tbuckley/cabot-search huggingface dataset:
Antenatal screening for Down's syndrome.
Authors: E. S. Williams
Journal: BMJ (1992)

whole screened population the number of babies with Down's syndrome was 25.With Wald and colleagues' screening test, the number of Down's syndrome babies detected was 12.With screening by maternal age > 37 years alone, the number detected could have been 7 out of 25.These proportions are not significantly different (Fisher's exact test p=0-24; odds ratio 2-37; 95% confidence interval 0 73 to 7 68).Even with the different uptake of amniocentesis in the two groups-that is, 75% for all ages and 63% for those ¢ 37 years- there was still no significant difference in the result (p=0-2; odds ratio 2-95 (0 77 to 11-3)).Only 4 9% of women were aged ¢ 37 years; the confidential enquiries into maternal deaths in the United Kingdom 1985-7 reported that 8% of pregnant women were over 352 and in our hospital in 1991 the proportion ¢ 37 years was 9-2%.This proportion is likely to rise as women delay their families for personal and financial reasons, and as this proportion rises the detection rates from the triple test and from maternal age alone will become even more similar.In any particular district the cost of introducing this programme will depend on the proportion of women ¢ 37 years; in addition, many authorities (including our own) have now abandoned co fetoprotein testing, relying for neural tube defect screening on ultrasonography alone, and the cost of reintroducing this test would need to be accounted for in the calculations.
High-dose per Fraction Radiotherapy Induces Both Antitumor Immunity and Immunosuppressive Responses in Prostate Tumors
Authors: Lin Lin, Nathanael Kane, Naoko Kobayashi, Evelyn A. Kono, Joyce M. Yamashiro, Nicholas G. Nickols, Robert E. Reiter
Journal: Clinical Cancer Research (2020)

The use of high-dose per fraction radiotherapy delivered as stereotactic body radiotherapy is a standard of care for prostate cancer. It is hypothesized that high-dose radiotherapy may enhance or suppress tumor-reactive immunity. The objective of this study was to assess both antitumor and immunosuppressive effects induced by high-dose radiotherapy in prostate cancer coclinical models, and ultimately, to test whether a combination of radiotherapy with targeted immunotherapy can enhance antitumor immunity.We studied the effects of high-dose per fraction radiotherapy with and without anti-Gr-1 using syngeneic murine allograft prostate cancer models. The dynamic change of immune populations, including tumor-infiltrating lymphocytes (TIL), T regulatory cells (Treg), and myeloid-derived suppressive cells (MDSC), was evaluated using flow cytometry and IHC.Coclinical prostate cancer models demonstrated that high-dose per fraction radiotherapy induced a rapid increase of tumor-infiltrating MDSCs and a subsequent rise of CD8 TILs and circulating CD8 T effector memory cells. These radiation-induced CD8 TILs were more functionally potent than those from nonirradiated controls. While systemic depletion of MDSCs by anti-Gr-1 effectively prevented MDSC tumor infiltration, it did not enhance radiotherapy-induced antitumor immunity due to a compensatory expansion of Treg-mediated immune suppression.In allograft prostate cancer models, high-dose radiotherapy induced an early rise of MDSCs, followed by a transient increase of functionally active CD8 TILs. However, systemic depletion of MDSC did not augment the antitumor efficacy of high-dose radiotherapy due to a compensatory Treg response, indicating blocking both MDSCs and Tregs might be necessary to enhance radiotherapy-induced antitumor immunity.
Histone Deacetylase Inhibitors Mimic BET Inhibitors and Cause RNA Polymerase Pausing at MYC, KIT, and Other Oncogenes in t(8;21) AML
Authors: Pankaj Acharya, Shilpa Sampathi, Yue Zhao, Jing Wang, Qi Liu, Kristy Stengel, Scott Hiebert
Journal: Blood (2017)
Abstract 15938: B-type Natriuretic Peptide Levels Do Not Predict the Need for Mechanical Ventilation in Hospitalized Patients With COVID-19
Authors: Daniel perry, Tariq U Azam, Husam Shadid, Michael Pan, Hannah Berlin, Chelsea Meloche, Rafey Feroze, Jeff Leya, Patrick O'Hayer, Elizabeth Anderson, Rayan Kaakati, Bitar Abbas, Kishan Padalia, Pennelope Blakley, Peiyao Zhao, Lili Zhao, Salim Hayek
Journal: Circulation (2020)

Introduction: B-type natriuretic peptide (BNP) is widely used as a biomarker of heart failure and typically rises in response to increased intracardiac pressure. BNP levels have been measured in patients with coronavirus disease 2019 (COVID-19) to assess the cardiovascular contribution to respiratory failure and guide diuresis. Whether BNP levels do predict the need for mechanical ventilation (MV) is however unknown. Methods: The Michigan Medicine Covid-19 Cohort (M 2 C 2 ) is an ongoing prospective observational study in which detailed clinical, laboratory and outcomes data were collected from chart review of consecutive adult patients hospitalized for COVID-19. Patients who were positive for SARS-CoV-2 infection but without symptoms of COVID-19 were not included in this cohort. We identified 495 patients admitted between March 1 st and May 1 st for COVID-19, of whom 290 (58.6%) had BNP levels measured during their hospitalization. We examined the association between BNP and the need for MV during their hospitalization. Results: Among the 290 patients evaluated, the mean age was 62 (SD 15), 169 (58.3%) were male, 135 (46.6%) were blacks, and 61 (21.0%) had pre-existing heart failure. The median BNP level was 50 pg/ml, and 104 (35.9%) of patients had a BNP level &gt; 100 pg/ml. A total of 130 (44.8%) required MV during their hospitalization. The median BNP level in patients who required MV was 63 pg/ml (IQR 25-171), compared to 46 pg /ml (IQR 17-187) in patients who did not, P=0.23. In multivariable analysis adjusting for age, gender, race, pre-existing heart failure, and serum creatinine on admission, BNP&gt;100 pg/ml was not associated with the need for MV. Conclusions: In patients hospitalized for COVID-19, BNP levels were not associated with the need for MV, suggesting that the cardiovascular contribution to respiratory failure in these patients is likely minor compared to the inflammatory response or direct impact of the virus.
Abstract 12235: Additional Factor With High Fat and High Sucrose Diet is Required for Endothelial Dysfunction in Aorta From Obese Mice
Authors: Ayumu Osaki, Atsushi Sato, Toyokazu Kimura, Shunpei Horii, Kei Ito, Takumi Toya, Yasuo Ido, Takayuki Namba, Nobuyuki Masaki, Takeshi Adachi
Journal: Circulation (2018)

Introduction: High fat and high sucrose diet (HFHSD) induces obesity and insulin resistance. Thus mice with HFHSD is widely used as the model of metabolic syndrome. However, we have found that the ...
FDA Approval Summary: Alpelisib Plus Fulvestrant for Patients with HR-positive, HER2-negative, PIK3CA-mutated, Advanced or Metastatic Breast Cancer
Authors: Preeti Narayan, Tatiana M. Prowell, Jennifer J. Gao, Laura L. Fernandes, Emily Li, Xiling Jiang, Junshan Qiu, Jianghong Fan, Pengfei Song, Jingyu Yu, Xinyuan Zhang, Bellinda L. King-Kallimanis, Wei Chen, Tiffany K. Ricks, Yutao Gong, Xing Wang, Katherine Windsor, Steve Y. Rhieu, Gerlie Geiser, Anamitro Banerjee, Xiaohong Chen, Francisca Reyes Turcu, Deb K. Chatterjee, Anand Pathak, Jeffrey Seidman, Soma Ghosh, Reena Philip, Kirsten B. Goldberg, Paul G. Kluetz, Shenghui Tang, Laleh Amiri-Kordestani, Marc R. Theoret, Richard Pazdur, Julia A. Beaver
Journal: Clinical Cancer Research (2020)

Abstract On May 24, 2019, the FDA granted regular approval to alpelisib in combination with fulvestrant for postmenopausal women, and men, with hormone receptor (HR)-positive, HER2-negative, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen. Approval was based on the SOLAR-1 study, a randomized, double-blind, placebo-controlled trial of alpelisib plus fulvestrant versus placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival (PFS) per RECIST v1.1 in the cohort of trial participants whose tumors had a PIK3CA mutation. The estimated median PFS by investigator assessment in the alpelisib plus fulvestrant arm was 11 months [95% confidence interval (CI), 7.5–14.5] compared with 5.7 months (95% CI, 3.7–7.4) in the placebo plus fulvestrant arm (HR, 0.65; 95% CI, 0.50–0.85; two-sided P = 0.001). The median overall survival was not yet reached for the alpelisib plus fulvestrant arm (95% CI, 28.1–NE) and was 26.9 months (95% CI, 21.9–NE) for the fulvestrant control arm. No PFS benefit was observed in trial participants whose tumors did not have a PIK3CA mutation (HR, 0.85; 95% CI, 0.58–1.25). The most common adverse reactions, including laboratory abnormalities, on the alpelisib plus fulvestrant arm were increased glucose, increased creatinine, diarrhea, rash, decreased lymphocyte count, increased gamma glutamyl transferase, nausea, increased alanine aminotransferase, fatigue, decreased hemoglobin, increased lipase, decreased appetite, stomatitis, vomiting, decreased weight, decreased calcium, decreased glucose, prolonged activated partial thromboplastin time, and alopecia.
Abstract 15098: New-Onset Diabetes Mellitus Risk in Statin Users Depends on Baseline HemoglobinA1c Value - Results of VA Database Analysis
Authors: Anna P Ziganshina, Darren Gemoets, Laurence Kaminsky, Aidar R Gosmanov
Journal: Circulation (2020)

Introduction: Statin use in non-diabetic patients is associated with an increased risk of development of new-onset diabetes mellitus (NODM). However, little is known if baseline hemoglobin A1c (HbA1c) can affect diabetogenic risks and mortality benefits of statin therapy. Methods: In a retrospective cohort study between 01/2011 and 12/2018 we collected the data of 152358 non-diabetic US veterans on statin and not on statin therapy who had available baseline HbA1c value and full demographic and clinical information prior to DM diagnosis. The risk of statin-induced DM and all-cause mortality rate were assessed in the whole cohort and based on baseline HbA1c categories: ≤5.6%, 5.7-5.9% and 6.0-6.4%. DM rate and mortality rate were calculated by Cox proportional hazards model adjusted for case-mix. Results: After mean follow up of 6.89 (SD 2.26) years in non-statin users and 3.85 (SD 2.29) years in statin users and adjustments for multiple covariates such as age, gender, ethnicity, obesity, hypertension (HTN), cardiovascular disease, and metformin use, we found that the rate of statin-induced DM depends on baseline HbA1c (Table 1). Analysis by HbA1c categories showed that NODM rate is inversely related to HbA1c level, while statin use in patients with HbA1c 6.0-6.4% was not associated with increased rate of NODM. We did not observe increase in all-cause mortality in statin users and statin users with HTN across HbA1c categories. Atorvastatin use was associated with decrease in all-cause mortality in HTN patients (Table 1). Conclusions: The results of this largest to date analysis of non-diabetic US veterans closely matched for baseline characteristics suggest that the rate of statin-induced DM depends on baseline HbA1c. The significant increase in NODM rate is only observed in patients with baseline HbA1c &lt;6.0% regardless of statin type prescribed. The increased NODM risk is not associated with all-cause mortality in statin users in general including patients with HTN.
Abstract 14433: High Intensity Exercise Training Safely Increases Cardiorespiratory Fitness in Patients With Hypertrophic Cardiomyopathy
Authors: Katrin A Dias, James P Macnamara, Christopher M Hearon, Mitchel Samels, Aslan Turer, Mark S Link, Satyam Sarma, Benjamin D LEVINE
Journal: Circulation (2020)

Introduction: Patients with hypertrophic cardiomyopathy (HCM) are excluded from high intensity activities due to perceived fear of sudden cardiac death. Observational data from athletes with HCM suggest that engaging in high intensity exercise (HIE) may be safe and is associated with higher cardiorespiratory fitness. Whether HIE can safely elicit a superior increase in fitness compared to moderate intensity exercise in patients with HCM is unclear. Methods: Nine HCM patients (49 ± 7 years, 3 female) were assessed for maximal oxygen uptake (VO 2 max, Douglas Bag method), cardiac output (Q c , acetylene rebreathing), and peripheral oxygen extraction (av-O 2 diff, Fick equation) before randomization and after 5 months of MIE or HIE training. Patients completed 3-4 sessions of MIE each week, while the HIE group also incorporated 1-2 supervised high intensity interval training sessions/week from month 3 onwards. Arrhythmias were monitored via pre-existing implantable cardiac defibrillators or implantable loop recorders placed prior to training. Results: Five months of MIE increased absolute VO 2 max by 3% and relative VO 2 max by 4%, while HIE consistently increased absolute VO 2 max by 6% and relative VO 2 max by 5% (Figure). Maximal Q c did not change after MIE but increased in all HIE patients (+1.2L/min, 95% CI -1.4 to 3.9), while maximal av-O 2 diff remained stable in both groups. Training compliance was 84 ± 15% in HIE and 93 ± 11% in MIE. There were no serious exercise-related adverse events in either group though two HIE subjects had arrhythmias at rest: 1) 14-beat run of wide complex tachycardia of uncertain mechanism given underlying conduction disease prior to a training session, and 2) 11 beats of non-sustained ventricular tachycardia prior to post exercise testing. Conclusions: Preliminary findings show that five months of HIE safely and consistently increased cardiorespiratory fitness in patients with HCM, though overall the improvements were comparable to MIE.
Functional reconstitution of HBV-specific CD8 T cells by in vitro polyphenol treatment in chronic hepatitis B
Authors: Greta Acerbi, Ilaria Montali, Gennaro Domenico Ferrigno, Valeria Barili, Simona Schivazappa, Arianna Alfieri, Diletta Laccabue, Alessandro Loglio, Marta Borghi, Marco Massari, Marzia Rossi, Andrea Vecchi, Amalia Penna, Carolina Boni, Gabriele Missale, Pietro Lampertico, Daniele Del Rio, Carlo Ferrari, Paola Fisicaro
Journal: Journal of Hepatology (2020)

In chronic HBV infection, mitochondrial functions and proteostasis are dysregulated in exhausted HBV-specific CD8 T cells. To better characterise the potential involvement of deregulated protein degradation mechanisms in T cell exhaustion, we analysed lysosome-mediated autophagy in HBV-specific CD8 T cells. Bioactive compounds able to simultaneously target both mitochondrial functions and proteostasis were tested to identify optimal combination strategies to reconstitute efficient antiviral CD8 T cell responses in patients with chronic HBV infection.Lysosome-mediated degradation pathways were analysed by flow cytometry in virus-specific CD8 T cells from patients with chronic HBV infection. Mitochondrial function, intracellular proteostasis, and cytokine production were evaluated in HBV-peptide-stimulated T cell cultures, in the presence or absence of the polyphenols resveratrol (RSV) and oleuropein (OLE) and their metabolites, either alone or in combination with other bioactive compounds.HBV-specific CD8 T cells from patients with CHB showed impaired autophagic flux. RSV and OLE elicited a significant improvement in mitochondrial, proteostasis and antiviral functions in CD8 T cells. Cytokine production was also enhanced by synthetic metabolites, which correspond to those generated by RSV and OLE metabolism in vivo, suggesting that these polyphenols may also display an effect after transformation in vivo. Moreover, polyphenolic compounds improved the T cell revitalising effect of mitochondria-targeted antioxidants and of programmed cell death protein 1/programmed cell death ligand 1 blockade.Simultaneously targeting multiple altered intracellular pathways with the combination of mitochondria-targeted antioxidants and natural polyphenols may represent a promising immune reconstitution strategy for the treatment of chronic HBV infection.In chronic hepatitis B, antiviral T lymphocytes are deeply impaired, with many altered intracellular functions. In vitro exposure to polyphenols, such as resveratrol and oleuropein, can correct some of the deregulated intracellular pathways and improve antiviral T cell function. This effect can be further strengthened by the association of polyphenols with antioxidant compounds in a significant proportion of patients. Thus, the combination of antioxidants and natural polyphenols represents a promising strategy for chronic hepatitis B therapy.
Antagonistic Inflammatory Phenotypes Dictate Tumor Fate and Response to Immune Checkpoint Blockade
Authors: Eduardo Bonavita, Christian P. Bromley, Gustav Jonsson, Victoria S. Pelly, Sudhakar Sahoo, Katherine Walwyn-Brown, Sofia Mensurado, Agrin Moeini, Eimear Flanagan, Charlotte R. Bell, Shih-Chieh Chiang, C.P. Chikkanna-Gowda, Neil Rogers, Bruno Silva-Santos, Sebastien Jaillon, Alberto Mantovani, Caetano Reis e Sousa, Nadia Guerra, Daniel M. Davis, Santiago Zelenay
Journal: Immunity (2020)

Inflammation can support or restrain cancer progression and the response to therapy. Here, we searched for primary regulators of cancer-inhibitory inflammation through deep profiling of inflammatory tumor microenvironments (TMEs) linked to immune-dependent control in mice. We found that early intratumoral accumulation of interferon gamma (IFN-γ)-producing natural killer (NK) cells induced a profound remodeling of the TME and unleashed cytotoxic T cell (CTL)-mediated tumor eradication. Mechanistically, tumor-derived prostaglandin E2 (PGE2) acted selectively on EP2 and EP4 receptors on NK cells, hampered the TME switch, and enabled immune evasion. Analysis of patient datasets across human cancers revealed distinct inflammatory TME phenotypes resembling those associated with cancer immune control versus escape in mice. This allowed us to generate a gene-expression signature that integrated opposing inflammatory factors and predicted patient survival and response to immune checkpoint blockade. Our findings identify features of the tumor inflammatory milieu associated with immune control of cancer and establish a strategy to predict immunotherapy outcomes.
Abstract 13641: Serum Vitamin D3 Levels, Left Ventricular Structure and Incident Hospitalization for Heart Failure With Preserved Ejection Fraction in African Americans: The Jackson Heart Study
Authors: Daisuke Kamimura, Amil M Shah, Adebamike Oshunbade, Arsalan Hamid, Robert Mentz, Takeki Suzuki, Solomon K Musani, Ervin R Fox, Adolfo Correa, Javed Butler, Michael E Hall
Journal: Circulation (2020)

Background: Lower serum vitamin D3 (VitD3) concentration has been associated with cardiovascular disease. However, the associations between serum VitD3 levels and left ventricular (LV) structure and function and heart failure with preserved ejection fraction (HFpEF) have not been well-characterized community. The prevalence of VitD3 deficiency is higher among African Americans than in other race/ethnicity groups. We hypothesized that serum VitD3 levels are associated with LV concentric remodeling and incident heart failure (HF) in African Americans. Methods and Results: Among 4872 African Americans in the Jackson Heart Study cohort, we investigated the relationships between serum VitD3 levels and LV structure and function, evaluated with echocardiography, and incident HF hospitalization, categorized either HF with reduced EF (HFrEF: EF&lt;50%) or HFpEF (EF≥50%). The median and interquartile serum VitD3 levels were 12.0 (8.6-16.7) ng/mL. After adjustment for age, sex, body mass index, systolic blood pressure, anti-hypertensive medication use, current smoking status, and estimated glomerular filtration rate, lower VitD3 levels were associated with greater septal and posterior wall thickness and plasma brain natriuretic peptide (BNP) levels, but not with LV mass index or LVEF (Table). Over a median follow-up period of 11 (10.3~11) years, 313 participants developed incident HF (7.79 cases per 1,000 person-years), including 128 (41%) HFrEF and 185 (59%) HFpEF cases. After adjustment, lower serum VitD3 levels were associated with higher incidence of HF overall and levels seemed to be mostly related to HFpEF (Table). Conclusion: In this community-based African American cohort, lower serum VitD3 levels were associated with LV concentric remodeling and incident HF, mainly HFpEF. Further investigation is required to examine whether the supplementation of VitD3 can prevent LV concentric remodeling and incident HFpEF in African Americans.
Proinflammatory IgG Fc structures in patients with severe COVID-19
Authors: Saborni Chakraborty, Joseph Gonzalez, Karlie Edwards, Vamsee Mallajosyula, Anthony S. Buzzanco, Robert Sherwood, Cindy Buffone, Nimish Kathale, Susan Providenza, Markus M. Xie, Jason R. Andrews, Catherine A. Blish, Upinder Singh, Haley Dugan, Patrick C. Wilson, Tho D. Pham, Scott D. Boyd, Kari C. Nadeau, Benjamin A. Pinsky, Sheng Zhang, Matthew J. Memoli, Jeffery K. Taubenberger, Tasha Morales, Jeffrey M. Schapiro, Gene S. Tan, Prasanna Jagannathan, Taia T. Wang
Journal: Nature Immunology (2020)

Severe acute respiratory syndrome coronavirus 2 infections can cause coronavirus disease 2019 (COVID-19), which manifests with a range of severities from mild illness to life-threatening pneumonia and multi-organ failure. Severe COVID-19 is characterized by an inflammatory signature, including high levels of inflammatory cytokines, alveolar inflammatory infiltrates and vascular microthrombi. Here we show that patients with severe COVID-19 produced a unique serologic signature, including an increased likelihood of IgG1 with afucosylated Fc glycans. This Fc modification on severe acute respiratory syndrome coronavirus 2 IgGs enhanced interactions with the activating Fcγ receptor FcγRIIIa; when incorporated into immune complexes, Fc afucosylation enhanced production of inflammatory cytokines by monocytes, including interleukin-6 and tumor necrosis factor. These results show that disease severity in COVID-19 correlates with the presence of proinflammatory IgG Fc structures, including afucosylated IgG1.