tbuckley/cabot-search huggingface dataset:
Phenformin alone or combined with gefitinib inhibits bladder cancer via AMPK and EGFR pathways
Authors: Yanjun Huang, Sichun Zhou, Caimei He, Jun Deng, Ting Tao, Qiongli Su, Kwame Oteng Darko, Mei Peng, Xiaoping Yang
Journal: Cancer Communications (2018)

Abstract Background In previous studies, we have shown that the combination of metformin and gefitinib inhibits the growth of bladder cancer cells. Here we examined whether the metformin analogue phenformin, either used alone or in combination with gefitinib, could inhibit growth of bladder cancer cells. Methods The growth‐inhibitory effects of phenformin and gefitinib were tested in one murine and two human bladder cancer cell lines using MTT and clonogenic assays. Effects on cell migration were assessed in a wound healing assay. Synergistic action between the two drugs was assessed using CompuSyn software. The potential involvement of AMPK and EGFR pathways in the effects of phenformin and gefitinib was explored using Western blotting. Results In MTT and clonogenic assays, phenformin was &gt; 10‐fold more potent than metformin in inhibiting bladder cancer cell growth. Phenformin also potently inhibited cell migration in wound healing assays, and promoted apoptosis. AMPK signaling was activated; EGFR signaling was inhibited. Phenformin was synergistic with gefitinib, with the combination of drugs showing much stronger anticancer activity and apoptotic activation than phenformin alone. Conclusions Phenformin shows potential as an effective drug against bladder cancer, either alone or in combination with gefitinib.
FDG PET-CT in Adrenal Multiple Myeloma
Authors: Sayak Choudhury, Nilendu Purandare, Archi Agrawal, Sneha Shah, Venkatesh Rangarajan
Journal: Clinical Nuclear Medicine (2018)

Extramedullary involvement in multiple myeloma is rare, but carries poor prognosis. We describe the FDG PET-CT findings of rare adrenal involvement in a case of multiple myeloma.
Erratum: "American cancer society guidelines for the early detection of cancer: Update of early detection guidelines for prostate, colorectal, and endometrial cancer" (CA A Cancer Journal for Clinicians) (2001) vol. 51 (38-75))
Authors: Robert A. Smith, Andrew C. Von Eschenbach, Richard Wender, Bernard Levin, Tim Byers, David A Rothenberger, Durado Brooks, William Creasman, Carmel Cohen, Carolyn Runowicz, Debbie Saslow, Vilma Cokkinides, Harmon Eyre
Journal: CA A Cancer Journal for Clinicians (2001)
Proton pump inhibitors and gastric cancer: association is not causation
Authors: Paul Moayyedi, Sander J O Veldhuyzen van Zanten, Lawrence Hookey, David Armstrong, Nicola Jones, Grigorios I Leontiadis
Journal: Gut (2018)

We read the article by Cheung et al 1 with interest. The research question whether there is a dose-related association between proton pump inhibitors (PPIs) and gastric cancer in a country where this malignancy is highly prevalent is an important one. They report that long-term PPI therapy is associated with an increased risk of gastric cancer in patients who have received Helicobacter pylori eradication therapy. The data suggest that patients taking PPI less than once per day had a lower risk of gastric cancer than did those taking PPIs at least daily, which would support there may be a dose-related response.

There are many concerns that were not adequately addressed in the paper. The paper claims that all the subjects became H. pylori negative as they had all been prescribed eradication therapy and none had received subsequent therapy. However, no data on proof of cure were provided. There …
Targeting USP7 Identifies a Metastasis-Competent State within Bone Marrow–Resident Melanoma CTCs
Authors: Monika Vishnoi, Debasish Boral, Haowen Liu, Marc L. Sprouse, Wei Yin, Debalina Goswami-Sewell, Michael T. Tetzlaff, Michael A. Davies, Isabella C. Glitza Oliva, Dario Marchetti
Journal: Cancer Research (2018)

Abstract Systemic metastasis is the major cause of death from melanoma, the most lethal form of skin cancer. Although most patients with melanoma exhibit a substantial gap between onset of primary and metastatic tumors, signaling mechanisms implicated in the period of metastatic latency remain unclear. We hypothesized that melanoma circulating tumor cells (CTC) home to and reside in the bone marrow during the asymptomatic phase of disease progression. Using a strategy to deplete normal cell lineages (Lin−), we isolated CTC-enriched cell populations from the blood of patients with metastatic melanoma, verified by the presence of putative CTCs characterized by melanoma-specific biomarkers and upregulated gene transcripts involved in cell survival and prodevelopment functions. Implantation of Lin− population in NSG mice (CTC-derived xenografts, i.e., CDX), and subsequent transcriptomic analysis of ex vivo bone marrow–resident tumor cells (BMRTC) versus CTC identified protein ubiquitination as a significant regulatory pathway of BMRTC signaling. Selective inhibition of USP7, a key deubiquinating enzyme, arrested BMRTCs in bone marrow locales and decreased systemic micrometastasis. This study provides first-time evidence that the asymptomatic progression of metastatic melanoma can be recapitulated in vivo using patient-isolated CTCs. Furthermore, these results suggest that USP7 inhibitors warrant further investigation as a strategy to prevent progression to overt clinical metastasis. Significance: These findings provide insights into mechanism of melanoma recurrence and propose a novel approach to inhibit systematic metastatic disease by targeting bone marrow-resident tumor cells through pharmacological inhibition of USP7. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/18/5349/F1.large.jpg. Cancer Res; 78(18); 5349–62. ©2018 AACR.
Abstract 14787: Improvement of the Diagnostic Accuracy for Ischemic Memory by a Combination of Intraventricular Activation Time Index and Post-Systolic Shortening
Authors: Hitomi Adachi, Toshihiko Asanuma, Kasumi Masuda, Toshiki Kamimukai, Yuki Sakakibara, Daisuke Sakurai, Satoshi Nakatani
Journal: Circulation (2016)

Background: Post-systolic shortening (PSS), subtle myocardial shortening in isovolumic relaxation time, is induced by myocardial ischemia and remains for a while after its resolution. Therefore, PSS is considered a marker of ischemic memory. However, the fact that PSS can also be seen in the normal myocardium hampers its routine clinical use. We found that a novel intraventricular activation time index (T30%), time from end-diastole to 30% value of peak strain, prolonged during ischemia showing it another promising index of myocardial ischemia. We hypothesized that the prolongation of T30% persisted after brief ischemia, and investigated whether the diagnostic accuracy of ischemic memory was improved by a combination of T30% and PSS. Methods: In 9 open-chest dogs, the left anterior descending coronary artery was occluded for 2 minutes. Left ventricular short-axis images were acquired with speckle tracking echocardiography (118 fps, Toshiba Aplio) at baseline and after reperfusion (10, 20 and 30 min). Circ...
OPLAH ablation leads to accumulation of 5-oxoproline, oxidative stress, fibrosis, and elevated fillings pressures: a murine model for heart failure with a preserved ejection fraction
Authors: Atze van der Pol, Andres Gil, Jasper Tromp, Herman H W Silljé, Dirk J van Veldhuisen, Adriaan A Voors, Elke S Hoendermis, Niels Grote Beverborg, Elisabeth-Maria Schouten, Rudolf A de Boer, Rainer Bischoff, Peter van der Meer
Journal: Cardiovascular Research (2018)

The prevalence of heart failure with a preserved ejection fraction (HFpEF) is increasing, but therapeutic options are limited. Oxidative stress is suggested to play an important role in the pathophysiology of HFpEF. However, whether oxidative stress is a bystander due to comorbidities or causative in itself remains unknown. Recent results have shown that depletion of 5-oxoprolinase (OPLAH) leads to 5-oxoproline accumulation, which is an important mediator of oxidative stress in the heart. We hypothesize that oxidative stress induced by elevated levels of 5-oxoproline leads to the onset of a murine HFpEF-like phenotype. Oplah full body knock-out (KO) mice had higher 5-oxoproline levels coupled to increased oxidative stress. Compared with wild-type (WT) littermates, KO mice had increased cardiac and renal fibrosis with concurrent elevated left ventricular (LV) filling pressures, impaired LV relaxation, yet a normal LV ejection fraction. Following the induction of cardiac ischaemia/reperfusion (IR) injury, 52.4% of the KO mice died compared with only 15.4% of the WT mice (P < 0.03). Furthermore, KO mice showed a significantly increased atrial, ventricular, kidney, and liver weights compared with WT mice (P < 0.05 for all). Cardiac and renal fibrosis were more pronounced following cardiac IR injury in the KO mice and these mice developed proteinuria post-IR injury. To further address the link between 5-oxoproline and HFpEF, 5-oxoproline was measured in the plasma of HFpEF patients. Compared with healthy controls (3.8 ± 0.6 µM), 5-oxoproline levels were significantly elevated in HFpEF patients (6.8 ± 1.9 µM, P < 0.0001). Furthermore, levels of 5-oxoproline were independently associated with more concentric remodelling on echocardiography. Oxidative stress induced by 5-oxoproline results in a murine phenotype reminiscent of the clinical manifestation of HFpEF without the need for surgical or pharmacological interference. Better understanding of the role of oxidative stress in HFpEF may potentially lead to novel therapeutic options.
Genetic sequence variant (GSV) in <i>TERT-CLPTM1L </i>(5p15.33 locus) and survival in platinum-treated stage-IV non-small cell lung cancer (NSCLC).
Authors: Abul Kalam Azad, Xiaoping Qiu, Sinead Cuffe, Xin Qiu, Kevin Boyd, Qin Kuang, Marjan Emami, Nicole Perera, Prakruthi R. Palepu, Devalben Patel, Zhuo Chen, Dangxiao Cheng, Ronald Feld, Natasha B. Leighl, Frances A. Shepherd, Ming Sound Tsao, Wei Xu, Geoffrey Liu
Journal: Journal of Clinical Oncology (2012)

1535 Background: Lung cancer is a leading cause of cancer-related mortality in North America. Besides tobacco smoking, inherited genetic factors can also influence the development of lung cancer. These genetic factors may lead to biologically distinct subsets of cancers that have different outcomes. We evaluated whether GSVs associated with lung cancer risk are also associated with overall survival (OS) and progress free survival (PFS) in platinum-treated stage-IV NSCLC patients. We chose this subset of patients with lung cancer because they are uniformly treated and followed up at our institute (Princess Margaret Hospital). Methods: A total of 32 candidate GSVs in 21 genes previously reported to be associated with lung cancer risk were genotyped in 188 platinum-treated NSCLC stage-IV patients. Illumina Custom GoldenGate Genotyping Panel was used for the genotyping assay platform. Multivariate Cox proportional hazard models adjusted for the potential clinical prognostic factors were generated for OS and PFS. Results: Median age is 60 yr (range: 31-81); 73% with adenocarcinoma. Median follow-up time is 27 mo; median OS is 16 mo and PFS is 8 mo. The top significant GSV was rs4975616 (g.1315660G&gt;A) in telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane 1-like (CLPTM1L) gene on chromosome 5p15.33. The adjusted hazard ratio (aHR) for OS was 0.76 (95% CI: 0.58-0.99; p=0.04) and for PFS aHR was 0.70 (95% CI: 0.55-0.90; p=0.005) for each protective allele, respectively. This GSV has previously been associated with lung cancer risk in genome-wide association study (PMID: 19654303). Conclusions: The TERT-CLPTM1L:rs4975616 GSV is not only a risk factor for lung cancer but also is associated with survival in patients with stage-IV NSCLC treated with platinum based chemotherapy. GSVs may be able to define subsets of patients with different risk and prognosis of NSCLC. Future studies should evaluate whether this GSV is predictive or prognostic.
Association of Ambulatory Blood Pressure with All-Cause and Cardiovascular Mortality in Hemodialysis Patients: Effects of Heart Failure and Atrial Fibrillation
Authors: Christopher C. Mayer, Julia Matschkal, Pantelis A. Sarafidis, Stefan Hagmair, Georg Lorenz, Susanne Angermann, Matthias C. Braunisch, Marcus Baumann, Uwe Heemann, Siegfried Wassertheurer, Christoph Schmaderer
Journal: Journal of the American Society of Nephrology (2018)

Background Evidence on the utility of ambulatory BP monitoring for risk prediction has been scarce and inconclusive in patients on hemodialysis. In addition, in cardiac diseases such as heart failure and atrial fibrillation (common among patients on hemodialysis), studies have found that parameters such as systolic BP (SBP) and pulse pressure (PP) have inverse or nonlinear (U-shaped) associations with mortality. Methods In total, 344 patients on hemodialysis (105 with atrial fibrillation, heart failure, or both) underwent ambulatory BP monitoring for 24 hours, starting before a dialysis session. The primary end point was all-cause mortality; the prespecified secondary end point was cardiovascular mortality. We performed linear and nonlinear Cox regression analyses for risk prediction to determine the associations between BP and study end points. Results During the mean 37.6-month follow-up, 115 patients died (47 from a cardiovascular cause). SBP and PP showed a U-shaped association with all-cause and cardiovascular mortality in the cohort. In linear subgroup analysis, SBP and PP were independent risk predictors and showed a significant inverse relationship to all-cause and cardiovascular mortality in patients with atrial fibrillation or heart failure. In patients without these conditions, these associations were in the opposite direction. SBP and PP were significant independent risk predictors for cardiovascular mortality; PP was a significant independent risk predictor for all-cause mortality. Conclusions This study provides evidence for the U-shaped association between peripheral ambulatory SBP or PP and mortality in patients on hemodialysis. Furthermore, it suggests that underlying cardiac disease can explain the opposite direction of associations.
Abstract 15372: Inhibition of Fatty Acid Synthase Plays a Protective Role in Vascular Smooth Muscle Cell Proliferation and Neointimal Formation
Authors: Naomi Oshima, Hiroki Matsui, Hiroaki Sunaga, Tasuya Iso, Clay F Semenkovich, Tomoyuki Yokoyama, Masahiko Kurabayashi
Journal: Circulation (2016)

Backgrounds: Fatty acid synthase (FASN), catalyzing the de novo lipogenesis of fatty acids (FA), is upregulated in several cancer cells and is thought to contribute to their growth and proliferatio...
SGLT2 Inhibitors in Combination Therapy: From Mechanisms to Clinical Considerations in Type 2 Diabetes Management
Authors: Michaël J.B. van Baar, Charlotte C. van Ruiten, Marcel H.A. Muskiet, Liselotte van Bloemendaal, Richard G. IJzerman, Daniël H. van Raalte
Journal: Diabetes Care (2018)

The progressive nature of type 2 diabetes (T2D) requires practitioners to periodically evaluate patients and intensify glucose-lowering treatment once glycemic targets are not attained. With guidelines moving away from a one-size-fits-all approach toward setting patient-centered goals and allowing flexibility in choosing a second-/third-line drug from the growing number of U.S. Food and Drug Administration–approved glucose-lowering agents, keen personalized management in T2D has become a challenge for health care providers in daily practice. Among the newer generation of glucose-lowering drug classes, sodium–glucose cotransporter 2 inhibitors (SGLT2is), which enhance urinary glucose excretion to lower hyperglycemia, have made an imposing entrance to the T2D treatment armamentarium. Given their unique insulin-independent mode of action and their favorable efficacy–to–adverse event profile and given their marked benefits on cardiovascular-renal outcome in moderate-to-high risk T2D patients, which led to updates of guidelines and product monographs, the role of this drug class in multidrug regimes is promising. However, despite many speculations based on pharmacokinetic and pharmacodynamic properties, physiological reasoning, and potential synergism, the effects of these agents in terms of glycemic and pleiotropic efficacy when combined with other glucose-lowering drug classes are largely understudied. In this perspective, we review the currently emerging evidence, discuss prevailing hypotheses, and elaborate on necessary future studies to clarify the potential risks and benefits of using an SGLT2i in dual combination with metformin and triple combination with a glucagon-like peptide 1 receptor agonist, dipeptidyl peptidase 4 inhibitor, or other glucose-lowering agent that is recommended by the American Diabetes Association and European Association for the Study of Diabetes (i.e., a sulfonylurea, thiazolidinedione, or insulin) to treat patients with T2D.
A Novel Human-Specific Soluble Vascular Endothelial Growth Factor Receptor 1
Authors: ShaySela, AhuvaItin, ShiraNatanson-Yaron, CarynGreenfield, DebraGoldman-Wohl, SimchaYagel, EliKeshet
Journal: Circulation Research (2008)

A human-specific splicing variant of vascular endothelial growth factor (VEGF) receptor 1 (Flt1) was discovered, producing a soluble receptor (designated sFlt1-14) that is qualitatively different from the previously described soluble receptor (sFlt1) and functioning as a potent VEGF inhibitor. sFlt1-14 is generated in a cell type-specific fashion, primarily in nonendothelial cells. Notably, in vascular smooth muscle cells, all Flt1 messenger RNA is converted to sFlt1-14, whereas endothelial cells of the same human vessel express sFlt1. sFlt1-14 expression by vascular smooth muscle cells is dynamically regulated as evidenced by its upregulation on coculture with endothelial cells or by direct exposure to VEGF. Increased production of soluble VEGF receptors during pregnancy is entirely attributable to induced expression of placental sFlt1-14 starting by the end of the first trimester. Expression is dramatically elevated in the placenta of women with preeclampsia, specifically induced in abnormal clusters of...
KIM-1 as a Blood-Based Marker for Early Detection of Kidney Cancer: A Prospective Nested Case–Control Study
Authors: Ghislaine Scelo, David C. Muller, Elio Riboli, Mattias Johansson, Amanda J. Cross, Paolo Vineis, Konstantinos K. Tsilidis, Paul Brennan, Heiner Boeing, Petra H.M. Peeters, Roel C.H. Vermeulen, Kim Overvad, H. Bas Bueno-de-Mesquita, Gianluca Severi, Vittorio Perduca, Marina Kvaskoff, Antonia Trichopoulou, Carlo La Vecchia, Anna Karakatsani, Domenico Palli, Sabina Sieri, Salvatore Panico, Elisabete Weiderpass, Torkjel M. Sandanger, Therese H. Nøst, Antonio Agudo, J. Ramón Quirós, Miguel Rodríguez-Barranco, Maria-Dolores Chirlaque, Timothy J. Key, Prateek Khanna, Joseph V. Bonventre, Venkata S. Sabbisetti, Rupal S. Bhatt
Journal: Clinical Cancer Research (2018)

Renal cell carcinoma (RCC) has the potential for cure with surgery when diagnosed at an early stage. Kidney injury molecule-1 (KIM-1) has been shown to be elevated in the plasma of RCC patients. We aimed to test whether plasma KIM-1 could represent a means of detecting RCC prior to clinical diagnosis.
Serum Sex Steroids as Prognostic Biomarkers in Patients Receiving Androgen Deprivation Therapy for Recurrent Prostate Cancer: A <i>Post Hoc</i> Analysis of the PR.7 Trial
Authors: Paul Toren, Azik Hoffman, Keyue Ding, France-Hélène Joncas, Véronique Turcotte, Patrick Caron, Frédéric Pouliot, Yves Fradet, Éric Lévesque, Chantal Guillemette, Laurence Klotz
Journal: Clinical Cancer Research (2018)

Purpose: Phenotypic biomarkers are a high priority for patients receiving androgen deprivation therapy (ADT) for prostate cancer given the increasing number of treatment options. This study evaluates serum sex steroids as prognostic biomarkers in men receiving ADT for recurrent prostate cancer.Experimental Design: Retrospective cohort study of Canadian patients in the PR.7 trial (accrual 1999-2005) who received continuous ADT for biochemical recurrence postradiotherapy. Patients were excluded with follow-up <2 years or who received estrogens or corticosteroids. Kaplan-Meier and multivariable Cox regression analyses adjusted for baseline prognostic factors assessed time to castration-resistant prostate cancer (CRPC), prostate cancer survival, and overall survival according to tertile of sex steroid measured by mass spectrometry.Results: Post-ADT initiation, we measured samples in 219 patients as well as two subsequent annual samples in a subset of 101 patients. Testosterone levels correlated with androstenedione (AD) and DHT, while DHT, AD, androsterone (AST), dehydroepiandrosterone (DHEA), and androstenediol (A5diol) were highly correlated to each other and negatively associated with age. Higher tertiles of estrone (E1) and estradiol (E2) were significantly associated with sooner time to CRPC. In patients with longitudinal samples, increases in serum DHEA and AST were significantly associated with sooner time to CRPC. Limitations include the number of events for some groups.Conclusions: Our data suggest the patient hormonal milieu has long-term prognostic value in men receiving ADT for recurrent prostate cancer, including increased levels of E1 and E2 and rising DHEA and AST levels, which predict a shorter time to CRPC. Clin Cancer Res; 24(21); 5305-12. ©2018 AACR.
Pay rise for doctors in England is announced
Authors: Abi Rimmer
Journal: BMJ (2018)

The government has announced a one year pay rise of 1.5% for consultants, 2% for trainees, 3% for specialty doctors, and a backdated 2% for GPs.

Matt Hancock, secretary of state for health and social care for England, set out the government’s proposals for doctors’ pay in response to the latest report from the Review Body on Doctors’ and Dentists’ Remuneration (DDRB).1

He said that the pay award would be worth between £1150 (€1290; $1510) and £1550 for consultants, between £1140 and £2120 for specialty doctors, between £1600 and £2630 for associate specialists, between £532 and £924 for junior doctors, and around £1052 for a salaried GP with a median taxable income of £52 600.

The award would be worth £2000 to a GP contractor with a median taxable income of £100 000.

In its report the DDRB recommended a 2% minimum increase for all salaried doctors in the UK and a 2% increase for GP partners.2

In his announcement, Hancock said that from 1 …
Chimeric liver transplantation reveals interspecific graft remodelling
Authors: Graziano Oldani, Andrea Peloso, Sandrine Vijgen, Elizabeth M. Wilson, Florence Slits, Quentin Gex, Philippe Morel, Vaihere Delaune, Lorenzo A. Orci, Tomoyuki Yamaguchi, Toshihiro Kobayashi, Laura Rubbia-Brandt, Hiromitsu Nakauchi, Stéphanie Lacotte, Christian Toso
Journal: Journal of Hepatology (2018)
<i>Cryptococcus neoformans</i> Meningoencephalitis
Authors: Raul Recio, Ana Perez-Ayala
Journal: New England Journal of Medicine (2018)

A 36-year-old man presented to the emergency department with a 2 week-history of headache, photophobia, and fever. Gram’s staining and India ink staining of the cerebrospinal fluid revealed encapsulated yeast, and C. neoformans was identified on culture.