tbuckley/cabot-search huggingface dataset:
Comet assay measures of cisplatin and mitomycin C-induced DNA crosslink formation correlate bladder cancer cell chemosensitivity in vitro
Authors: Manar M. Al-Moneef, Benedict T. Sherwood, Karen J. Bowman, R. Paul Symonds, J. Kilian Mellon, William P. Steward, George D. Jones
Journal: Cancer Research (2004)

1545  Systemic chemotherapy is used extensively in cancer therapy, but suffers from limited response rates in many tumor types. Moreover, it is frequently associated with significant morbidity and mortality. Therefore, where alternative treatment options exist (for example, radiotherapy or surgery), it is desirable to reserve chemotherapy for patients whose tumours will respond. To facilitate this, attention is turning to the development of techniques that provide predictive information about tumor chemosensitivity, as a means of enhancing patient selection for treatment with chemotherapy. The alkaline comet assay (ACA) is a technique for assessing DNA damage formation and repair, at the level of individual cells. Recently, we have demonstrated ACA to be predictive of cell radiosensitivity for a panel of human bladder cancer cell lines, with a greater comet response and a poorer extent of damage repair being noted in the radiosensitive cell lines (AL Moneef et al. British J. Cancer (2003) in press). ACA is ideal as a clinical test; it is simple, rapid, inexpensive and requires low cell numbers. In the present study we demonstrate that ACA also predicts chemosensitivity in bladder cancer cell lines exposed to two commonly used DNA crosslinking chemotherapeutic agents. Using the same panel of bladder cancer cell lines, levels of cisplatin and mitomycin C (MMC)-induced DNA crosslink damage, as assessed using a modified version of ACA, were compared to measures of cell survival (clonogenic) and cell viability (MTT). For both agents, clear dose response curves were obtained, with the more chemosensitive cell lines displaying higher levels of crosslink formation and the most chemoresistant cell lines lower levels. In particular, there were high degrees of correlation between measures of cell viability and crosslink formation (R2 >0.91), including an anomalous differential behaviour noted for T24 cells treated with MMC. Interestingly, the most chemosensitive cells tended to be the most radiosensitive and vice versa. This suggests that for these cell lines the same factor(s) may be responsible for radiosensitivity and chemosensitivity, both of which are predicted by ACA. These preliminary studies demonstrate that ACA can predict cancer cell chemosensitivity in vitro. To determine whether this technique can be applied to identify patients with chemosensitive tumors, clinical studies using cells derived from tumour biopsies need to be undertaken. If ACA is demonstrated to be predictive of chemosensitivity/outcome in vivo, then patients with sensitive tumors could be considered suitable candidates for treatment with chemotherapy. Alternatively, patients with chemo-resistant disease could be offered alternative intervention, for example, surgery.
Genome-scale screens identify JNK–JUN signaling as a barrier for pluripotency exit and endoderm differentiation
Authors: Qing V. Li, Gary Dixon, Nipun Verma, Bess P. Rosen, Miriam Gordillo, Renhe Luo, Chunlong Xu, Qiong Wang, Chew-Li Soh, Dapeng Yang, Miguel Crespo, Abhijit Shukla, Qing Xiang, Friederike Dündar, Paul Zumbo, Matthew Witkin, Richard Koche, Doron Betel, Shuibing Chen, Joan Massagué, Ralph Garippa, Todd Evans, Michael A. Beer, Danwei Huangfu
Journal: Nature Genetics (2019)
Review: In adults without CVD, aspirin reduces CV events and increases major bleeding compared with no aspirin
Authors: Adrienne Atencio, Calvin Hirsch
Journal: Annals of Internal Medicine (2019)

Source Citation Zheng SL, Roddick AJ. Association of aspirin use for primary prevention with cardiovascular events and bleeding events: a systematic review and meta-analysis. JAMA. 2019;321:277-87. 30667501
FDG PET/CT of Gardnerella vaginalis Infection
Authors: Thibault Foret, Anthony Dhomps, Olivier Dauwalder, Andrea Skanjeti, Jeremie Tordo
Journal: Clinical Nuclear Medicine (2019)

Abstract We report the case of a 23-year-old woman with a history of cystic fibrosis and bilung transplantation, who presented clinically cervical swollen lymph nodes with alteration of her general state. 18 F-FDG PET/CT was performed because of lymphoma suspicion and showed cervical and pelvic hypermetabolic lymphadenopathies, with linear vaginal hypermetabolism. There was an increase of lactate dehydrogenase, and Epstein-Barr virus detection was negative. A right cervical lymph node biopsy was performed, with no lymphoma involvement. Complementary microbiological investigations showed positive results for Gardnerella vaginalis. 18 F-FDG PET/CT lymphatic node hypermetabolism is not specific to lymphoma, particularly in immunocompromised patients.
MALIGNANT TRANSFORMATION OF SESSILE SERRATED ADENOMAS – NBI DIAGNOSIS AND ESD OF TWO CASES
Authors: A Lupu, D Lippai, J Rivory, F Rostain, JC Saurin, T Ponchon, M Pioche
Journal: Endoscopy (2019)

Sessile serrated adenomas (SSA) are potentially responsible for the apparition of interval colorectal cancer (CRC) [1]. Their malignant transformation does not follow the classical molecular pattern [2].
Localization, Morphologic Features, and Chemical Composition of Calciphylaxis-Related Skin Deposits in Patients With Calcific Uremic Arteriolopathy
Authors: Hester Colboc, Philippe Moguelet, Dominique Bazin, Priscille Carvalho, Anne-Sophie Dillies, Guillaume Chaby, Hervé Maillard, Diane Kottler, Elisa Goujon, Christine Jurus, Marine Panaye, Vincent Frochot, Emmanuel Letavernier, Michel Daudon, Ivan Lucas, Raphaël Weil, Philippe Courville, Jean-Benoit Monfort, François Chasset, Patricia Senet
Journal: JAMA Dermatology (2019)

Calcific uremic arteriolopathy (CUA), a rare, potentially fatal, disease with calcium deposits in skin, mostly affects patients with end-stage renal disease who are receiving dialysis. Chemical composition and structure of CUA calcifications have been poorly described.To describe the localization and morphologic features and determine the precise chemical composition of CUA-related calcium deposits in skin, and identify any mortality-associated factors.A retrospective, multicenter cohort study was conducted at 7 French hospitals including consecutive adults diagnosed with CUA between January 1, 2006, and January 1, 2017, confirmed according to Hayashi clinical and histologic criteria. Patients with normal renal function were excluded. For comparison, 5 skin samples from patients with arteriolosclerosis and 5 others from the negative margins of skin-carcinoma resection specimens were also analyzed.Localization and morphologic features of the CUA-related cutaneous calcium deposits were assessed with optical microscopy and field-emission-scanning electron microscopy, and the chemical compositions of those deposits were evaluated with μ Fourier transform infrared spectroscopy, Raman spectroscopy, and energy dispersive radiographs.Thirty-six patients (median [range] age, 64 [33-89] years; 26 [72%] female) were included, and 29 cutaneous biopsies were analyzed. Calcific uremic arteriolopathy and arteriolosclerosis skin calcifications were composed of pure calcium-phosphate apatite. Calcific uremic arteriolopathy vascular calcifications were always circumferential, found in small to medium-sized vessels, with interstitial deposits in 22 (76%) of the samples. A thrombosis, most often in noncalcified capillary lumens in the superficial dermis, was seen in 5 samples from patients with CUA. Except for calcium deposits, the vessel structure of patients with CUA appeared normal, unlike thickened arteriolosclerotic vessel walls. Twelve (33%) patients died of CUA.Calcific uremic arteriolopathy-related skin calcifications were exclusively composed of pure calcium-phosphate apatite, localized circumferentially in small to medium-sized vessels and often associated with interstitial deposits, suggesting its pathogenesis differs from that of arteriolosclerosis. Although the chemical compositions of CUA and arteriolosclerosis calcifications were similar, the vessels' appearances and deposit localizations differed, suggesting different pathogenetic mechanisms.
Inhibiting BRAF Oncogene–Mediated Radioresistance Effectively Radiosensitizes BRAFV600E-Mutant Thyroid Cancer Cells by Constraining DNA Double-Strand Break Repair
Authors: Ryan Robb, Linlin Yang, Changxian Shen, Adam R. Wolfe, Amy Webb, Xiaoli Zhang, Marall Vedaie, Motoyasu Saji, Sissy Jhiang, Matthew D. Ringel, Terence M. Williams
Journal: Clinical Cancer Research (2019)

Activating BRAF mutations, most commonly BRAFV600E, are a major oncogenic driver of many cancers. We explored whether BRAFV600E promotes radiation resistance and whether selectively targeting BRAFV600E with a BRAF inhibitor (vemurafenib, BRAFi) sensitizes BRAFV600E thyroid cancer cells to radiotherapy.Immunoblotting, neutral comet, immunocytochemistry, functional reporter, and clonogenic assays were used to analyze the outcome and molecular characteristics following radiotherapy with or without BRAFV600E or vemurafenib in thyroid cancer cells.BRAFV600E thyroid cancer cell lines were associated with resistance to ionizing radiation (IR), and expression of BRAFV600E into wild-type BRAF thyroid cancer cells led to IR resistance. BRAFi inhibited ERK signaling in BRAFV600E mutants, but not BRAF wild-type thyroid cancer cell lines. BRAFi selectively radiosensitized and delayed resolution of IR-induced γH2AX nuclear foci in BRAFV600E cells. Moreover, BRAFi impaired global DNA repair and altered the resolution of 53BP1 and RAD51 nuclear foci in BRAFV600E cells following IR. BRAFV600E mutants displayed enhanced nonhomologous end-joining (NHEJ) repair activity, which was abolished by BRAFi. Intriguingly, BRAFV600E mutation led to upregulation of XLF, a component of NHEJ, which was prevented by BRAFi. Importantly, BRAFi in combination with radiotherapy resulted in marked and sustained tumor regression of BRAFV600E thyroid tumor xenografts.BRAFV600E mutation promotes NHEJ activity leading to radioresistance and BRAFi selectively radiosensitizes BRAFV600E thyroid cancer cells through inhibiting NHEJ. Our findings suggest that combining BRAFi and radiation may improve the therapeutic outcome of patients with BRAFV600E-mutant thyroid cancer.
Leukemogenic Nup98-homeobox fusion proteins are targeted to a novel nuclear compartment and cause mistargeting of endogenous Nup98
Authors: Mei Yee Koh, Garth Powis
Journal: Cancer Research (2006)

1734  Myelogenous leukemia typically arises from chromosomal translocations that fuse portions of unrelated genes, producing a hybrid protein with an aberrant activity. The gene encoding the nucleoporin Nup98 is a recurring target of such translocations, resulting in Nup98-partner chimeras. Many of the Nup98 fusion partners are homeobox transcription factors, others are nuclear proteins with diverse functions including topoisomerase and an RNA helicase. In order to obtain insight into the leukemogenic functions of Nup98 fusions, we have studied the nature of Nup98 homeobox fusions in Hela cells. We found that Nup98-homeobox fusions, Nup98-HoxA9, Nup98-PMX1 and Nup98-HoxD13, are similarly localized in small granular bodies which are different from either parental fragment, and formation of these bodies requires the presence of both the Nup98 and homeodomain sequences, suggesting a synergistic interaction. Our results also revealed that all three fusions co-localize to the same foci in the nucleus. Additionally, we have looked at dynamics of the Nup98 homeobox fusions in living cells. Like wild type Nup98, the fusions are mobile and mobility is inhibited by the transcription inhibitor, Actinomycin D. Strikingly, we have shown that expression of leukemic fusion proteins causes disassembly of the nuclear bodies containing endogenous Nup98. Our results suggest that Nup98 homeobox fusion proteins share a similar mechanism of leukemogenic transformation. Further, they suggest that Nup98 fusions contribute to leukemogenesis both through altered targeting and transcriptional activation by homeobox factors and through altered compartmentalization of endogenous Nup98.
Nivolumab Alone and With Ipilimumab in Previously Treated Metastatic Urothelial Carcinoma: CheckMate 032 Nivolumab 1 mg/kg Plus Ipilimumab 3 mg/kg Expansion Cohort Results
Authors: Padmanee Sharma, Arlene Siefker-Radtke, Filippo de Braud, Umberto Basso, Emiliano Calvo, Petri Bono, Michael A. Morse, Paolo A. Ascierto, Jose Lopez-Martin, Peter Brossart, Kristoffer Rohrberg, Begoña Mellado, Bruce S. Fischer, Stephanie Meadows-Shropshire, None Abdel Saci, Margaret K. Callahan, Jonathan Rosenberg
Journal: Journal of Clinical Oncology (2019)

CheckMate 032 is an open-label, multicohort study that includes patients with unresectable locally advanced or metastatic urothelial carcinoma (mUC) treated with nivolumab 3 mg/kg monotherapy every 2 weeks (NIVO3), nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO3+IPI1), or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO1+IPI3). We report on the expanded NIVO1+IPI3 cohort and extended follow-up for the NIVO3 and NIVO3+IPI1 cohorts.Patients with platinum-pretreated mUC were enrolled in this phase I/II multicenter study to receive NIVO3, NIVO3+IPI1, or NIVO1+IPI3 until disease progression or unacceptable toxicity. Primary end point was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, including duration of response.Seventy-eight patients were treated with NIVO3 (minimum follow-up, 37.7 months), 104 with NIVO3+IPI1 (minimum follow-up, 38.8 months), and 92 with NIVO1+IPI3 (minimum follow-up, 7.9 months). Objective response rate was 25.6%, 26.9%, and 38.0% in the NIVO3, NIVO3+IPI1, and NIVO1+IPI3 arms, respectively. Median duration of response was more than 22 months in all arms. Grade 3 or 4 treatment-related adverse events occurred in 21 (26.9%), 32 (30.8%), and 36 (39.1%) patients treated with NIVO3, NIVO3+IPI1, and NIVO1+IPI3, respectively. Grade 5 treatment-related pneumonitis occurred in one patient each in the NIVO3 and NIVO3+IPI1 arms.With longer follow-up, NIVO3 demonstrated sustained antitumor activity alone and in combination with ipilimumab. NIVO1+IPI3 provided the greatest antitumor activity of all regimens, with a manageable safety profile. This result not only supports additional study of NIVO1+IPI3 in mUC, but demonstrates the potential benefit of immunotherapy combinations in this disease.
Pharmacy‐based interdisciplinary intervention for patients with chronic heart failure: results of the PHARM‐CHF randomized controlled trial
Authors: Martin Schulz, Nina Griese‐Mammen, Stefan D. Anker, Friedrich Koehler, Peter Ihle, Christian Ruckes, Pia M. Schumacher, Dietmar Trenk, Michael Böhm, Ulrich Laufs
Journal: European Journal of Heart Failure (2019)

Medication non-adherence is frequent and is associated with high morbidity and mortality in patients with chronic heart failure (CHF). We investigated whether an interdisciplinary intervention improves adherence in elderly CHF patients.The study population (mean age 74 years, 62% male, mean left ventricular ejection fraction 47%, 52% in New York Heart Association class III) consisted of 110 patients randomized into the pharmacy care and 127 into the usual care group. The median follow-up was 2.0 years (interquartile range 1.2-2.7). The pharmacy care group received a medication review followed by regular dose dispensing and counselling. Control patients received usual care. The primary endpoint was medication adherence as proportion of days covered (PDC) within 365 days for three classes of heart failure medications (beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and mineralocorticoid receptor antagonists). The main secondary outcome was the proportion of adherent patients (PDC ≥ 80%). The primary safety endpoint was days lost due to unplanned cardiovascular hospitalizations (blindly adjudicated) or death. Pharmacy care compared with usual care resulted in an absolute increase in mean adherence to three heart failure medications for 365 days [adjusted difference 5.7%, 95% confidence interval (CI) 1.6-9.8, P = 0.007]. The proportion of patients classified as adherent increased (odds ratio 2.9, 95% CI 1.4-5.9, P = 0.005). Pharmacy care improved quality of life after 2 years (adjusted difference in Minnesota Living with Heart Failure Questionnaire scores -7.8 points (-14.5 to -1.1; P = 0.02), compared to usual care. Pharmacy care did not affect the safety endpoints of hospitalizations or deaths.Pharmacy care safely improved adherence to heart failure medications and quality of life.
Targeting TMEM176B Enhances Antitumor Immunity and Augments the Efficacy of Immune Checkpoint Blockers by Unleashing Inflammasome Activation
Authors: Mercedes Segovia, Sofia Russo, Mathias Jeldres, Yamil D. Mahmoud, Valentina Perez, Maite Duhalde, Pierre Charnet, Matthieu Rousset, Sabina Victoria, Florencia Veigas, Cédric Louvet, Bernard Vanhove, R. Andrés Floto, Ignacio Anegon, Maria Cristina Cuturi, M. Romina Girotti, Gabriel A. Rabinovich, Marcelo Hill
Journal: Cancer Cell (2019)

Although immune checkpoint blockers have yielded significant clinical benefits in patients with different malignancies, the efficacy of these therapies is still limited. Here, we show that disruption of transmembrane protein 176B (TMEM176B) contributes to CD8+ T cell-mediated tumor growth inhibition by unleashing inflammasome activation. Lack of Tmem176b enhances the antitumor activity of anti-CTLA-4 antibodies through mechanisms involving caspase-1/IL-1β activation. Accordingly, patients responding to checkpoint blockade therapies display an activated inflammasome signature. Finally, we identify BayK8644 as a potent TMEM176B inhibitor that promotes CD8+ T cell-mediated tumor control and reinforces the antitumor activity of both anti-CTLA-4 and anti-PD-1 antibodies. Thus, pharmacologic de-repression of the inflammasome by targeting TMEM176B may enhance the therapeutic efficacy of immune checkpoint blockers.
Olfactory Dysfunction Mediates Adiposity in Cognitive Impairment of Type 2 Diabetes: Insights From Clinical and Functional Neuroimaging Studies
Authors: Zhou Zhang, Bing Zhang, Xin Wang, Xin Zhang, Qing X. Yang, Zhao Qing, Wen Zhang, Dalong Zhu, Yan Bi
Journal: Diabetes Care (2019)

OBJECTIVE Large numbers of people with type 2 diabetes are obese. However, changes in cognition and related brain function in obese people with diabetes have not been characterized. Here, we investigated cognition, olfactory function, and odor-induced brain alterations in these patients and therapeutic effects of glucagon-like peptide 1 receptor agonists (GLP-1Ras) on their psychological behavior and olfactory networks. RESEARCH DESIGN AND METHODS Cognitive, olfactory, and odor-induced brain activation assessments were administered to 35 obese and 35 nonobese people with type 2 diabetes and 35 control subjects matched for age, sex, and education. Among them, 20 obese individuals with diabetes with inadequate glycemic control and metformin monotherapy received GLP-1Ra treatment for 3 months and were reassessed for metabolic, cognitive, olfactory, and neuroimaging changes. RESULTS Obese subjects with diabetes demonstrated lower general cognition and olfactory threshold scores, decreased left hippocampal activation, and disrupted seed-based functional connectivity with right insula compared with nonobese subjects with diabetes. Negative associations were found between adiposity and episodic memory and between fasting insulin and processing speed test time in diabetes. Mediation analyses showed that olfactory function and left hippocampus activation mediated these correlations. With 3-month GLP-1Ra treatment, obese subjects with diabetes exhibited improved Montreal Cognitive Assessment (MoCA) score, olfactory test total score, and enhanced odor-induced right parahippocampus activation. CONCLUSIONS Obese subjects with type 2 diabetes showed impaired cognition and dysfunctional olfaction and brain networks, the latter of which mediated adiposity in cognitive impairment of diabetes. GLP-1Ras ameliorated cognitive and olfactory abnormalities in obese subjects with diabetes, providing new perspectives for early diagnosis and therapeutic approaches for cognitive decrements in these patients.
COMBINED RETROGRADE/ANTEGRADE ENDOSCOPIC APPROACH TO DISCONNECTED BILE-DUCT (DBD) AS A RESULT OF SEVERE POSTOPERATIVE INJURY
Authors: M de Benito, AY Carbajo, I Peñas-Herrero, FJ García-Alonso, S Bazaga, J Tejedor-Tejeda, R Sánchez-Ocaña, C De la Serna, F García-Pajares, C Almohalla, G Sánchez-Antolín, M Pérez-Miranda
Journal: Endoscopy (2019)

DBD is defined at ERCP by lack of proximal filling under pressure cholangiography with/without contrast extravasation. Combined percutaneous-endoscopic approaches are encouraging. We hypothesized that aggressive retrograde (ERCP) and/or antegrade (EUS) attempts at recanalization might salvage DBD for endotherapy. To assess feasibility and efficacy of an endoscopic treatment algorithm of DBD and characterize the heterogeneous techniques used.
Plasmodium vivax morbidity after radical cure: A cohort study in Central Vietnam
Authors: Thanh Vinh Pham, Hong Van Nguyen, Angel Rosas Aguirre, Van Van Nguyen, Mario A. Cleves, Xa Xuan Nguyen, Thao Thanh Nguyen, Duong Thanh Tran, Hung Xuan Le, Niel Hens, Anna Rosanas-Urgell, Umberto D’Alessandro, Niko Speybroeck, Annette Erhart
Journal: PLoS Medicine (2019)

In Vietnam, the importance of vivax malaria relative to falciparum during the past decade has steadily increased to 50%. This, together with the spread of multidrug-resistant Plasmodium falciparum, is a major challenge for malaria elimination. A 2-year prospective cohort study to assess P. vivax morbidity after radical cure treatment and related risk factors was conducted in Central Vietnam.The study was implemented between April 2009 and December 2011 in four neighboring villages in a remote forested area of Quang Nam province. P. vivax-infected patients were treated radically with chloroquine (CQ; 25 mg/kg over 3 days) and primaquine (PQ; 0.5 mg/kg/day for 10 days) and visited monthly (malaria symptoms and blood sampling) for up to 2 years. Time to first vivax recurrence was estimated by Kaplan-Meier survival analysis, and risk factors for first and recurrent infections were identified by Cox regression models. Among the 260 P. vivax patients (61% males [159/260]; age range 3-60) recruited, 240 completed the 10-day treatment, 223 entered the second month of follow-up, and 219 were followed for at least 12 months. Most individuals (76.78%, 171/223) had recurrent vivax infections identified by molecular methods (polymerase chain reaction [PCR]); in about half of them (55.61%, 124/223), infection was detected by microscopy, and 84 individuals (37.67%) had symptomatic recurrences. Median time to first recurrence by PCR was 118 days (IQR 59-208). The estimated probability of remaining free of recurrence by month 24 was 20.40% (95% CI [14.42; 27.13]) by PCR, 42.52% (95% CI [35.41; 49.44]) by microscopy, and 60.69% (95% CI [53.51; 67.11]) for symptomatic recurrences. The main risk factor for recurrence (first or recurrent) was prior P. falciparum infection. The main limitations of this study are the age of the results and the absence of a comparator arm, which does not allow estimating the proportion of vivax relapses among recurrent infections.A substantial number of P. vivax recurrences, mainly submicroscopic (SM) and asymptomatic, were observed after high-dose PQ treatment (5.0 mg/kg). Prior P. falciparum infection was an important risk factor for all types of vivax recurrences. Malaria elimination efforts need to address this largely undetected P. vivax transmission by simultaneously tackling the reservoir of P. falciparum and P. vivax infections.