tbuckley/cabot-search huggingface dataset:
Association Between Aging of the US Population and Heart Disease Mortality From 2011 to 2017
Authors: Stephen Sidney, Alan S. Go, Marc G. Jaffe, Matthew D. Solomon, Andrew P. Ambrosy, Jamal S. Rana
Journal: JAMA Cardiology (2019)

A deceleration in the rate of decrease of heart disease (HD) mortality between 2011 and 2014 has been reported. In the context of the rapid increase in the population of adults aged 65 years and older, extending the examination of HD mortality through 2017 has potentially important implications for public health and medical care.To examine changes in the age-adjusted mortality rate and the number of deaths within subcategories of HD from 2011 to 2017 in conjunction with the change in the size of the US population during the same period.In this quality improvement study, the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) data set was used to identify national changes in the US population aged 65 years and older and in the age-adjusted mortality rates and number of deaths that were listed with an underlying cause of HD, coronary heart disease (CHD), heart failure, and other HDs from January 1, 2011, to December 31, 2017.Changes from 2011 to 2017 in the US population and in age-adjusted mortality rates and number of deaths that were listed with an underlying cause of HD, CHD, heart failure (both as an underlying and a contributing cause), and other HDs overall, by sex and race/ethnicity.The total size of this population of US adults aged 65 years and older increased 22.9% from 41.4 million to 50.9 million between January 1, 2011, and December 31, 2017, while the population of adults younger than 65 years increased by only 1.7%. During this period, the age-adjusted mortality rate decreased 5.0% for HD and 14.9% for CHD while increasing 20.7% for heart failure and 8.4% for other HDs. The number of deaths increased 8.5% for HD, 38.0% for heart failure, and 23.4% for other HDs while decreasing 2.5% for CHD. A total of 80% of HD deaths occurred in the group of adults aged 65 years and older.The substantial increase in the growth rate of the group of adults aged 65 years and older who have the highest risk of HD was associated with an increase in the number of HD deaths in this group despite a slowly declining HD mortality rate in the general population. With the number of adults aged 65 years and older projected to increase an additional 44% from 2017 to 2030, innovative and effective approaches to prevent and treat HD, particularly the substantially increasing rates of heart failure, are needed.
Inhibition of mitochondrial translation overcomes venetoclax resistance in AML through activation of the integrated stress response
Authors: David Sharon, Severine Cathelin, Sara Mirali, Justin M. Di Trani, David J. Yanofsky, Kristine A. Keon, John L. Rubinstein, Aaron D. Schimmer, Troy Ketela, Steven M. Chan
Journal: Science Translational Medicine (2019)

Venetoclax is a specific B cell lymphoma 2 (BCL-2) inhibitor with promising activity against acute myeloid leukemia (AML), but its clinical efficacy as a single agent or in combination with hypomethylating agents (HMAs), such as azacitidine, is hampered by intrinsic and acquired resistance. Here, we performed a genome-wide CRISPR knockout screen and found that inactivation of genes involved in mitochondrial translation restored sensitivity to venetoclax in resistant AML cells. Pharmacologic inhibition of mitochondrial protein synthesis with antibiotics that target the ribosome, including tedizolid and doxycycline, effectively overcame venetoclax resistance. Mechanistic studies showed that both tedizolid and venetoclax suppressed mitochondrial respiration, with the latter demonstrating inhibitory activity against complex I [nicotinamide adenine dinucleotide plus hydrogen (NADH) dehydrogenase] of the electron transport chain (ETC). The drugs cooperated to activate a heightened integrated stress response (ISR), which, in turn, suppressed glycolytic capacity, resulting in adenosine triphosphate (ATP) depletion and subsequent cell death. Combination treatment with tedizolid and venetoclax was superior to either agent alone in reducing leukemic burden in mice engrafted with treatment-resistant human AML. The addition of tedizolid to azacitidine and venetoclax further enhanced the killing of resistant AML cells in vitro and in vivo. Our findings demonstrate that inhibition of mitochondrial translation is an effective approach to overcoming venetoclax resistance and provide a rationale for combining tedizolid, azacitidine, and venetoclax as a triplet therapy for AML.
How We Know What Not To Think
Authors: Jonathan Phillips, Adam Morris, Fiery Cushman
Journal: Trends in Cognitive Sciences (2019)

Humans often represent and reason about unrealized possible actions - the vast infinity of things that were not (or have not yet been) chosen. This capacity is central to the most impressive of human abilities: causal reasoning, planning, linguistic communication, moral judgment, etc. Nevertheless, how do we select possible actions that are worth considering from the infinity of unrealized actions that are better left ignored? We review research across the cognitive sciences, and find that the possible actions considered by default are those that are both likely to occur and generally valuable. We then offer a unified theory of why. We propose that (i) across diverse cognitive tasks, the possible actions we consider are biased towards those of general practical utility, and (ii) a plausible primary function for this mechanism resides in decision making.
P1.20 Metabolic Responses to Metformin in Early-Stage NSCLC Treated with Definitive Radiotherapy: Results of a Phase II Trial
Authors: S. Chun, Z. Liao, M. Jeter, J. Chang, S. Lin, R. Komaki, T. Guerrero, R. Mayo, B. Korah, S. Koshy, J. Heymach, A. Koong, H. Skinner
Journal: Journal of Thoracic Oncology (2019)
A 44 year old woman with episodic sweating and hypertension
Authors: Mehdi Mirzazadeh, Ehsan Alijani, Mahdieh Fani, Shahin Jamili
Journal: BMJ (2019)

A 44 year old woman with hypertension and type 2 diabetes (treated with insulin) presented with recurrent 10-15 minute episodes of sweating, tachycardia with regular pulse (110-120 beats/minute), pallor, and occasional increase in blood pressure (from ~130/90 mmHg to ~175/120). These episodes happened two to three times a week over eight months.

Glucose readings during these episodes were always greater than 8 mmol/L, ruling out hypoglycaemia.

Her medications included doxazosin, metformin, and insulin. She had a body mass index of 32 kg/m2. Physical examination, baseline blood tests, and renal artery doppler were normal.

Further investigations were carried out as outlined …
The use of micelles to deliver potential hedgehog pathway inhibitor for the treatment of liver fibrosis
Authors: Virender Kumar, Yuxiang Dong, Vinod Kumar, Saud Almawash, Ram I Mahato
Journal: Theranostics (2019)

Rationale: Hedgehog (Hh) pathway plays an essential role in liver fibrosis by promoting the proliferation of hepatic stellate cells (HSCs) by enhancing their metabolism via yes-associated protein 1 (YAP1). Despite the presence of several inhibitors, Hh signaling cannot be controlled exclusively due to their poor efficacy and the lack of a suitable delivery system to the injury site. Therefore, it is rationale to develop new potent Hh inhibitors and suitable delivery carriers. Methods: Based on the structure and activity of Hh inhibitor GDC-0449, we replaced its sulfonamide group with two methylpyridine-2yl at amide nitrogen to synthesize MDB5. We compared the Hh pathway inhibition and anti-fibrotic effect of MDB5 with GDC-0449 in vitro. Next, we developed MDB5 loaded micelles using our methoxy poly(ethylene glycol)-blockpoly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol (PEG-PCC-g-DC) copolymer and characterized for physicochemical properties. We evaluated the therapeutic efficacy of MDB5 loaded micelles in common bile duct ligation (CBDL) induced liver fibrosis, mouse model. We also determined the intrahepatic distribution of fluorescently labeled micelles after MDB5 treatment. Results: Our results show that MDB5 was more potent in inhibiting Hh pathway components and HSC proliferation in vitro. We successfully developed MDB5 loaded micelles with particle size of 40 ± 10 nm and drug loading up to 10% w/w. MDB5 loaded micelles at the dose of 10 mg/kg were well tolerated by mice, without visible sign of toxicity. The serum enzyme activities elevated by CBDL was significantly decreased by MDB5 loaded micelles compared to GDC-0449 loaded micelles. MDB5 loaded micelles further decreased collagen deposition, HSC activation, and Hh activity and its target genes in the liver. MDB5 loaded micelles also prevented liver sinusoidal endothelial capillarization (LSEC) and therefore restored perfusion between blood and liver cells. Conclusions: Our study provides evidence that MDB5 was more potent in inhibiting Hh pathway in HSC-T6 cells and showed better hepatoprotection in CBDL mice compared to GDC-0449.
A self-enforcing HOXA11/Stat3 feedback loop promotes stemness properties and peritoneal metastasis in gastric cancer cells
Authors: Chao Wang, Min Shi, Jun Ji, Qu Cai, Jinling Jiang, Huan Zhang, Zhenggang Zhu, Jun Zhang
Journal: Theranostics (2019)

Rationale: Peritoneal metastasis is one of the most common and life-threatening metastases in gastric cancer patients. The disseminated gastric cancer cells forming peritoneal metastasis exhibit a variety of characteristics that contrast with those of adjacent epithelial cell of gastric mucosa and even primary gastric cancer cells. We hypothesized that the gene expression profiles of peritoneal foci could reveal the identities of genes that might function as metastatic activator. Methods: In this study, we show, using in vitro, in vivo, in silico and gastric cancer tissues studies in humans and mice, that Homoebox A11 (HOXA11) potently promote peritoneal metastasis of gastric cancer cells. Results: Its mechanism of action involves alternation of cancer stemness and subsequently enhancement of the adhesion, migration and invasion and anti-apoptosis. This is achieved, mainly, through formation of a positive feedback loop between HOXA11 and Stat3, which is involved in the stimulation of Stat3 signaling pathway. Conclusions: These observations uncover a novel peritoneal metastatic activator and demonstrate the association between HOXA11, Stat3 and cancer stemness of gastric cancer cells, thereby revealing a previously undescribed mechanism of peritoneal metastasis.
P1.14 Immune Profiling Data and Mutational Status Improves Prediction of Risk of Death in Non-Small Cell Lung Carcinoma
Authors: E. Parra, M. Jang, J. Machado-Rugolo, C. Farhat, M. Nagai, T. Takagaki, R. Terra, A. Fabro, V. Capelozzi
Journal: Journal of Thoracic Oncology (2019)
International prognostic scoring system for mastocytosis (IPSM): a retrospective cohort study
Authors: Wolfgang R Sperr, Michael Kundi, Ivan Alvarez-Twose, Bjorn van Anrooij, Joanna N G Oude Elberink, Aleksandra Gorska, Marek Niedoszytko, Karoline V Gleixner, Emir Hadzijusufovic, Roberta Zanotti, Patrizia Bonadonna, Massimiliano Bonifacio, Cecelia Perkins, Anja Illerhaus, Chiara Elena, Serena Merante, Khalid Shoumariyeh, Nikolas von Bubnoff, Roberta Parente, Mohamad Jawhar, Anna Belloni Fortina, Francesca Caroppo, Knut Brockow, Alexander Zink, David Fuchs, Alex J Kilbertus, Akif Selim Yavuz, Michael Doubek, Hans Hägglund, Jens Panse, Vito Sabato, Agnes Bretterklieber, Dietger Niederwieser, Christine Breynaert, Karin Hartmann, Massimo Triggiani, Boguslaw Nedoszytko, Andreas Reiter, Alberto Orfao, Olivier Hermine, Jason Gotlib, Michel Arock, Hanneke C Kluin-Nelemans, Peter Valent
Journal: The Lancet Haematology (2019)
Drug-Resistant <i>E. coli</i> Bacteremia Transmitted by Fecal Microbiota Transplant
Authors: Zachariah DeFilipp, Patricia P. Bloom, Mariam Torres Soto, Michael K. Mansour, Mohamad R.A. Sater, Miriam H. Huntley, Sarah Turbett, Raymond T. Chung, Yi-Bin Chen, Elizabeth L. Hohmann
Journal: New England Journal of Medicine (2019)

Fecal microbiota transplantation (FMT) is an emerging therapy for recurrent or refractory Clostridioides difficile infection and is being actively investigated for other conditions. We describe two patients in whom extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli bacteremia occurred after they had undergone FMT in two independent clinical trials; both cases were linked to the same stool donor by means of genomic sequencing. One of the patients died. Enhanced donor screening to limit the transmission of microorganisms that could lead to adverse infectious events and continued vigilance to define the benefits and risks of FMT across different patient populations are warranted.
A Novel, Small Non-Peptidyl Butyzamide Activates Human Thrombopoietin Receptor and Promotes Megakaryopoiesis.
Authors: Wataru Nogami, Hiroshi Yoshida, Kenzo Koizumi, Hajime Yamada, Kenji Abe, Akinori Arimura, Noriko Yamane, Koji Takahashi, Yoshikazu Tanaka, Akiko Yamane, Hiroshi Takemoto, Yasuyuki Ohnishi, Yasuo Ikeda, Yoshitaka Miyakawa
Journal: Blood (2007)
Moving the Needle Forward With Locoregional Treatment in Unresectable Cholangiocarcinoma—The Jury Is Still Out
Authors: Aaron J. Scott, Rachna T. Shroff
Journal: JAMA Oncology (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 Oncology HomeNew OnlineCurrent IssueFor Authors Podcast 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 Oncology journal
Metabolic reprogramming associated with aggressiveness occurs in the G-CIMP-high molecular subtypes of IDH1mut lower grade gliomas
Authors: Victor Ruiz-Rodado, Tathiane M Malta, Tomohiro Seki, Adrian Lita, Tyrone Dowdy, Orieta Celiku, Alejandra Cavazos-Saldana, Aiguo Li, Yang Liu, Sue Han, Wei Zhang, Hua Song, Dionne Davis, Sunmin Lee, Jane B Trepel, Thais S Sabedot, Jeeva Munasinghe, Chunzhang Yang, Christel Herold-Mende, Mark R Gilbert, Murali Krishna Cherukuri, Houtan Noushmehr, Mioara Larion
Journal: Neuro-Oncology (2019)

Abstract Background Early detection of increased aggressiveness of brain tumors is a major challenge in the field of neuro-oncology because of the inability of traditional imaging to uncover it. Isocitrate dehydrogenase (IDH)-mutant gliomas represent an ideal model system to study the molecular mechanisms associated with tumorigenicity because they appear indolent and non-glycolytic initially, but eventually a subset progresses toward secondary glioblastoma with a Warburg-like phenotype. The mechanisms and molecular features associated with this transformation are poorly understood. Methods We employed model systems for IDH1 mutant (IDH1mut) gliomas with different growth and proliferation rates in vivo and in vitro. We described the metabolome, transcriptome, and epigenome of these models in order to understand the link between their metabolism and the tumor biology. To verify whether this metabolic reprogramming occurs in the clinic, we analyzed data from The Cancer Genome Atlas. Results We reveal that the aggressive glioma models have lost DNA methylation in the promoters of glycolytic enzymes, especially lactate dehydrogenase A (LDHA), and have increased mRNA and metabolite levels compared with the indolent model. We find that the acquisition of the high glycolytic phenotype occurs at the glioma cytosine-phosphate-guanine island methylator phenotype (G-CIMP)-high molecular subtype in patients and is associated with the worst outcome. Conclusion We propose very early monitoring of lactate levels as a biomarker of metabolic reprogramming and tumor aggressiveness.
Dysgerminoma of the ovary 35 years on: A single institutional experience
Authors: D. Vicus, M. Beiner, S. Klachook, L. Le, O. Ginsburg, S. Laframboise, H. Mackay
Journal: Journal of Clinical Oncology (2009)

e16523 Background: Ovarian dysgerminomas are rare but are relatively more common in women under 20 years of age in whom fertility is likely to be an issue. The aim of this study was to review our institutional experience in treating patients (pts) diagnosed with pure dysgerminoma. Methods: We performed a retrospective chart review of all pts diagnosed with ovarian dysgerminoma at the Princess Margaret Hospital, Toronto, between 1970 and 2005. Results: 65 pts were diagnosed with ovarian dysgerminoma, median age 21.9 years (range 8.1–64.1 yrs). 40 pts (62.5%) presented with FIGO stage IA disease; 3 (4.7%) stage IB; 6 (9.4%) stage IC; 2 (3.1%) stage II; and 13 (20.3%) at stage III, 1 unknown. Initial management was surgical for all pts: unilateral oopherectomy 47 pts (72.2%), 14 (21.5%) bilateral oophorectomy ± hysterectomy (12 pts), 3 (4.6%) cystectomy alone. 17 pts received chemotherapy, 15 adjuvant and 2 for residual disease (all post 1988); 8 for stage I, 1 for stage II, and 8 for stage III. 12 pts received etoposide and cisplatin (EP); 4 bleomycin, etoposide, and cisplatin (BEP); and 1 vincristine and cisplatin. 20 pts received adjuvant radiotherapy (all prior to 1985); 14 stage I; 1 stage II; and 5 stage III. 1 pt received a combination of adjuvant chemotherapy and radiation. 6 (9.2%) pts recurred all within 19 months of initial diagnosis. 5 of the 6 pts that recurred had stage IA disease treated with a unilateral oophorectomy, 1 received adjuvant EP. 1 pt with stage IIIC disease recurred following bilateral oophorectomy + hysterectomy and radiotherapy. Treatment of recurrent disease was by salvage surgery and chemotherapy (3 pts), radiotherapy (2 pts), and EP (1 pt). All pts who recurred responded to treatment and were alive at last follow up, median follow up 22.5 yrs (range 9.3–31.4 yrs). Median follow up, all pts, was 10.5 yrs (range 1.1 to 31.9 yrs). 15 pts attempted to conceive posttreatment; 6 had received adjuvant treatment; 4 EP; and 2 whole abdominal radiotherapy. 13 successful pregnancies and 13 live births were reported in 9 women (3 had received adjuvant EP). Conclusions: The long-term outcome of patients with an ovarian dysgerminoma is excellent. Recurrences occured within 2 years of diagnosis and are treatable. Patients can be treated with fertility sparing surgery and can expect good reproductive outcomes. No significant financial relationships to disclose.
Dapagliflozin: A Review in Type 1 Diabetes
Authors: Julia Paik, Hannah A. Blair
Journal: Drugs (2019)

Oral dapagliflozin (Edistride®, Forxiga®) is approved in the EU at a dosage of 5 mg/day as an adjunct to insulin in adults with type 1 diabetes (T1D) and a body mass index (BMI) of ≥ 27 kg/m2, when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy. As a highly selective SGLT2 inhibitor, dapagliflozin decreases plasma glucose levels independently of insulin action and enables glycaemic control improvement without increasing the risks associated with intensive insulin therapy. In the phase III DEPICT-1 and -2 trials, dapagliflozin 5 mg/day as an adjunct to insulin improved glycaemic control and reduced total daily insulin dose and bodyweight relative to placebo in adults with inadequately controlled T1D, including in patients with a BMI of ≥ 27 kg/m2, over 24 weeks of treatment. In extensions of these trials, these improvements were maintained up to 52 weeks. Dapagliflozin was generally well tolerated with a manageable safety profile and a hypoglycaemia profile generally similar to placebo. The incidence of diabetic ketoacidosis with dapagliflozin in patients with a BMI ≥ 27 kg/m2 was less than half that of the overall population who received dapagliflozin. Dapagliflozin is the first SGLT2 inhibitor to be approved for use in T1D and, while further clinical experience in T1D is required to more definitively establish its efficacy and safety profile, it provides a promising adjunctive treatment option for adults with T1D and a BMI of ≥ 27 kg/m2, when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy.
Mediators of the Effects of Canagliflozin on Heart Failure in Patients With Type 2 Diabetes
Authors: JingWei Li, Mark Woodward, Vlado Perkovic, Gemma A. Figtree, Hiddo J.L. Heerspink, Kenneth W. Mahaffey, Dick de Zeeuw, Frank Vercruysse, Wayne Shaw, David R. Matthews, Bruce Neal
Journal: JACC Heart Failure (2019)

The purpose of this study was to explore potential mediators of the effects of canagliflozin on heart failure in the CANVAS Program (CANagliflozin cardioVascular Assessment Study; NCT01032629 and CANagliflozin cardioVascular Assessment Study-Renal; NCT01989754).Canagliflozin reduced the risk of heart failure among patients with type 2 diabetes in the CANVAS Program. The mechanism of protection is uncertain.The percentages of mediating effects of 19 biomarkers were determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the biomarker of interest. Multivariable analyses were used to assess the joint effects of biomarkers that mediated most strongly in univariable analyses.Early changes after randomization in levels of 3 biomarkers (urinary albumin:creatinine ratio, serum bicarbonate, and serum urate) were identified as mediating the effect of canagliflozin on heart failure. Average post-randomization levels of 14 biomarkers (systolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol, total cholesterol, urinary albumin:creatinine ratio, weight, body mass index, gamma glutamyltransferase, hematocrit, hemoglobin concentration, serum albumin, erythrocyte concentration, serum bicarbonate, and serum urate) were identified as significant mediators. Individually, the 3 biomarkers with the largest mediating effect were erythrocyte concentration (45%), hemoglobin concentration (43%), and serum urate (40%). In a parsimonious multivariable model, erythrocyte concentration, serum urate, and urinary albumin:creatinine ratio were the 3 biomarkers that maximized cumulative mediation (102%).A diverse set of potential mediators of the effect of canagliflozin on heart failure were identified. Some mediating effects were anticipated, whereas others were not. The mediators that were identified support existing and novel hypothesized mechanisms for the prevention of heart failure with sodium glucose cotransporter 2 inhibitors.