survival analyses a high expression of pCXCR4 in tumor cells lost its association with a better overall survival (HR = 0.99; 95%CI = 0.99–1.00, p = 0.098).

Conclusion

Our results show that high densities of CXCR4 and pCXCR4 positive TICs are favorable prognostic factors in CRC.

http://ift.tt/2zfSWVV

Expression of inflammatory lipopolysaccharide binding protein (LBP) predicts the progression of conventional renal cell carcinoma - a short report

Abstract

Background

The mortality of conventional renal cell carcinoma (RCC) correlates directly with the presence or postoperative development of metastases. The aim of this study was to identify new markers associated with the postoperative progression of conventional RCC.

Methods

Tissue microarrays (TMA) of conventional RCC from a cohort of 414 patients were analysed by immunohistochemistry for expression of the lipopolysaccharide binding protein (LBP), which was identified as a candidate biomarker through Affymetrix U133 Plus 2.0 array analysis. Univariate and multivariate Cox regression models were addressed to cancer-specific survival in association with age, sex, clinicopathological parameters and LBP expression. The survival time of the patients was estimated by Kaplan-Meier analyses, and comparisons of survival curves were made using the Log rank test.

Results

Univariate analysis revealed an association of patient survival with all clinicopathological parameters tested and LBP expression. In multivariate analysis only T classification, grade and LBP staining showed a significant association with postoperative cancer-specific survival (p < 0.001). LBP expression was found to be associated with a poor patient survival in Kaplan-Meier analyses. The estimated median survival time for patients with tumours showing LBP expression was 74 months, whereas the overall survival time was 142 months.

Conclusion

LBP expression in conventional RCC defines a group of patients at a high risk of postoperative progression and may help to direct optimized active surveillance and timely adjuvant therapy.

http://ift.tt/2zu52f6

Opposing roles of the aldo-keto reductases AKR1B1 and AKR1B10 in colorectal cancer

Abstract

Purpose

Aldo-keto reductases (including AKR1B1 and AKR1B10) constitute a family of oxidoreductases that have been implicated in the pathophysiology of diabetes and cancer, including colorectal cancer (CRC). Available data indicate that, despite their similarities in structure and enzymatic functions, their roles in CRC may be divergent. Here, we aimed to determine the expression and functional implications of AKR1B1 and AKR1B10 in CRC.

Methods

AKR1B1 and AKR1B10 gene expression levels were analyzed using publicly available microarray data and ex vivo CRC-derived cDNA samples. Gene Set Enrichment Analysis (GSEA), The Cancer Genome Atlas (TCGA) RNA-seq data and The Cancer Proteome Atlas (TCPA) proteome data were analyzed to determine the effect of high and low AKR1B1 and AKR1B10 expression levels in CRC patients. Proliferation, cell cycle progression, cellular motility, adhesion and inflammation were determined in CRC-derived cell lines in which these genes were either exogenously overexpressed or silenced.

Results

We found that the expression of AKR1B1 was unaltered, whereas that of AKR1B10 was decreased in primary CRCs. GSEA revealed that, while high AKR1B1 expression was associated with increased cell cycle progression, cellular motility and inflammation, high AKR1B10 expression was associated with a weak inflammatory phenotype. Functional studies carried out in CRC-derived cell lines confirmed these data. Microarray data analysis indicated that high expression levels of AKR1B1 and AKR1B10 were significantly associated with shorter and longer disease-free survival rates, respectively. A combined gene expression signature of AKR1B10 (low) and AKR1B1 (high) showed a better prognostic stratification of CRC patients independent of confounding factors.

Conclusions

Despite their similarities, the expression levels and functions of AKR1B1 and AKR1B10 are highly divergent in CRC, and they may have prognostic implications.

http://ift.tt/2zfSPcX

Glucosidase II beta subunit (GluIIβ) plays a role in autophagy and apoptosis regulation in lung carcinoma cells in a p53-dependent manner

Abstract

Purpose

Glucosidase II plays a major role in regulating the post-translational modification of N-linked glycoproteins. Previously, we found that the beta subunit of glucosidase II (GluIIβ) levels are significantly increased in lung carcinoma tissues, indicating a potential role in lung tumorigenesis. Here, we investigated the role of GluIIβ in the regulation of autophagy and apoptosis in lung carcinoma- and immortalized human bronchial epithelial-derived cells.

Methods

A selective glucosidase II inhibitor, bromoconduritol, was used to inhibit GluII enzyme activity and a siRNA-based technology was used to suppress the expression of the GluIIβ encoding gene PRKCSH in lung carcinoma cells differing in p53 status. Cell viability was assessed using a MTT assay, cell cycle progression was assessed using flow cytometry, autophagy was assessed using Western blotting and apoptosis was assessed using an annexin V-FITC/PI double labeling method.

Results

We found that GluIIβ inhibition resulted in the induction of autophagy in all cell lines tested, but apoptosis in only wild-type p53 cells. We also found that GluIIβ inhibition dose-dependently decreased activation of the EGFR/RTK and PI3K/AKT signaling pathways. Although the apoptosis inducing effect of GluIIβ inhibition appeared to be p53-dependent, we found that a combined treatment with lysosomal inhibitors to block autophagy enhanced the apoptotic effect of GluIIβ inhibition in both wild-type p53 and p53-null cells.

Conclusions

Our data indicate that GluIIβ inhibition results in autophagy and apoptosis in lung carcinoma-derived cells, supporting the hypothesis that this enzyme may play a role in blocking these two tumor suppressive processes. Since blocking autophagy by lysosomal inhibitors enhanced the apoptosis-inducing effect of bromoconduritol, independent of p53 status, their combined use may hold promise for the treatment of cancer, particularly lung cancer.

http://ift.tt/2zu4VjG

CA19-9 kinetics during systemic chemotherapy in patients with advanced or recurrent biliary tract cancer

Abstract

Purpose

The role of carbohydrate antigen 19-9 (CA19-9) kinetics in patients with biliary tract cancer (BTC) receiving chemotherapy remains to be elucidated.

Methods

A total of 185 advanced or recurrent BTC patients receiving a first line chemotherapy between January 2006 and March 2016, were retrospectively studied. Serum CA19-9 was measured at baseline and after two cycles of chemotherapy, and patients were categorized based on CA19-9 response: CA19-9 decrease group (≥ 30% decrease), stable group (< 30% decrease and < 20% increase) and increase group (≥ 20% increase). The associations of CA19-9 response with radiological tumor response, progression-free survival (PFS) and overall survival (OS) were investigated.

Results

There was a statistically significant association between CA19-9 response and radiological tumor responses (p < 0.001). The median PFS and OS were significantly different among three groups according to CA19-9 response: PFS of 8.0, 5.7 and 3.5 months in CA19-9 decrease, stable and increase groups (p < 0.001) and OS of 18.8, 16.0 and 7.5 months in CA19-9 decrease, stable and increase groups, respectively (p < 0.001). Multivariate analyses showed that CA19-9 response was prognostic both of OS and PFS in addition, to CA19-9 at baseline, and performance status.

Conclusion

CA19-9 kinetics after the first two cycles of a first line chemotherapy was a prognostic factor for OS and PFS in patients with advanced and recurrent BTC.

http://ift.tt/2ztBZsg

Old materials with new properties II: The metal carbides

Publication date: Available online 16 October 2017
Source:Nano Today
Author(s): Tianchao Niu
Metal carbides with particular phases have shown to be promising catalysts and supporting materials for high efficiency catalysis by choosing suitable decorating elements. Thinning metal carbides down to two-dimension can result in nontrivial properties such as superconductivity. The versatile chemistry of metal carbides offers the tunability for applications in Li-ion, Na-ion batteries and supercapacitors. However, from the point of view of surface and interface science, fundamental study at molecular/atomic levels which is crucial for understanding the origin of these superior properties, as well as the mechanism underlying interface catalysis is still missing. Furthermore, deviation of theoretical calculations from real conditions requires the building of model catalysts to mimic surface processes. In analogy with classical oxide/metal systems, we propose that scanning tunneling microscopy combined with in-situ chemical vapor deposition and molecular beam epitaxy would be powerful tools for both the controllable growth of two-dimensional metal carbides and the realization of atomic information during surface reactions.

Graphical abstract

http://ift.tt/2gpc2W2

Eosinophils and Eosinophil-Associated Diseases: an Update

Publication date: Available online 16 October 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Jeremy A. O'Sullivan, Bruce S. Bochner
The goal of this series is to offer a survey of the latest literature for clinicians and scientists alike, providing a list of important recent advances relevant to the broad field of allergy and immunology. This particular assignment was to cover the topic of eosinophils. In an attempt to highlight major ideas, themes, trends and advances relevant to basic and clinical aspects of eosinophil biology, a search of papers published since 2015 in JACI and other high impact journals was performed. Manuscripts were then reviewed and organized, and then key findings were summarized. Given space limitations, many outstanding papers could not be included, but the hope is that what follows provides a succinct overview of recently published work that has significantly added to our knowledge of eosinophils and eosinophil-associated diseases.



http://ift.tt/2yqXrxI

Fibrinogen-cleavage products and TLR4 promote the generation of programmed cell death 1 ligand 2(PD-L2)+ dendritic cells in allergic asthma

Publication date: Available online 14 October 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Minkyoung Cho, Jeong-Eun Lee, Hoyong Lim, Hyun-Woo Shin, Roza Khalmuratova, Garam Choi, Hyuk Soon Kim, Wahn Soo Choi, Young-Jun Park, Inbo Shim, Byung-Seok Kim, Chang-Yuil Kang, Jae-Ouk Kim, Shinya Tanaka, Masato Kubo, Yeonseok Chung
BackgroundInhaled protease allergens preferentially trigger Th2-mediated inflammation in allergic asthma. The role of dendritic cells (DCs) on the induction of Th2 cell responses in allergic asthma has been well documented; however, the mechanism by which protease allergens induce Th2-favorable DCs in the airway remains unclear.ObjectiveWe sought to determine a subset of DCs responsible for Th2 cell responses in allergic asthma and the mechanism by which protease allergens induce the DC subset in the airway.MethodsMice were intranasally challenged with protease allergens or fibrinogen-cleavage product (FCP) to induce allergic airway inflammation. DCs isolated from the mediastinal lymph nodes were analyzed for surface phenotype and T cell stimulatory function. Anti-Thy1.2 and Mas-TRECK mice were used to deplete innate lymphoid cells and mast cells, respectively. Adoptive cell transfer, bone marrow DC culture, anti-IL-13, and TLR4-deficient mice were used for further mechanistic studies.ResultsProtease allergens induced a remarkable accumulation of Th2-favorable PD-L2⁺ DCs in the mediastinal lymph nodes, which was significantly abolished in mice depleted of mast cells and, to a lesser extent, innate lymphoid cells. Mechanistically, FCP generated by protease allergens triggered IL-13 production from wild-type mast cells but not from TLR4-deficient mast cells, which resulted in the increase of PD-L2⁺ DCs. Intranasal administration of FCP induced an increase of PD-L2⁺ DCs in the airway, which was significantly abolished in TLR4- and mast cell-deficient mice. Injection of IL-13 restored PD-L2⁺ DC population in mice lacking mast cells.ConclusionOur findings unveil the 'protease-FCP-TLR4-mast cell-IL-13' axis as a molecular mechanism for the generation of Th2-favorable PD-L2⁺ DCs in allergic asthma, and suggest that targeting PD-L2⁺ DC pathway might be effective in suppressing allergic T cell responses in the airway.

Graphical abstract

http://ift.tt/2ysVKjp

Clinical relevance of sensitization to hydrolyzed wheat protein in wheat-sensitized individuals

Publication date: Available online 13 October 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Morten J. Christensen, Per Stahl Skov, Lars K. Poulsen, Carsten Bindslev-Jensen, Charlotte G. Mortz




http://ift.tt/2ysVBMT

Interaction of DJ-1 with Lyn is essential for IgE-mediated stimulation of human mast cells

Publication date: Available online 13 October 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Do-Kyun Kim, Michael A. Beaven, Dean D. Metcalfe, Ana Olivera
BackgroundDJ-1 is a redox-sensitive protein with multiple roles in cell homeostasis whose levels are altered in mast cell (MC)-related disorders. However, whether DJ-1 can regulate human MC function is unknown.ObjectiveWe sought to investigate the potential role of DJ-1 in the responses of human MCs to antigen stimulation.MethodsDJ-1 was silenced in human CD34⁺-derived and LAD2 MCs using lentiviral sh-RNA constructs. Release of β-hexosaminidase, PGD2 and GM-CSF and changes in reactive oxygen species (ROS) levels were measured after FcεRI engagement. Enzymatic assays, sucrose density gradient centrifugation, immunoprecipitations, dot and Western blots, and confocal imaging were performed for signaling, cellular localization and co-association studies.ResultsDJ-1 knockdown substantially reduced mediator release as well as Lyn and Syk kinase activation and signaling by mechanisms which appeared largely unrelated to DJ-1 antioxidant activity. Upon FcεRI activation, non-oxidized rather than oxidized DJ-1 translocated to lipid rafts where it associated with Lyn, an interaction that appeared critical for maximal Lyn activation and initiation of signaling. Using purified recombinant proteins, we demonstrated that DJ-1 bound to Lyn directly but no other Src kinases, and this interaction was specific for human but not mouse proteins. In addition, DJ-1 reduced SHP-2 phosphatase activity by scavenging ROS thus preventing Syk dephosphoryation and perpetuating MC signaling.ConclusionWe demonstrate a novel role for DJ-1 in the early activation of Lyn by FcεRI that is essential for human MC responses and which provides the basis for an alternative target in allergic diseases therapy.

Graphical abstract

Teaser

We demonstrate a previously unrecognized interaction between DJ-1 and the Src kinase Lyn in antigen-activated human mast cells that is essential for maximal Lyn activation and the release of bioactive allergic and inflammatory mediators.


http://ift.tt/2x05sZ5

Transcriptional determinants of individualized inflammatory responses at anatomically separate sites

Publication date: Available online 13 October 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Lam C. Tsoi, Jingjing Yang, Yun Liang, Mrinal K. Sarkar, Xianying Xing, Maria A. Beamer, Abhishek Aphale, Kalpana Raja, Jeffrey H. Kozlow, Spiro Getsios, John J. Voorhees, J. Michelle Kahlenberg, James T. Elder, Johann E. Gudjonsson




http://ift.tt/2x1jHwK

LAIR-1 limits neutrophil extracellular trap formation in viral bronchiolitis

Publication date: Available online 16 October 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Ruben J. Geerdink, Marije P. Hennus, Geertje H.A. Westerlaken, Alferso C. Abrahams, Kim I. Albers, Jona Walk, Esther Wesselink, Riny Janssen, Louis Bont, Linde Meyaard




http://ift.tt/2yr69MD

Advances in mechanisms of allergic disease in 2016

Publication date: Available online 13 October 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Marc E. Rothenberg, Hirohisa Saito, R. Stokes Peebles
This review highlights advances in mechanisms of allergic disease, particularly type 2 innate lymphoid cells; TH2 lymphocytes; eicosanoid regulation of inflammation; extracellular vesicles in allergic responses; IL-33; microbiome properties, especially as they relate to mucosal barrier function; and a series of findings concerning the allergic inflammatory cells eosinophils, basophils, and mast cells. During the last year, mechanistic advances occurred in understanding type 2 innate lymphoid cells, particularly related to their response to ozone, involvement with experimental food allergy responses, and regulation by IL-33. Novel ways of regulating TH2 cells through epigenetic regulation of GATA-3 through sirtuin-1, a class III histone deacetylase, were published. The understanding of eicosanoid regulation of inflammation increased and focused on additional properties of phospholipase A2 and the role of prostaglandin D2 and its receptors and inhibitory prostaglandin E2 pathways. Mechanisms through which extracellular vesicles are released and contribute to allergic responses were reported. There was a deeper appreciation of mucosal barrier function, the epithelial alarmin IL-33, and the microbiome. Finally, there were advances concerning allergic inflammatory cells (mast cells, basophils, and eosinophils) that will undoubtedly have an effect on disease understanding and new therapeutic strategies.



http://ift.tt/2x1jARQ

Lower Airway Microbiota and Mycobiota in Children with Severe Asthma

Publication date: Available online 13 October 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): David L. Goldman, Zigui Chen, Viswanathan Shankar, Michael Tyberg, Alfin Vicencio, Robert Burk




http://ift.tt/2yr63Vh