tbuckley/cabot-search huggingface dataset:
Abstract 11133: Endogenous Ketone Bodies Have Cardioprotective Effects in Obesity Related Heart Failure with Preserved Ejection Fraction
Authors: Toshihiro Yamada, Toshifumi Ishida, Xu Yuquing, Seiji Takashio, Shinsuke Hanatani, Satoshi Araki, Eiichiro Yamamoto, Taishi Nakamura, Kenichi Matsushita, Koichi Nishiyama, Yuichiro Arima, Kenichi Tsujita
Journal: Circulation (2021)

We recently developed a murine model of insufficient ketogenesis by disrupting the rate-limiting enzyme of ketogenesis, HMG-CoA synthase 2 ( Hmgcs2 -/- ; Keto-less mice), and reported a mitochondrial protection by ketone body metabolism (Arima. et. al., Nature Metabolism 2021). While new evidence has suggested a cardiovascular-protective role by ketone bodies, the precise impact of ketone bodies on heart failure remains unknown. Using our new model in this study, we aimed to elucidate the role of ketone bodies in heart failure. We first generated a pressure-overload model using transverse aortic constriction and compared keto-less mice with wild-type mice. While Keto-less mice showed a tendency for increased cardiomyocytes size, there was no significant difference in mortality and heart weight. Our previous report revealed that fatty acid overload enhances ketogenesis. Therefore, we employed a dietary heart failure mouse model with preserved ejection fraction (HFpEF) using a high-fat diet and Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME). The HFpEF model confirmed increased ketogenesis and hyperacetylation of mitochondrial protein. We then tested the impact of ketone bodies by using hepatic-specific keto-less mice. Hepatic keto-less mice showed significantly decreased ketone body concentration, but did not show significant changes in body weight and blood pressure. However, cardiomyocyte hypertrophy was exacerbated in the HFpEF model with hepatic specific keto-less mice compared to wild-type mice (WT 325±90um2; hKL 402±110um2, p&lt;0.0001). We examined the multifaceted effects of the ketone body, and addressed a significant reduction in sequential enzymatic reactions in the TCA cycle.These data suggested that ketone bodies have a protective role against heart failure by modulating cardiomyocyte energetics.
Systematic Profiling of <i>DNMT3A</i> Variants Reveals Protein Instability Mediated by the DCAF8 E3 Ubiquitin Ligase Adaptor
Authors: Yung-Hsin Huang, Chun-Wei Chen, Venkatasubramaniam Sundaramurthy, Mikołaj Słabicki, Dapeng Hao, Caroline J. Watson, Ayala Tovy, Jaime M. Reyes, Olga Dakhova, Brielle R. Crovetti, Christina Galonska, Minjung Lee, Lorenzo Brunetti, Yubin Zhou, Katrina Tatton-Brown, Yun Huang, Xiaodong Cheng, Alexander Meissner, Peter J.M. Valk, Lionel Van Maldergem, Mathijs A. Sanders, Jamie R. Blundell, Wei Li, Benjamin L. Ebert, Margaret A. Goodell
Journal: Cancer Discovery (2021)

Clonal hematopoiesis is a prevalent age-related condition associated with a greatly increased risk of hematologic disease; mutations in DNA methyltransferase 3A (DNMT3A) are the most common driver of this state. DNMT3A variants occur across the gene with some particularly associated with malignancy, but the functional relevance and mechanisms of pathogenesis of the majority of mutations are unknown. Here, we systematically investigated the methyltransferase activity and protein stability of 253 disease-associated DNMT3A mutations, and found that 74% were loss-of-function mutations. Half of these variants exhibited reduced protein stability and, as a class, correlated with greater clonal expansion and acute myeloid leukemia development. We investigated the mechanisms underlying the instability using a CRISPR screen and uncovered regulated destruction of DNMT3A mediated by the DCAF8 E3 ubiquitin ligase adaptor. We establish a new paradigm to classify novel variants that has prognostic and potential therapeutic significance for patients with hematologic disease. SIGNIFICANCE: DNMT3A has emerged as the most important epigenetic regulator and tumor suppressor in the hematopoietic system. Our study represents a systematic and high-throughput method to characterize the molecular impact of DNMT3A missense mutations and the discovery of a regulated destruction mechanism of DNMT3A offering new prognostic and future therapeutic avenues.See related commentary by Ma and Will, p. 23.This article is highlighted in the In This Issue feature, p. 1.
Impact of Pain on Employment and Financial Outcomes Among Cancer Survivors
Authors: Michael T. Halpern, Janet S. de Moor, K. Robin Yabroff
Journal: Journal of Clinical Oncology (2021)

PURPOSE Although pain is a frequently reported symptom among individuals with cancer, there is limited information on the impact of pain on employment or financial outcomes. This study used nationally representative data to examine the role of pain levels on employment and financial outcomes. METHODS We used data from the 2016-2017 Medical Expenditure Panel Survey Experiences with Cancer Survivorship Supplement to identify 1,213 adults diagnosed with cancer. Multivariable logistic regression analyses were used to examine association of pain levels and self-reported employment and financial outcomes. RESULTS Approximately 43% of adults with a cancer history reported no pain, 29% mild pain, 18% moderate pain, and 10% severe pain over the past 7 days. Compared with those reporting no pain, individuals reporting any pain had significantly increased likelihood of adverse employment outcomes including early retirement, feeling less productive, and staying at a job because of concerns about losing insurance. Individuals with any pain (compared with no pain) also had significantly increased likelihood of adverse financial outcomes including borrowing money or going into debt, inability to cover medical costs, and worrying about paying medical bills. For both employment and financial outcomes, there were dose-response relationships, with worse outcomes generally associated with greater pain levels. CONCLUSION Pain is frequently associated with adverse employment and financial outcomes among cancer survivors, and greater pain is associated with worse outcomes. Better assessment of pain severity among survivors and implementation of strategies to assist with employment and financial objectives may be important steps to enhance patient-centered care.
Progress in Transplants for Acute Lymphoblastic Leukemia
Authors: Robert Peter Gale
Journal: Clinical Cancer Research (2022)

Hematopoietic cell transplants are used to treat some adults with acute lymphoblastic leukemia, especially those with high-risk features, such as those with BCR::ABL1. This strategy may be changing given the safety and efficacy of modern tyrosine kinase inhibitors. Although these transplants are often successful, leukemia relapse remains the dominant cause of transplant failure. There are several approaches to this problem discussed by the authors of a recent article in the journal. The good news is therapy of recurrent leukemia posttransplant seems increasingly successful and for diverse reasons, survival is increasing substantially. See related article by Bazarbachi et al., p. 1004.
Sortilin restricts secretion of apolipoprotein B-100 by hepatocytes under stressed but not basal conditions
Authors: Donna M. Conlon, Carolin V. Schneider, Yi-An Ko, Amrith Rodrigues, Kathy Guo, Nicholas J. Hand, Daniel J. Rader
Journal: Journal of Clinical Investigation (2022)

Genetic variants at the SORT1 locus in humans, which cause increased SORT1 expression in the liver, are significantly associated with reduced plasma levels of LDL cholesterol and apolipoprotein B (apoB). However, the role of hepatic sortilin remains controversial, as genetic deletion of sortilin in mice has resulted in variable and conflicting effects on apoB secretion. Here, we found that Sort1-KO mice on a chow diet and several Sort1-deficient hepatocyte lines displayed no difference in apoB secretion. When these models were challenged with high-fat diet or ER stress, the loss of Sort1 expression resulted in a significant increase in apoB-100 secretion. Sort1-overexpression studies yielded reciprocal results. Importantly, carriers of SORT1 variant with diabetes had larger decreases in plasma apoB, TG, and VLDL and LDL particle number as compared with people without diabetes with the same variants. We conclude that, under basal nonstressed conditions, loss of sortilin has little effect on hepatocyte apoB secretion, whereas, in the setting of lipid loading or ER stress, sortilin deficiency leads to increased apoB secretion. These results are consistent with the directionality of effect in human genetics studies and suggest that, under stress conditions, hepatic sortilin directs apoB toward lysosomal degradation rather than secretion, potentially serving as a quality control step in the apoB secretion pathway in hepatocytes.
Subacute Cerebral Infarction With Accumulation of 99mTc-TRODAT in the Parkinson Disease Patient
Authors: Chun-Hao Kao, Chuang-Hsin Chiu
Journal: Clinical Nuclear Medicine (2021)

Abstract We report the accumulation of 99m Tc-TRODAT-1 in the region of subacute cerebral ischemic infarction in an 81-year-old woman with Parkinson disease. The dopamine transporter SPECT imaging was performed on the 15th day after the onset of acute cerebral ischemic clinical symptoms. Overexpression of dopamine transporters after infarction in subacute phase may explain the accumulation.
Risk Factors Associated with Durable Progression-Free Survival in Patients with Relapsed or Refractory Multiple Myeloma Treated with Anti-BCMA CAR T-cell Therapy
Authors: Mingming Zhang, Linghui Zhou, Houli Zhao, Yanlei Zhang, Guoqing Wei, Ruimin Hong, Wenjun Wu, Huijun Xu, Linqin Wang, Fang Ni, Jiazhen Cui, Shuixiu Peng, Chih-Hua Huang, Alex H. Chang, Yongxian Hu, He Huang
Journal: Clinical Cancer Research (2021)

Abstract Purpose: B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy results in high remission rates in patients with relapsed/refractory (R/R) multiple myeloma. However, the factors associated with prognosis following CAR T-cell therapy are unknown. Patients and Methods: Between July 1, 2018 and July 31, 2020, 61 patients with R/R multiple myeloma received anti-BCMA CAR T-cell therapy (Chictr.org number, ChiCTR1800017404). Step-wise multivariate Cox regression and competing risk analyses were conducted to identify poor prognosis–associated risk factors. Results: Sixty patients (98.4%) experienced cytokine release syndrome (CRS), including 33, 23, and 4 cases of CRS grades 1 to 2, 3, and 4, respectively. The objective response rate (ORR) was 98.3%, and the complete remission (CR) rate was 70.3%. With a median follow-up period of 21.1 months, the 1-year overall survival (OS) and progression-free survival (PFS) rates were 78.0% and 50.2%, respectively. The median PFS was 12.7 months. Cox modeling revealed that poor PFS was associated with extramedullary disease [HR = 2.59, 95% confidence interval (95% CI) = 1.29–5.21, P = 0.008], light chain multiple myeloma (HR = 2.53, 95% CI = 1.03–5.97, P = 0.035), high-risk cytogenetics (HR = 2.80, 95% CI = 1.27–6.14, P = 0.01), and prior treatment with more than 3 therapeutic lines (HR = 3.14, 95% CI = 1.34–7.34, P = 0.008). Among the 41 CR cases, competing risk analyses demonstrated higher relapse predispositions in those with extramedullary disease (HR = 4.51, 95% CI = 1.86–10.9, P = 0.001), light chain multiple myeloma (HR = 4.89, 95% CI = 1.52 – 15.7, P = 0.008), or high-risk cytogenetics (HR = 5.09, 95% CI = 1.63–15.9, P = 0.005). Conclusions: Anti-BCMA CAR T-cell therapy is safe and effective for R/R multiple myeloma. For patients with high-risk factors, improvements to extend remission and more specific individualized therapies are needed.
The TAZ-CAMTA1 Fusion Protein Promotes Tumorigenesis via Connective Tissue Growth Factor and Ras–MAPK Signaling in Epithelioid Hemangioendothelioma
Authors: Shuang Ma, Ryan Kanai, Ajaybabu V. Pobbati, Shuo Li, Kepeng Che, Caleb N. Seavey, Andrea Hallett, Ashley Burtscher, John M. Lamar, Brian P. Rubin
Journal: Clinical Cancer Research (2022)

Abstract Purpose: A consistent genetic alteration in vascular cancer epithelioid hemangioendothelioma (EHE) is the t(1;3)(p36;q25) chromosomal translocation, which generates a WWTR1(TAZ)-CAMTA1 (TC) fusion gene. TC is a transcriptional coactivator that drives EHE. Here, we aimed to identify the TC transcriptional targets and signaling mechanisms that underlie EHE tumorigenesis. Experimental Design: We used NIH3T3 cells transformed with TC (NIH3T3/TC) as a model system to uncover TC-dependent oncogenic signaling. These cells proliferated in an anchorage-independent manner in suspension and soft agar. The findings of the cell-based studies were validated in a xenograft model. Results: We identified connective tissue growth factor (CTGF) as a tumorigenic transcriptional target of TC. We show that CTGF binds to integrin αIIbβ3, which is essential for sustaining the anchorage-independent proliferation of transformed NIH3T3/TC cells. NIH3T3/TC cells also have enhanced Ras and MAPK signaling, and the activity of these pathways is reduced upon CTGF knockdown, suggesting that CTGF signaling occurs via the Ras-MAPK cascade. Further, pharmacologic inhibition of MAPK signaling through PD 0325901 and trametinib abrogated TC-driven anchorage-independent growth. Likewise, for tumor growth in vivo, NIH3T3/TC cells require CTGF and MAPK signaling. NIH3T3/TC xenograft growth was profoundly reduced upon CTGF knockdown and after trametinib treatment. Conclusions: Collectively, our results demonstrated that CTGF and the Ras-MAPK signaling cascade are essential for TC-mediated tumorigenesis. These studies provided the preclinical rationale for SARC033 (NCI 10015-NCT03148275), a nonrandomized, open-label, phase II study of trametinib in patients with unresectable or metastatic EHE.
Abstract MP62: Sex-specific Associations Of Vascular Risk Factors And Brain Mri Measures In The Framingham Offspring
Authors: Rodica E Petrea, Daniel Kojis, Matthew R Scott, Alexa S Beiser, Jose R Romero, Charles De Carli, Sudha Seshadri
Journal: Circulation (2022)

Aim: To examine if the associations between vascular risk factors (VRF) and brain MRI measures of brain aging and cerebral small vessel disease are different in men and women. Background: Men and women differ in their propensity to develop stroke and this is reflected in sex-specific versions of the widely used Framingham Stroke Risk Prediction (FSRP) index, that provides an estimate of 10-year risk of incident clinical stroke. However, sex-specific associations between the individual risk factor components of FSRP and subclinical vascular brain injury have not been previously explored in our data. Methods/Design: We related levels of blood pressure, diabetes, current smoking and prevalent non-stroke cardiovascular disease (CVD) to brain MRI measures of total cerebral brain, hippocampal and white matter hyperintensity volumes (TCBV, HPV, WMHV) and covert brain infarcts (CBI) in 1,579 stroke- and dementia-free Framingham Offspring who attended their 8th quadrennial examination (53% F; age 66±9 years). We examined age-adjusted, sex-stratified linear or logistic regression analyses for all VRF that suggested a sex-interaction at a p&lt;0.1. Results: Higher blood pressure (assessed as systolic blood pressure (SBP) or as JNC7 defined Stage 1 HTN (≥140/90 mm Hg or use of antihypertensive medication), had a greater adverse impact on WMHV in women compared to men (SBP: β±SE: 0.009±0.002, p&lt;0.001 versus 0.004±0.002, p&lt;0.031; HTN: β 0.176±0.066, p=0.008 versus non-significant association, in women and men respectively), although prevalent CVD, reflecting lifetime vascular risk factor exposure and injury, had a larger adverse effect on WMHV in men (β -0.221±0.087, p=0.012, versus a non-significant association in women). In addition, both Stage 1 HTN and diabetes had larger adverse effects on TCBV in men (β -0.309±0.141, p&lt;0.029 and -0.853±0.177, p&lt;0.001 respectively, versus non-significant associations in women). Conclusions: In our cohort of young-old participants, wherein most women were post-menopausal, current levels of VRF at the time of examination, were associated with a greater burden of vascular brain injury in women than in men of the same age, whereas current VRF levels appeared to have a greater global impact on brain volumes in men. Our data suggest that the greater risk of dementia noted in older women compared to men may be substantially attributable to modifiable vascular risk factors; more aggressively controlling these in women may reduce sex disparities.
DNMT3A-dependent DNA methylation is required for spermatogonial stem cells to commit to spermatogenesis
Authors: Mathilde Dura, Aurélie Teissandier, Mélanie Armand, Joan Barau, Clémentine Lapoujade, Pierre Fouchet, Lorraine Bonneville, Mathieu Schulz, Michael Weber, Laura G. Baudrin, Sonia Lameiras, Deborah Bourc’his
Journal: Nature Genetics (2022)
First-In-Human Phase I Study of a Next-Generation, Oral, TGFβ Receptor 1 Inhibitor, LY3200882, in Patients with Advanced Cancer
Authors: Timothy A. Yap, Maria Vieito, Capucine Baldini, Juan Manuel Sepúlveda-Sánchez, Shunsuke Kondo, Matteo Simonelli, Rasha Cosman, Andre van der Westhuizen, Victoria Atkinson, Antoine F. Carpentier, Mario Löhr, Rebecca Redman, Warren Mason, Andres Cervantes, Emilie Le Rhun, Sebastian Ochsenreither, Louise Warren, Yumin Zhao, Sophie Callies, Shawn T. Estrem, Michael Man, Leena Gandhi, Emin Avsar, Davide Melisi
Journal: Clinical Cancer Research (2021)

A novel, selective, next-generation transforming growth factor beta (TGFβ) receptor type-1 small molecule inhibitor, LY3200882, demonstrated promising preclinical data. This first-in-human trial evaluated safety, tolerability, recommended phase II dose (RP2D), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of LY3200882 as monotherapy or with other anticancer agents in patients with advanced cancer. This phase I multicenter study of oral LY3200882 (NCT02937272) comprised dose escalation, monotherapy expansion in grade 4 glioma, and combination therapy in solid tumors (LY3200882 and PD-L1 inhibitor LY3300054), pancreatic cancer (LY3200882, gemcitabine, and nab-paclitaxel), and head and neck squamous cell cancer (LY3200882, cisplatin, and radiation). Overall, 139 patients with advanced cancer were treated. The majority (93.5%) of patients experienced ≥1 treatment-emergent adverse events (TEAE), with 39.6% LY3200882-related. Grade 3 LY3200882-related toxicities were only observed in combination therapy arms. One patient in the pancreatic cancer arm experienced cardiovascular toxicity. The LY3200882 monotherapy RP2Ds were established in two schedules: 50 mg twice a day 2-weeks-on/2-weeks-off and 35 mg twice a day 3-weeks-on/1-week-off. Four patients with grade 4 glioma had durable Revised Assessment in Neuro Oncology (RANO) partial responses (PR) with LY3200882 monotherapy (n = 3) or LY3200882-LY3300054 combination therapy (n = 1). In treatment-naïve patients with advanced pancreatic cancer, 6 of 12 patients achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 PR and 3 of 12 patients demonstrated stable disease, for an overall 75% disease-control rate with the combination of LY3200882, gemcitabine, and nab-paclitaxel. LY3200882 as monotherapy and combination therapy was safe and well tolerated with preliminary antitumor activity observed in pancreatic cancer. Further studies to evaluate the efficacy of LY3200882 with gemcitabine and nab-paclitaxel in advanced pancreatic cancer are warranted.
MIBG Uptake in a Gastric Gastrointestinal Stromal Tumor
Authors: Kun Zheng, Hongli Jing, Yimin Liu, Fang Li
Journal: Clinical Nuclear Medicine (2022)

Abstract MIBG scintigraphy is the imaging choice in the evaluation of pheochromocytoma and neuroblastoma. 131 I-MIBG uptake by gastrointestinal stromal tumors was rare. Here we report a case in which an increased 131 I-MIBG activity in an endoluminal gastric gastrointestinal stromal tumor was noted.
Immunogenicity and Safety of COVID-19 Vaccine BNT162b2 for Patients with Solid Cancer: A Large Cohort Prospective Study from a Single Institution
Authors: Vincenzo Di Noia, Fulvia Pimpinelli, Davide Renna, Vittoria Barberi, Maria Teresa Maccallini, Ludovica Gariazzo, Martina Pontone, Alessandro Monti, Flaminia Campo, Emanuela Taraborelli, Maria Di Santo, Fabrizio Petrone, Chiara Mandoj, Virginia Ferraresi, Gianluigi Ferretti, Paolo Carlini, Ornella Di Bella, Laura Conti, Antonia Marina La Malfa, Raul Pellini, Domenico Bracco, Diana Giannarelli, Aldo Morrone, Francesco Cognetti
Journal: Clinical Cancer Research (2021)

We assessed the immunogenicity and safety of the BNT162b2 vaccine in a large cohort of patients with cancer (CP).From March 1, 2021 to March 20, 2021, this prospective cohort study included 816 CP afferent to our institution and eligible for the vaccination. A cohort of 274 health care workers (HCW) was used as age- and sex-matched control group. BNT162b2 was administered as a two-dose regimen given 21 days apart. Blood samples to analyze anti-Spike (S) IgG antibodies (Ab) were collected prevaccination [timepoint (TP) 0], and at 3 weeks (TP1) and 7 weeks (TP2) after the first dose.Patients characteristics: median age 62 (range, 21-97); breast/lung cancer/others (31/21/48%); active treatment/follow-up (90/10%). In the whole CP cohort, the serologic response rate (RR) and the titre of anti-S IgG significantly increased across the TPs; at TP2, the responders (IgG >15 AU/mL) were 94.2%. Active chemotherapy and chronic use of steroids were independent predictors of lower RR. Adverse events (AE) after the booster predicted higher likelihood of response (OR, 4.04; 95% confidence interval, 1.63-9.99; P = 0.003). Comparing the matched cohorts, the responders were significantly lower in CP than in HCW at TP1 (61.2% vs. 93.2%) and TP2 (93.3% vs. 100%), while the geometric mean concentration of IgG did not significantly differ at TP2 being significantly lower in CP (23.3) than in HCW (52.1) at TP1. BNT162b2 was well tolerated in CP; severe-grade AEs were 3.5% and 1.3% after the first and second doses, respectively.BNT162b2 assures serologic immunization without clinically significant toxicity in CP. The second dose is needed to reach a satisfactory humoral response.
Changes in lung function in European adults born between 1884 and 1996 and implications for the diagnosis of lung disease: a cross-sectional analysis of ten population-based studies
Authors: James P Allinson, Shoaib Afzal, Yunus Çolak, Debbie Jarvis, Helena Backman, Maarten van den Berge, H Marike Boezen, Marie-Kathrin Breyer, Robab Breyer-Kohansal, Guy Brusselle, Otto C Burghuber, Rosa Faner, Sylvia Hartl, Lies Lahousse, Arnulf Langhammer, Bo Lundbäck, Bright I Nwaru, Eva Rönmark, Sigrid A Aalberg Vikjord, Judith M Vonk, Sara R A Wijnant, Peter Lange, Børge G Nordestgaard, Nuria Olvera, Alvar Agusti, Gavin C Donaldson, Jadwiga A Wedzicha, Jørgen Vestbo, Lowie E G W Vanfleteren
Journal: The Lancet Respiratory Medicine (2021)
Impact of booster vaccination on the control of COVID-19 Delta wave in the context of waning immunity: application to France in the winter 2021/22
Authors: Paolo Bosetti, Cécile Tran Kiem, Alessio Andronico, Juliette Paireau, Daniel Levy-Bruhl, Lise Alter, Arnaud Fontanet, Simon Cauchemez
Journal: Eurosurveillance (2022)

Europe has experienced a large COVID-19 wave caused by the Delta variant in winter 2021/22. Using mathematical models applied to Metropolitan France, we find that boosters administered to ≥ 65, ≥ 50 or ≥ 18 year-olds may reduce the hospitalisation peak by 25%, 36% and 43% respectively, with a delay of 5 months between second and third dose. A 10% reduction in transmission rates might further reduce it by 41%, indicating that even small increases in protective behaviours may be critical to mitigate the wave.