tbuckley/cabot-search huggingface dataset:
Impact of type 1 diabetes on the composition and functional potential of gut microbiome in children and adolescents: possible mechanisms, current knowledge, and challenges
Authors: Pari Mokhtari, Julie Metos, Pon Velayutham Anandh  Babu
Journal: Gut Microbes (2021)

Diabetes prevalence and incidence among youth have been increasing globally. Type 1 Diabetes (T1D) in children or adolescents accounts for 5-10% of all diagnosed cases of diabetes. Emerging evidence indicates that genetic factors, especially genes in the human leukocyte antigen region, are not the only factors involved in the predisposition of an individual to T1D. The pathogenesis and development of T1D is driven by both genetic predisposition and environmental factors. Studies indicate that gut microbiota is one of the potential environmental influencers involved in the pathophysiology of TID. Gut microbiota mediates the development of diabetes by altering intestinal permeability, modifying intestinal immunity, and molecular mimicry. The gut microbial diversity, taxonomic profile, and functional potential of gut microbes are significantly altered in individuals with T1D as compared to healthy individuals. However, studies are still needed to identify the specific microbes and microbial metabolites that are involved in the development and pathogenesis of T1D. This will help the development of microbiome-based therapeutic strategies for the prevention and treatment of T1D. The present review article highlights the following: (i) the current knowledge and knowledge gaps in understanding the association between T1D and gut microbiome specifically focusing on the composition and functional potential of gut microbiome in children and adolescents, (ii) the possible mechanisms involved in gut microbiome-mediated T1D pathogenesis, and (iii) challenges and future direction in this field.Abbreviations: B/F ratio: Bacteroidetes to Firmicutes ratio; F/B ratio: Firmicutes to Bacteroidetes ratio; FDR: First-degree relatives; GPR: G protein-coupled receptors; HLA: human leucocyte antigen; IL: interleukin; IFN- γ: interferon-γ; KEGG: Kyoto Encyclopedia of Genes and Genomes; LPS: lipopolysaccharide; mTOR: mammalian target of rapamycin; PICRUSt: Phylogenetic Investigation of Communities by Reconstruction of Unobserved States; SCFA: short chain fatty acids; T1D: Type 1 diabetes; T2D: Type 2 diabetes; TJ: tight junction; Tregs: regulatory T cells.
Nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for advanced non-small cell lung cancer (NSCLC): 4-year update from CheckMate 227.
Authors: Luis G. Paz-Ares, Tudor-Eliade Ciuleanu, Jong-Seok Lee, Laszlo Urban, Reyes Bernabe Caro, Keunchil Park, Hiroshi Sakai, Yuichiro Ohe, Makoto Nishio, Adam Pluzanski, Suresh S. Ramalingam, Julie R. Brahmer, Hossein Borghaei, Kenneth John O'Byrne, Matthew D. Hellmann, Arteid Memaj, Judith Bushong, Phuong Tran, Martin Reck
Journal: Journal of Clinical Oncology (2021)

9016 Background: 1L NIVO + IPI was shown to provide durable long-term overall survival (OS) benefit vs chemo regardless of tumor programmed death ligand 1 (PD-L1) expression in patients (pts) with advanced NSCLC in CheckMate 227 Part 1 (NCT02477826); 3-year OS rates were 33% vs 22% in pts with PD-L1 ≥ 1% (HR, 0.79 [95% CI, 0.67–0.93]) and 34% vs 15% in pts with PD-L1 &lt; 1% (HR, 0.64 [95% CI, 0.51–0.81]). Here we report updated results from the study with 4 years’ minimum follow-up. Methods: Adults with previously untreated stage IV / recurrent NSCLC, no known EGFR/ ALK alterations , and ECOG performance status ≤ 1 were enrolled; pts were stratified by squamous (SQ) and non-squamous (NSQ) histology. Pts with PD-L1 ≥ 1% (n = 1189) were randomized 1:1:1 to receive NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), NIVO alone (240 mg Q2W), or chemo. Pts with PD-L1 &lt; 1% (n = 550) were randomized 1:1:1 to receive NIVO + IPI, NIVO (360 mg Q3W) + chemo, or chemo. OS with NIVO + IPI vs chemo in pts with PD-L1 ≥ 1% was the primary endpoint. Results: With minimum follow-up of 49.4 months (database lock, Feb 18, 2021), pts were at least 2 years beyond the protocol-specified end of immunotherapy treatment. Pts with PD-L1 ≥ 1% continued to show durable benefit with NIVO + IPI vs chemo (HR, 0.76 [95% CI, 0.65–0.90]); 4-year OS rates were 29% (NIVO + IPI), 21% (NIVO), and 18% (chemo). At 4 years, 14% (NIVO + IPI), 10% (NIVO), and 4% (chemo) remained progression free. Among responders, 34%, 30%, and 7% remained in response, respectively. In an exploratory analysis in pts with PD-L1 ≥ 50%, 4-year OS rates were 37% (NIVO + IPI), 26% (NIVO), and 20% (chemo). In pts with PD-L1 &lt; 1%, OS HR for NIVO + IPI vs chemo was 0.64 (95% CI, 0.51–0.81); 4-year OS rates were 24% (NIVO + IPI), 13% (NIVO + chemo) and 10% (chemo). At 4 years, 12% (NIVO + IPI), 7% (NIVO + chemo), and 0% (chemo) remained progression free. Among responders, 31%, 13%, and 0% remained in response, respectively. Among pts who progressed on NIVO + IPI vs chemo, 7% vs 40% (PD-L1 ≥ 1%), and 9% vs 33% (PD-L1 &lt; 1%), received subsequent immunotherapy. Benefit with NIVO + IPI vs chemo was observed for both SQ and NSQ histology (Table). With long-term follow-up, no new safety signals were identified. Conclusions: With 4 years’ minimum follow-up, 1L NIVO + IPI continued to provide durable, long-term OS benefit vs chemo in pts with advanced NSCLC regardless of PD-L1 expression or histology. Clinical trial information: NCT02477826. [Table: see text]
Polymorphism of genes of hemostasis system and methionin exchange in patients with gastrointestinal tumors.
Authors: Oleg I. Kit, Liubov Yu Vladimirova, Tatiana A. Zykova, Oksana V. Katelnitskaya, Andrey A. Maslov, Elena A. Shevyakova, Natalia A. Abramova, Anna E. Storozhakova, Irina L. Popova, Kristina A. Novoselova, Natalia M. Tikhanovskaya, Aza A. Agieva, Ludmila A. Ryadinskaya, Anna V. Tishina, Irina S. Tishchenko, Sergey N. Kabanov, Elena A. Kalabanova, Valeria S. Karnaukhova, Maria A. Teplyakova
Journal: Journal of Clinical Oncology (2021)

e16011 Background: The purpose of the study was to analyze the rates of polymorphic allelic variants of genes of the hemostasis system and methionin exchange in patients with gastrointestinal cancers (GICs). Methods: The study included 69 patients with histologically verified GICs (main group): gastric cancer (GC) – 17, colon cancer (CC) – 42, other tumors – 10 (pancreatic cancer – 6, liver cancer – 3, gallbladder cancer – 1) and 50 patients without cancer (control group). 12 polymorphic loci were determined in genomic DNA samples by Real-time PCR: F2 (G20210А, rs1799963), F5 (G1691A, rs6025), F7 (G10976A, rs6046), F13 (G226A, rs5985), FGB G(-455)A (rs1800790), ITGA2-α2 (C807T, rs1126643), ITGB3-b (Т1565С, rs5918), PAI-1 4G(-675)5G, rs1799889), MTHFR (С677Т, rs1801133 and A1298C, rs1801131), MTR (А2756G, rs1805087), MTRR (A66G, rs1801394). Results: The ratio of genotype frequencies maintained in the Hardy-Weinberg equilibrium in all gene loci except FGB G(-455)A in GC patients (p = 0.02). The rate of an alternative allele in the F2 gene among patients with GICs was 1.4%, in the control group – 1.0%; F5 – 1.0% and 4.0%; F7 – 13.0% and 11.0%; F13 – 31.9% and 32.0%; FGB – 29.7% and 22.0%; ITGA2 – 37.7% and 38.0%; ITGB3 – 17.4% and 21.0%; PAI-1 – 55.1% and 56.0%, MTHFR (Т) – 26.6% and 31.3%; MTHFR (С) – 33.0% and 27.5%; MTR – 29.8% and 26.3%; MTRR – 51.1% and 57.5%, respectively (p &gt; 0.05). AA homozygotes at the FGB G(-455)A locus were more frequent in the main group, compared to controls: 4.3% vs 4.0%; p = 0.02. No differences in the frequency of alternative alleles of the studied genes were found between patients with GC and CC. GG genotype at the FGB G(-455)A locus was found in GC patients in 29.4%, in controls – in 60.0% (OR = 0.28, 95% CI 0.08-0.91); GA genotype – in 70.6% and 36.0% (OR = 4.27, 95% CI 1.29-14.06), AA genotype – in 0% and 4.0% (p = 0.04, χ2 = 6.34), respectively. Conclusions: The univariate analysis demonstrated that carriage of the GA genotype at the FGB G(-455)A (rs1800790) locus could be found more often in patients with GC.
Comprehensive T-cell receptor repertoire of Chinese lung cancer patients related with age.
Authors: Huaxia Yang, Xiaoguang Li, Xinyu Liu, Yadong Wang, Jianchao Xue, Ziqi Jia, Xiaoying Yang, Huihui Xu, Zhongxing Bing, Chao Guo, Zhenyu Tian, Chao Gao, Dejian Gu, Rongrong Chen, Xuefeng Xia, Shanqing Li, Naixin Liang
Journal: Journal of Clinical Oncology (2021)

e21076 Background: Cancer is most commonly diagnosed disease worldwide and also a leading cause of death. Cancer is more common in older people, but it can also be found in younger people. As the importance of T cell receptor (TCR) repertoire gains appreciation, particularly given their potential utility for cancer immunotherapeutic prognostication, the characteristics of TCR repertoire are needed. We detected the complementarity determining region 3 (CDR3) by TCR sequence to describe the correlation between diversity and clonality in human’s immune system and age. Methods: The TCRβ repertoire of 47 stage Ia lung cancer patients were analyzed. Genomic DNA was extracted from peripheral blood or tissue, and used to amplified and sequenced the CDR3 region of rearranged TCRβ genes. Finally, we got the relative frequencies of patients T cell clones. Shannon index was calculated on the clonal abundance of all productive TCR sequences. Simpson index also was calculated to measure the clonality of TCR repertoire. MOI was a measure of the similarity in the T cell repertoire between tissue and blood taking into account the specific rearrangements and their respective frequencies. Results: In tissue, the Simpson index ranged from 0.00075 to 0.11466 (mean = 0.01343); Shannon index ranged from 2.91 to 8.95 (mean = 6.26). The age ranged from 27 to 78 (median = 63). Patients were divided into two groups based on median age. The older showed higher Shannon index (p = 0.005) but lower Simpson index (p = 0.0072) than younger patients in tissue. Further, the higher Shannon index was found in younger group in blood(p = 0.0411). Interestingly, the MOI of the older group was significantly higher than that of the younger group (p = 0.0181), suggesting that the older group had a relatively better TME immune response. Then, the usage of V and J gene segments were analyzed. Through statistical analysis and the frequencies of V and J gene usage, we identified that more V and J gene usage were different in older and younger patients. The TRBJ1-1 and TRBJ1-2 were more common in younger patients and TRBJ2-1 and TRBJ2-2 were more common in older patients. There was also more V gene usage different in both groups. Conclusions: Given that the use of certain TRBV regions is predominant in tumor tissues, our results suggested that there may be differences in immune responses of TME to tumors in younger and older patients.
HGG-02. NEUROPHYSIOLOGICAL SMALL MOLECULE SCREEN TO TARGET NEURON-GLIOMA INTERACTIONS IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: David Rogawski, Sara Mulinyawe, Craig Thomas, Michelle Monje
Journal: Neuro-Oncology (2021)

Abstract Neurons stimulate glioma growth via synaptic and paracrine signaling mechanisms. We recently demonstrated that neurons form AMPA receptor-dependent synapses with glioma cells, and that neuronal activity also induces potassium-evoked currents that are amplified by gap junctions coupling glioma cells. However, our understanding of the neurotransmitters, receptors, and ion channels participating in neuron-glioma signaling remains incomplete. We have recently developed a high-throughput neuron-glioma co-culture strategy to screen small molecules for agents that may disrupt neuron-glioma signaling. Glioma cell proliferation is increased tenfold when cultured together with neurons; this robust biological effect can be probed in a targeted screen of compounds influencing neurotransmitter receptors and ion channels. The neurophysiological small molecule library used was curated to include approved anti-epileptics, neuroleptics, and antidepressants, as well as a variety of other compounds acting on different neurotransmitter types and ion channels. Hits from the primary screen were run through a counter-screen using glioma cells grown alone without neurons, to identify compounds that specifically affect neuron-glioma interactions. Correlation of the screening results with drug mechanisms of action will allow us to map out the key neurotransmitter pathways regulating glioma growth, which can be further validated using genetic and in vivo experiments. Drugs identified in this glioma neuroscience screen may be readily translated into much-needed therapeutics for children with high-grade glioma.
Health-related quality of life (HRQoL) in patients (pts) with locally advanced basal cell carcinoma (laBCC) treated with cemiplimab: Analysis of a phase II, open-label clinical trial.
Authors: Alexander J. Stratigos, Chieh-I Chen, Cristina Ivanescu, Karl D. Lewis, Ketty Peris, Oliver Edgar Bechter, James Harnett, Vera Mastey, Matthew Reaney, Christina Daskalopoulou, Patrick R. LaFontaine, Gerasimos Konidaris, Denise Bury, Suk Young Yoo, Kosalai Kal Mohan, Ebony Coates, Timothy Geoffrey Bowler, Matthew G. Fury, Aleksandar Sekulic
Journal: Journal of Clinical Oncology (2021)

9566 Background: Cemiplimab-rwlc is the first immunotherapy to receive approval in the US, fully for pts with laBCC and accelerated for metastatic BCC, post hedgehog inhibitors or for whom hedgehog inhibitors are not appropriate. Cemiplimab resulted in clinically meaningful anti-tumor activity in pts with laBCC who progressed on or were intolerant to hedgehog inhibitor therapy (NCT03132636). This analysis evaluated HRQoL in these pts. Methods: Adults with laBCC and ECOG performance status ≤1 (n=84) received IV cemiplimab 350 mg Q3W for up to 9 treatment cycles. At baseline (BL) and day 1 of each cycle (C), pts completed EORTC QLQ-C30 and SKINDEX-16 questionnaires that assess Global Health Status (GHS)/QoL, functioning, and BCC-related symptoms. Mixed-effects repeated measures (MMRM) models were used to estimate least squares (LS) mean (standard error [SE]) change from BL during treatment (i.e., across C2 to C9); changes ≥|10| points were considered clinically meaningful. Responder analyses were conducted in pts with non-missing data from BL to determine the proportions with clinically meaningful improvement or deterioration, or stability on QLQ-C30 and SKINDEX-16 at C2 and C9; a 10-point threshold was considered meaningful for both instruments. Results: BL scores showed moderate to high levels of functioning and low symptom burden. In MMRM models, overall changes from BL on QLQ-C30 indicated stability for GHS/QoL and all scales except for clinically meaningful worsening of fatigue (LS mean [SE] change 12.5 [3.9]; P&lt;.05). In responder analysis, the majority of pts reported clinically meaningful improvement or stability at C2 and C9 on all QLQ-C30 functioning scales and the key symptom of pain but not fatigue (Table). On SKINDEX-16, MMRM models showed clinically meaningful improvement on the emotional subscale (LS mean [SE] change –13.2 [3.9]; P&lt;.05) and stability on the symptom and functional subscales. Responder analysis showed clinically meaningful improvements or stability across the SKINDEX-16 subscales in approximately 80% of pts at C2, and 70–80% of pts at C9. Conclusions: In laBCC pts treated with cemiplimab, the majority reported clinically meaningful improvement or stability in GHS/QoL and functional status while maintaining a low symptom burden except for fatigue. Clinical trial information: NCT03132636. [Table: see text]
Patterns and costs of hospital-based cancer care in the last year of life: A national data linkage study in Scotland.
Authors: Katharina Diernberger, Joanna Bowden, Marie T. Fallon, Xhyljeta Luta, Joanne Droney, Elizabeth Lemmon, Ewan Gray, Holly Ennis, Joachim Marti, Peter S Hall
Journal: Journal of Clinical Oncology (2021)

e18732 Background: Approximately thirty thousand people in Scotland are diagnosed with cancer each year, of whom 10,000 live less than one year. Hospital is the most common place of death for people with cancer, despite most expressing a preference for community-based care. There is inadequate understanding of the nature and value of hospital-based care for people with advanced cancer. This study aimed to describe patterns of hospital-based healthcare use and associated costs for cancer decedents in their last year of life. Methods: A population-wide administrative data linkage study of hospital-based healthcare use for cancer decedents aged 60+ at death who died between 2012 and 2017 was conducted in Scotland. Linkage was established between the Scottish Morbidity Record, Scottish Cancer Registry and the National Records of Scotland. Hospital admissions, length of stay (LoS), number and nature of outpatient and day case appointments were extracted. Associated costs were estimated using generalised linear models, adjusted for age, gender, primary cause of death, socioeconomic deprivation status, rural-urban (RU) status and comorbidity. Results: The study population included 85,732 decedents with a cancer diagnosis, for whom 64,553 (75.3%) cancer was the underlying cause of death. Mean age at death was 84 years. The mean number of inpatient stays in the last year of life was 5.88 (SD 5.68), with a mean LoS of 7 days. Mean total 1-year inpatient, outpatient and day-case costs per patient were £10,261, £1,275 and £977 respectively. People who died of haematological cancers had the most hospital admissions (mean 11.8). Admission rates rose sharply in the last month of life and were most common in those who died of haematological and lung cancers. One year adjusted and unadjusted costs decreased with increasing age. Unadjusted costs for the youngest group (60-64) were £15,895, double the cost for those aged 90+. People dying of haematological cancers had the highest hospital-based costs (mean £24,772) followed by those with ovarian cancer (mean £17,556). The largest single contributor to hospital-based costs in the last year of life was unscheduled admissions. Conclusions: People in Scotland in their last year of life with cancer use substantial hospital-based care. Unscheduled admission rates are high, particularly in the last month of life when the value of acute intervention may be uncertain. Further research is needed to examine triggers for hospitalisation and to assess the value of hospital-based care to people living with advanced cancer.
The impact of the COVID-19 pandemic on the mental health and wellbeing of UK healthcare workers
Authors: James Gilleen, Aida Santaolalla, Lorena Valdearenas, Clara Salice, Montserrat Fuste
Journal: American Journal of Psychiatry (2020)

Abstract  Background  There is an urgent need to understand the psychological impact the COVID-19 pandemic has had on UK healthcare workers (HCW).  Aims  To reveal risk and protective factors associated with poor mental wellbeing of HCW working during the COVID-19 pandemic in the UK.  Method  2773 UK HCWs completed a survey between 22ndApril and 10th May 2020 containing scales measuring anxiety, depression, PTSD, and stress, and questions about roles and COVID-19-related factors including workplace preparation and risk management. Respondents were classified as high or low symptomatic on each mental health scale and logistic regression revealed risk and protective factors associated with each outcome. Change in wellbeing from pre to during COVID-19 was also quantified.  Results  A large proportion of UK HCW had high mental health symptoms. ‘Fixed’ risk factors of poor mental health included being female, being ‘frontline’, pre-existing mental health diagnoses, and experience of stressful/traumatic events. An additional set of ‘controllable’ factors also significantly increased risk: PPE availability, workload, lack of COVID-19 preparation and training, and insufficient communication of clinical procedures. Resilience and sharing stress reduced risk, as did ethical support for those making treatment decisions. Allied HCW and managers were at elevated risk of high symptoms particularly PTSD. Wellbeing, especially of frontline workers, had significantly worsened compared to before COVID-19.  Conclusions  Poor mental wellbeing was prevalent in HCW during the UK COVID-19 response. A number of controllable factors should be targeted, and protective factors promoted, to reduce the detrimental effect of COVID-19 and other pandemics on HCW mental health.
Surrogates of response to treatment of non-small cell lung cancer with immunotherapy: Toxicity and leukocyte ratios—Experience of a center.
Authors: Alba Moratiel Pellitero, Ines Ruiz Moreno, Mara Cruellas, Natalia Alonso Marin, Maitane Ocáriz, Marta Gascon Ruiz, Andrea Sesma Goñi, Maria Zapata-Garcia, Maria Zurera Berjaga, Maria Marti Pi, Ana Goas Gomez, Carlos Camacho Fuentes, Carla Sanchez Cortes, Maria Alvarez, Elisa Quilez, Irene Torres, Julio Jose Lambea- Sorrosal, Dolores Isla, Rodrigo Lastra
Journal: Journal of Clinical Oncology (2021)

e21052 Background: Immunotherapy is proposed as a therapeutic novelty in metastatic non-small cell lung cancer (NSCLC), in many cases already in front line. It presents different adverse effects than traditional schemes, due to the stimulation of the immune system. There is a possible relationship between toxicity and response. Neutrophil-to-lymphocyte ratio (NLR) as a possible predictive factor of response. Objectives: Evaluating the response according to the toxicity degree in NSCLC patients in real clinical practice. Analyze whether pretreatment NLR high patients have a worse prognosis. Methods: Observational, retrospective, analytical, single-center study. HCULB stage IV NSCLC patients with inmunotherapy treatment during 2016-2018. Descriptive and multivariate analysis. Toxicity grade: CTCAE version 4.0. Response assessment: RECIST 2.0 and immunorelated criteria. Toxicity degree and response (global and individualized results according to treatment and histology). Neutrophil-to-lymphocyte ratio and response. Results: N = 43 patients (35 men, 8 women). Average age 64 years. Response: 3 complete response (CR) (toxicity ≥2), 13 partial response (PR) (toxicity ≥1), 13 stable disease (SD), 12 progression (P) (only 4 toxicity and ≤2), 2 not evaluated. Hypothyroidism as the most common irAE. Relationship between toxicity and response: the absence of irAEs conditions worse prognosis p &lt; 0.05. Histology: 25 adenocarcinoma [18 with irAES (1 CR, 7 PR, 8 SD,) and 7 without (1 SD, 5 P, 1 no ev.)]; 17 squamous [13 with irAES (1 CR, 6 PR, 4 SD) and 4 without (3 P, 1 no ev.)]; 1 adenosquamous with irAES and CR. Drug: Atezolizumab N = 8 [6 with irAES (2 PR, 3 SD, 1 P) and 2 without (both P)], Nivolumab N = 16 [9 with irAES (1 CR, 3 PR, 3 SD, 2 P) and 7 without (1 SD, 4 P, 2 no ev.)], Pembrolizumab N = 19 [17 with irAEs (2 CR, 8 PR, 6 SD, 1 P) and 2 without (both P)]. Significant positive correlation between toxicity and response (p &lt; 0.001) R = 0.067, (CI 99% 0.378-0.837), regardless of histology and drug. It is observed a better response in those patients who presented a NRL close to 3 or less at the beginning of treatment. On the contrary, it is observed that subjects with NRL greater than 4 obtained worse results when they were treated with immunotherapy. Conclusions: The appearance of irAES like a response indicator of immune system, seem to conditione better evolution. In contrast, the absence of toxicity predicts a worse prognosis. Further studies with a larger sample are needed to confirm our findings about the predictive value of NLR and optimize therapeutic regimens if necessary.