tbuckley/cabot-search huggingface dataset:
The potential role of melatonin in retarding intervertebral disc ageing and degeneration: A systematic review
Authors: Zhangrong Cheng, Qian Xiang, Juntan Wang, Yukun Zhang
Journal: Ageing Research Reviews (2021)

Intervertebral disc degeneration (IDD) is a common degenerative disease of the musculoskeletal system that develops with age. It is regarded as the main cause of chronic low back pain in the elderly. IDD has various causes, including ageing, mechanical overloading, and nutritional deficiency. Melatonin is a pleiotropic indole hormone secreted by the pineal gland and plays an important role in resisting various degenerative diseases. The serum levels of melatonin decline with age and are reported to be negatively correlated with the symptomatic and histopathological scores of IDD. In vivo studies have shown that exogenous administration of melatonin could maintain the structural integrity of the intervertebral disc and inhibit the development of IDD. Mechanistically, by interacting with its membrane or intracellular receptors, melatonin can promote autophagic flux, scavenge free radicals, inhibit the release of pro-inflammatory factors, and block apoptotic pathways, thereby enhancing anti-stress abilities and matrix anabolism in different types of disc cells. Therefore, melatonin supplementation may be a promising therapeutic strategy for IDD. This review aimed to summarize the latest findings regarding the therapeutic potential of melatonin in IDD.
Predictors of response in EGFR-mutant metastatic non-small cell lung cancer patients treated with tyrosine kinase inhibitors.
Authors: Adnan Aydiner, Izzet Dogan, Nijat Khanmammadov, Pinar Saip, Sezai Vatansever
Journal: Journal of Clinical Oncology (2021)

e21149 Background: EGFR mutations are detected in 15-62% of patients with non-small cell (NSCLC) lung cancer. We can use tyrosine kinase inhibitors (such as erlotinib, gefitinib, afatinib) to treat patients with EGFR-mutant lung cancer. Tyrosine kinase inhibitors improve the survival outcomes of the patients. This study aimed to assess predictors of overall response rate (complete or partial response) in EGFR-mutant non-small cell lung cancer patients treated with EGFR inhibitors. Methods: Data of the EGFR-mutant lung cancer patients were evaluated retrospectively. Clinical, pathological, radiological, and treatment features of the patients were recorded. SPSS 25 version was used for statistical analysis. Kaplan-Meier and Cox-regression methods were used for survival analysis. Also, predictors of overall response were evaluated with logistic regression analysis. Results: 105 patients were included in the study. The female/male patients ratio was 1.25, and the median age was 61 (range, 33-85) years. Adenocarcinoma (90.4%) was the most common histopathological type. The ratios of Exon 19, exon 21, and other (rare or multiple) mutations were 59%, 25%, and 16%, respectively. 89 (84.9%) patients were de-novo metastatic at diagnosis. Before EGFR inhibitor therapy, the patients had received chemotherapy (22.9%) and palliative radiotherapy (40%). The patients received erlotinib (83.8%) or other EGFR inhibitors (16.2%) for treatment. Median overall survival was 30.8 (range 20.2-41.4) months. Overall response rate (complete or partial response) was 61.9%, stable response 11.4%, and progressive disease 26.7%. In logistic regression analysis, we found that age (p = 0.008), number of metastasis sites (p = 0.037), pathological type (adenocarcinoma or other types) (p = 0.001) were statistically significant for the overall response rate. However, gender (p = 0.98), tumor localizations (left or right lung) (p = 0.39), de-novo metastasis (p = 0.81), EGFR mutations type (p = 0.13), and type of EGFR inhibitör (p = 0.30) were not statistically significant. Conclusions: In this study, we showed real-life outcomes of the patients with EGFR-mutant metastatic non-small cell lung cancer. The data of predictors of overall response for EGFR inhibitors is limited. We detected that age, the number of metastatic organs, and histopathological type of tumor were affected the response of treatment.
Authors' reply
Authors: A. J. Fisher, P. A. Corris
Journal: Thorax (2010)

We welcome the letter from Dr Iles and the opportunity to make additional comments on the subject of our recent editorial. 1 It is correct that the mortality rate in normotensive patients with acute pulmonary embolus (PE) reported in the recent study by Boca et al 2 refers to all-cause mortality at 3 months and not inpatient mortality, and we are pleased to have the opportunity to clarify this.A wide range of mortality rates in acute PE have been reported in published studies, depending on whether hypotensive and normotensive patients are included together or reported separately and whether inpatient, 30-day or 3-month mortality is quoted as an end point.Furthermore, identifying the exact cause of death in studies of PE is very difficult and few if any have been able to provide accurate data on this, therefore most report all-cause mortality.In the recent European Society of Cardiology guidelines on acute PE 3 it states that the risk of early mortality in normotensive patients with acute PE is dependent on the presence of right ventricular dysfunction (RVD) on transthoracic echocardiography, with studies reporting rates of 3e15% in those who are normotensive with RVD and <3% in those without RVD.Indeed, in the ICOPER
The marginal diagnostic benefit of pancreatic cancer molecular profiling after germline testing.
Authors: Evan Justin Walker, Amie Blanco, Julia C. Carnevale, Pelin Cinar, Eric Andrew Collisson, Margaret A. Tempero, Andrew H. Ko
Journal: Journal of Clinical Oncology (2021)

10513 Background: Germline genetic testing is now universally recommended for patients (pts) with pancreatic ductal adenocarcinoma (PDAC) for purposes of both familial screening and therapeutic guidance. Treatment selection can be further informed by tumor molecular profiling (TMP) to identify targetable somatic alterations in pts with advanced disease, but this is inconsistently applied. Determination of the rate of actionable findings identified with TMP after germline testing, which we term marginal diagnostic benefit, may inform practice patterns and workflow in this patient population. Methods: This retrospective analysis included all pts with PDAC who underwent germline testing and TMP at UCSF over a 4-yr period. Medical records were reviewed for demographics, disease-specific data, and germline testing/TMP clinical reports. Alterations classified as ‘pathogenic’ or ‘likely pathogenic’ were included, and were deemed ‘actionable’ if there was clinical or preclinical evidence of benefit from targeted therapy in any cancer, as previously described. Results: From 1/2016-1/2020, 144/738 (20%) UCSF pts with PDAC completed both germline testing and TMP. Germline testing identified actionable pathogenic alterations in 10 (7%). TMP confirmed 8/10 of these alterations and identified 3 additional therapeutic targets. Among the 134 pts without actionable germline findings, TMP identified 45 new therapeutic targets in 41 (31%) pts, increasing the overall rate of actionable findings from 7% to 35%. Most (35/58, 60%) actionable alterations involved genes associated with the Homologous Recombination DNA Damage Repair (HR-DDR) pathway (Table). 80% of pts with HR-DDR pathway alterations (9/10 germline, 19/25 somatic) received platinum-based chemotherapy. Four pts were treated with targeted therapy based on test results: PARP-inhibitor (n = 2, germline BRCA1 and PALB2 mutations), PARP-inhibitor + ATR inhibitor (n = 1, somatic ARID1A mutation) and mTOR inhibitor (n = 1, somatic STK11 deletion). Conclusions: In this analysis, PDAC TMP after germline testing increased the detection of actionable alterations (the marginal diagnostic benefit) by five-fold. As more somatic tumor alterations become actionable with the development of targeted therapeutics, TMP is a necessary complement to germline testing to fully inform personalized treatment decisions for all pts with PDAC.[Table: see text]
Phase I study investigating the safety of stereotactic body radiotherapy (SBRT) with anti-PD-1 and anti-IL-8 for the treatment of multiple metastases in advanced solid tumors.
Authors: Lilit Karapetyan, Adam C. Olson, William E. Gooding, Riyue Bao, Steven J. Chmura, Jason J. Luke
Journal: Journal of Clinical Oncology (2021)

TPS2681 Background: Anti-PD-(L)1 immunotherapy improves outcomes for patients across various cancers; however, many patients do not benefit. Previous studies combining multi-site SBRT with anti-PD1 have confirmed feasibility and revealed induction of interferon signaling by SBRT. Elevated levels of serum IL8 (sIL8) associate with lack of response to anti-PD1 and we have observed that elevated IL8 is strongly associated with lack of response to immunotherapy and SBRT combinations. Overcoming IL8 induced epithelial-mesenchymal transitioning and trafficking of myeloid derived suppressor cells in tumor microenvironment therefore represents a promising strategy to overcome resistance. BMS-986253 is a fully human neutralizing antibody that binds to sIL8. The combination of BMS-986253 and nivolumab was safe in patients with advanced solid tumors. The present study aims to evaluate safety and preliminary efficacy of combining BMS-986253 with nivolumab and SBRT in patients with advanced solid tumors, Melanoma (MEL) and Renal Cell Carcinoma (RCC). Methods: This is a phase 1 open label single arm study (CT.gov: NCT04572451) which will include safety and efficacy cohorts. Patients will receive SBRT in 1-4 tumor lesions, in 3 or 5 fractions, at the total of 30 or 45 or 50 Gy based on the irradiated organ site. This will be followed by intravenous (IV) nivolumab (480mg q4 weeks (W)) and IV BMS-986253 (2400mg q2W) within seven days of completing SBRT. In the initial safety portion of the clinical trial, we will include 30 patients with advanced/metastatic solid tumors in order to evaluate safety. The primary endpoint of dose limiting toxicity will be assessed by continual Bayesian monitoring. The toxicities will be attributed to combination of SBRT/Immunotherapy as opposed to individual components. The secondary objective of the study is efficacy with an endpoint of objective response rate (ORR) as assessed by RECIST v1.1 in Mel and RCC. We will include 20 patients with MEL and RCC and compare against a historical benchmark of 20% ORR as sufficient signal of activity for further study. ORR will be assessed for association with serum IL-8 levels and radiation-induced changes in peripheral blood T cell populations. Clinical trial information: NCT04572451.
Generation of a HuTCR mouse platform-derived MAGE-A1-directed high-affinity TCR with superior potency versus human-derived TCRs.
Authors: Ioannis Gavvovidis, Matthias Leisegang, Jenifer Oduro, Matthias Obenaus, Eugen Leo, Thomas Blankenstein, Elisa Kieback
Journal: Journal of Clinical Oncology (2021)

e14515 Background: As cancer-testis antigens are self-antigens, T cells expressing high-affinity TCRs against such antigens are suppressed via negative thymic selection. Therefore, patient- or donor-derived TCRs are typically of low affinity and result in a reduced antitumor effect. Using our proprietary HuTCR platform, which consists of mouse lines carrying the full human TCR α/β loci in combination with common human HLA alleles, we have isolated high-affinity TCRs specific for the cancer-testis antigen MAGE-A1 and compared them to human-derived MAGE-A1-specific TCRs that are currently reported to be in clinical development. Furthermore, we validated MAGE-A1 as a potential cancer therapy target by using immunohistochemistry to evaluate expression in several major tumor types and healthy tissue. Methods: Using scRNAseq, TCRs were isolated from HuTCR mice. Human-derived MAGE-A1-specific TCR sequences were obtained from publicly available databases. All TCRs were expressed in primary human T cells as verified using peptide-MHC-multimer staining. Functional avidity of the TCRs was analyzed by coculture with T2 target cells loaded with titrated amounts of epitope peptides and measuring cytokine concentration by ELISA. Reactivity of TCRs to endogenously processed MAGE-A1 protein was assessed by co-culture with a panel of tumor cell lines varying in MAGE-A1 and/or MHC-class-I expression. MAGE-A1 expression on protein level was evaluated by immunohistochemistry. Results: Immunization of HuTCR mice with the antigen resulted in robust CD8+ T cell responses and several TCR clonotypes were identified by scRNAseq, with the majority of clonotypes being specific to the MAGE-A1-derived peptide KVLEYVIKV and TCR affinities ranging from 0.3 nM to 3 nM. By comparison, human-derived TCRs exhibited generally lower functional avidity from 3 nM to 60 nM. In addition, HuTCR-mouse-derived TCRs were more sensitive in recognition of tumor cell lines expressing low MAGE-A1 and/or HLA-A2. Immunohistochemical analysis of MAGE-A1 expression in healthy tissues demonstrated highly selective expression of MAGE-A1 in testis, only. Screening for expression confirmed that a significant proportion of several major cancer types expresses MAGE-A1 as reported by various other groups [reviewed in Curr Opin Cell Biol. 2015 December; 37: 1–8]. Conclusions: The HuTCR mouse platform allows for the generation of high-affinity MAGE-A1-specific TCRs with increased anti-tumor efficacy as compared to human-derived TCRs against the same cancer antigen. In addition, it was confirmed that MAGE-A1 has a highly selective expression pattern in healthy tissues (testis, only), but shows distinct expression in several major human tumor types.
The Minnesota Refined Acute GVHD Score Predicts Response to Initial Therapy, Survival and Non-Relapse Mortality after Haploidentical Transplantation with Post-Transplant Cyclophosphamide
Authors: Jacopo Mariotti, Angela Granata, Raynier Devillier, Stefania Bramanti, Barbara Sarina, Sabine Furst, Catherine Faucher, Samia Harbi, Lucio Morabito, Christian Chabannon, Carmelo Carlo-Stella, Reda Bouabdallah, Armando Santoro, Didier Blaise, Luca Castagna
Journal: Blood (2017)
Treatments and outcomes of generalized pustular psoriasis: A cohort of 1516 patients in a nationwide inpatient database in Japan
Authors: Hideaki Miyachi, Takaaki Konishi, Ryosuke Kumazawa, Hiroki Matsui, Sayuri Shimizu, Kiyohide Fushimi, Hiroyuki Matsue, Hideo Yasunaga
Journal: Journal of the American Academy of Dermatology (2021)
“Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies
Authors: Yuxing Xia, Stefan Prokop, Benoit I. Giasson
Journal: Molecular Neurodegeneration (2021)

Phosphorylation is one of the most prevalent post-translational modifications found in aggregated tau isolated from Alzheimer's disease (AD) patient brains. In tauopathies like AD, increased phosphorylation or hyperphosphorylation can contribute to microtubule dysfunction and is associated with tau aggregation. In this review, we provide an overview of the structure and functions of tau protein as well as the physiologic roles of tau phosphorylation. We also extensively survey tau phosphorylation sites identified in brain tissue and cerebrospinal fluid from AD patients compared to age-matched healthy controls, which may serve as disease-specific biomarkers. Recently, new assays have been developed to measure minute amounts of specific forms of phosphorylated tau in both cerebrospinal fluid and plasma, which could potentially be useful for aiding clinical diagnosis and monitoring disease progression. Additionally, multiple therapies targeting phosphorylated tau are in various stages of clinical trials including kinase inhibitors, phosphatase activators, and tau immunotherapy. With promising early results, therapies that target phosphorylated tau could be useful at slowing tau hyperphosphorylation and aggregation in AD and other tauopathies.
18F-Choline PET/CT, MRI, and Software-Based Image Fusion Analysis in Patients With Primary Hyperparathyroidism
Authors: Thomas Hofer, Juergen Kronbichler, Helmut Huber, Benedikt Hergan, Bernhard Kaiser, Andreas Shamiyeh, Franz Fellner, Michael Gabriel
Journal: Clinical Nuclear Medicine (2021)

Purpose The aim of this study was to evaluate the diagnostic performance of 18 F-choline PET and MRI in patients with primary hyperparathyroidism. Furthermore, the additional value of software-based PET/MRI scan fusion was analyzed. Patients and Methods This retrospective study includes 42 patients (38 women) with an age between 32.5 and 79.1 years. PET/CT scans were performed on a dedicated system after injection of 250 to 350 MBq 18 F-choline. For the MRI examination, T1-weighted images of the cervical region were used. The image fusion was made by anatomical coregistration using an automated algorithm based on mutual information. Results A total of 46 lesions were discovered and histologically confirmed in 42 patients. Histopathological examination revealed 38 adenomas and 8 hyperplasias. This means that, in 4 of these 42 patients, 2 lesions per patient were discovered. PET/CT also detected 46 abnormal findings, but only 43 were correctly recognized, whereas the other 3 were false-positive (FP). Six lesions could not be detected correctly: 3 were FP and 3 false-negative, which resulted in a sensitivity of 93.5% and a specificity of 97.5%. The site-specific evaluation showed 18 true-positive enlarged parathyroid glands with MRI, but also produced 13 FP findings and failed to detect 28 lesions; the sensitivity and specificity are thus 39.1% and 89.3%, respectively. The difference in detection rate between 18 F-choline PET/CT and MRI was statistically significant ( P &lt; 0.001). Conclusions 18 F-choline PET/CT is clearly superior to MRI for localization diagnostics in primary hyperparathyroidism. Image fusion of both modalities can be helpful for more precise anatomical assignment.
Racial Differences in Adiponectin in Youth
Authors: SoJung Lee, Fida Bacha, Neslihan Gungor, Silva A. Arslanian
Journal: Diabetes Care (2006)

OBJECTIVE—The purpose of this study was to investigate 1) whether adiponectin is associated with insulin sensitivity independent of visceral adipose tissue in African-American and Caucasian youth and 2) whether adiponectin is associated with racial differences in insulin sensitivity. RESEARCH DESIGN AND METHODS—Total body fat was measured by dual-energy X-ray absorptiometry and abdominal adipose tissue with computed tomography. Insulin sensitivity was measured by a 3-h hyperinsulinemic-euglycemic clamp. RESULTS—Adiponectin was inversely associated (P &amp;lt; 0.01) with visceral adipose tissue, fasting insulin, and proinsulin and was positively related (P &amp;lt; 0.01) to insulin sensitivity after controlling for Tanner stage and sex independent of race. Stepwise multiple regression revealed that adiponectin was a strong independent predictor of insulin sensitivity, explaining 27% of the variance in insulin sensitivity. When subjects were categorized into tertiles of visceral adipose tissue and further low (≤50th) and high (&amp;gt;50th) adiponectin groups, insulin sensitivity was significantly different across the visceral adipose tissue groups (main effect, P &amp;lt; 0.01) in both races. However, within each visceral adipose tissue group, subjects with high adiponectin had higher insulin sensitivity (main effect, P &amp;lt; 0.05) than subjects with low adiponectin, independent of race. Racial differences in insulin sensitivity remained significant (P &amp;lt; 0.01) after controlling for leptin and visceral adipose tissue but not (P &amp;gt; 0.05) after additional adjustment for adiponectin. CONCLUSIONS—Adiponectin is associated with insulin sensitivity independent of visceral adipose tissue in both African-American and Caucasian youth. Low adiponectin in African-American youth may be a biological marker that predisposes them to a greater risk of insulin resistance.
HIPAA and the Leak of “Deidentified” EHR Data
Authors: Kenneth D. Mandl, Eric D. Perakslis
Journal: New England Journal of Medicine (2021)

Interview with Dr. Anita Allen on progress in protecting health information privacy and the current direction of regulatory momentum. (13:14)Download Although patients (and their physicians) still have difficulty obtaining complete medical record information in a timely fashion, HIPAA policies permit massive troves of digital health data to traverse the medical–industrial complex unmonitored and unregulated.
A phase II study of epirubicin combined with anlotinib followed by anlotinib in the first-line treatment of advanced unresectablesoft tissue sarcoma.
Authors: Yuhong Zhou, Zhiming Wang, Rongyuan Zhuang, Xi Guo, Chenlu Zhang, Yang You, Lisha Chen, Wenshuai Liu, Yong Zhang, Weiqi Lu
Journal: Journal of Clinical Oncology (2021)

e23536 Background: Anlotinib, a multi-target TKI,showed well efficiency and tolerance for the treatment of recurrent or metastatic soft tissue sarcoma (STS). Moreover, the synergistic activity of anlotinib plus epirubicin on the sarcoma PDX modelwas confirmed in our previous preclinical study. This phase II clinical study was designed to assess the efficacy and safety of epirubicin combined with anlotinib followed by anlotinib in the first-line treatment of advanced unresectable STS. Methods: This study is an open-label, prospective, single-arm phase II clinical study. Patients (pts) with locally advanced or metastatic soft tissue sarcomas confirmed by histopathology and not suitable for surgery were recruited, and treated with 6 cycles of anlotinib and epirubicin (epirubicin 90mg/m 2 CIV for 48 hours on day 1 and anlotinib 12 mg QD on day1-14, 21 days per cycle), followed by anlotinib alone unless the pts experienced progression or intolerance. Tumor imaging evaluations and echocardiography were performed every 2 cycles during combined therapy, and were performed every 3 cycles during the sequential anlotinib treatment. The primary end point was the progression-free rate at 12 weeks (PFR 12w ) and 6 months (PFR 6m ), secondary endpoints included ORR, PFS, safety, DCR and OS. Results: 33 eligible pts were enrolled from June 2019 to August 2020, and 3 pts dropped out without completing one cycle of treatment. Of 30efficacy-evaluable pts,10 were man, median age was 48 (range 18-74). The main subtypes included 10 leiomyosarcoma, 8 fibrosarcoma, 5 dedifferentiated liposarcoma, 4 synovial sarcoma, 2 undifferentiated pleomorphic sarcoma, and 1 epithelioid sarcoma. The average number of combined treatment cycle is 4.7 (range 2-6), 13 pts had entered into anlotinib maintenance treatment. The PFR 12w , PFR 6m , ORR, DCR were 70%,53.8%, 13.3%, and 80%,respectively. Median PFS was 11.5 months (95%CI: 5.0-NA), median OS has not been reached. As cut-off on Jan 20th 2020, 6 pts are still in treatment. The other pts discontinued trial due to disease progression (16/24), adverse events (AEs) (3/24), changes in treatment strategy because of tumor shrinkage (3/24), cytoreductive surgery (1/24), and opt-out (1/24). The main AEs were grade III-IV neutropenia (8/30, 26.7%), and 7 of them were febrile neutropenia (7/30, 23.3%). Until now, no cardiac-related AEswere observed. Conclusions: Advanced unresectable STS pts could benefit from epirubicin combined with anlotinib followed by anlotinibtreatment in first line. And it is generally well tolerated especially with no short-term cardiac toxicity. Clinical trial information: ChiCTR1900024928.