tbuckley/cabot-search huggingface dataset:
Effect of the vaccine Ad5 [E1-, E2b-]-CEA(6D) on CEA-directed CMI responses in patients with advanced CEA-expressing malignancies in a phase I/II clinical trial.
Authors: Michael Morse, Amy Hobeika, Arvind Chaudhry, Andrea Amalfitano, Donna Niedzwiecki, Timothy M. Clay, Takuya Osada, Gayathri Devi, Bruce K. Burnett, Kent Weinhold, Shiaowen David Hsu, Gerard C. Blobe, Younong Xu, Susan Nguyen, Rajesh Dua, Stephanie Balcaitis, Elizabeth Gabitzsch, Joseph Balint, Frank Jones, H. Kim Lyerly
Journal: Journal of Clinical Oncology (2012)

2585 Background: Adenovirus (Ad) vectors are promising platforms for use as cancer vaccines because of their substantial immunogenicity; however, Ad-specific neutralizing antibodies, present due to natural infection, limit their use. We created a new vector containing additional deletions of the E2b gene and observed that this Ad5 [E1-, E2b-] vector, engineered to express carcinoembryonic antigen (CEA(6D)), could induce antitumor immune responses in mice despite pre-existing Ad5 immunity. The purpose of the current translational study was to evaluate the immunologic effect of increasing doses of Ad5 [E1-, E2b-]-CEA(6D) in mice and then to extended these pre-clinical observations into a phase I/II study. Methods: Ad5 naïve female C57Bl/6 mice, 4-6 weeks old, were immunized subcutaneously 3 times at 2 week intervals with doses of 1.4X10 7 viral particles (vp) up to1.4X10 9 vp of Ad5 [E1-, E2b-]-CEA(6D). Two weeks after the last immunization, splenocytes were harvested for immune determinations. Cohorts of patients (n=25 total) with advanced colorectal cancer, refractory to prior therapies, received escalating doses of Ad5 [E1-, E2B-]-CEA(6D) (10 9 to 10 11 vp) subcutaneously every 3 weeks for 3 immunizations.CEA-specific cell mediated immunity was measured by ELISPOT. Results: Increasing doses of Ad5 [E1-, E2b-]-CEA(6D) in mice induced increasing CEA-specifc CMI responses. Similarly, patients who received the highest dose of Ad5 [E1-, E2b-]-CEA(6D) exhibited the highest levels of CEA-specific CMI responses. The induction of CEA-specific CMI responses increased over the course of the 3 injections despite the presence of pre-existing Ad5 immunity in the majority (75%) of patients. There were no drug related grade 3/4 toxicities.Two patients with stable disease remained so during the study. All other patients experienced progressive disease; however, 1-year survival was 54%. Conclusions: Multiple homologous doses of Ad5 [E1-, E2b-]-CEA(6D) could break tolerance and generate CEA-specific CMI responses in the setting of Ad specific immunity in colorectal cancer patients.
The long noncoding RNA H19 promotes tamoxifen resistance in breast cancer via autophagy
Authors: Ji Wang, Shuduo Xie, Jingjing Yang, Hanchu Xiong, Yunlu Jia, Yulu Zhou, Yongxia Chen, Xiaogang Ying, Cong Chen, Chenyang Ye, Linbo Wang, Jichun Zhou
Journal: Journal of Hematology & Oncology (2019)

Tamoxifen resistance remains a clinical challenge for hormone receptor-positive breast cancer. Recently, dysregulations in autophagy have been suggested as a potential mechanism for tamoxifen resistance. Although the long noncoding RNA H19 is involved in various stages of tumorigenesis, its role in tamoxifen resistance remains unknown. Here, we assessed the role of H19 in the development of tamoxifen-resistant breast cancer. Quantitative real-time PCR analyzed expression of H19 in tamoxifen-resistant breast cancer tissues. Knockdown of H19 was used to assess the sensitivity to tamoxifen in vitro and in vivo. Both knockdown and overexpression of H19 were used to analyze the status of autophagy. Real-time quantitative methylation-specific polymerase chain reaction, chromatin immunoprecipitation, immunofluorescence, and Western blot were used to explore the tamoxifen resistance mechanism of H19. In this study, we observed that the expression of H19 was substantially upregulated in tamoxifen-resistant breast cancer cell line and tumor tissues, and knockdown of H19 enhanced the sensitivity to tamoxifen both in vitro and in vivo. Furthermore, knockdown of H19 significantly inhibited autophagy in MCF7 tamoxifen-resistant (MCF7/TAMR) cells. Conversely, overexpression of H19 promoted autophagy. Interestingly, overexpression of H19 in MCF7 tamoxifen-sensitive cells could recapitulate tamoxifen resistance. Moreover, an increase in methylation in the promoter region of Beclin1 was observed in MCF7/TAMR-shH19 cells. In the double knockdown groups, both shH19+shSAHH and shH19+shDNMT3B rescued the Beclin1 promoter region methylation levels and reactivated autophagy functions. A chromatin immunoprecipitation assay further validated that DNMT3B binds to the Beclin1 promoter region and the knockdown of H19 increases this binding. Our findings demonstrate that H19 induces autophagy activation via the H19/SAHH/DNMT3B axis, which could contribute to tamoxifen resistance in breast cancer.
Adjusting for treatment crossover in the BREAK-3 metastatic melanoma trial for dabrafenib: Preliminary analysis.
Authors: Nicholas Latimer, Keith R. Abrams, Mayur Amonkar, Ceilidh Stapelkamp, R. Suzanne Swann
Journal: Journal of Clinical Oncology (2013)

9044 Background: In BREAK-3, dabrafenib improved PFS (hazard ratio [HR]=0.30 [95% CI 0.18–0.51; p&lt;0.0001] as of Dec 19, 2011) vs dacarbazine (DTIC) in patients (pts) with previously untreated BRAF V600E+unresectable or metastatic melanoma. In an updated analysis (data as of June 25, 2012), PFS HR=0.37 (95% CI 0.24–0.58; p&lt;0.0001). Overall survival (OS) results may underestimate the effect of dabrafenib as DTIC pts could cross over to dabrafenib at progression. This analysis attempts to adjust for confounding effects of crossover on OS using BREAK-3 results from June 2012 data. Methods: Randomization-based crossover adjustment methods – Rank Preserving Structural Failure Time Models (RPSFTM) and the Iterative Parameter Estimation (IPE) algorithm – were used. We conducted 2 sets of analyses testing different assumptions regarding the durability of the treatment (trt) effect. “Trt group” analyses adjusted for crossover under the assumption that the trt effect is maintained until death regardless of trt duration; “On trt – observed” analyses adjusted for crossover under the assumption that the trt effect disappears upon trt discontinuation. Results are presented as HRs. Results: 187 and 63 pts were randomized to dabrafenib and DTIC, respectively. At the time of this analysis, 55.6% of DTIC pts crossed over to dabrafenib. Median duration of follow-up was 10.5 months and 76 (30.4%) pts died. Median OS has not yet been reached. Crossover adjustment results are presented in the Table. Conclusions: All RPSFTM and IPE analyses resulted in point estimates for the OS HR that represented a substantial increase in trt effect compared with the unadjusted HR of 0.75. Results are exploratory, as the OS data are not mature. Analyses will be updated when further data are available. [Table: see text]
Doctors should feel confident apologising
Authors: Caroline Fryar
Journal: BMJ (2019)

The Medical Defence Union (MDU) agrees with Leung and Porter about the importance of a proper apology when things have gone wrong in a patient’s care.1 To err is human, and doctors should follow their instinct to apologise without fear of interference with claims.

In the MDU’s experience, an early sincere and frank apology and explanation can restore a …
Abstract 10579: Beneficial Effect of Mitochondrial Calcium Uniporter Overexpression in a Guinea Pig Heart Failure and Sudden Cardiac Death Model
Authors: Ting Liu, Brian O’Rourke
Journal: Circulation (2018)

Introduction: In the heart, excessive mitochondrial Ca2+ (mCa2+) can cause permeability transition pore opening and cell death. On the other hand, insufficient mCa2+ can also compromise energy supply/demand matching and mitochondrial reactive oxygen species scavenging capacity, especially at high wo
CD36 tango in cancer: signaling pathways and functions
Authors: Jingchun Wang, Yongsheng Li
Journal: Theranostics (2019)

CD36, a scavenger receptor expressed in multiple cell types, mediates lipid uptake, immunological recognition, inflammation, molecular adhesion, and apoptosis.CD36 is a transmembrane glycoprotein that contains several posttranslational modification sites and binds to diverse ligands, including apoptotic cells, thrombospondin-1 (TSP-1), and fatty acids (FAs).Beyond fueling tumor metastasis and therapy resistance by enhancing lipid uptake and FA oxidation, CD36 attenuates angiogenesis by binding to TSP-1 and thereby inducing apoptosis or blocking the vascular endothelial growth factor receptor 2 pathway in tumor microvascular endothelial cells.Moreover, CD36-driven lipid metabolic reprogramming and functions in tumor-associated immune cells lead to tumor immune tolerance and cancer development.Notable advances have been made in demonstrating the regulatory networks that govern distinct physiological properties of CD36, and this has identified targeting CD36 as a potential strategy for cancer treatment.Here, we provide an overview on the structure, regulation, ligands, functions, and clinical trials of CD36 in cancer.
Relationship between treatment duration and outcomes in patients receiving concurrent chemoradiotherapy (CCRT) and surgery for locoregionally advanced (LRA) esophageal and gastroesophageal junction (E/GEJ) adenocarcinoma (ACA).
Authors: Michael J. McNamara, Lisa A. Rybicki, Thomas W. Rice, Cristina P. Rodriguez, Gregory M.M. Videtic, Jerrold P. Saxton, Joanna Bodmann, Denise I. Ives, David J. Adelstein
Journal: Journal of Clinical Oncology (2012)

e14665 Background: Retrospective studies in breast, colon, and head and neck cancer have suggested that delays in administration of adjuvant chemotherapy result in inferior outcomes. We explore this question in patients with LRA E/GEJ ACA. Methods: From 11/99 to 7/06, 152 patients with cT3, N1, or M1a disease were enrolled on one of two clinical trials at the Cleveland Clinic. Two courses of CCRT consisting of 30Gy radiation (@1.5Gy BID) with continuous infusion cisplatin (20mg/m2/day x 4 days) and 5Fu (1000mg/m2/d x 4 days) were given both before and after surgical resection. In the second trial, 75 patients also received gefitinib during the 4 week induction and for a total of two years postoperatively. Using recursive partitioning analysis (RPA), we retrospectively explored the relationship between treatment duration and loco-regional control (LRC), distant metastatic control (DMC), freedom from recurrence (FFR), and overall survival (OS) in the 115 patients (76%) who completed all treatment. Outcomes were estimated using the Kaplan-Meier method and compared among groups using the log-rank test. Results: RPA analysis identified three groups of patients: 19 patients in whom resection occurred ≤45 days from the start of CCRT to resection (short treatment), 63 patients who underwent resection &gt;45 days from the start of CCRT and required &lt;50 days to complete treatment after surgery (intermediate treatment), and 33 patients who underwent resection &gt;45 days from the start of CCRT but required ≥50 days to complete treatment after surgery (prolonged treatment). With a median follow-up of 90 (range 57-126) months, we found that patients with shorter treatment times had better 5 year DMC [64% (short) v 26% (intermediate) v 16% (prolonged); p=0.004], FFR [57% (short) v 23% (intermediate) v 16% (prolonged); p=0.015)], and OS [42% (short) v 30% (intermediate) v 12% (prolonged); p=0.08]. LRC was not different between the groups. Conclusions: Treatment delays in patients receiving multimodality therapy for LRA E/GEJ ACA may result in a greater risk of recurrence and decreased survival.
National Experience on Down‐Staging of Hepatocellular Carcinoma Before Liver Transplant: Influence of Tumor Burden, Alpha‐Fetoprotein, and Wait Time
Authors: Neil Mehta, Jennifer L. Dodge, Joshua D. Grab, Francis Y. Yao
Journal: Hepatology (2019)

United Network for Organ Sharing (UNOS) recently implemented a national policy granting priority listing for liver transplantation (LT) in patients who achieved down-staging of hepatocellular carcinoma (HCC) to Milan criteria. We aimed to evaluate the national experience on down-staging by comparing two down-staging groups with (1) tumor burden meeting UNOS down-staging (UNOS-DS) inclusion criteria and (2) "all-comers" (AC-DS) with initial tumor burden beyond UNOS-DS criteria versus patients always within Milan.
The molecular mechanism of LncRNA34a-mediated regulation of bone metastasis in hepatocellular carcinoma
Authors: Li Zhang, Hao Niu, Jie Ma, Bao-Ying Yuan, Yu-Han Chen, Yuan Zhuang, Gen-Wen Chen, Zhao-Chong Zeng, Zuo-Lin Xiang
Journal: Molecular Cancer (2019)

Bone metastasis (BM) has long been recognized as a major threat to the quality of life of hepatocellular cancer (HCC) patients. While LncRNA34a (Lnc34a) has been shown to regulate colon cancer stem cell asymmetric division, its effect on HCC BM remains unknown.In situ hybridization and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression of Lnc34a in HCC tissues and cell lines. Ventricle injection model was constructed to explore the effect of Lnc34a on BM in vivo. The methylation of miR-34a promoter and histones deacetylation were examined by using bisulfate-sequencing PCR and chromatin immunoprecipitation assays. RNA pull down and RNA immunoprecipitation were performed to investigated the interaction between Lnc34a and epigenetic regulators. Dual-luciferase reporter assay was conducted to find miR-34a target. The involvement of TGF-β pathway in the BM from HCC was determined by qRT-PCR, western, and elisa assays.We found that Lnc34a was significantly overexpressed in HCC tissues and associated with BM. Both in vitro and in vivo experiments indicate that the restoration or knockdown of Lnc34a expression in HCC cells had a marked effect on cellular migration, invasion, and metastasis. Mechanistic analyses suggested that Lnc34a epigenetically suppresses miR-34a expression through recruiting DNMT3a via PHB2 to methylate miR-34a promoter and HDAC1 to promote histones deacetylation. On the other hand, miR-34a targets Smad4 via the TGF-β pathway, followed by altering the transcription of the downstream genes (i.e., CTGF and IL-11) that are associated with BM.Our study is the first to document the pro-bone metastatic role of Lnc34a in BM of HCC and reveal a novel mechanism for the activation of the TGF-β signaling pathway in HCC BM, providing evidence of a potential therapeutic strategy in HCC BM.
The Commercial Differential for Hospital Prices
Authors: Christopher F. Koller, Dhruv Khullar
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
A phase II study of gemcitabine (G), peghilated liposomal doxorubicin (PLD) and docetaxel (D) in locally advanced breast cancer (LABC): An interim analysis
Authors: G. Artioli, F. Bozza, G. Cartei, S. Zovato, R. Mencarelli, G. Zavagno, M. Michelotto
Journal: Journal of Clinical Oncology (2006)

10789 Background: On the basis of general and our own experience neoadjuvant therapy is justified in patients with locally advanced breast cancer to reduce cancer and to perform a conservative surgery. In this study we evaluated the efficacy of G plus D and PLD as first-line therapy in LABC. Methods: To date sixteen consecutive patients with LABC have been enrolled into the study. All patients before neoadjuvant treatment, underwent biopsy for hormonal receptors and c-erb-B2 assessment. Patients received G 1250 mg/m 2 on day 1 and G 1000 mg/m 2 , T 75 mg/m 2 and D 25–30 mg/m 2 on day 8 (escalation dose was 25 mg/m 2 at first cycle, 27.5 mg/m 2 at second cycle and 30 mg/m2 at third cycle), every 21 days with G-CSF support on day 3, 10, 12 and 14. Tumor response was evaluated on the basis of surgeon consultation and breast MRI after 4 cycles. If tumor response was higher than 50% patients underwent 2 more cycles; if it was 50% ore less or because of unacceptable toxicity they underwent surgery after 4 cycles. Microscopic assessment of the extent and type of residual tumour was made. Results: 16 patients were enrolled comprehensive of 2 with no symptomatic bone metastases. Median age was 50 years-old, and 100% had a WHO performance status (PS) of 0 and EORTC QoL was submitted. Four patients were submitted to surgery after 4 cycles, one after 5 cycles of CT with 5 pPR more than 50%. Three patients had a pathological complete response, 2 partial response more than 50% and 1 stable disease after 6 cycles. (a total of 70% of pPR, 30% of pRC, 10% of pSD). Five patients are still on treatment. One patient died because of acute respiratory distress syndrome. Major toxicity was mucositis G3–4 in one patient. PPE was G3–4 in 3 patients, one discontinued chemotherapy with PLD and continued with Epirubicin. 2 patients received Epirubicin after the first cycle of PLG because of acute allergic reaction. Conclusions: This regimen of chemotherapy seems feasible and active in LABC. At the interim analysis results it has been noted that the best response to chemotherapy was among patients having worse prognostic factors (histology and staging). No significant financial relationships to disclose.
Epigenomics and Single-Cell Sequencing Define a Developmental Hierarchy in Langerhans Cell Histiocytosis
Authors: Florian Halbritter, Matthias Farlik, Raphaela Schwentner, Gunhild Jug, Nikolaus Fortelny, Thomas Schnöller, Hanja Pisa, Linda C. Schuster, Andrea Reinprecht, Thomas Czech, Johannes Gojo, Wolfgang Holter, Milen Minkov, Wolfgang M. Bauer, Ingrid Simonitsch-Klupp, Christoph Bock, Caroline Hutter
Journal: Cancer Discovery (2019)

Abstract Langerhans cell histiocytosis (LCH) is a rare neoplasm predominantly affecting children. It occupies a hybrid position between cancers and inflammatory diseases, which makes it an attractive model for studying cancer development. To explore the molecular mechanisms underlying the pathophysiology of LCH and its characteristic clinical heterogeneity, we investigated the transcriptomic and epigenomic diversity in primary LCH lesions. Using single-cell RNA sequencing, we identified multiple recurrent types of LCH cells within these biopsies, including putative LCH progenitor cells and several subsets of differentiated LCH cells. We confirmed the presence of proliferative LCH cells in all analyzed biopsies using IHC, and we defined an epigenomic and gene-regulatory basis of the different LCH-cell subsets by chromatin-accessibility profiling. In summary, our single-cell analysis of LCH uncovered an unexpected degree of cellular, transcriptomic, and epigenomic heterogeneity among LCH cells, indicative of complex developmental hierarchies in LCH lesions. Significance: This study sketches a molecular portrait of LCH lesions by combining single-cell transcriptomics with epigenome profiling. We uncovered extensive cellular heterogeneity, explained in part by an intrinsic developmental hierarchy of LCH cells. Our findings provide new insights and hypotheses for advancing LCH research and a starting point for personalizing therapy. See related commentary by Gruber et al., p. 1343. This article is highlighted in the In This Issue feature, p. 1325
Out-of-hours: Welsh government must actively recruit GPs, report says
Authors: Abi Rimmer
Journal: BMJ (2019)

The Welsh government must develop policies to recruit more GPs to improve out-of-hours services in the country, a report has said.

A report from the National Assembly for Wales public accounts committee1 says that it is concerned about the general decline in GP numbers, not just for out-of-hours services but also for daytime services. “We recommend the Welsh government actively develop policies …
Health Care Autonomy of Women Living with HIV
Authors: Robert R. Redfield, Surbhi Modi, Cynthia A. Moore, Augustina Delaney, Margaret A. Honein, Hank L. Tomlinson
Journal: New England Journal of Medicine (2019)

Health Care Autonomy of Women Living with HIV HIV policy discussions have focused on a potential link between dolutegravir-based HIV treatment in pregnant women and neural-tube defects in infants, ...
Co-Production: An Ethical Model for Mental Health Research?
Authors: Sapfo Lignou, Liliana Capitao, Julia Madeleine Hamer-Hunt, Ilina Singh
Journal: The American Journal of Bioethics (2019)

In this commentary we argue for the value of involving people with a diagnosis of mental health disorders and/or their caregivers as co-researchers in mental health research. We claim that co-produ...
AKR1D1 is a novel regulator of metabolic phenotype in human hepatocytes and is dysregulated in non-alcoholic fatty liver disease
Authors: Nikolaos Nikolaou, Laura L. Gathercole, Lea Marchand, Sara Althari, Niall J. Dempster, Charlotte J. Green, Martijn van de Bunt, Catriona McNeil, Anastasia Arvaniti, Beverly A. Hughes, Bruno Sgromo, Richard S. Gillies, Hanns-Ulrich Marschall, Trevor M. Penning, John Ryan, Wiebke Arlt, Leanne Hodson, Jeremy W. Tomlinson
Journal: Metabolism (2019)

ObjectiveNon-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome. Steroid hormones and bile acids are potent regulators of hepatic carbohydrate and lipid metabolism. Steroid 5β-reductase (AKR1D1) is highly expressed in human liver where it inactivates steroid hormones and catalyzes a fundamental step in bile acid synthesis.MethodsHuman liver biopsies were obtained from 34 obese patients and AKR1D1 mRNA expression levels were measured using qPCR. Genetic manipulation of AKR1D1 was performed in human HepG2 and Huh7 liver cell lines. Metabolic assessments were made using transcriptome analysis, western blotting, mass spectrometry, clinical biochemistry, and enzyme immunoassays.ResultsIn human liver biopsies, AKR1D1 expression decreased with advancing steatosis, fibrosis and inflammation. Expression was decreased in patients with type 2 diabetes. In human liver cell lines, AKR1D1 knockdown decreased primary bile acid biosynthesis and steroid hormone clearance. RNA-sequencing identified disruption of key metabolic pathways, including insulin action and fatty acid metabolism. AKR1D1 knockdown increased hepatocyte triglyceride accumulation, insulin sensitivity, and glycogen synthesis, through increased de novo lipogenesis and decreased β-oxidation, fueling hepatocyte inflammation. Pharmacological manipulation of bile acid receptor activation prevented the induction of lipogenic and carbohydrate genes, suggesting that the observed metabolic phenotype is driven through bile acid rather than steroid hormone availability.ConclusionsGenetic manipulation of AKR1D1 regulates the metabolic phenotype of human hepatoma cell lines, driving steatosis and inflammation. Taken together, the observation that AKR1D1 mRNA is down-regulated with advancing NAFLD suggests that it may have a crucial role in the pathogenesis and progression of the disease.