tbuckley/cabot-search huggingface dataset:
Overall survival at 5 years of follow-up in a phase III trial comparing ipilimumab 10 mg/kg with 3 mg/kg in patients with advanced melanoma
Authors: Paolo Antonio Ascierto, Michele Del Vecchio, Andrzej Mackiewicz, Caroline Robert, Vanna Chiarion-Sileni, Ana Arance, Céleste Lebbé, Inge Marie Svane, Catriona McNeil, Piotr Rutkowski, Carmen Loquai, Laurent Mortier, Omid Hamid, Lars Bastholt, Brigitte Dreno, Dirk Schadendorf, Claus Garbe, Marta Nyakas, Jean-Jacques Grob, Luc Thomas, Gabriella Liszkay, Michael Smylie, Christoph Hoeller, Virginia Ferraresi, Florent Grange, Ralf Gutzmer, Joanna Pikiel, Fareeda Hosein, Burcin Simsek, Michele Maio
Journal: Journal for ImmunoTherapy of Cancer (2020)

We have previously reported significantly longer overall survival (OS) with ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with advanced melanoma, with higher incidences of adverse events (AEs) at 10 mg/kg. This follow-up analysis reports a 5-year update of OS and safety.This randomized, multicenter, double-blind, phase III trial included patients with untreated or previously treated unresectable stage III or IV melanoma. Patients were randomly assigned (1:1) to ipilimumab 10 mg/kg or 3 mg/kg every 3 weeks for 4 doses. The primary end point was OS.At a minimum follow-up of 61 months, median OS was 15.7 months (95% CI 11.6 to 17.8) at 10 mg/kg and 11.5 months (95% CI 9.9 to 13.3) at 3 mg/kg (HR 0.84, 95% CI 0.71 to 0.99; p=0.04). In a subgroup analysis, median OS of patients with asymptomatic brain metastasis was 7.0 months (95% CI 4.0 to 12.8) in the 10 mg/kg group and 5.7 months (95% CI 4.2 to 7.0) in the 3 mg/kg group. In patients with wild-type or mutant BRAF tumors, median OS was 13.8 months (95% CI 10.2 to 17.0) and 33.2 months (95% CI 19.4 to 45.2) in the 10 mg/kg group, and 11.2 months (95% CI 9.2 to 13.8) and 19.7 months (95% CI 11.6 to 25.3) in the 3 mg/kg group, respectively. The incidence of grade 3/4 treatment-related AEs was 36% in the 10 mg/kg group vs 20% in the 3 mg/kg group, and deaths due to treatment-related AEs occurred in four (1%) and two patients (1%), respectively.This 61-month follow-up of a phase III trial showed sustained long-term survival in patients with advanced melanoma who started metastatic treatment with ipilimumab monotherapy, and confirmed the significant benefit for those who received ipilimumab 10 mg/kg vs 3 mg/kg. These results suggest the emergence of a plateau in the OS curve, consistent with previous ipilimumab studies.NCT01515189.
Iodoacetate and 3-bromopyruvate modulate cell signaling to decrease the pancreatic cancer cell survival
Authors: Vikas Bhardwaj, Nisha Rizvi, Maria Lai, James Lai, Alok Bhushan
Journal: Cancer Research (2008)

4336  Cancer cells’ dependence on glycolysis for their energy requirements was suggested by Warburg in the1920’s (the Warburg hypothesis). There has been renewed interest to derived novel experimental paradigms using this hypothesis. In this study, we investigated the functional relation between the glycolytic pathway and tumor cell survival and proliferation by determining the effects on pancreatic cancer cells (PANC-1) of two glycolytic enzyme inhibitors, iodoacetate (IAA), an inhibitor of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and 3-bromopyruvate (3BP), an inhibitor of hexokinase II (HKII). We hypothesized that IAA and 3BP inhibit the functional roles of GAPDH and HKII leading to decreased survival of pancreatic cancer cells. To test our hypothesis, we performed cell survival (MTT) assay on IAA- or 3BP-treated PANC-1cells and found that both inhibitors induced decreases in survival of PANC-1cells in a dose-related manner. However, IAA was approximately six times more potent than 3BP, the IC50 for IAA and 3BP being 3 and 17µM, respectively. To elucidate the putative mechanism of cell death induced by IAA and 3BP, we determined lactate dehydrogenase (LDH) release from treated cells into the medium which correlates with the extent of necrotic cell damage/death. Our results revealed treatment with both inhibitors induced increases in cellular necrosis. However, although IAA is more potent than 3BP in lowering survival of PANC-1 cells, when the cells were treated at their respective IC50 concentrations, IAA produced no increase in the LDH release while 3BP induced 35% increase in the LDH release as compared to that in untreated cells. To assess the putative signaling mechanism(s) mediating the effects of IAA and 3BP on PANC-1 cells, western blot analysis was performed. We found that 3BP treatment of the cells reduced the expression of K-ras and phosphorylation of AKT but not that of ERK-1, whereas IAA treatment neither affected the expression of K-ras nor the phosphorylation of ERK-1 and AKT. We conclude that there may be a cross-talk between signaling pathways and glycolysis in regulating pancreatic cancer cell survival and death. Thus, a combination of agents that inhibit both glycolytic and signaling mechanisms may provide a novel approach to target pancreatic cancer effectively.
The protective effect of <i>Bifidobacterium bifidum</i> G9-1 against mucus degradation by <i>Akkermansia muciniphila</i> following small intestine injury caused by a proton pump inhibitor and aspirin
Authors: Tsutomu Yoshihara, Yosuke Oikawa, Takayuki Kato, Takaomi Kessoku, Takashi Kobayashi, Shingo Kato, Noboru Misawa, Keiichi Ashikari, Akiko Fuyuki, Hidenori Ohkubo, Takuma Higurashi, Yoko Tateishi, Yoshiki Tanaka, Shunji Nakajima, Hiroshi Ohno, Koichiro Wada, Atsushi Nakajima
Journal: Gut Microbes (2020)

Background Proton pump inhibitors (PPIs) can alleviate upper gastrointestinal injury but paradoxically exacerbate aspirin (ASA)-induced small intestine injury. In this study, our goal was to simulate this exacerbation by developing an appropriate animal model, which may help in establishing treatments. Methods: Male mice were fed a 60% fructose diet for 9 weeks, then administered 200 mg/kg ASA 3 h before sacrifice. The PPI omeprazole was administered intraperitoneally once daily for 9 weeks. Bifidobacterium bifidum G9-1 was administered orally for the last week. In addition, Akkermansia muciniphila was administered orally for 9 weeks instead of omeprazole. Results: ASA-induced small-intestine injury was observed in high-fructose fed mice. Omeprazole exacerbated ASA-induced intestinal damage, significantly decreased Bifidobacteria levels, and significantly increased A. muciniphila counts in the jejunum. The direct administration of A. muciniphila caused thinning of the jejunum mucus layer, which was also observed in mice that received ASA and omeprazole. On the other hand, the administration of Bifidobacterium bifidum G9-1 inhibited A. muciniphila growth and reduced thinning of the mucus layer. The number of goblet cells in the jejunum was reduced by the administration of ASA and omeprazole, while Bifidobacterium bifidum G9-1 prevented the reduction. Conclusions: These results suggest that omeprazole-induced gut dysbiosis promotes Akkermansia growth and inhibits Bifidobacterium growth, leading to a thinning of the mucus layer through a reduction in goblet cells in the small intestine. Probiotics are, therefore, a promising approach for the treatment of small intestine injury.
Second cancers in adults with acute promyelocytic leukemia treated with or without arsenic trioxide: a SEER-medicare analysis
Authors: Kelly J. Norsworthy, Armen Avagyan, Steven T. Bird, Yuchen Li, Sandia Akhtar, Jiemin Liao, Michael Wernecke, Albert B. Deisseroth, Meredith Chuk, Thomas E. MaCurdy, Richard Swain, Jeffrey A. Kelman, Ann T. Farrell, R. Angelo de Claro, Richard Pazdur, Gideon Blumenthal, David J. Graham
Journal: Leukemia (2020)
Abstract 15901: Radiofrequency Ablation for Persistent Atrial Fibrillation: Earlier Catheter-based Interventions are associated With Better Outcomes and in Direct Association With Markers of Pathways of Atrial Remodeling
Authors: Amr F Barakat, Ayman A Hussein, Mohammed Bassiouny, Ali Hakim, Shadi Al Halabi, Khaldoun Tarakji, Bryan Baranowski, Daniel Cantillon, Thomas Dresing, Patrick Tchou, David O Martin, Niraj Varma, Mandeep Bhargava, Thomas Callahan, Mark Niebauer, Mohamed Kanj, Mina Chung, Walid I Saliba, Andrea Natale, Bruce D Lindsay, Oussama M Wazni
Journal: Circulation (2015)

Introduction: Persistent atrial fibrillation (PerAF) ablation has been associated with significant recurrence rates which could reflect progressive AF-related atrial remodeling. We hypothesized that the first-diagnosis to ablation time for PerAF is a major determinant of success rates and in direct association with pathways of atrial remodeling. Methods: Two-year outcomes were assessed in 1241 patients undergoing first time ablation of PerAF between January 2005 and December 2012 at our institution. The time intervals between the first diagnosis of PerF and the ablation procedures were determined. Patients had echocardiograms and measures of B-type natriuretic peptide (BNP) and C-reactive protein (CRP) before the ablation procedures. During ablations, patients with atrial scarring by voltage were identified. Results: The median time-to-ablation since the first PerAF diagnosis was 3 years (interquartile range 1-6.5). With longer diagnosis-to-ablation time (based on quartiles), there was a significant increase in BNP levels (p=0.01), CRP levels (p&lt;0.0001), left atrial size (p=0.03) and scarring (p=0.04). Atrial arrhythmia recurred after a single ablation in 555 patients (44.7%); and 364 (29.3%) underwent repeat ablations. At last follow-up, 1005 patients (81.0%, 390 on antiarrhythmic medications) were either arrhythmia free or had their arrhythmia controlled. In Cox Proportional Hazard analyzes, BNP levels, CRP levels, left atrial size and scarring were associated with arrhythmia recurrence. The diagnosis-to-ablation time had the strongest association with success rates which persisted in multivariate Cox analyzes (HR for recurrence per +1Log diagnosis-to-ablation time 1.25, 95%CI 1.11-1.42, p&lt;0.0001; 4th vs. 1st quartile 2.27, 95%CI 1.52-3.47, p&lt;0.0001). Conclusions: The success rates with PerAF ablation are highest with early intervention, that is ablation before the progression of atrial remodeling.
Primary therapy and relative survival among elderly patients with chronic myeloid leukemia: a population-based study in the Netherlands, 1989–2017
Authors: Geneviève I. C. G. Ector, Otto Visser, Peter E. Westerweel, Jeroen J. W. M. Janssen, Nicole M. A. Blijlevens, Avinash G. Dinmohamed
Journal: Leukemia (2020)
Covid-19: Doctors launch judicial review over PPE failures
Authors: Abi Rimmer
Journal: BMJ (2020)

Doctors have launched judicial review proceedings after the government decided not to open an inquiry into failures to provide adequate personal protective equipment (PPE) for frontline workers.

On 8 June, the Doctors’ Association UK (DAUK), in conjunction with the Good Law Project, a not-for-profit membership organisation, and elder abuse charity Hourglass, instructed solicitors to start the legal challenge.

They believe that, under the Human Rights Act 1998 and article 2 of the European Convention on Human Rights, the government has a legal obligation to launch an independent public inquiry into whether failures …
Abstract PR01: Developmental reprogramming via Hedgehog pathway activation in nonmyogenic endothelial progenitors drives fusion-negative rhabdomyosarcoma
Authors: Catherine J. Drummond, Kathrine E. Gadek, Madeline Bush, Matthew R. Garcia, Mark E. Hatley
Journal: Cancer Research (2020)

Abstract Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Despite aggressive chemotherapy, radiotherapy, and surgery, clinical outcomes for RMS have not improved for three decades, emphasizing the need to uncover the molecular underpinnings of the disease. RMS has been presumed to originate from derailed muscle progenitors based on the histologic appearance and gene expression pattern of the tumors, resembling embryonic developing skeletal muscle. However, an origin restricted to skeletal muscle does not explain RMS occurring in tissues devoid of skeletal muscle such as the prostate, bladder, salivary gland, biliary tree, and omentum. Previously, we described that activation of Sonic Hedgehog signaling through expression of a conditional, constitutively active Smoothened allele, SmoM2, under control of a presumed adipocyte-restricted adipose protein 2 (aP2)-Cre recombinase transgene in mice, gives rise to aggressive skeletal muscle tumors that display the histologic and molecular characteristics of human embryonal RMS (ERMS). With the short latency and anatomically restricted tumor location in the neck, we sought to leverage this model to explore the cell of origin of ERMS. Lineage tracing experiments identified aP2-Cre labeled cells are distinctly nonmyogenic and were identified as endothelial cells found in the interstitium between muscle fibers. We illustrate that aP2-Cre is not expressed in the quiescent or activated muscle stem cells or satellite cells. Expression of oncogenic SmoM2 with aP2-Cre results in proliferation and expansion of the aP2-Cre labeled muscle interstitial endothelial cells and myogenic transdifferentiation resulting in ERMS. Activation of the hedgehog pathway in aP2-Cre labeled endothelial progenitors results in expression of skeletal muscle specification factors specific in the head and neck development, including TBX1, PITX2, TCF21, and MSC. We illustrate that endothelium and skeletal muscle within the head and neck arise from KDR (VEFGR2)-expressing progenitors. Hedgehog pathway activation in committed KDR+ endothelial progenitors results in Tbx1 expression and subsequent MYOD1 expression driving a partially myogenic program characteristic of ERMS. Our work identifies reprogramming cell fate as a mechanism of transformation in pediatric sarcoma and illustrates that it is dangerous to assume the cell of origin from the characteristics of the tumor cell. Citation Format: Catherine J. Drummond, Kathrine E. Gadek, Madeline Bush, Matthew R. Garcia, Mark E. Hatley. Developmental reprogramming via Hedgehog pathway activation in nonmyogenic endothelial progenitors drives fusion-negative rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr PR01.
Camrelizumab Plus Gemcitabine, Vinorelbine, and Pegylated Liposomal Doxorubicin in Relapsed/Refractory Primary Mediastinal B-Cell Lymphoma: A Single-Arm, Open-Label, Phase II Trial
Authors: Qian Mei, Wenying Zhang, Yang Liu, Qingming Yang, John E.J. Rasko, Jing Nie, Jiejie Liu, Xiang Li, Liang Dong, Meixia Chen, Yan Zhang, Lu Shi, Huitao Wu, Weidong Han
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Patients with relapsed/refractory primary mediastinal B-cell lymphoma (rrPMBCL) represent a particularly challenging population to treat, with few life-saving treatment options in the context of a dismal prognosis. Patients and Methods: In this open-label, single-arm, phase II study, the safety and efficacy of combined regimen of chemotherapy consisting of gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD) plus anti-PD-1 antibody camrelizumab was assessed in rrPMBCL. Patients received chemo-immunotherapy every 3 weeks until the second confirmed complete response (CR) or up to 12 cycles, followed by camrelizumab monotherapy for up to 1 year. The primary endpoints were objective response rate (ORR) and safety. Results: Twenty-seven response evaluable patients were enrolled, who received a median of three first-line therapies, 59% with bulky disease. The ORR was 74%, including 56% with a CR. A median time of 1.7 months to response was observed, with 78% exhibiting tumor shrinkage at the first evaluation. After 24.8 months median follow-up, the median duration of response was not reached, with a 65% 2-year estimated response rate. Thirteen responders remained in sustained complete remission. Estimated 24-month progression-free survival and overall survival rates were 48.2% and 81.5%, respectively. Any grade and grade 3 treatment-related adverse events (AE) occurred in 93% and 33% of patients, respectively; with no grade 4 or 5 AEs. Baseline levels of IL10, IFNγ, and soluble Fas were associated with objective response. Conclusions: Camrelizumab plus GVD chemotherapy offers a potent option as life-saving chemo-immunotherapy with promising efficacy and a manageable safety profile for patients with rrPMBCL, especially with bulky aggressive disease.
COVID-19 in liver transplant recipients: preliminary data from the ELITA/ELTR registry
Authors: Luca S Belli, Christophe Duvoux, Vincent Karam, Rene Adam, Valentin Cuervas-Mons, Luisa Pasulo, Carmelo Loinaz, Federica Invernizzi, Damiano Patrono, Sherrie Bhoori, Olga Ciccarelli, Maria Cristina Morelli, Lluis Castells, Victor Lopez-Lopez, Sara Conti, Costantino Fondevila, Wojchiech Polak
Journal: The Lancet. Gastroenterology & hepatology (2020)
Mechanism of the panaxydol-induced cell death in human cancer cells
Authors: Jooyoung Kim, Sujin Yu, Jeongwon Sohn
Journal: Cancer Research (2006)

4045  Panaxydol, a polyacetylenic compound of the Panax ginseng root has been shown to inhibit the growth of several human malignant tumor cell lines. In vitro growth inhibition by panaxydol can be ascribed to both cell cycle arrest and cell death. Previously, we showed that panaxydol induced G1 cell cycle arrest in SK-MEL-1 cells by increasing the level of the p27CIP1 protein, and inhibiting Cdk2 activity. Here, we investigated panaxydol-induced apoptosis in human cancer cell lines. Activation of caspases 2, 3, 7, 8 and 9 in Jurkat cells, and caspase 7 in MCF-7 was observed in 4-8 hrs after panaxydol treatment. PARP-1 cleavage and annexin V staining could also be demonstrated. To test whether mitochondrial pathway is involved in the apoptosis by panaxydol, cytochrome c release from mitochondria, Bid cleavage, and mitochondrial membrane permeabilization (MMP) were analyzed. Cytochrome c in the cytosol fraction and the 15 kD cleaved form of Bid were detected by Western blot analysis at 2 hrs after panaxydol treatment. Flow cytometry analysis of JC-1 staining in panaxydol-treated Jurkat and MCF-7 cells showed MMP. Moreover, pretreatment of an inhibitor of the mitochondrial pore, cyclosporine A, significantly reduced apoptosis by panaxydol when assayed by annexin V staining. Nuclear translocation of mitochondrial AIF was observed from 2 hr after panaxydol treatment. Since the mitochondrial pathway of apoptosis is often activated by reactive oxygen species (ROS), it was tested whether panaxydol generated ROS. Both in Jurkat and MCF-7 cells, ROS generation could be demonstrated as early as 10 min after panaxydol treatment by 2’,7’-dichloro fluorescein diacetate (H2DCFDA) staining. N-acetyl-L-cysteine (NAC) blocked both ROS generation and apoptosis by panaxydol, suggesting panaxydol-induced apoptosis was mediated by ROS. Phosphorylation of JNK which is often activated by ROS was found to be increased by panaxydol, and SP600125, a JNK inhibitor, inhibited panaxydol-induced apoptosis. In summary, we showed here that panaxydol immediately induced ROS generation in cancer cells, resulting in MMP and the release of cytochrome c and AIF from mitochondria, which, in turn, activated caspases leading to apoptosis.
Response by Zhang et al to Letter Regarding Article, “Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19”
Authors: Peng Zhang, Lihua Zhu, Jingjing Cai, Fang Lei, Juan-Juan Qin, Yibin Wang, Yufeng Yuan, Rohit Loomba, Peter P. Liu, Hongliang Li
Journal: Circulation Research (2020)
Abstract B40: Minimal mutational determinants of human squamous cell carcinoma
Authors: Vicente Planells-Palop, Angie Koo, Heydi Malave, Katharine Lee, Aaron Tward
Journal: Cancer Research (2020)

Abstract Dozens of driver mutations and copy number changes have been implicated in human squamous cell carcinomas (SCCs), and each tumor harbors multiple putative driver mutations. However, the minimal set of mutations sufficient to transform a normal keratinocyte into squamous cell carcinoma is unknown. By analyzing TCGA data and previously published datasets, we have identified common combinations of driver mutations in SCCs. Among the most common driver events are mutations in TP53, CDKN2A, and NOTCH1. Using CRISPR editing at endogenous loci in primary human keratinocytes, we demonstrate that no single driver mutation is sufficient to transform keratinocytes, and in fact many single gene mutations appear toxic to keratinocytes. The combination of loss-of-function mutations in TP53 and CDKN2A is sufficient to immortalize both skin and oral primary human keratinocytes in 2D culture and confer a selective advantage in competition assays. Simultaneous mutation of TP53, CDKN2A, and NOTCH1 demonstrates a very similar phenotype in 2D culture as mutation of TP53 and CDKN2A alone. However, using 3D organotypic squamous epithelial cultures consisting of genome-edited keratinocytes grown on decellularized dermis impregnated with fibroblasts and grown at an air-liquid interface demonstrates that keratinocytes with TP53 and CDKN2A mutation alone are sufficient to induce dysplasia, whereas keratinocytes harboring TP53, CDKN2A, and NOTCH1 mutation exhibit an SCC-like phenotype, including invasion through the basement membrane. RNAseq analysis demonstrates that the transition to SCC by NOTCH1 loss involves a partial EMT-like program. Targeted hybrid capture sequencing of edited keratinocytes revealed no other driver mutations or copy number changes other than the experimentally induced ones, consistent with the notion that TP53, CDKN2A, and NOTCH1 mutations alone are sufficient to reprogram a normal keratinocyte into SCC. Thus, despite a high mutation burden and frequent chromosomal instability, as few as three mutational events appear to be sufficient to induce SCC. Citation Format: Vicente Planells-Palop, Angie Koo, Heydi Malave, Katharine Lee, Aaron Tward. Minimal mutational determinants of human squamous cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr B40.