tbuckley/cabot-search huggingface dataset:
Survival after inpatient or outpatient pulmonary rehabilitation in patients with fibrotic interstitial lung disease: a multicentre retrospective cohort study
Authors: Sabina Anna Guler, Seo Am Hur, Michael K Stickland, Patrick Brun, Luc Bovet, Anne E Holland, Janet Bondarenko, Nathan Hambly, Joshua Wald, Nima Makhdami, Michael Kreuter, Rainer Gloeckl, Inga Jarosch, Benjamin Tan, Kerri A Johannson, S Ainslie McBride, Kaissa De Boer, Jacqueline S Sandoz, Kelly Sun, Deborah Assayag, Surya P Bhatt, Julie Morisset, Vincent Ferraro, Chris Garvey, Pat G Camp, Christopher J Ryerson
Journal: Thorax (2021)

The impact of pulmonary rehabilitation (PR) on survival in patients with fibrotic interstitial lung disease (ILD) is unknown. Given the challenges conducting a large randomised controlled trial, we aimed to determine whether improvement in 6-minute walk distance (6MWD) was associated with better survival.This retrospective, international cohort study included patients with fibrotic ILD participating in either inpatient or outpatient PR at 12 sites in 5 countries. Multivariable models were used to estimate the association between change in 6MWD and time to death or lung transplantation accounting for clustering by centre and other confounders.701 participants (445 men and 256 women) with fibrotic ILD were included. The mean±SD ages of the 196 inpatients and 505 outpatients were 70±11 and 69±12 years, respectively. Baseline/changes in 6MWD were 262±128/55±83 m for inpatients and 358±125/34±65 m for outpatients. Improvement in 6MWD during PR was associated with lower hazard rates for death or lung transplant on adjusted analysis for both inpatient (HR per 10 m 0.94, 95% CI 0.91 to 0.97, p<0.001) and outpatient PR (HR 0.97, 95% CI 0.95 to 1.00, p=0.042). Participation in ≥80% of planned outpatient PR sessions was associated with a 33% lower risk of death (95% CI 0.49% to 0.92%).Patients with fibrotic ILD who improved physical performance during PR had better survival compared with those who did not improve performance. Confirmation of these hypothesis-generating findings in a randomised controlled trial would be required to definitely change clinical practice, and would further support efforts to improve availability of PR for patients with fibrotic ILD.
Clinical and genetic characterization of cancer patients with multiple germline variants.
Authors: Hong Zheng, Min Gao, Weijiao Gao, Nan Zhang, Hongguo Wang, Nan Song, Naiyi Zhang, Wei Wang, Qian Li, Mingming Yuan, Rongrong Chen, Xuefeng Xia, Yunong Gao
Journal: Journal of Clinical Oncology (2021)

e22523 Background: Hereditary tumors are generally monogenic diseases with autosomal dominant inheritance. However, we noticed that some individuals may harbor ≥2 germline mutations in one or multiple genes, which remains to be explored. Methods: Genetic mutations were reviewed in more than 50,000 cancer patients who underwent hybridization capture based next-generation sequencing (NGS). Germline variants were interpreted following ACMG guideline, and only pathogenic and likely pathogenic variants were included in this study. Results: Multiple germline variants were identified in 42 individuals with the detection rate of 0.075%. The median age at diagnosis was 48 years (range 31-73). Two thirds of patients were female and 26.2% of patients has cancer family history. Prostate cancer is the most common cancer type (0.6%, 2/332), followed by carcinomas of ovarian or fallopian tube (0.48%, 7/1461), breast (0.24%, 8/3302), pancreas (0.2%, 2/982) and so on. Surprisingly, 7 patients with lung cancer also harbored ≥2 germline mutations (0.02%). Most of these germline variants affected DNA damage repair pathways [75.6% homologous recombination repair (HR), 8.1% mismatch repair (MMR), 1.2% base excision repair (BER)]. Four patients had two germline variants identified on a single gene (2 ATM, 1 BRCA1, 1 BRCA2). Three variants were identified in 2 patients, and 2 variants were identified in the remaining 36 patients. Two or more germline variants in HRR pathway were identified in 64.3% of patients, among which 18.5% patients had BRCA1+ BRCA2 double variants. The efficacy of poly ADP-ribose polymerase inhibitors (PARPi) in this specific population should raise concern. Besides, double variants in HRR and MMR pathway were found in 5 patients, which suggested the potential benefit of immunotherapy and PARPi combination therapy. Conclusions: In addition to identify variants contributing to the personal and family cancer history, NGS can accidentally identify germline variants that may suggest the susceptibility of other hereditary tumors. Multiple variants on HRR or MMR genes may have important implications for the treatment strategy for these patients.
Resection of a tubular adenoma in the distal common bile duct through percutaneous choledochoscopy
Authors: Long He, Shuai Bai, Liansong Ye, Bing Hu
Journal: Endoscopy (2021)

A 59-year-old man was admitted to our hospital with a neoplasm in the distal common bile duct ([Fig. 1]), which had been detected during laparoscopic exploration for biliary stone in a local hospital 2 months earlier. Magnetic resonance cholangiopancreatography showed a filling defect without invasion of surrounding organs ([Fig. 2]). Combining the result of multidisciplinary discussion and the wishes of the patient, percutaneous choledochoscopic treatment through the T-tube tract was performed for him ([Video 1]).
The Lancet Commission on water, sanitation and hygiene, and health
Authors: Argaw Amebelu, Radu Ban, Jay Bhagwan, Joe brown, Roma Chilengi, Clare Chandler, John Matthew Colford, Oliver Cumming, Valerie Curtis, Barbara Elvy Evans, Matthew Charles Freeman, Raymond Guiteras, Guy Howard, Jean Humphrey, Gagandeep Kang, Robinah Kulabako, Claudio Franco Lanata, Maggie Ann Montgomery, Amy Janel Pickering, Clair Null, Jennyfer Wolf
Journal: The Lancet (2021)
Malignant Lymphoma Diagnosed as Gallbladder Carcinoma on 18F-FDG PET/CT
Authors: Lian Xu, Xiaofeng Yu, Yumei Chen, Jianjun Liu
Journal: Clinical Nuclear Medicine (2021)

Abstract Extranodal primary lymphoma of gallbladder is extremely rare. We report a 48-year-old woman initially diagnosed as gallbladder carcinoma with lymph nodes metastases by contrast-enhanced CT and MRI. Meanwhile the images of 18 F-FDG PET/CT highly suggested gallbladder carcinoma due to the necrosis in one of the enlarged lymph nodes. However, it was proved to be diffuse large B-cell lymphoma by the histopathological diagnosis.
Patients with mesenchymal tumours and high<i>Fusobacteriales</i>prevalence have worse prognosis in colorectal cancer (CRC)
Authors: Manuela Salvucci, Nyree Crawford, Katie Stott, Susan Bullman, Daniel B Longley, Jochen H M Prehn
Journal: Gut (2021)

Transcriptomic-based subtyping, consensus molecular subtyping (CMS) and colorectal cancer intrinsic subtyping (CRIS) identify a patient subpopulation with mesenchymal traits (CMS4/CRIS-B) and poorer outcome. Here, we investigated the relationship between prevalence of Fusobacterium nucleatum (Fn) and Fusobacteriales, CMS/CRIS subtyping, cell type composition, immune infiltrates and host contexture to refine patient stratification and to identify druggable context-specific vulnerabilities.We coupled cell culture experiments with characterisation of Fn/Fusobacteriales prevalence and host biology/microenviroment in tumours from two independent colorectal cancer patient cohorts (Taxonomy: n=140, colon and rectal cases of The Cancer Genome Atlas (TCGA-COAD-READ) cohort: n=605).In vitro, Fn infection induced inflammation via nuclear factor kappa-light-chain-enhancer of activated B cells/tumour necrosis factor alpha in HCT116 and HT29 cancer cell lines. In patients, high Fn/Fusobacteriales were found in CMS1, microsatellite unstable () tumours, with infiltration of M1 macrophages, reduced M2 macrophages, and high interleukin (IL)-6/IL-8/IL-1β signalling. Analysis of the Taxonomy cohort suggested that Fn was prognostic for CMS4/CRIS-B patients, despite having lower Fn load than CMS1 patients. In the TCGA-COAD-READ cohort, we likewise identified a differential association between Fusobacteriales relative abundance and outcome when stratifying patients in mesenchymal (either CMS4 and/or CRIS-B) versus non-mesenchymal (neither CMS4 nor CRIS-B). Patients with mesenchymal tumours and high Fusobacteriales had approximately twofold higher risk of worse outcome. These associations were null in non-mesenchymal patients. Modelling the three-way association between Fusobacteriales prevalence, molecular subtyping and host contexture with logistic models with an interaction term disentangled the pathogen-host signalling relationship and identified aberrations (including NOTCH, CSF1-3 and IL-6/IL-8) as candidate targets.This study identifies CMS4/CRIS-B patients with high Fn/Fusobacteriales prevalence as a high-risk subpopulation that may benefit from therapeutics targeting mesenchymal biology.
P-282 Factors predicting response to neoadjuvant chemotherapy in gastric cancer
Authors: P. Kumar CG, D. Muduly, M. Imaduddin, S. Ambre, L. Colney, M. Sultania, J. Swain, S. Majumdar, S. Mohakud, S. Patra, M. Kar
Journal: Annals of Oncology (2021)
Relationship between genetically determined telomere length and glioma risk
Authors: Charlie N Saunders, Ben Kinnersley, Richard Culliford, Alex J Cornish, Philip J Law, Richard S Houlston
Journal: Neuro-Oncology (2021)

Abstract Background Telomere maintenance is increasingly recognized as being fundamental to glioma oncogenesis with longer leukocyte telomere length (LTL) reported to increase risk of glioma. To gain further insight into the relationship between telomere genetics and risk of glioma, we conducted several complementary analyses, using genome-wide association studies data on LTL (78 592 individuals) and glioma (12 488 cases and 18 169 controls). Methods We performed both classical and summary Mendelian randomization (SMR), coupled with heterogeneity in dependent instruments tests, at genome-wide significant LTL loci to examine if an association was mediated by the same causal variant in glioma. To prioritize genes underscoring glioma-LTL associations, we analyzed gene expression and DNA methylation data. Results Genetically increased LTL was significantly associated with increased glioma risk, random-effects inverse variance weighted ORs per 1 SD unit increase in the putative risk factor (odds ratio [OR]SD) 4.79 (95% confidence interval: 2.11-10.85; P = 1.76 × 10−4). SMR confirmed the previously reported LTL associations at 3q26.2 (TERC; PSMR = 1.33 × 10−5), 5p15.33 (TERT; PSMR = 9.80 × 10−27), 10q24.33 (STN1 alias OBFC1; PSMR = 4.31 × 10−5), and 20q13.3 (STMN3/RTEL1; PSMR = 2.47 × 10−4) glioma risk loci. Our analysis implicates variation at 1q42.12 (PSMR = 1.55 × 10−2), 6p21.3 (PSMR = 9.76 × 10−3), 6p22.2 (PSMR = 5.45 × 10−3), 7q31.33 (PSMR = 6.52 × 10−3), and 11q22.3 (PSMR = 8.89 × 10−4) as risk factors for glioma risk. While complicated by patterns of linkage disequilibrium, genetic variation involving PARP1, PRRC2A, CARMIL1, POT1, and ATM-NPAT1 was implicated in the etiology of glioma. Conclusions These observations extend the role of telomere-related genes in the development of glioma.
Tissue factor cytoplasmic domain exacerbates post-infarct left ventricular remodeling via orchestrating cardiac inflammation and angiogenesis
Authors: Suet Yen Chong, Olga Zharkova, Siti Maryam J.M. Yatim, Xiaoyuan Wang, Xiong Chang Lim, Chenyuan Huang, Chia Yee Tan, Jianming Jiang, Lei Ye, Michelle Siying Tan, Veronique Angeli, Henri H. Versteeg, Mieke Dewerchin, Peter Carmeliet, Carolyn S.P. Lam, Mark Y. Chan, Dominique P.V. de Kleijn, Jiong-Wei Wang
Journal: Theranostics (2021)

The coagulation protein tissue factor (TF) regulates inflammation and angiogenesis via its cytoplasmic domain in infection, cancer and diabetes. While TF is highly abundant in the heart and is implicated in cardiac pathology, the contribution of its cytoplasmic domain to post-infarct myocardial injury and adverse left ventricular (LV) remodeling remains unknown. Methods: Myocardial infarction was induced in wild-type mice or mice lacking the TF cytoplasmic domain (TF∆CT) by occlusion of the left anterior descending coronary artery. Heart function was monitored with echocardiography. Heart tissue was collected at different time-points for histological, molecular and flow cytometry analysis. Results: Compared with wild-type mice, TF∆CT had a higher survival rate during a 28-day follow-up after myocardial infarction. Among surviving mice, TF∆CT mice had better cardiac function and less LV remodeling than wild-type mice. The overall improvement of post-infarct cardiac performance in TF∆CT mice, as revealed by speckle-tracking strain analysis, was attributed to reduced myocardial deformation in the peri-infarct region. Histological analysis demonstrated that TF∆CT hearts had in the infarct area greater proliferation of myofibroblasts and better scar formation. Compared with wild-type hearts, infarcted TF∆CT hearts showed less infiltration of proinflammatory cells with concomitant lower expression of protease-activated receptor-1 (PAR1) - Rac1 axis. In particular, infarcted TF∆CT hearts displayed markedly lower ratios of inflammatory M1 macrophages and reparative M2 macrophages (M1/M2). In vitro experiment with primary macrophages demonstrated that deletion of the TF cytoplasmic domain inhibited macrophage polarization toward the M1 phenotype. Furthermore, infarcted TF∆CT hearts presented markedly higher peri-infarct vessel density associated with enhanced endothelial cell proliferation and higher expression of PAR2 and PAR2-associated pro-angiogenic pathway factors. Finally, the overall cardioprotective effects observed in TF∆CT mice could be abolished by subcutaneously infusing a cocktail of PAR1-activating peptide and PAR2-inhibiting peptide via osmotic minipumps. Conclusions: Our findings demonstrate that the TF cytoplasmic domain exacerbates post-infarct cardiac injury and adverse LV remodeling via differential regulation of inflammation and angiogenesis. Targeted inhibition of the TF cytoplasmic domain-mediated intracellular signaling may ameliorate post-infarct LV remodeling without perturbing coagulation.
A phase 2 trial of apatinib combined with intensity modulated radiation therapy for patients with unresectable hepatocelluar carcinoma.
Authors: Shaobo Ke, Hu Qiu, Jin Peng, Gaoke Cai, Yutian Zhangcai, Hao Cheng, Yuxin Cai, Lingling Xia, Xixi Luo, Yong Wu, Yi Gong, Jing Wang, Wei Shi, Jiamei Chen, Wensi Zhao, Shasha Ruan, Yongshun Chen
Journal: Journal of Clinical Oncology (2021)

e16136 Background: To estimate the clinical outcomes and safety for patients with unresectable advanced hepatocelluar carcinoma (HCC) treated with apatinib in combination with intensity modulated radiation therapy (IMRT). Methods: This study was an open-label, single-arm, phase 2 clinical trial of apatinib combined with IMRT for treatment of patients with unresectable advanced HCC. Patients aged between 18 and 75 years with adequate hematologic, liver, and renal functions, and ECOG performance status of 1 or less were included in the study between March 2017 and September 2020. Patients received IMRT (biologically effective dose(BED): 46-60Gy), and continuous apatinib (250-500 mg/d) orally until disease progression or unacceptable toxic effects. The primary end point was progression-free survival(PFS), the secondary end points included overall survival(OS), disease control rate (DCR), objective response rate(ORR) and safety. The data were analyzed for this report with cutoff on February 1, 2021. Results: A total of 46 patients were screened and 33 were enrolled in this study. The cohort had a median age of 56.7 years (range 21-77), 28(84.85%) were men. 25(75.76%) patients had hepatitis B, 32(96.7%) were BCLC stage B-C, 31(93.9%) were Child-Pugh A-B，and 8(24.2%) had portal vein involvement. Receiving first-line and second- or later-line treatment were 21(63.6%) and 12(36.4%), respectively. At a median follow-up of 11.6 months, the median PFS was 7.68 months(95% confidence interval:5.39-9.76) .The 6-month and 12-month overall survival rates were 100% and 96.2%, respectively. According to Response Evaluation Criteria in Solid Tumors Version 1.1, the ORR and DCR were 15% and 82%, respectively. There were 15 (15.2%) grade 3-4 treatment-related adverse events including neutropenia, thrombocytopenia, hypertension, proteinuria and hand and foot syndrome. There were no treatment-related deaths. Conclusions: Apatinib in combination with IMRT was safe and effective in improving PFS and DCR, and suggested an encouraging anti-tumor activity in patients with unresectable advanced HCC. Clinical trial information: ChiCTR-OPC-17011890.
P13.19 Bi-modular G-quadruplex DNA-crypto-aptamers diminish viability of glioma primary cell cultures of patients
Authors: A M Kopylov, N Samoylenkova, A Bizayeva, A Arutyunyan, V Tashlitsky, D Golbin, D Usachev, G Pavlova
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND G-quadruplex oligonucleotides (GQs) exhibit specific anti-survival activity in human cancer cell lines; they can selectively inhibit the viability/proliferation. The most studied, AS1411, had been in clinical trials. This anti-proliferative ability of GQs could be translated into glioma, which currently has poor prognosis and low-efficiency therapeutic treatments for glioblastoma multiform (GBM). Set of GQs have been designed, synthesized, and tested: they have different amount of Q-quartets, they have dimers of different GQ modules: either covalent dimers or non-covalent ones; all of them could be coined as ‘twins’. MATERIAL AND METHODS Folding of synthetic DNA oligonucleotides into GQs and thermal stability have been studied by circular dichroism, melting with unfolding-folding regimes, oligomerization was followed by original SE-HPLC. Conventional human cell lines U87 and fibroblasts from human embryo (HEF) were provided from the collection of the Centre of Neurosurgery (Moscow, Russia). GBM primary cell cultures N1, G11, Sus/fP2, G22, G23, and G01 were developed in Burdenko National Medical Research Centre of Neurosurgery (NMRCN) from the surgery samples of patients (PCC_SSP). All samples had WT IDH1. This study was approved by the Ethics Committee of Burdenko NMRCN, Russian Academy of Medical Sciences (№_12/2020, 15.12.2020). All subjects gave written informed consent in accordance with the guidelines of Declaration of Helsinki. Cell viability was tested by conventional MTT-test. RESULTS Novel bi-modular GQ, bi-(AID-1-T), twin of three-quartet AID-1-T, was designed by covalent conjugation of two AID-1-Ts via three thymidine link, TTT; and linking did not interfere with its GQ structure. Comparison of bi-(AID-1-T) with mono-modular AID-1-T, mono-modular two-quartet HD1, bi-modular bi-HD1, and two-quartet AS1411, was made. Among five GQs, bi-(AID-1-T) had the highest anti-survival activity for U87, while not affecting the control, HEF. GQs, for the first time, were tested on several PCC_SSP. Sensitivity of PCC_SSP toward GQs varied, with apparent IC50 of less than 1 μM for bi-(AID-1-T) toward the most sensitive G11 (glioma, Grade III). CONCLUSION GQs as anti-proliferative crypto-aptamers with moderate activity due to restricted functioning of apparent GQ-binding proteins could be applied toward real glioma PCC_SSP. Variety of effects reflects glioma inter-tumor heterogeneity.Research was funded by Ministry of Education and Science of Russia, grant number № 075-15-2020-809 (13.1902.21.0030) and by Russian Foundation for Basic Research, grants number №18-29-01047
Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial
Authors: JoAnn Lindenfeld, Michael R Zile, Akshay S Desai, Kunjan Bhatt, Anique Ducharme, Douglas Horstmanshof, Selim R Krim, Alan Maisel, Mandeep R Mehra, Sara Paul, Samuel F Sears, Andrew J Sauer, Frank Smart, Marcel Zughaib, Paige Castaneda, Jean Kelly, Nessa Johnson, Poornima Sood, Greg Ginn, John Henderson, Philip B Adamson, Maria Rosa Costanzo
Journal: The Lancet (2021)
Convergent Phenotypic Evolution of Rhodopsin for Dim-Light Sensing across Deep-Diving Vertebrates
Authors: Yu Xia, Yimeng Cui, Aishan Wang, Fangnan Liu, Hai Chi, Joshua H T Potter, Joseph Williamson, Xiaolan Chen, Stephen J Rossiter, Yang Liu
Journal: Molecular Biology and Evolution (2021)

Abstract Rhodopsin comprises an opsin attached to a retinal chromophore and is the only visual pigment conferring dim-light vision in vertebrates. On activation by photons, the retinal group becomes detached from the opsin, which is then inactive until it is recharged. Of all vertebrate species, those that dive face unique visual challenges, experiencing rapid decreases in light level and hunting in near darkness. Here, we combine sequence analyses with functional assays to show that the rhodopsin pigments of four divergent lineages of deep-diving vertebrates have undergone convergent increases in their retinal release rate. We compare gene sequences and detect parallel amino acids between penguins and diving mammals and perform mutagenesis to show that a single critical residue fully explains the observed increases in retinal release rate in both the emperor penguin and beaked whale. At the same time, we find that other shared sites have no significant effect on retinal release, implying that convergence does not always signify adaptive significance. We propose that accelerated retinal release confers rapid rhodopsin recharging, enabling the visual systems of diving species to adjust quickly to changing light levels as they descend through the water column. This contrasts with nocturnal species, where adaptation to darkness has been attributed to slower retinal release rates.
Microalgae‐Derived Health Supplements to Therapeutic Shifts: Redox‐Based Study Opportunities with AIE‐Based Technologies
Authors: A. H. M. Mohsinul Reza, Xiaochen Zhu, Jianguang Qin, Youhong Tang
Journal: Advanced Healthcare Materials (2021)

Abstract Reactive oxygen species (ROS) are highly reactive molecules, serve the normal signaling in different cell types. Targeting ROS as the chemical signals, different stress based strategies have been developed to synthesis different anti‐inflammatory molecules in microalgae. These molecules could be utilized as health supplements in human. To provoke the ROS‐mediated defence systems, their connotation with the associated conditions must be well understood, therefore, proper tools for studying ROS in natural state are essential. The in vivo detection of ROS with phosphorescent probes offers promising opportunities to study these molecules in a non‐invasive manner. Most of the common problems in the traditional fluorescent probes are lower photostability, excitation intensity, slow responsiveness, and the microenvironment that challenge their performance. Some ROS‐specific aggregationinduced emission luminogens (AIEgens) with pronounced spatial and temporal resolution have recently demonstrated high selectivity, rapid responsiveness, and efficacies to resolve the aggregation‐caused quenching issues. The nanocomposites of some AIE‐photosensitizers can also improve the ROS‐mediated photodynamic therapy. These AIEgens could be used to induce bioactive components in microalgae through altering the ROS signaling, therefore are more auspicious for biomedical research. This study reviews the prospects of AIEgen‐based technologies to understand the ROS mediated bio‐physiological processes in microalgae for better healthcare benefits.