Clinicians should consider travel location as a possible indicator for resistance to common antimicrobials in returning travelers. Repeated outbreaks of shigellosis among men who have sex with men highlight the importance of prevention and control measures in this group.
Primary amebic meningoencephalitis (PAM) is a fulminant central nervous system infection caused by the thermophilic free-living ameba Naegleria fowleri. Few survivals have been documented and adequate treatment is lacking. We report two PAM cases, one fatal and one surviving, treated with the novel antiparasitic agent miltefosine.
Viable MERS-Cov could be isolated from the environment surfaces and respiratory specimens from clinically recovered patients. Our results suggested that MERS-CoV can be transmitted through contaminated fomites, hence strict environmental hygiene, and sufficient isolation period are essential for MERS-CoV control.
Retention after starting ART is best understood by examining multiple outcomes including stopping care, deaths in care, deaths out of care and silent transfers.
Background
Identification of genetic changes in CNS tumors is important for the appropriate clinical management of patients. Our objective was to develop a next-generation sequencing (NGS) assay for simultaneously detecting the various types of genetic alterations characteristic for adult and pediatric CNS tumors that can be applied to small brain biopsies.
MethodsWe report an amplification-based targeted NGS assay (GlioSeq) that analyzes 30 genes for single nucleotide variants (SNVs) and indels, 24 genes for copy number variations (CNVs), and 14 types of structural alterations in BRAF, EGFR, and FGFR3 genes in a single workflow. GlioSeq performance was evaluated in 54 adult and pediatric CNS tumors, and the results were compared with fluorescence in-situ hybridization, Sanger sequencing, and reverse transcription PCR.
ResultsGlioSeq correctly identified 71/71 (100%) genetic alterations known to be present by conventional techniques, including 56 SNVs/indels, 9 CNVs, 3 EGFRvIII, and 3 KIAA1549-BRAF fusions. Only 20 ng of DNA and 10 ng of RNA were required for successful sequencing of 100% frozen and 96% formalin-fixed, paraffin-embedded tissue specimens. The assay sensitivity was 3%–5% of mutant alleles for SNVs and 1%–5% for gene fusions. The most commonly detected alterations were IDH1, TP53, TERT, ATRX. CDKN2A, and PTEN in high-grade gliomas, followed by BRAF fusions in low-grade gliomas and H3F3A mutations in pediatric gliomas.
ConclusionsGlioSeq NGS assay offers accurate and sensitive detection of a wide range of genetic alterations in a single workflow. It allows rapid and cost-effective profiling of brain tumor specimens and thus provides valuable information for patient management.
Background
Glioblastoma (GBM) is the most common malignant brain tumor, and glioma stem cells (GSCs) are considered a major source of treatment resistance for glioblastoma. Identifying new compounds that inhibit the growth of GSCs and understanding their underlying molecular mechanisms are therefore important for developing novel therapy for GBM.
MethodsWe investigated the potential inhibitory effect of isorhapontigenin (ISO), an anticancer compound identified in our recent investigations, on anchorage-independent growth of patient-derived glioblastoma spheres (PDGS) and its mechanism of action.
ResultsISO treatment resulted in significant anchorage-independent growth inhibition, accompanied with cell cycle G0-G1 arrest and cyclin D1 protein downregulation in PDGS. Further studies established that cyclin D1 was downregulated by ISO at transcription levels in a SOX2-dependent manner. In addition, ISO attenuated SOX2 expression by specific induction of miR-145, which in turn suppressed 3'UTR activity of SOX2 mRNA without affecting its mRNA stability. Moreover, ectopic expression of exogenous SOX2 rendered D456 cells resistant to induction of cell cycle G0-G1 arrest and anchorage-independent growth inhibition upon ISO treatment, whereas inhibition of miR-145 resulted in D456 cells resistant to ISO inhibition of SOX2 and cyclin D1 expression. In addition, overexpression of miR-145 mimicked ISO treatment in D456 cells.
ConclusionsISO induces miR-145 expression, which binds to the SOX2 mRNA 3'UTR region and inhibits SOX2 protein translation. Inhibition of SOX2 leads to cyclin D1 downregulation and PDGS anchorage-independent growth inhibition. The elucidation of the miR-145/SOX2/cyclin D1 axis in PDGS provides a significant insight into understanding the anti-GBM effect of ISO compound.
Background
The proteasome plays a vital role in the physiology of glioblastoma (GBM), and proteasome inhibition can be used as a strategy for treating GBM. Marizomib is a second-generation, irreversible proteasome inhibitor with a more lipophilic structure that suggests the potential for penetrating the blood-brain barrier. While bortezomib and carfilzomib, the 2 proteasome inhibitors approved for treatment of multiple myeloma, have little activity against malignant gliomas in vivo, marizomib could be a novel therapeutic strategy for primary brain tumors.
MethodsThe in-vitro antitumor activity of marizomib was studied in glioma cell lines U-251 and D-54. The ability of marizomib to cross the blood-brain barrier and regulate proteasome activities was evaluated in cynomolgus monkeys and rats. The antitumor effect of marizomib in vivo was tested in an orthotopic xenograft model of human GBM.
ResultsMarizomib inhibited the proteasome activity, proliferation, and invasion of glioma cells. Meanwhile, free radical production and apoptosis induced by marizomib could be blocked by antioxidant N-acetyl cysteine. In animal studies, marizomib distributed into the brain at 30% of blood levels in rats and significantly inhibited (>30%) baseline chymotrypsin-like proteasome activity in brain tissue of monkeys. Encouragingly, the immunocompromised mice, intracranially implanted with glioma xenografts, survived significantly longer than the control animals (P < .05) when treated with marizomib.
ConclusionsThese preclinical studies demonstrated that marizomib can cross the blood-brain barrier and inhibit proteasome activity in rodent and nonhuman primate brain and elicit a significant antitumor effect in a rodent intracranial model of malignant glioma.
We report two cases of Ebola Viral Disease (EVD) in pregnant women. Both women were in the second trimester and survived. The foetus was initially alive. After respectively 31-32 days post negativation maternal blood EVD-PCR, both patients delivered a stillborn foetus with persistent PCR positivity of the amniotic fluid.
Edoxaban, a direct factor Xa inhibitor, was extensively studied in the prevention and treatment of venous thromboembolism and in patients with nonvalvular atrial fibrillation (AF). The aim of this review is to focus specifically on the efficacy and safety profile of edoxaban in patients with AF from preclinical development through the phase III trial that led to regulatory approval.
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For the production of tumor-specific vaccines, including dendritic cell (DC) vaccines, the tumor cells themselves are an ideal source. Floating tumor cells in the ascites fluid from patients with malignant ascites are a good candidate source, but it is not easy to obtain pure tumor cells from ascites because of various types of cell contamination as well as protein aggregates. We here report an effective method to recover pure tumor cells from malignant ascites. We used lavage fluid from 13 patients with malignant ascites who were treated with modified cell-free and concentrated ascites reinfusion therapy (KM-CART). Cellular components were separated from the lavage fluid by centrifugation, enzymatic digestion and hemolysis. Tumor cells were purified by depleting CD45 + leukocytes with antibody-conjugated magnetic beads. The tumor cell lysate was extracted by freeze-and-thaw cycles. The mean obtained total cell number was 7.50 × 10 7 cells (range 4.40 × 10 6 –2.48 × 10 8 cells). From this fraction, 6.39 × 10 6 (range 3.23 × 10 5 –2.53 × 10 7 ) CD45 − cells were collected, and the tumor cell purity was over 80 % defined as CD45 − CD326 + . A sufficient amount of tumor lysate, average = 2416 μg (range 25–8743 μg), was extracted from CD45 − CD326 + tumor cells. We here established an effective method to produce highly purified tumor cells from KM-CART lavage fluid. The clinical feasibility of this simple preparation method for generating tumor lysate should be examined in clinical studies of DC vaccines.
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• RNAseq of neuroblastoma cell lines isolated pre- and post treatment• Identified 42 differentially expressed miRNAs• 8 miRNAs were upregulated and 34 downregulated• 65% of the downregulated miRNAs are encoded by the 14q32 miRNA clusters• Reduced expression of 14q32 miRNAs in tumors is associated with poor prognosis factors• IPA reveals functions and pathways associated with cancer progression and drug resistance
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Background:
The purpose of GORTEC 2000–01 was to compare the long-term efficacy and safety of induction chemotherapy with cisplatin (P) and 5-fluorouracil (F) with or without docetaxel (T) for larynx preservation.
Methods:
Operable patients with untreated stage III or IV larynx or hypopharynx invasive squamous cell carcinoma who required total laryngectomy were randomly assigned to three cycles of induction chemotherapy with either TPF or PF, followed by radiation therapy for responders. The primary endpoint was three-year larynx preservation rate. Secondary endpoints included larynx dysfunction–free survival (LDFFS), overall survival (OS), disease-free survival (DFS), loco-regional control rate (LCR), cause of death, and later toxicity rates. Survival and other data were analyzed by Kaplan-Meier methods. All statistical tests were two-sided.
Results:
Two hundred thirteen patients were treated with median follow-up of 105 months. The five- and 10-year larynx preservation rates were 74.0% (95% CI = 0.64 to 0.82) vs 58.1% (95% CI = 0.47 to 0.68) and 70.3% (95% CI = 0.58 to 0.8) vs 46.5% (95% CI = 0.31 to 0.63, P = .01) in the TPF vs PF arm, respectively. The five- and 10-year LDFFS rates were 67.2% (95% CI = 0.57 to 0.76) vs 46.5% (95% CI = 0.36 to 0.57) and 63.7% (95% CI = 0.52 to 0.74) vs 37.2% (95% CI = 0.24 to 0.52, P = .001), respectively. OS, DFS, and LCR were not statistically improved in the TPF vs the PF arm. Statistically fewer grade 3–4 late toxicities of the larynx occurred with the TPF regimen compared with the PF arm (9.3% vs 17.1%, G-test, P = .038).
Conclusion:
Long-term follow-up confirms that induction chemotherapy with TPF increased larynx preservation and larynx dysfunction–free survival. In this larynx preservation approach using induction chemotherapy, TPF should be recommended, followed by radiation therapy.
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Thyroid Dec 2015, Vol. 25, No. 12: 1381-1382.
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Thyroid Dec 2015, Vol. 25, No. 12: 1383-1384.
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Thyroid , Vol. 0, No. 0.
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Thyroid , Vol. 0, No. 0.
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Thyroid , Vol. 0, No. 0.
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Oral blood blisters and purpura are rare features of primary systemic amyloidosis (amyloid light-chain (AL) amyloidosis). We report a case in which these unusual presentations led to a diagnosis of amyloidosis, which enabled effective treatment before organ failure.
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Oral blood blisters and purpura are rare features of primary systemic amyloidosis (amyloid light-chain (AL) amyloidosis). We report a case in which these unusual presentations led to a diagnosis of amyloidosis, which enabled effective treatment before organ failure.
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Patients with HPV positive oropharyngeal squamous cell carcinoma (OPSCC) are known to have a significantly more favorable prognosis than their HPV negative counterparts [1]. The substantially better prognosis of these patients has created new challenges in determining the optimal treatment approach. While concurrent chemoradiotherapy to 70Gy is presently the standard of care for OPSCC, this recommendation is based on randomized clinical trials which were dominated by HPV negative patients. As a result, it is difficult to extrapolate from historical trials to determine the optimal treatment strategy for the HPV positive patient.
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Although the radial forearm free flap (RFF) is a commonly-used microvascular flap for orofacial reconstruction, we are aware of few prospective biomechanical studies of the donor site. We have therefore evaluated the donor site morbidity biomechanically of 30 consecutive RFF for orofacial reconstruction preoperatively and three months postoperatively. This included the Mayo wrist score, the Disabilities of the Arm, Shoulder and Hand (DASH) score, grip strength, followed by tip pinch, key pinch, palmar pinch, and range of movement of the wrist.
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Although the radial forearm free flap (RFF) is a commonly-used microvascular flap for orofacial reconstruction, we are aware of few prospective biomechanical studies of the donor site. We have therefore evaluated the donor site morbidity biomechanically of 30 consecutive RFF for orofacial reconstruction preoperatively and three months postoperatively. This included the Mayo wrist score, the Disabilities of the Arm, Shoulder and Hand (DASH) score, grip strength, followed by tip pinch, key pinch, palmar pinch, and range of movement of the wrist.
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 Windsor Star | Canadian runner Bishop says she's stronger for troubles she, coach have faced Windsor Star After beating cancer of the larynx, the 62-year-old was diagnosed two years ago with progressive supranuclear palsy — PSP — a degenerative condition that results from deterioration of cells in the brain that control body movement and thinking. It has … and more » |
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Endogenous immunoglobulins (Igs) are of fundamental importance in the host defense after microbial infections. However, the therapeutic administration of intravenous IgG (IVIgG) has not yet been shown to improve clinical outcomes in patients suffering from sepsis, and in the case of IgM-containing preparations (IVIgGMA) the positive evidence is only weak. Recently published studies implicate that Ig levels on admission could have an impact on the patient's response to IVIg treatment and on outcomes of critically ill patients.
In this noninterventional study, the serum levels of IgG, IgM, and IgA were determined in 340 medical patients on ICU admission, and clinical outcomes were prospectively recorded (ICU mortality, need for renal replacement therapy (RRT), need for mechanical ventilation, substitution of coagulation factors, and amount of red cell transfusions). Patients were prospectively grouped according to their main reason for ICU admission (sepsis, respiratory failure, cardiovascular diseases, acute renal failure, postoperative condition, state after cardiopulmonal resuscitation, gastrointestinal diseases, and others).
There was no correlation between the Ig levels on admission and ICU mortality neither in the total cohort of medical ICU patients nor in any prespecified subgroup. However, in a logistic regression model that was adjusted for APACHE II score on admission, an increase in serum IgG was associated with a reduced need for mechanical ventilation in patients suffering from cardiovascular disease. On the other hand, in patients suffering from sepsis, an increased level of IgM was linked to an increased administration of coagulation factors.
Our data do not support the hypothesis that serum levels of immunoglobulins are linked to mortality in medical ICU patients.
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Die Sterblichkeit bei Patienten mit kardiogenem Schock nach Herzstillstand bleibt trotz der Fortschritte bei den Wiederbelebungsmaßnahmen und der frühen Revaskularisierung sehr hoch. Gegenwärtig wird der Einsatz der milden therapeutischen Hypothermie (MTH) zur Verbesserung des Überlebens und neurologischen Outcomes bei diesem Patientenkollektiv neu diskutiert.
Detektion von Einflussfaktoren auf Morbidität und Mortalität bei Patienten nach präklinischer Reanimation [„out-of-hospital cardiac arrest" (OHCA)] unter MTH im kardiogenen Schock.
Retrospektive Analyse von 80 konsekutiven Patienten (mittleres Alter 60 ± 3,2 Jahre) im kardiogenen Schock. Alle Patienten wurden mithilfe eines endovaskulären Kühlkatheters für 24 h gekühlt. Das neurologische Outcome der Patienten wurde 2 Monate nach OHCA basierend auf der Glasgow-Pittsburgh Cerebral Performance Category (CPC) erhoben und mit verschiedenen Blutwerten korreliert.
Zwei Monate nach Indexereignis zeigten 31 Patienten (39 %) eine gute neurologische Erholung (CPC 1–2), 20 Patienten (25 %) wiesen ein schlechtes neurologisches Outcome (CPC 3–4) auf. 29 Patienten (36 %) waren verstorben (CPC 5). Bei den Patienten mit schlechtem neurologischem Outcome fanden sich signifikant höhere Laktat-, Kreatinin- und Harnstoffwerte. Zudem kam es bei diesen Patienten, im Gegensatz zu den Patienten mit gutem neurologischem Outcome, zu einem kontinuierlichen Anstieg der neuronenspezifischen Enolase (NSE; ∆ NSE, Ankunft zu Tag 1, CPC 1–2: − 10,6 ± 3 µg/l; CPC 3–5: 33 ± 12 µg/l; p = 0,02).
Der Verlauf von Kreatinin, Harnstoff und NSE im Serum innerhalb der ersten 72 h nach OHCA könnte bei Patienten unter MTH wertvolle ergänzende Informationen zur frühzeitigen Beurteilung der neurologischen Prognose bieten.
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Thyroid Dec 2015, Vol. 25, No. 12: 1381-1382.
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Background:
The purpose of GORTEC 2000–01 was to compare the long-term efficacy and safety of induction chemotherapy with cisplatin (P) and 5-fluorouracil (F) with or without docetaxel (T) for larynx preservation.
Methods:Operable patients with untreated stage III or IV larynx or hypopharynx invasive squamous cell carcinoma who required total laryngectomy were randomly assigned to three cycles of induction chemotherapy with either TPF or PF, followed by radiation therapy for responders. The primary endpoint was three-year larynx preservation rate. Secondary endpoints included larynx dysfunction–free survival (LDFFS), overall survival (OS), disease-free survival (DFS), loco-regional control rate (LCR), cause of death, and later toxicity rates. Survival and other data were analyzed by Kaplan-Meier methods. All statistical tests were two-sided.
Results:Two hundred thirteen patients were treated with median follow-up of 105 months. The five- and 10-year larynx preservation rates were 74.0% (95% CI = 0.64 to 0.82) vs 58.1% (95% CI = 0.47 to 0.68) and 70.3% (95% CI = 0.58 to 0.8) vs 46.5% (95% CI = 0.31 to 0.63, P = .01) in the TPF vs PF arm, respectively. The five- and 10-year LDFFS rates were 67.2% (95% CI = 0.57 to 0.76) vs 46.5% (95% CI = 0.36 to 0.57) and 63.7% (95% CI = 0.52 to 0.74) vs 37.2% (95% CI = 0.24 to 0.52, P = .001), respectively. OS, DFS, and LCR were not statistically improved in the TPF vs the PF arm. Statistically fewer grade 3–4 late toxicities of the larynx occurred with the TPF regimen compared with the PF arm (9.3% vs 17.1%, G-test, P = .038).
Conclusion:Long-term follow-up confirms that induction chemotherapy with TPF increased larynx preservation and larynx dysfunction–free survival. In this larynx preservation approach using induction chemotherapy, TPF should be recommended, followed by radiation therapy.
Publication date: Available online 17 December 2015
Source:Acta Histochemica
Author(s): Ilan Hammel, Isaac Meilijson
The pancreatic gland secretes most of the enzymes and many other macromolecules needed for food digestion in the gastrointestinal tract. These molecules play an important role in digestion, host defense and lubrication. The secretion of pancreatic proteins ensures the availability of the correct mix of proteins when needed. This review describes model systems available for the study of the econobiology of secretory granule content. The secretory pancreatic molecules are stored in large dense-core secretory granules that may undergo either constitutive or evoked secretion, and constitute the granule inventory of the cell. It is proposed that the Golgi complex functions as a distribution center for secretory proteins in pancreatic acinar cells, packing the newly formed secretory molecules into maturing secretory granules, also known functionally as condensing vacuoles. Mathematical modelling brings forward a process underlying granule inventory maintenance at various physiological states of condensation and aggregation by homotypic fusion. These models suggest unique but simple mechanisms accountable for inventory buildup and size, as well as for the distribution of secretory molecules into different secretory pathways in pancreatic acinar cells.
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Staphylococcus epidermidis has emerged as the main causative agent for graft-related and nosocomial infections. Rampant use of antibiotics and biofilm formed by the organism results in poor penetration of the drug and further aggravates the antibiotic resistance, emphasizing an urgent need to explore alternative treatment modalities. Antimicrobial peptides (AMPs), produced as effector molecules of the innate immunity of living organisms, have therapeutic potential that can be used to inhibit the growth of microbes. In addition, the susceptibility of a microbe to become resistant to an AMP is relatively low. The AMPs are amphipathic peptides of 12 to 100 residues, which have a broad spectrum activity against microbes. There are scattered reports of AMPs listed against S. epidermidis and there is an urgent need to systematically study the AMPs. Various natural AMPs as well as synthetic peptides have been investigated against S. epidermidis. These peptides have shown to inhibit both planktonic culture as well as S. epidermidis biofilm effectively. The multiple modes of action in killing the organism minimize the chances for development of resistance. This review focused on various natural and synthetic peptides that demonstrate activity against S. epidermidis.
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The attitude of Indian classical singers toward seeking vocal health care is a dimension yet to be explored. The current study was aimed to determine the attitudes of these singers toward seeking vocal health care and further understand the influence of age and gender.
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Elbow fractures are a common injury seen among emergency department trauma patients. Despite its high frequency, there is no standardized method of diagnosis using conventional x-ray imaging for trauma patients presenting with elbow pain and restricted elbow movement.
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After stereotactic lung radiotherapy, a residual mass is occasionally observed when radiation pneumonitis minimal. We evaluated the fate of such residual masses. Among 50 patients in whom tumor shadow persisted for >1 year on CT, only 8 developed local recurrence. The 3-year local control was 81%. The persistence of lung masses did not necessarily indicate future local recurrence.
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Objectives: The aim of this study was to investigate the elastic properties of the aorta and myocardial performance index of left ventricule in patients with Lichen Planus (LP). Subjects and Methods: A total of 54 patients with lichen planus and 50 controls were enrolled to the study. Patients in the two groups were well matched regarding age, gender, body mass index, any smoking history, diabetes mellitus, systolic blood pressure, diastolic blood pressure. The echocardiographic examination was performed in study subjects and the controls. Aortic elasticity parameters and myocardial performance index of left ventricule were calculated. Student's t-test, chi-square analysis, multiple linear regression analysis were used for statistical analysis. Results: Aortic strain (AS) (4.77±1.81 vs 8.95±2.22, p
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A 68-year-old man with recent history of a fall presented with dyspnea on exertion, and underwent computed tomography pulmonary angiography (CTPA) for possible pulmonary embolism (PE). The CTPA was first read by the radiology resident as nondiagnostic for segmental PE. Subsequent planar perfusion (Q) images were normal; meanwhile, the attending radiologist revised the CTPA results as subsegmental PE in the left upper lobe. Further Q-SPECT images were obtained and fused with CTPA for clarification, which showed normal perfusion in the region of PE. The patient was monitored without anticoagulation treatment and remained uneventful for 12 months. This case illustrates that CTPA can lead to overdiagnosis and overtreatment of nonocclusive subsegmental PE.
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Outcomes remain poor in advanced stage non-small cell lung cancer (NSCLC) treated with platinum-based combination chemotherapy.1-3 The identification of driver mutations in oncogenes such as EGFR and ALK, however, has shifted focus towards use of targeted molecular therapies instead. Mutations in the BRAF oncogene occur less frequently in NSCLC with an incidence of 1-4%; however, studies describing BRAF-mutant NSCLC are emerging.4-7 Here, we present the case of a lifetime non-smoker diagnosed with stage IV BRAF-mutant NSCLC who has achieved a long-term survival of nine years.
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Endoplasmic reticulum (ER) and mitochondria are not discrete intracellular organelles but establish close physical and functional interactions involved in several biological processes including mitochondrial bioenergetics, calcium homeostasis, lipid synthesis and the regulation of apoptotic cell death pathways. As many cell types might face a transient and sublethal ER stress during their lifetime, it is thus likely that the adaptive UPR response might affect the mitochondrial population. The aim of this work was to study the putative effects of a non-lethal and transient endoplasmic reticulum stress on the mitochondrial population in HepG2 cells. The results show that thapsigargin and brefeldin A, used to induce a transient and sublethal ER stress, rapidly lead to the fragmentation of the mitochondrial network associated with a decrease in mitochondrial membrane potential, O2•− production and less efficient respiration. These changes in mitochondrial function are transient and preceeded by the phosphorylation of JNK. Inhibition of JNK activation by SP600125 prevents the decrease in O2•− production and the mitochondrial network fragmentation observed in cells exposed to the ER stress but has no impact on the reduction of the mitochondrial membrane potential. In conclusion, our data shows that a non-lethal and transient ER stress triggers a rapid activation of JNK without inducing apoptosis, leading to the fragmentation of the mitochondrial network and a reduction of O2•− production. This article is protected by copyright. All rights reserved
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The aim of this study was to evaluate the clinical usefulness of additional low-dose high-resolution lung computed tomography (LD-HRCT) combined with 18F-fluoro-2-deoxyglucose positron emission tomography with CT (18F-FDG PET/CT) compared with conventional lung setting image of 18F-FDG PET/CT for the detection of metastatic lung nodules from colorectal cancer.
From January 2011 to September 2011, 649 patients with colorectal cancer underwent additional LD-HRCT at maximum inspiration combined with 18F-FDG PET/CT. Forty-five patients were finally diagnosed to have lung metastasis based on histopathologic study or clinical follow-up. Twenty-five of the 45 patients had ≤5 metastatic lung nodules and the other 20 patients had >5 metastatic nodules. One hundred and twenty nodules in the 25 patients with ≤5 nodules were evaluated by conventional lung setting image of 18F-FDG PET/CT and by additional LD-HRCT respectively. Sensitivities, specificities, diagnostic accuracies, positive predictive values (PPVs), and negative predictive values (NPVs) of conventional lung setting image of 18F-FDG PET/CT and additional LD-HRCT were calculated using standard formulae. The McNemar test and receiver-operating characteristic (ROC) analysis were performed.
Of the 120 nodules in the 25 patients with ≤5 metastatic lung nodules, 66 nodules were diagnosed as metastatic. Eleven of the 66 nodules were confirmed histopathologically and the others were diagnosed by clinical follow-up. Conventional lung setting image of 18F-FDG PET/CT detected 40 of the 66 nodules and additional LD-HRCT detected 55 nodules. All 15 nodules missed by conventional lung setting imaging but detected by additional LD-HRCT were <1 cm in size. The sensitivity, specificity, and diagnostic accuracy of the modalities were 60.6 %, 85.2 %, and 71.1 % for conventional lung setting image and 83.3 %, 88.9 %, and 85.8 % for additional LD-HRCT. By ROC analysis, the area under the ROC curve (AUC) of conventional lung setting image and additional LD-HRCT were 0.712 and 0.827 respectively.
Additional LD-HRCT with maximum inspiration was superior to conventional lung setting image of 18F-FDG PET/CT for the detection of metastatic lung nodules from colorectal cancer (P < 0.05).
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Osteosarcoma (OS), an aggressive highly invasive and metastatic bone-malignancy, shows therapy resistance and recurrence, two features that likely depend on cancer stem cells (CSCs), which hold both self-renewing and malignant potential. So, effective anticancer therapies against OS should specifically target and destroy CSCs. We previously found that the let-7d microRNA was downregulated in the 3AB-OS-CSCs, derived from the human OS-MG63 cells. Here, we aimed to assess whether let-7d modulation affected tumorigenic and stemness properties of these OS-CSCs. We found that let-7d-overexpression reduced cell proliferation, by decreasing CCND2 and E2F2 cell-cycle-activators and increasing p21 and p27 CDK-inhibitors. Let-7d also decreased sarcosphere-and-colony forming ability, two features associated with self-renewing, and it reduced the expression of stemness genes, including Oct3/4, Sox2, Nanog, Lin28B and HMGA2. Moreover, let-7d induced mesenchymal-to-epithelial-transition, as shown by both N-Cadherin-E-cadherin-switch and decrease in vimentin. Surprisingly, such switch was accompanied by enhanced migratory/invasive capacities, with a strong increase in MMP9, CXCR4 and VersicanV1. Let-7d- overexpression also reduced cell sensitivity to apoptosis induced by both serum-starvation and various chemotherapy drugs, concomitant with decrease in caspase-3 and increase in BCL2 expression. Our data suggest that let-7d in 3AB-OS-CSCs could induce plastic-transitions from CSCs-to-non-CSCs and vice-versa. To our knowledge this is the first study to comprehensively examine the expression and functions of let-7d in OS-CSCs. By showing that let-7d has both tumor suppressor and oncogenic functions in this context, our findings suggest that, before prospecting new therapeutic strategies based on let-7d modulation, it is urgent to better define its multiple functions. This article is protected by copyright. All rights reserved
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Malignant rhabdoid tumor (MRT) is a rare aggressive pediatric cancer characterized by inactivation of SNF5, a core subunit of SWI/SNF complexes. Previously, we showed that SNF5 contributes to transcriptional activation of NOXA, a pro-apoptotic protein that binds and inhibits the anti-apoptotic protein MCL-1. In this study, we found that NOXA expression was downregulated in MRT cell lines as well as in clinical MRT samples and that ectopically expressed NOXA bound MCL-1 and increased the sensitivity of MRT cell lines to doxorubicin (DOX) by promoting apoptosis. Consistent with this finding, knockdown of MCL-1 in MRT cell lines induced apoptosis and increased DOX sensitivity in MRT cells, and the MCL-1 inhibitor TW-37 synergized with DOX to induce MRT cell death. Our results suggest that modulation of the NOXA/MCL-1 pathway may be a potential strategy for the treatment of patients with MRT. This article is protected by copyright. All rights reserved
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Publication date: Available online 17 December 2015
Source:Experimental Cell Research
Author(s): John S. Torday, Virender K. Rehan
The pulmonary alveolar lipofibroblast was first reported in 1970. Since then its development, structure, function and molecular characteristics have been determined. Its capacity to actively absorb, store and 'traffic' neutral lipid for protection of the alveolus against oxidant injury, and for the active supply of substrate for lung surfactant phospholipid production have offered the opportunity to identify a number of specialized functions of these strategically placed cells. Namely, Parathyroid Hormone-related Protein (PTHrP) signaling, expression of Adipocyte Differentiation Related Protein, leptin, peroxisome proliferator activator receptor gamma, and the prostaglandin E2 receptor EP2- which are all stretch-regulated, explaining how and why surfactant production is 'on- demand' in service to ventilation-perfusion matching. Because of the central role of the lipofibroblast in vertebrate lung physiologic evolution, it is a Rosetta Stone for understanding how and why the lung evolved in adaptation to terrestrial life, beginning with the duplication of the PTHrP Receptor some 300 mya. Moreover, such detailed knowledge of the workings of the lipofibroblast have provided insight to the etiology and effective treatment of Bronchopulmonary Dysplasia based on physiologic principles rather than on pharmacology.
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After stereotactic lung radiotherapy, a residual mass is occasionally observed when radiation pneumonitis minimal. We evaluated the fate of such residual masses. Among 50 patients in whom tumor shadow persisted for >1 year on CT, only 8 developed local recurrence. The 3-year local control was 81%. The persistence of lung masses did not necessarily indicate future local recurrence.
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Outcomes remain poor in advanced stage non-small cell lung cancer (NSCLC) treated with platinum-based combination chemotherapy.1-3 The identification of driver mutations in oncogenes such as EGFR and ALK, however, has shifted focus towards use of targeted molecular therapies instead. Mutations in the BRAF oncogene occur less frequently in NSCLC with an incidence of 1-4%; however, studies describing BRAF-mutant NSCLC are emerging.4-7 Here, we present the case of a lifetime non-smoker diagnosed with stage IV BRAF-mutant NSCLC who has achieved a long-term survival of nine years.
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Osteosarcoma (OS), an aggressive highly invasive and metastatic bone-malignancy, shows therapy resistance and recurrence, two features that likely depend on cancer stem cells (CSCs), which hold both self-renewing and malignant potential. So, effective anticancer therapies against OS should specifically target and destroy CSCs. We previously found that the let-7d microRNA was downregulated in the 3AB-OS-CSCs, derived from the human OS-MG63 cells. Here, we aimed to assess whether let-7d modulation affected tumorigenic and stemness properties of these OS-CSCs. We found that let-7d-overexpression reduced cell proliferation, by decreasing CCND2 and E2F2 cell-cycle-activators and increasing p21 and p27 CDK-inhibitors. Let-7d also decreased sarcosphere-and-colony forming ability, two features associated with self-renewing, and it reduced the expression of stemness genes, including Oct3/4, Sox2, Nanog, Lin28B and HMGA2. Moreover, let-7d induced mesenchymal-to-epithelial-transition, as shown by both N-Cadherin-E-cadherin-switch and decrease in vimentin. Surprisingly, such switch was accompanied by enhanced migratory/invasive capacities, with a strong increase in MMP9, CXCR4 and VersicanV1. Let-7d- overexpression also reduced cell sensitivity to apoptosis induced by both serum-starvation and various chemotherapy drugs, concomitant with decrease in caspase-3 and increase in BCL2 expression. Our data suggest that let-7d in 3AB-OS-CSCs could induce plastic-transitions from CSCs-to-non-CSCs and vice-versa. To our knowledge this is the first study to comprehensively examine the expression and functions of let-7d in OS-CSCs. By showing that let-7d has both tumor suppressor and oncogenic functions in this context, our findings suggest that, before prospecting new therapeutic strategies based on let-7d modulation, it is urgent to better define its multiple functions. This article is protected by copyright. All rights reserved
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