tbuckley/cabot-search huggingface dataset:
Targeting cholesterol biosynthesis promotes anti-tumor immunity by inhibiting long noncoding RNA SNHG29-mediated YAP activation
Authors: Wen Ni, Hui Mo, Yuanyuan Liu, Yuanyuan Xu, Chao Qin, Yunxia Zhou, Yuhui Li, Yuqing Li, Aijun Zhou, Su Yao, Rong Zhou, Jianping Huo, Liheng Che, Jianming Li
Journal: Molecular Therapy (2021)

Anti-tumor immunity through checkpoint inhibitors, specifically anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) interaction, is a promising approach for cancer therapy. However, as early clinical trials indicate that colorectal cancers (CRCs) do not respond well to immune-checkpoint therapies, new effective immunotherapy approaches to CRC warrant further study. Simvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (CoA) reductase (HMGCR), the rate-limiting enzyme of the mevalonate (MVA) pathway for the cholesterol biosynthesis. However, little is known about the functions of simvastatin in the regulation of immune checkpoints or long noncoding RNA (lncRNA)-mediated immunoregulation in cancer. Here, we found that simvastatin inhibited PD-L1 expression and promoted anti-tumor immunity via suppressing the expression of lncRNA SNHG29. Interestingly, SNHG29 interacted with YAP and inhibited phosphorylation and ubiquitination-mediated protein degradation of YAP, thereby facilitating downregulation of PD-L1 transcriptionally. Patient-derived tumor xenograft (PDX) models and the clinicopathological analysis in samples from CRC patients further supported the role of the lncRNA SNHG29-mediated PD-L1 signaling axis in tumor microenvironment reprogramming. Collectively, our study uncovers simvastatin as a potential therapeutic drug for immunotherapy in CRC, which suppresses lncRNA SNHG29-mediated YAP activation and promotes anti-tumor immunity by inhibiting PD-L1 expression.
Abstract P153: Dose-Response Associations Between Physical Activity And All-Cause Mortality Among A Multi-Ethnic Sample With Diabetes: NHANES 1999-2006
Authors: William Boyer, Madison Brenton, Allison Milano
Journal: Circulation (2021)

Introduction: Emerging evidence has suggested that those identifying as non-Hispanic white (NHW) or non-Hispanic black (NHB) have consistent and similar all-cause mortality risk reductions across dose of aerobic PA. In the same analyses, those identifying as Mexican American (MA) receive no protection from all-cause mortality across dose of aerobic PA. However, a single study has suggested that MAs meeting both the aerobic and muscular strengthening activity (MSA) recommendations have similar all-cause mortality risk reductions compared to NHW and NHB, highlighting the importance of MSA among MA. It is unknown, however, if these results translate to those who have diabetes. Hypothesis: NHW or NHB participants will have similar all-cause mortality risk reductions associated with aerobic PA independent of MSA participation. MA meeting both recommendations will have significant all-cause mortality risk reductions. Methods: The study sample (n=1,999) included adult (≥20 years of age) participants with diabetes from the 1999-2006 NHANES. Diabetes was defined as having one of the following: reported physician diagnosis, reported taking anti-hyperglycemic medication, or HbA1c ≥6.5%. PA was categorized into 6 categories based around the 2018 PA guidelines: category 1 (no aerobic PA and insufficient MSA), category 2 (insufficient aerobic PA and insufficient MSA), category 3 (active and insufficient MSA), category 4 (no aerobic PA and sufficient MSA), category 5 (insufficient aerobic PA and sufficient MSA), and category 6 (meeting both recommendations). Cox-proportional hazard models were used for all analyses. Results: A significant interaction (p&lt;0.001) was found between categories of PA and race. Statistically significant risk reductions were found for categories 2,3 and 6 among NHW, and categories 2 and 3 among NHB; with a non-statistically significant risk reduction of 67% in category 6 (p=0.13) for NHB. A 45% reduction in risk was found among MA for category 6, however the estimate did not attain statistical significance (p=0.17). Conclusions: Similar to previous studies in those without diabetes, aerobic PA of any volume significantly reduced risk for all-cause mortality only among NHW and NHB with diabetes. While the risk reductions were clinically meaningful for both NHB and MA in category 6 compared to category 1, there was a lack of statistical significance. It is probable this may be, in part, influenced by a relatively low sample size within these two race-ethnic groups.
Abstract 17316: Association Between Time From Atrial Fibrillation Diagnosis to First Catheter Ablation With Long-Term Clinical Outcomes: Insights From the UC San Diego AF Ablation Registry
Authors: Praneet Mylavarapu, Omar M Aldaas, Chaitanya Malladi, Florentino Lupercio, Frederick Han, Kurt S Hoffmayer, David E Krummen, Gordon Ho, Farshad Raissi, Gregory Feld, Jonathan C Hsu
Journal: Circulation (2020)

Background: While the optimal timing for atrial fibrillation (AF) ablation is unknown, several studies have reported increased freedom from atrial arrhythmias among persistent AF patients with shorter time to first ablation after diagnosis. However, these studies have only examined two-year post-ablation outcomes. Methods: We performed a retrospective study of all patients who underwent first-time radiofrequency catheter ablation enrolled in the UC San Diego AF Ablation Registry. The primary outcome was freedom from atrial arrhythmias on or off antiarrhythmic drugs (AAD). Median follow-up duration was 3.9 (0.4 - 6.8) years. Patients were categorized into quartiles by time from diagnosis of AF to first ablation (0-250, 251-855, 856-2200, and &gt;2200 days respectively). Results: Among 534 total patients, the median diagnosis-to-ablation time was 2.3 years (25th-75th percentiles 0.7-6.0 years). At 5 years post-ablation, freedom from atrial arrhythmia significantly decreased as time to ablation increased in both paroxysmal and persistent AF (Parox: 50.5%, 46.8%, 35.6%, 36.6%, p-trend=0.042; Persist: 36.9%, 23.6%, 16.3%, and 22.6%, p-trend&lt;0.01 for 1st, 2nd, 3rd, and 4th quartiles respectively). After adjustment, clinically significant differences in freedom from atrial arrhythmia were found in both paroxysmal and persistent AF when compared to the 0-250 day time category: 250-855: Adjusted Hazard Ratio (AHR)=1.11, p=0.69 (parox), AHR=1.48, p=0.26 (persist); 856-2200: AHR=1.24, p=0.40 (parox), AHR=2.16, p=0.04 (persist); and &gt;2200: AHR=1.69, p=0.03 (parox), AHR=2.73, p&lt;0.01 (persist). Among all patients, all-cause mortality increased as first ablation was delayed beyond 2.3 years after diagnosis (AHR 3.05, p = 0.047). Conclusion: In this registry analysis, delayed time to first ablation after diagnosis of both persistent and paroxysmal AF was associated with higher rates of atrial arrhythmia recurrence and all-cause mortality after 5 years.
Tumor hypoxia is associated with resistance to PD-1 blockade in squamous cell carcinoma of the head and neck
Authors: Dan P Zandberg, Ashley V Menk, Maria Velez, Daniel Normolle, Kristin DePeaux, Angen Liu, Robert L Ferris, Greg M Delgoffe
Journal: Journal for ImmunoTherapy of Cancer (2021)

The majority of patients with recurrent/metastatic squamous cell carcinoma of the head and neck (HNSCC) (R/M) do not benefit from anti-PD-1 therapy. Hypoxia induced immunosuppression may be a barrier to immunotherapy. Therefore, we examined the metabolic effect of anti-PD-1 therapy in a murine MEER HNSCC model as well as intratumoral hypoxia in R/M patients. In order to characterize the tumor microenvironment in PD-1 resistance, a MEER cell line was created from the parental line that are completely resistant to anti-PD-1. These cell lines were then metabolically profiled using seahorse technology and injected into C57/BL6 mice. After tumor growth, mice were pulsed with pimonidazole and immunofluorescent imaging was performed to analyze hypoxia and T cell infiltration. To validate the preclinical results, we analyzed tissues from R/M patients (n=36) treated with anti-PD-1 mAb, via immunofluorescent imaging for number of CD8+ T cells (CD8), Tregs and the percent area (CAIX) and mean intensity (I) of carbonic anhydrase IX in tumor. We analyzed disease control rate (DCR), progression free survival (PFS), and overall survival (OS) using proportional odds and proportional hazards (Cox) regression. We found that anti-PD-1 resistant MEER has significantly higher oxidative metabolism, while there was no difference in glycolytic metabolism. Intratumoral hypoxia was significantly increased and CD8+ T cells decreased in anti-PD-1 resistant tumors compared with parental tumors in the same mouse. In R/M patients, lower tumor hypoxia by CAIX/I was significantly associated with DCR (p=0.007), PFS, and OS, and independently associated with response (p=0.028) and PFS (p=0.04) in a multivariate model including other significant immune factors. During PD-1 resistance, tumor cells developed increased oxidative metabolism leading to increased intratumoral hypoxia and a decrease in CD8+ T cells. Lower tumor hypoxia was independently associated with increased efficacy of anti-PD-1 therapy in patients with R/M HNSCC. To our knowledge this is the first analysis of the effect of hypoxia in this patient population and highlights its importance not only as a predictive biomarker but also as a potential target for therapeutic intervention.
Abstract 16158: The CardiAMP Heart Failure Trial: Efficacy Outcomes From Roll-In Phase
Authors: Peter V Johnston, Henricus J Duckers, Amish N Raval, Thomas D Cook, Jay H Traverse, William T Abraham, Peter A Altman, Carl J Pepine
Journal: Circulation (2018)

Introduction: Stem cell therapy shows promise in ischemic cardiomyopathy, although results in clinical trials are variable. Growing data suggests significant differences in autologous stem cell reg...
治療を受けていない多発性骨髄腫(基調-185)患者に対するペンブロリliz+レナalとデキサメタゾン:無作為化,非盲検,第3相試験【JST・京大機械翻訳】
Authors: Usmani Saad Zafar, Schjesvold Fredrik, Oriol Albert, Karlin Lionel, Cavo Michele, Rifkin Robert M, Yimer Habte Aragaw, LeBlanc Richard, Takezako Naoki, McCroskey Robert Donald, Lim Andrew Boon Ming, Suzuki Kenshi, Kosugi Hiroshi, Grigoriadis George, Avivi Irit, Facon Thierry, Jagannath Sundar, Lonial Sagar, Ghori Razi Uddin, Farooqui Mohammed Z H, Marinello Patricia, San-Miguel Jesus
Journal: The Lancet Haematology (2019)
Genomic analysis of cellular hierarchy in acute myeloid leukemia using ultrasensitive LC-FACSeq
Authors: Caner Saygin, Eileen Hu, Pu Zhang, Steven Sher, Arletta Lozanski, Tzyy-Jye Doong, Deedra Nicolet, Shelley Orwick, Jadwiga Labanowska, Jordan N. Skinner, Casey Cempre, Tierney Kauffman, Virginia M. Goettl, Nyla A. Heerema, Lynne Abruzzo, Cecelia Miller, Rosa Lapalombella, Gregory Behbehani, Alice S. Mims, Karilyn Larkin, Nicole Grieselhuber, Alison Walker, Bhavana Bhatnagar, Clara D. Bloomfield, John C. Byrd, Gerard Lozanski, James S. Blachly
Journal: Leukemia (2021)

Abstract Hematopoiesis is hierarchical, and it has been postulated that acute myeloid leukemia (AML) is organized similarly with leukemia stem cells (LSCs) residing at the apex. Limited cells acquired by fluorescence activated cell sorting in tandem with targeted amplicon-based sequencing (LC-FACSeq) enables identification of mutations in small subpopulations of cells, such as LSCs. Leveraging this, we studied clonal compositions of immunophenotypically-defined compartments in AML through genomic and functional analyses at diagnosis, remission and relapse in 88 AML patients. Mutations involving DNA methylation pathways, transcription factors and spliceosomal machinery did not differ across compartments, while signaling pathway mutations were less frequent in putative LSCs. We also provide insights into TP53 -mutated AML by demonstrating stepwise acquisition of mutations beginning from the preleukemic hematopoietic stem cell stage. In 10 analyzed cases, acquisition of additional mutations and del(17p) led to genetic and functional heterogeneity within the LSC pool with subclones harboring varying degrees of clonogenic potential. Finally, we use LC-FACSeq to track clonal evolution in serial samples, which can also be a powerful tool to direct targeted therapy against measurable residual disease. Therefore, studying clinically significant small subpopulations of cells can improve our understanding of AML biology and offers advantages over bulk sequencing to monitor the evolution of disease.
Phase I Study of Ceralasertib (AZD6738), a Novel DNA Damage Repair Agent, in Combination with Weekly Paclitaxel in Refractory Cancer
Authors: Seung Tae Kim, Simon A. Smith, Peter Mortimer, Arsene-Bienvenu Loembé, Heejin Cho, Kyoung-Mee Kim, Claire Smith, Sophie Willis, Itziar Irurzun-Arana, Alienor Berges, Jung Yong Hong, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang, Iwanka Kozarewa, Andrew J. Pierce, Emma Dean, Jeeyun Lee
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Ceralasertib is a potent and selective oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3-related (ATR) protein. Patients and Methods: Eligible patients with solid tumors, enriched for melanoma, received ceralasertib in combination with a fixed dose of paclitaxel (80 mg/m2 on D1, D8, D15) in 28-day cycles. The dose of ceralasertib was escalated to reach an MTD in a rolling 6 design. The starting dose of ceralasertib was 40 mg QD. Fifty-seven patients (33 patients with melanoma who failed prior PD1/L1 treatment) were enrolled in 7 dose cohorts ranging from 40 mg QD to 240 mg BD plus weekly paclitaxel. Results: The RP2D was established as ceralasertib 240 mg BD days 1–14 plus paclitaxel 80 mg/m2 on D1, D8, D15 every 28 days. The most common toxicities were neutropenia (n = 39, 68%), anemia (n = 25, 44%), and thrombocytopenia (n = 21, 37%). In the full analysis set of 57 patients, the overall response rate (ORR) was 22.6% (95% CI, 12.5–35.3). In 33 patients with melanoma, resistant to prior anti-PD1 therapy, the ORR was 33.3% (95% CI, 18.0–51.8). In the melanoma subset, the mPFS was 3.6 months (95% CI, 2.0–5.8), the median duration of response was 9.9 months (95% CI, 3.7–23.2), and the mOS was 7.4 months (95% CI, 5.7–11.9). Conclusions: Ceralasertib in combination with paclitaxel was well tolerated in patients with advanced malignancies and showed evidence of antitumor activity. Durable responses were observed in patients with advanced cutaneous, acral, and mucosal melanoma resistant to anti-PD1/L1 treatment. See related commentary by Ashworth, p. 4667
Arsenic-induced oxidative stress and cytotoxicity in human liver carcinoma (HepG2) cells
Authors: Erika Brown, Clement Yedjou, Paul Tchounwou
Journal: Cancer Research (2006)

3560  Abstract: Arsenic is a natural and ubiquitous element found in the environment that is both odorless and tasteless. Whether ingested or inhaled, arsenic induces both systemic and carcinogenic effects. Epidemiological findings show that exposure to arsenic results in vascular disorders, peripheral neuropathy, and various neoplastic diseases, such as, skin, lung, bladder, liver and kidney cancers. However, its molecular mechanisms of action are still largely unknown. In this study, we used HepG2 cells as a model to study the cytotoxicity and oxidative stress associated with exposure to arsenic trioxide (AT). We hypothesized that oxidative stress plays a key role in arsenic induced cytotoxicity. To test this hypothesis, we performed the MTT-assay for cell viability and the thiobarbituric acid test for lipid peroxidation. Data obtained from the MTT assay indicated that AT significantly reduced the viability of HepG2 cells, showing a LD50 value of 23.2 ± 6.4 μg/mL upon 24 hours of exposure, indicating a dose-dependent response. Data from the thiobarbituric acid test showed a significant (p ≤ 0.05) increase in MDA and HNE levels in AT-treated HepG2 cells compared to control cells. AT treatment significantly increased cellular content of reactive oxygen species (ROS), as evidenced by the increase in lipid peroxidation by-products. However, the addition of the antioxidant N-acetyl-L-cysteine (NAC) to AT-treated cells resulted in a gradual decrease of MDA plus HNE. Taken together, these results indicate that AT is highly cytotoxic to HepG2 cells. This cytotoxicity is found to be mediated by oxidative stress, and the antioxidant NAC has proved to be effective in blocking this oxidative stress and cellular damage. Keywords: arsenic trioxide (As2O3), N-acetyl cysteine (NAC), cytotoxicity, lipid peroxidation, oxidative stress, HepG2 cells Acknowledgements: This research was financially supported in part by the National Institutes of Health (Grant # 1G12RR13459), through the RCMI-Center for Environmental Health at Jackson State University, and in part by the National Science Foundation’s Louis Stokes Mississippi Alliance for Minority Participation (LSMAMP) Bridge to the Doctorate Program (Grant # HRD-0115807) at Jackson State University.
Hepatic patch by stacking patient-specific liver progenitor cell sheets formed on multiscale electrospun fibers promotes regenerative therapy for liver injury
Authors: Yohan Kim, Young Won Kim, Seung Bum Lee, Kyojin Kang, Sangtae Yoon, Dongho Choi, Suk-Hee Park, Jaemin Jeong
Journal: Biomaterials (2021)

Recently, use of cell sheets with bio-applicable fabrication materials for transplantation has been an attractive approach for the treatment of patients with liver failure. However, renewable and scalable cell sources for engineered tissue patches remain limited. We previously reported a new type of proliferating bipotent human chemically derived hepatic progenitor cells (hCdHs) developed by small molecule-mediated reprogramming. Here, we developed a patient-specific hepatic cell sheet constructed from liver biopsy-derived hCdHs on a multiscale fibrous scaffold by combining electrospinning and three-dimensional printing. Analysis of biomaterial composition revealed that the high-density electrospun sheet was superior in increasing the functional properties of hCdHs. Furthermore, the hepatic patch assembled by multilayer stacking with alternate cell sheets of hCdHs and human umbilical vein endothelial cells (HUVECs) recapitulated a liver tissue-like structure, with histological and morphological shape and size similar to those of primary human hepatocytes, and exhibited a significant increase in hepatic functions such as albumin secretion and activity of cytochrome P450 during in vitro hepatic differentiation compared with that in hCdH cells cultured in a two-dimensional monolayer. Interestingly, in the hepatic patch, the induction of functional hepatocytes was associated with both the electrospun fibrous-facilitated oncostatin M signaling and selective activation of AKT signaling by HUVECs. Notably, upon transplantation into a mouse model of therapeutic liver repopulation, the hepatic patch effectively repopulated the damaged parenchyma and induced the restoration of liver function with healthy morphology in the lobe and an improved survival rate (>70%) in mice. Overall, these results suggested that liver biopsy-derived hCdHs can be an efficient alternative source for developing hepatic cell sheets and patches with potential clinical applications in tissue engineering to advance liver regeneration.
Abstract P058: Risk Of Heart Failure In Type 2 Diabetes Has Decreased Over Time - A Danish Nationwide Cohort Study
Authors: Brian Schwartz, Vasan S Ramachandran, Christian Torp-Pedersen, Morten Schou, Asya Lyass, Gunnar Gislason, Lars Kober, Charlotte Andersson
Journal: Circulation (2021)

Introduction: Although type 2 diabetes (T2DM) is one of the strongest risk factors for heart failure (HF), there is limited data on contemporary lifetime risk estimates in this segment. Incident HF appears to be decreasing in the general population, but little is known how the risk has changed over time in patients with T2DM. The increasing prevalence and rapidly evolving management of T2DM has furthered interest in the epidemiological relationship between HF and T2DM. We therefore sought to investigate the lifetime risk of HF in people with T2DM and how the long term risk of HF has changed over time in patients with T2DM. Hypothesis: We assessed the hypothesis that there would be a statistically significant reduction in the ten- year risk of HF among patients with T2DM over time in all age groups except the youngest (&lt;50 years old), mimicking trends in the general population and that men would have a higher cumulative risk than women. Methods: We employed the Danish nationwide databases which included information on all Danish citizens’ hospitalizations, outpatient visits, and medication use since 1978 (diagnoses) and 1995 (medications). Using this data, we calculated the cumulative incidence of HF among patients with T2DM who were free from HF at age 30, 40, 50, 60, and 70 years, respectively. We censored people at time of emigration or at Dec 31, 2017 and we used Aalen-Johnsen estimators to adjust for the competing risk of death. Results: A total of 473,685 patients (47% women) had a diagnosis of T2DM between Jan 1, 1995 and Dec 31, 2017. Of those who were free from HF before T2DM onset, 21,030 were diagnosed before the age of 30; 33,786 before age 40; 55,537 before 50 years of age; 85,108 before age 60; and 98,631 before age 70. During follow-up, 48,026 (10%) were diagnosed with HF and 133,561 were censored for death. The cumulative life-time risk of developing HF among people with diabetes at age 50 was 24% (95% CI 21-27%) in females and 27% (25-29%) in men, p for difference &lt;0.0001. Among patients aged 50 years, the 10-year risk of HF decreased from 12.2% (1995-2005) to 9.6% (2005- 2015), p&lt;0.0001. Similar 10-year risks decreased for those free from HF at age 60 year (from 19.0% in 1995-2005 to 13.3% in 2005-2015, p&lt;0.0001) and 70 years old (from 22.2% to 17.1% between 1995-2005 and 2005-2015, p&lt;0.0001). Conclusion: The lifetime risk of HF among patients with T2DM exceeds 1 in 4 for both men and women. There was, however, a decrease in ten-year cumulative incidence of HF over time among patients with T2DM in all age groups.
Latent Autoimmune Diabetes of Adults (LADA) Is Likely to Represent a Mixed Population of Autoimmune (Type 1) and Nonautoimmune (Type 2) Diabetes
Authors: Angus G. Jones, Timothy J. McDonald, Beverley M. Shields, William Hagopian, Andrew T. Hattersley
Journal: Diabetes Care (2021)

Latent autoimmune diabetes of adults (LADA) is typically defined as a new diabetes diagnosis after 35 years of age, presenting with clinical features of type 2 diabetes, in whom a type 1 diabetes-associated islet autoantibody is detected. Identifying autoimmune diabetes is important since the prognosis and optimal therapy differ. However, the existing LADA definition identifies a group with clinical and genetic features intermediate between typical type 1 and type 2 diabetes. It is unclear whether this is due to
GP leaders pass vote of no confidence in NHS England over appointments letter
Authors: Gareth Iacobucci
Journal: BMJ (2021)

The BMA’s General Practitioners Committee has passed a motion of no confidence in NHS England in response to a “tone deaf” letter sent to general practices last week instructing them to return to offering face-to-face appointments without prior triage.

The motion,1 passed at the GPC’s online meeting on 20 May, said the committee was “outraged by NHS England and NHS Improvement’s lack of understanding of the pressures facing general practice” and urged the GPC executive to “immediately cease” all formal meetings with NHS England until the issue had been resolved.

Earlier this week the GPC’s chair, Richard Vautrey, called for an urgent meeting with England’s health and social care secretary, Matt Hancock,2 to discuss the profession’s “widespread anger, frustration, and disappointment” at the letter, sent on 13 May by NHS England’s medical director for primary care, Nikki Kanani, and its director of primary care, Ed Waller.34

Before issuing the letter the NHS had …