tbuckley/cabot-search huggingface dataset:
Targeting FBW7 as a Strategy to Overcome Resistance to Targeted Therapy in Non–Small Cell Lung Cancer
Authors: Mingxiang Ye, Yong Zhang, Xinxin Zhang, Jianbin Zhang, Pengyu Jing, Liang Cao, Nan Li, Xia Li, Libo Yao, Jian Zhang, Jian Zhang
Journal: Cancer Research (2017)

Inhibition of EGFR and anaplastic lymphoma kinase (ALK) signaling is highly effective in a subgroup of non-small cell lung cancer (NSCLC) patients with distinct clinicopathologic features. However, resistance to EGFR and ALK inhibitors inevitably occurs, and the molecular mechanism underlying resistance is not fully understood. In this study, we report a PI3K/Akt- and MEK/ERK-independent resistance mechanism by which loss of the E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBW7α) leads to targeted therapy resistance via stabilization of antiapoptotic protein MCL-1. Using a panel of in vitro and in vivo studies, we showed that the regulatory machinery responsible for MCL-1 protein degradation was a step-wise event involving phosphorylation and nucleus translocation. ERK cooperated with GSKβ to phosphorylate MCL-1 Ser159 residue, which enabled MCL-1 to translocate into the nucleus and bind FBW7. Defects in this sequence impaired MCL-1 degradation and cell apoptosis, recapitulating phenotypes observed in FBW7 deficiency. Downregulation of FBW7 was found in EGFR inhibitor-resistant human NSCLC specimens and correlated with increased MCL-1 protein expression. Reactivation of FBW7 sensitized resistant cells to targeted therapy and facilitated MCL-1 degradation. Overall, our study provides proof-of-principle insight into a PI3K/Akt- and MEK/ERK-independent resistant model and suggests that targeting FBW7 can overcome resistance to targeted therapy. Cancer Res; 77(13); 3527-39. ©2017 AACR.
Biologic Concomitants of Alcoholism
Authors: Jack H. Mendelson, Nancy K. Mello
Journal: New England Journal of Medicine (1979)

ALCOHOLISM and alcohol-related illness are among the major medical and public-health problems in contemporary society. The development of alcoholism, like that of most diseases, reflects a complex interaction between the socioenvironmental context, the individual at risk and the availability of alcohol. It is obvious that alcohol is a necessary but not a sufficient condition for alcohol abuse. During the past decade there has been substantial progress toward understanding the causation and natural history of alcoholism. Inquiry into the biologic effects of alcohol has been facilitated by the development of animal models of alcoholism. Alcohol problems are now being examined by . . .
Do quality of life, physical function, or the Wheatley Index at diagnosis predict 1-year survival with intensive chemotherapy in older and younger acute myeloid leukemia patients?
Authors: Narhari Timilshina, Henriette Breunis, George A. Tomlinson, Joseph M. Brandwein, Shabbir M.H. Alibhai
Journal: Journal of Clinical Oncology (2015)

9544 Background: Treatment decision-making is complicated in older adults with acute myeloid leukemia (AML) because of poor prognosis and significant treatment toxicities. Improved prognostication at the time of diagnosis, such as with the Wheatley Index, may aid clinical decision-making. However, the Wheatley Index has not been validated outside clinical trials. Additionally, quality of life (QOL) or objective physical performance measures (PPM) may predict outcomes such as survival in oncology. We investigated the predictive value of baseline QOL, physical function, and the Wheatley Index at diagnosis on 1-year survival during IC in younger ( < 60 years) and older (60+ years) AML patients. Methods: AML patients undergoing intensive chemotherapy (IC) at the Princess Margaret Cancer Centre were enrolled in a prospective study. At the baseline assessment (pre-IC), patients completed the EORTC QLQ-30 questionnaire in addition to 3 PPMs (grip strength, 2-minute walk test, and timed chair stands). The prognostic risk category (good, standard and poor) was categorized according to the index defined by Wheatley et al. for older adults and modified for younger adults. Predictive value for 1-year survival was analyzed with multivariable Cox proportional hazards regression. Results: 140 younger and 97 older patients were recruited. Overall 1-year mortality was 22.1% in younger and 37.1 % in older patients. One-year mortality was significantly higher among the poor Wheatley risk category than the other 2 risk categories in both younger and older groups (40.0% and 63.3%, P < 0.05, respectively). Global health and PPMs were not predictive of 1-year survival. Poor Wheatley risk category was the most significant predictor in both univariate and multivariate survival models (p < 0.001) in both older and younger groups. Conclusions: Although QOL and PPMs at diagnosis were not good predictors of 1-year survival among younger and older AML patients, the Wheatley index may help inform clinicians and patients about up-front therapy in AML.
FDG PET-CT in breast cancer: A single institution experience from India.
Authors: Nalini K Rao, Basavalinga S Ajaikumar, Kumar G Kallur, P S Sridhar, Bhattacharjee Somorat, Nayak Radheshyam, Mallarajapatna Govindarajan, Bandemegal Mahesh, Kanakapura Ramanna Nagaraj
Journal: Journal of Clinical Oncology (2012)

e11027 Background: Whole body FDG PET CT is a useful tool in diagnosis, staging and prognosis; and its timely use is critical for early intervention and achieving long term survival in patients with early and advanced breast cancer. Methods: In this observational retrospective study, we report FDG PET CT findings of all breast cancer patients enrolled in our hospital based cancer registry between the years 2008 to 2011. Results: One thousand and fifty three women underwent a total of 1638 scans. Two hundred and forty five scans (14.96%) were done for staging /restaging/diagnosis, 1208 (73.75%) were for response evaluation to chemotherapy and 185 (11.29%) were for surveillance. The median age at diagnosis was 53 years. We identified a possible synchronous breast primary in 28 (2.66%) women and a probable new or existing second non-breast primary in 21(1.99%) women. Internal nodal metastasis was identified in 76 (7.21%) women at diagnosis. There were 26 (2.47%) patients with multicentric tumors. There was an increased uptake in the thyroid gland in 49(2.99%) and in the adrenal in 41 (2.50%) women. There were other random ‘Incidental findings of concern’ in 7 (0.37%) of women, diagnosed either on the CT or PET-CT component. Findings on PET-CT, including- upstaging of the breast primary and unexpected new findings, unrelated to the breast primary, changed the treatment plan in approximately 7% -10% of the patients. We did find that PET-CT did not impact early tumors; however, it did contribute in, 1) the assessment of internal mammary nodes, 2) prognostication based on tumor burden and, 3) aggressive management of oligometastases. Conclusions: Whole body FDG PET CT is a useful tool for staging and prognostication in breast cancer patients. However, the timing of such scans for surveillance needs to be defined for early detection of progression to have an impact on survival.
Modified docetaxel and cisplatin in combination with capecitabine (DCX) as first-line treatment in HER2-negative advanced gastric cancer.
Authors: Ahmet Bilici, Fatih Selcukbiricik, Nazan Demir, Bala Basak Oven Ustaalioglu, Mustafa Dikilitas, Ozcan Yildiz
Journal: Journal of Clinical Oncology (2014)

e15055 Background: Docetaxel and cisplatin in combination with fluorouracil (DCF) is accepted to be one of the standard regimens in advanced gastric cancer, but substantial toxicity has limited the use of this regimen in daily clinical practice. Therefore, modification of DCF regimen, including introduction of capecitabine have been investigated to improve the safety profiles. In the present study, the efficacy and toxicity of a modified dose docetaxel and cisplatin in combination with oral capecitabine (DCX) were evaluated in untreated patients with HER-2 negative advanced gastric cancer. Methods: Totally,fifty-fourpatients withHER-2 negative locally advanced or metastatic gastric cancer were included. Patients received docetaxel 60 mg/m2 plus cisplatin 60 mg/m2 (day 1) combined with capecitabine 1650 mg/m2(days 1-14), every 3 weeks. Treatment response, survivals and toxicity were retrospectively analyzed. Results: The median age was 54 years (range: 24-76) and the majority of patients (70%) had metastatic disease, while 11 patients (21%) had relapse disease who underwent curative gastrectomy and 5 patients (9%) had locally advanced disease (LAD). The median DCX cycles was 4. There were 31 partial reponses and 11 complete responses, with an overall response rate of 77%. Curative surgery could be performed in four patients of 5 with LAD. At the median follow-up of 10 months, the median progression-free (PFS) and overall survival (OS) intervals for the entire cohort of patients were 10.2 and 17.6 months, retrospectively. After relapse patients who had undergone curative gastrectomy were excluded, the median PFS and OS times were found to be 8 and 13 months, retrospectively. Dose modification was done in 12 patients due to toxicity in 8 and uncompliance in 4 patients. The most common hematological toxicity was neutropenia, which occured at grade ¾ intensity in 8 of 54 patients (14.8%). Febrile neutropenia was detected in two cases. Conclusions: DCX regimen offers a prominent antitumor activity, thus may be considered effective first-line treatment with suitable toxicity profiles for patients with HER-2 negative advanced gastric cancer.
Predicted vitamin D status and colon cancer recurrence and mortality in CALGB 89803 (Alliance)
Authors: M.A. Fuchs, C. Yuan, K. Sato, D. Niedzwiecki, X. Ye, L.B. Saltz, R.J. Mayer, R.B. Mowat, R. Whittom, A. Hantel, A. Benson, D. Atienza, M. Messino, H. Kindler, A. Venook, F. Innocenti, R.S. Warren, M.M. Bertagnolli, S. Ogino, E.L. Giovannucci, E. Horvath, J.A. Meyerhardt, K. Ng
Journal: Annals of Oncology (2017)
Transdifferentiation Requires iNOS ActivationNovelty and Significance
Authors: Shu Meng, Gang Zhou, Qilin Gu, Palas K. Chanda, Frank Ospino, John P. Cooke
Journal: Circulation Research (2016)

Rationale: We have previously shown that innate immunity is necessary for transdifferentiation of fibroblasts to endothelial cells. A major signaling molecule involved in innate immunity is inducible nitric oxide synthase (iNOS). Accordingly, we hypothesized that iNOS-generated nitric oxide (NO) might enhance transdifferentiation.

Objective: To elucidate the role of NO in epigenetic plasticity during transdifferentiation.

Methods and Results: We exposed the BJ fibroblasts to transdifferentiation formulation that included endothelial growth factors and innate immune activator polyinosinic:polycytidylic acid to induce endothelial cells. Generation of transdifferentiated endothelial cells was associated with iNOS expression and NO elaboration. In the absence of polyinosinic:polycytidylic acid, or in the presence of antagonists of NFκB (nuclear factor kappa B) or iNOS activity, NO synthesis and induce endothelial cell generation was reduced. Furthermore, genetic knockout (in murine embryonic fibroblasts) or siRNA knockdown (in BJ fibroblasts) of iNOS nearly abolished transdifferentiation, an effect that could be reversed by iNOS overexpression. Notably, polyinosinic:polycytidylic acid induced nuclear localization of iNOS, and its binding to, and nitrosylation of, the epigenetic modifier ring finger protein 1A (RING1A) as assessed by immunostaining, Co-IP, and mass spectrometry. Nitrosylation of RING1A reduced its binding to chromatin and reduced global levels of repressive histone marker H3K27 trimethylation. Overexpression of a mutant form of RING1A (C398A) lacking the nitrosylation site almost abrogated transdifferentiation.

Conclusions: Overall, our data indicate that during transdifferentiation, innate immune activation increases iNOS generation of NO to S-nitrosylate RING1A, a key member of the polycomb repressive complex. Nitrosylation of RING1A reduces its binding to chromatin and decreases H3K27 trimethylation level. The release of epigenetic repression by nitrosylation of RING1A is critical for effective transdifferentiation.

# Novelty and Significance {#article-title-50}
Unusual Presentations of Thoracic Tumors
Authors: Anil Potti, Debra A. Schell
Journal: Journal of Clinical Oncology (2001)

Article Tools DIAGNOSIS IN ONCOLOGY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2001.19.17.3780 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11533102 Unusual Presentations of Thoracic Tumors Case 1. Acute Adrenal Insufficiency Due to Metastatic Lung Cancer Anil PottixAnil PottiSearch for articles by this author , Debra A. SchellxDebra A. SchellSearch for articles by this author Show More Veterans Affairs Medical Center and University of North Dakota School of Medicine and Health Sciences, Fargo, ND https://doi.org/10.1200/JCO.2001.19.17.3780 First Page Full Text PDF Figures and Tables © 2001 by American Society of Clinical Oncology
Culture matters for life history trade-offs
Authors: Polly Wiessner
Journal: Behavioral and Brain Sciences (2017)

Abstract Van Lange et al. add important life history perspectives to understanding violence. However, direct links between climate and violence are unlikely because cultural institutions modify human responses. Examples are given from the Bushmen of the Kalahari and Enga of Papua New Guinea. The correlations identified may occur because many countries closer to the equator are caught in the gap between the demise of traditional cultural institutions and the rise of modern forms of governance.
2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention
Authors: Glenn N. Levine, Eric R. Bates, James C. Blankenship, Steven R. Bailey, John A. Bittl, Bojan Cercek, Charles E. Chambers, Stephen G. Ellis, Robert A. Guyton, Steven M. Hollenberg, Umesh N. Khot, Richard A. Lange, Laura Mauri, Roxana Mehran, Issam D. Moussa, Debabrata Mukherjee, Brahmajee K. Nallamothu, Henry H. Ting
Journal: Journal of the American College of Cardiology (2011)
Tracing and Characterizing the Development of Transplanted Female Germline Stem Cells In Vivo
Authors: Changqing Wu, Bo Xu, Xiaoyong Li, Wenzhi Ma, Ping Zhang, Xuejin Chen, Ji Wu
Journal: Molecular Therapy (2017)

It has long been believed that most female mammalian species lose the ability to generate oocytes in postnatal ovaries. Recent evidence has demonstrated the isolation and culture of female germline stem cells (FGSCs) from adult mice and humans. However, the process and mechanisms of FGSC differentiation in vivo following transplantation have not yet been studied. Here, we isolated and characterized FGSCs from a single EGFP-transgenic mouse, and traced the development and behavior of transplanted FGSCs (F-TFs) in vivo. Comparisons of folliculogenesis between recipients with FGSC transplantation and wild-type (WT) mice were performed by single follicle RNA-sequencing (RNA-seq). Results showed that FGSCs exhibited a homing ability and began to differentiate into early-stage oocytes only when they reached the edge of the ovarian cortex. The F-TFs restored function of premature ovarian failure (gdf9iCre; PtenloxP/loxP genotype) and generated offspring. Furthermore, results demonstrated that the developmental mechanisms of follicles derived from F-TFs were similar to that of WT follicles. Weighted gene co-expression network analysis identified two potential sub-networks and core genes that played a critical role in follicular development. These findings provide a theoretical basis and lay a technology platform for specific or personalized medical treatment of ovarian failure or other ovarian diseases.
Changing nomenclature for PBC: from ‘cirrhosis’ to ‘cholangitis’
Authors: Ulrich Beuers, M Eric Gershwin, Robert G Gish, Pietro Invernizzi, David E J Jones, Keith Lindor, Xiong Ma, Ian R Mackay, Albert Parés, Atsushi Tanaka, John M Vierling, Raoul Poupon
Journal: Gut (2015)
Abstract 360: Development of a Human Tissue-Engineered Blood Vessel from Adipose-Derived Stem Cells
Authors: Jaclyn A Brennan, Julien H Arrizabalaga, Matthias U Nollert
Journal: Circulation Research (2012)

There exists a clear need for alternative sources of small-diameter vascular grafts for treating the millions of patients who suffer from cardiovascular disease each year. Bypass surgery or replacement of defective vessels is often required to treat coronary heart disease, but there is a limited supply of suitable autologous grafts, and synthetic grafts are ineffective for replacement of small-diameter vessels. Inherent thrombogenicity, compliance mismatch, and limited patency rates are all complications with current options. Tissue engineering has the potential to overcome these limitations by producing a readily-available vascular graft completely from biological material. It is the objective of this study to fabricate such a small-diameter tissue engineered blood vessel (TEBV) by using the human amniotic membrane as a mechanically-sound biological substrate. Our technology begins by differentiating adipose-derived stem cells into smooth muscle cells (SMCs) and seeding them onto a flat sheet of the amniotic membrane. We assessed our hypothesis that several types of SMCs can successfully attach and proliferate on this membrane by fluorescently staining cell nuclei with DAPI and characteristic SMC actin filaments with phallotoxins. After 7 days in static culture, the cell-seeded sheet was wrapped around a 3mm O.D. removable mandrel with 6-7 revolutions to develop a tubular construct with architecture akin to that of a muscular artery’s tunica media layer. After a 2 week static culture period, the TEBV was characterized for its biochemical and mechanical properties. We examined the contraction of the vessel in response to carbachol, a specific agonist for SMCs, and compared our results with the contraction of porcine coronary arteries. Burst pressure and elastic modulus tests were also performed. The mechanical integrity of this construct can be further improved upon its exposure to appropriate physiological conditions in a perfusion bioreactor. We show that adipose-derived endothelial cells (ECs) can be also be seeded into the lumen of this construct to prevent platelet adhesion. In conclusion, we have developed a small-diameter TEBV with off-the-shelf availability using a completely biological material seeded with patient-own stem cells.
Abstract 274: Spatiotemporal Regulation of β Adrenergic Signaling In Heart failure
Authors: Yang K Xiang, Federica Barbagallo, Bing Xu, Qin Fu
Journal: Circulation Research (2014)

Our long-term goal is to understand mechanisms that govern spatiotemporal regulation of cAMP/PKA signaling in cardiac myocytes under physiological and pathophysiological conditions, and their implication in cardiac disease therapy. Here we use a series of biosensors to measure cAMP/PKA activity under βAR subtype regulation. In failing cardiac myocytes, the cAMP and PKA activity are shifted from the plasma membrane to the intracellular sarcoplasmic reticulum and the myofilaments. Meanwhile, β2AR displays an increased role in signaling to the myofilaments in failing myocytes when compared to the control myocytes. Moreover, we show that an increased βAR association with phosphodiesterases promotes the alteration in spatiotemporal propagation of cAMP/PKA signaling in failing myocytes. These observations and the underlying mechanisms and functional implications will be discussed.
Diagnostic Strategy for Hematology and Oncology Patients with Acute Respiratory Failure
Authors: Elie Azoulay, Djamel Mokart, Jérôme Lambert, Virginie Lemiale, Antoine Rabbat, Achille Kouatchet, François Vincent, Didier Gruson, Fabrice Bruneel, Géraldine Epinette-Branche, Ariane Lafabrie, Rebecca Hamidfar-Roy, Christophe Cracco, Benoît Renard, Jean-Marie Tonnelier, François Blot, Sylvie Chevret, Benoît Schlemmer
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Rationale: Respiratory events are common in hematology and oncology patients and manifest as hypoxemic acute respiratory failure (ARF) in up to half the cases. Identifying the cause of ARF is crucial. Fiberoptic bronchoscopy with bronchoalveolar lavage (FO-BAL) is an invasive test that may cause respiratory deterioration. Recent noninvasive diagnostic tests may have modified the risk/benefit ratio of FO-BAL.Objectives: To determine whether FO-BAL in cancer patients with ARF increased the need for intubation and whether noninvasive testing alone was not inferior to noninvasive testing plus FO-BAL.Methods: We performed a multicenter randomized controlled trial with sample size calculations for both end points. Patients with cancer and ARF of unknown cause who were not receiving ventilatory support at intensive care unit admission were randomized to early FO-BAL plus noninvasive tests (n = 113) or noninvasive tests only (n = 106). The primary end point was the number of patients needing intubation and mechanical ventilation. The major secondary end point was the number of patients with no identified cause of ARF.Measurements and Main Results: The need for mechanical ventilation was not significantly greater in the FO-BAL group than in the noninvasive group (35.4 vs. 38.7%; P = 0.62). The proportion of patients with no diagnosis was not smaller in the noninvasive group (21.7 vs. 20.4%; difference, −1.3% [−10.4 to 7.7]).Conclusions: FO-BAL performed in the intensive care unit did not significantly increase intubation requirements in critically ill cancer patients with ARF. Noninvasive testing alone was not inferior to noninvasive testing plus FO-BAL for identifying the cause of ARF.Clinical trial registered with www.clinicaltrials.gov (NCT00248443).
Is foetal hyperexposure to androgens a cause of PCOS?
Authors: Panagiota Filippou, Roy Homburg
Journal: Human Reproduction Update (2017)

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting reproductive-aged women. The pathophysiology of this syndrome is still not completely understood but recent evidence suggests that the intra-uterine environment may be a key factor in the pathogenesis of PCOS, in particular, hyperexposure of the foetus to androgens. High concentrations of maternal serum testosterone during pregnancy have been shown to influence behaviour during childhood, the prevalence of autism disorders and anti-Mullerian hormone (AMH) concentrations in adolescence. They are also thought to re-programme the female reproductive axis to induce the features of PCOS in later life: oligo/anovulation, polycystic ovaries, hyperandrogenism and insulin resistance (IR). Support for this developmental theory for the aetiology of PCOS is gathering momentum, following results from first animal studies and now human data, which lend credence to many aspects of this hypothesis.In this review the recent available evidence is presented to support the hypothesis that hyperandrogenic changes in the intra-uterine environment could play a major part in the aetiological basis of PCOS.An extensive PubMED and MEDline database search was conducted. Relevant studies were identified using a combination of search terms: 'polycystic ovary syndrome', 'PCOS', 'aetiology', 'anti-Mullerian hormone', 'AMH', 'pathogenesis', 'kisspeptin', 'hyperandrogenism', 'insulin resistance', 'metabolic factors', 'placenta', 'developmental hypothesis', 'genetic and epigenetic origins'.A total of 82 studies were finally included in this review. There is robust evidence that a hyperandrogenic intra-uterine environment 'programmes' the genes concerned with ovarian steroidogenesis, insulin metabolism, gonadotrophin secretion and ovarian follicle development resulting in the development of PCOS in adult life.Once the evidence supporting this hypothesis has been expanded by additional studies, the door would be open to find innovative treatments and preventative measures for this very prevalent condition. Such measures could considerably ease the human and economic burden that PCOS creates.