tbuckley/cabot-search huggingface dataset:
Modulation of protein fate decision by small molecules: targeting molecular chaperone machinery
Authors: Lei Wang, Xiaoli Xu, Zhengyu Jiang, Qidong You
Journal: Acta Pharmaceutica Sinica B (2020)

Modulation of protein fate decision and protein homeostasis plays a significant role in altering the protein level, which acts as an orientation to develop drugs with new mechanisms. The molecular chaperones exert significant biological functions on modulation of protein fate decision and protein homeostasis under constantly changing environmental conditions through extensive protein–protein interactions (PPIs) with their client proteins. With the help of molecular chaperone machinery, the processes of protein folding, trafficking, quality control and degradation of client proteins could be arranged properly. The core members of molecular chaperones, including heat shock proteins (HSPs) family and their co-chaperones, are emerging as potential drug targets since they are involved in numerous disease conditions. Development of small molecule modulators targeting not only chaperones themselves but also the PPIs among chaperones, co-chaperones and clients is attracting more and more attention. These modulators are widely used as chemical tools to study chaperone networks as well as potential drug candidates for a broader set of diseases. Here, we reviewed the key checkpoints of molecular chaperone machinery HSPs as well as their co-chaperones to discuss the small molecules targeting on them for modulation of protein fate decision.
Amino acid-based compound activates atypical PKC and leptin receptor pathways to improve glycemia and anxiety like behavior in diabetic mice
Authors: Aejin Lee, Yuan Sun, Tao Lin, No-Joon Song, McKensie L. Mason, Jacob H. Leung, Devan Kowdley, Jennifer Wall, Alessandro Brunetti, Julie Fitzgerald, Lisa A. Baer, Kristin I. Stanford, Joana Ortega-Anaya, Laisa Gomes-Dias, Bradley Needleman, Sabrena Noria, Zachary Weil, Joshua J. Blakeslee, Rafael Jiménez-Flores, Jon R. Parquette, Ouliana Ziouzenkova
Journal: Biomaterials (2020)
Prognostic role of mismatch repair deficiency (MMR-D) in patients receiving first-line fluoropyrimidine and platinum (FP) doublet chemotherapy for metastatic and locally advanced unresectable gastric cancers (GCs).
Authors: Eo Jin Kim, Heejung Chae, Min-hee Ryu, Yoon-Koo Kang
Journal: Journal of Clinical Oncology (2020)

4566 Background: Although chemotherapy has been suggested to have the potential to cause a detrimental effect on treatment outcomes of localized GC with MMR-D, it remains unclear whether chemotherapy for metastatic/recurrent/unresectable GC with MMR-D would also adversely affect the survival outcomes. Anti PD-1 antibody (Ab) showed remarkable efficacy in patients with MMR-D and is being actively investigated in combination with cytotoxic chemotherapy. Hence, we aim to evaluate the impact of MMR status on treatment outcomes of advanced GC. Methods: We reviewed our database to identify all patients with HER2 negative, metastatic, recurrent, and locally advanced unresectable GC who received FP doublet chemotherapy from January 2015 to August 2018. For those who had an available tumor tissue, MMR protein expression was assessed by immunohistochemistry (IHC) and correlated with clinical characteristics and treatment outcomes. Results: Out of 895 patients identified from the database, 543 underwent IHC testing for MMR. The median age was 58 years (range, 24 – 86) with male comprising 64.0%. Most patients had initially metastatic disease (n = 382, 70.3%) followed by recurrent (n = 127, 23.3%) and locally advanced unresectable disease (n = 34, 6.3%). MMR-D was found in 4.4% (n = 24) and associated with age ≥ 65 years (50% vs. 29.9%; P = 0.04) and signet ring cell histology (0% vs. 17.7%, P = 0.01). According to our prognostic model (Koo DH et al, 2011), only 4.2% of patients with MMR-D were classified as Poor-risk group (vs. 16.8% of patients with MMR-P, p= 0.10). In the Good-risk group, patients with MMR-D (n = 10) had significantly shorter median progression-free survival (PFS, 6.0 vs. 9.0 months, P = 0.05) and overall survival (OS, 10.1 vs 20.9 months, P = 0.047) compared to those with MMR-P (n = 188), while there was no significant difference in survival outcomes depending on MMR status in the Moderate and Poor-risk groups. In multivariate analysis for OS, MMR status was a significant prognostic factor for OS in Good-risk group GC patients. Conclusions: GC patients with MMR-D had poorer median PFS and OS than those with MMR-P on standard cytotoxic chemotherapy in the Good-risk group. Thus, for Good-risk GC patients with MMR-D, anti PD-1 Ab alone might be considered rather than combining cytotoxic chemotherapy. Further investigation with next-generation sequencing is in process to determine underlying molecular mechanisms and will be presented in ASCO 2020.
Thermal Proteome Profiling Identifies Oxidative-Dependent Inhibition of the Transcription of Major Oncogenes as a New Therapeutic Mechanism for Select Anticancer Compounds
Authors: Sylvain Peuget, Jiawei Zhu, Gema Sanz, Madhurendra Singh, Massimiliano Gaetani, Xinsong Chen, Yao Shi, Amir Ata Saei, Torkild Visnes, Mikael S. Lindström, Ali Rihani, Lidia Moyano-Galceran, Joseph W. Carlson, Elisabet Hjerpe, Ulrika Joneborg, Kaisa Lehti, Johan Hartman, Thomas Helleday, Roman Zubarev, Galina Selivanova
Journal: Cancer Research (2020)

Identification of the molecular mechanism of action (MoA) of bioactive compounds is a crucial step for drug development but remains a challenging task despite recent advances in technology. In this study, we applied multidimensional proteomics, sensitivity correlation analysis, and transcriptomics to identify a common MoA for the anticancer compounds RITA, aminoflavone (AF), and oncrasin-1 (Onc-1). Global thermal proteome profiling revealed that the three compounds target mRNA processing and transcription, thereby attacking a cancer vulnerability, transcriptional addiction. This led to the preferential loss of expression of oncogenes involved in PDGF, EGFR, VEGF, insulin/IGF/MAPKK, FGF, Hedgehog, TGFβ, and PI3K signaling pathways. Increased reactive oxygen species level in cancer cells was a prerequisite for targeting the mRNA transcription machinery, thus conferring cancer selectivity to these compounds. Furthermore, DNA repair factors involved in homologous recombination were among the most prominently repressed proteins. In cancer patient samples, RITA, AF, and Onc-1 sensitized to poly(ADP-ribose) polymerase inhibitors both in vitro and ex vivo These findings might pave a way for new synthetic lethal combination therapies.Significance: These findings highlight agents that target transcriptional addiction in cancer cells and suggest combination treatments that target RNA processing and DNA repair pathways simultaneously as effective cancer therapies.
PD-L1 targeted engineered toxin body provides direct cytotoxicity and T-cell mediated tumor targeting.
Authors: Roger J. Waltzman, Brigitte Brieschke, Sara LeMar, Joseph Dekker, Garrett Cornelison, Garrett L. Robinson, Asis Sarkar, Jay Zhao, Aimee T. Iberg, Hilario J. Ramos, Erin K. Willert
Journal: Journal of Clinical Oncology (2020)

12 Background: Engineered toxin bodies (ETBs) comprised of a proprietarily engineered Shiga-like Toxin A subunit (SLT-A) genetically fused to antibody-like binding domains work through novel mechanisms of action and can force internalization, self-route through intracellular compartments to the cytosol, and induce potent cell-kill via the enzymatic and permanent inactivation of ribosomes. Our PD-L1 targeted ETB includes antigen seeding technology (AST), and additionally delivers a viral antigen for presentation in complex with MHC-I to resident viral-specific cytotoxic T lymphocytes (CTLs). The fusion protein provides a powerful, dual mechanism of action to specifically target and destroy PD-L1+ tumor and inhibitory immune cells. Methods: In vitro activity of ETBs was measured by cell viability and kinetic imaging of labeled target cells in an effector T-cell co-culture assay. Repeat dosing in non-human primates (NHPs) and murine models harboring human PD-L1+ patient derived tumors were used to evaluate tolerability and efficacy. Results: ETBs targeting PD-L1 have potent direct and specific activity across human tumor cell lines and human donor derived monocytes expressing PD-L1 in vitro. In co-culture assays, AST capable ETBs had a deeper response when target cells express both PD-L1 and the appropriate MHC-I allele in the presence of antigen specific CTLs. In vivo, PD-L1 targeted ETBs induced tumor growth delay, regression and survival benefit in multiple PD-L1+ NSCLC PDX models. These ETBs were also tolerated in repeat dosing NHP studies. Conclusions: The potent targeted activity of ETB mediated tumor cell destruction is demonstrated across tumor cell lines from multiple indications, on PD-L1+ immune cells ex-vivo, and by tumor growth and survival benefits in PDX models in vivo. The AST capable, PD-L1 targeted ETBs provide dual novel mechanisms to deplete PD-L1+ cells and control malignancies. Both the SLT-A mediated direct cell kill and activation of viral-specific CTLs circumvents a need for high mutational burden or anti-tumor immune-cell infiltrate at the tumor site, providing a potential treatment option for patients whose disease has progressed after checkpoint therapy.
糖PEG化遺伝子組み換え因子IXにおける薬物速度論的特性向上: 血友病B患者を対象としたはじめてのヒト投与試験 | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: Negrier Claude, Knobe Karin, Tiede Andreas, Giangrande Paul, Moss Judi
Journal: Blood (2011)
Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children
Authors: Scott L. Weiss, Mark J. Peters, Waleed Alhazzani, Michael S. D. Agus, Heidi R. Flori, David P. Inwald, Simon Nadel, Luregn J. Schlapbach, Robert C. Tasker, Andrew C. Argent, Joe Brierley, Joseph Carcillo, Enitan D. Carrol, Christopher L. Carroll, Ira M. Cheifetz, Karen Choong, Jeffry J. Cies, Andrea T. Cruz, Daniele De Luca, Akash Deep, Saul N. Faust, Claudio Flauzino De Oliveira, Mark W. Hall, Paul Ishimine, Etienne Javouhey, Koen F. M. Joosten, Poonam Joshi, Oliver Karam, Martin C. J. Kneyber, Joris Lemson, Graeme MacLaren, Nilesh M. Mehta, Morten Hylander Møller, Christopher J. L. Newth, Trung C. Nguyen, Akira Nishisaki, Mark E. Nunnally, Margaret M. Parker, Raina M. Paul, Adrienne G. Randolph, Suchitra Ranjit, Lewis H. Romer, Halden F. Scott, Lyvonne N. Tume, Judy T. Verger, Eric A. Williams, Joshua Wolf, Hector R. Wong, Jerry J. Zimmerman, Niranjan Kissoon, Pierre Tissieres
Journal: Intensive Care Medicine (2020)
Treatment decisions for acute Achilles tendon ruptures
Authors: Nicola Maffulli, Giuseppe M Peretti
Journal: The Lancet (2020)

Acute ruptures of the Achilles tendon are common. They result in major impairment to mobility, persisting even a decade after the tear, 1 Maffulli N Rupture of the Achilles tendon. J Bone Joint Surg Am. 1999; 81: 1019-1036 Crossref PubMed Scopus (467) Google Scholar and a return to regular activity or sport can be compromised. 2 Olsson N Nilsson-Helander K Karlsson J et al. Major functional deficits persist 2 years after acute Achilles tendon rupture. Knee Surg Sports Traumatol Arthrosc. 2011; 19: 1385-1393 Crossref PubMed Scopus (177) Google Scholar Any form of clinical management should restore and maximise function, and minimise complications. Recent research efforts have mostly tried to identify optimal methods of either surgical or non-surgical treatment in randomised controlled trials, with prevention of re-ruptures as the primary outcome. In The Lancet, Matthew Costa and colleagues 3 Costa ML Achten J Marian IR et al. Plaster cast versus functional brace for non-surgical treatment of Achilles tendon rupture (UKSTAR): a multicentre randomised controlled trial and economic evaluation. Lancet. 2020; 395: 441-448 Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar report findings from UKSTAR, a randomised superiority trial performed in 39 hospitals in the UK. 540 physically active patients (mean age 48∙7 years, 79% men) who were being managed non-surgically for an acute (<14 days) Achilles tendon rupture were randomly assigned to receive a plaster cast (n=266) or functional bracing (n=274). The primary outcome was Achilles tendon Rupture Score (ATRS), 4 Nilsson-Helander K Thomeé R Silbernagel KG et al. The Achilles tendon Total Rupture Score (ATRS): development and validation. Am J Sports Med. 2007; 35: 421-426 Crossref PubMed Scopus (334) Google Scholar a well validated patient-reported outcome score, at 9 months, and the main safety outcome was the incidence of re-rupture. 3 Costa ML Achten J Marian IR et al. Plaster cast versus functional brace for non-surgical treatment of Achilles tendon rupture (UKSTAR): a multicentre randomised controlled trial and economic evaluation. Lancet. 2020; 395: 441-448 Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar There was no difference between groups in terms of ATRS (plaster cast group: n=244, mean score 74∙4 [SD 19∙8]; functional brace group: n=259, mean 72∙8 [20∙4]; adjusted mean difference –1∙38 [95% CI –4∙9 to 2∙1]) or in the incidence of re-rupture of the tendon. Plaster cast versus functional brace for non-surgical treatment of Achilles tendon rupture (UKSTAR): a multicentre randomised controlled trial and economic evaluationTraditional plaster casting was not found to be superior to early weight-bearing in a functional brace, as measured by ATRS, in the management of patients treated non-surgically for Achilles tendon rupture. Clinicians may consider the use of early weight-bearing in a functional brace as a safe and cost-effective alternative to plaster casting. Full-Text PDF Open Access
FVC variability in patients with idiopathic pulmonary fibrosis and role of 6-min walk test to predict further change
Authors: Steven D. Nathan, Ming Yang, Elizabeth A. Morgenthien, John L. Stauffer
Journal: European Respiratory Journal (2020)

<b>Variability in 3-month changes in FVC was examined in 954 patients with IPF (n=3966 observations) from phase 3 trials; concurrent 3-month decline in the FVC and 6MWD (n=1321 observations) predicted further decline in FVC over the subsequent 3 months</b>http://bit.ly/2GfBKW3
Preclinical evaluation of anti-ROR1 CAR T cells employing a ROR1 binding SCFV derived from the clinical stage mab cirmtuzumab.
Authors: Charles E. Prussak, Christopher Oh, Juliana Velez Lujan, Sharon Lam, Jieyu Zhang, Jayde Fernandez, Navyaa Sinha, Jessica Pham, Haoming Shi, Caitlin Shin, Gunnar F. Kaufman, George F. Widhopf II, Ezra E.W. Cohen, Thomas J. Kipps
Journal: Journal of Clinical Oncology (2020)

41 Background: Chimeric antigen receptor (CAR)-modified T cells (CAR-T) were generated targeting cells expressing ROR1, which is present on many malignant cancers and has been associated with cancer stemness and chemo-resistance. The ROR1 CAR utilizes the humanized single-chain fragment variable (scFv) binding domain of UC-961 (cirmtuzumab), which exhibits high affinity and specificity for human ROR1 and has demonstrated an excellent safety profile in Phase 1 studies. Methods: CAR constructs with varying spacer regions and intracellular co-stimulatory domains, using the scFV of cirmtuzumab, were constructed and used to generate CAR-T cells from healthy donors. These ROR1 CAR-T cells were tested for cytotoxicity against lymphoid cancer cells in vitro and in vivo studies that employed immune-deficient mice engrafted with labeled human leukemia cells MEC1 or MEC1-ROR1, which had been transfected to stably express ROR1. Results: The 2nd generation and 3rd generation CAR-T-cells with analogous spacer regions were comparably potent and selectively cytotoxic for cells bearing the ROR1 target antigen. But the 2nd generation CARs demonstrated greater potency in vitro even at low effector to target ratios. For the in vivo studies, mice received a single injection of ROR1 CAR-T cells or activated T cells from the same donor as a control. The ROR1 CAR-T cells rapidly cleared the leukemic cells from the animals, whereas animals receiving control T cells or no therapy quickly succumbed to progressive disease within 3 weeks. The administered CAR-T products remained highly active following administration and could be detected for ≥ 3 months without evidence for T cell exhaustion. Conclusions: The generated CAR-T cells utilizing constructs with the Fv of cirmtuzumab, a humanized mAb highly specific for ROR1, onco-embryonic surface antigen, effectively and selectively killed neoplastic cells bearing ROR1 both in vitro and in vivo. As ROR1 expression and signaling has been associated with cancer stemness and chemo-resistance utilizing ROR1 CAR-T therapy to target cancer cells might mitigate tumor escape. These data strongly support the rationale for continued development of our ROR1 CAR-T.
Vasomodulators and Liver Transplantation for Portopulmonary Hypertension: Evidence From a Systematic Review and Meta‐Analysis
Authors: Rebecca Deroo, Eric Trépo, Tom Holvoet, Michel De Pauw, Anja Geerts, Xavier Verhelst, Isabelle Colle, Hans Van Vlierberghe, Michael B. Fallon, Sarah Raevens
Journal: Hepatology (2020)

Untreated portopulmonary hypertension (PoPH) carries a poor prognosis. Previous reports have described vasomodulator (VM) therapy and liver transplantation (LT) as treatment options. We aimed to provide summary estimates on the endpoints of pulmonary hemodynamics and survival in patients with PoPH, treated with different modalities.We performed a systematic review with meta-analysis of mainly observational and case-control studies describing no treatment, VM, LT, or VM + LT in patients with PoPH. Twenty-six studies (1,019 patients) were included. Both VM and VM + LT improve pulmonary hemodynamics. A substantial proportion of patients treated with VM become eligible for LT (44%; 95% confidence interval [CI], 31-58). Pooled estimates for 1-, and 3-year postdiagnosis survival in patients treated with VM were 86% (95% CI, 81-90) and 69% (95% CI, 50-84) versus 82% (95% CI, 52-95) and 67% (95% CI, 53-78) in patients treated with VM + LT. Of note, studies reporting on the effect of VM mainly included Child-Pugh A/B patients, whereas studies reporting on VM + LT mainly included Child-Pugh B/C. Seven studies (238 patients) included both patients who received VM only and patients who received VM + LT. Risk of death in VM-only-treated patients was significantly higher than in patients who could be transplanted as well (odds ratio, 3.5; 95% CI, 1.4-8.8); however, importantly, patients who proceeded to transplant had been selected very strictly. In 50% of patients, VM can be discontinued post-LT (95% CI, 38-62).VM and VM + LT both improve pulmonary hemodynamics and prognosis in PoPH. In a strictly selected subpopulation of cases where LT is indicated based on severe liver disease and where LT is considered safe and feasible, treatment with VM + LT confers a better prognosis. Considering successful VM, 44% can proceed to LT, with half being able to postoperatively stop medication.
Distinct genomic landscape in colorectal mucinous carcinoma via comprehensive genomic profiling.
Authors: Liang Huang, Shuangling Luo, FangQin Xue, Yi Xiao, Ziqiang Wang, Sicong Lai, Zhanzhen Liu, Huanxin Hu, Ziwei Zeng, Tengjiao Lin, Shiyue Zhang, Jian Wang, Kai Wang, Gong Chen, Liang Kang
Journal: Journal of Clinical Oncology (2020)

222 Background: Mucinous carcinoma (MC), accounting for 10-15% of colorectal cancer (CRC), has long been associated with an inferior response to treatment. MC as an unfavorable prognostic factor in early stage CRC remains questionable. In this study, we used a large CRC cohort to define the genomic landscape of MC and identify prognostic and clinically actionable information. Methods: The 1226 CRC patient cohort included 997 adenocarcinomas (AC), 129 MC, and 110 adenocarcinomas with mucous composition (AMC). All of the pathological sections were verified by an experienced pathologist. FFPE tumor samples and matched peripheral blood were sequenced using a 450-cancer-related gene panel. Results: MC was significantly associated with right colon (p&lt;0.001) and regional lymph node metastasis (p=0.004) compared to AC. We found a higher mutation rate of BRAF V600E (10.9% vs. 3.3%), PIK3CA (28.7% vs. 19.2%), SMAD4 (34.1% vs. 19.1%), BRCA1/2 (16.3% vs. 6.8%) and homology recombination pathway (40.3% vs. 22.7%), and a lower rate of TP53 (53.5% vs. 79.5%), APC (46.5% vs. 75.1%,), and HER2 amplification (0% vs. 2.1%,) in MC than in AC. MC had a significantly higher proportion of microsatellite instability-high (MSI-H) tumors (22.5% vs. 6.8%, p&lt;0.001). Furthermore, in tumors with MSI stable, POLE mutation was more frequent in MC than in AC (7.0% vs. 2.6%, p=0.094) and resulted in dramatic elevated tumor mutational burden (TMB, range 79.5-591.5 muts/Mb), indicating up to 30% of MC patients may benefit from immunotherapy. MSI-H was associated with better prognosis (5-y DFS, MSI-H 86.7% vs. MSS 56.7%) in stage II/III CRC patients with MC. Importantly, AMC mimicked the genomic features of MC rather than AC. Conclusions: For the first time, comprehensive genomic analysis revealed that MC had distinct molecular features, indicating promising clinically application for both immunotherapy and targeted therapy. Early stage MC had a diverse prognosis due to MSI status and should be interpreted differently. The similarity of molecular profile between AMC and MC suggested the possible usage of MC, but not AC, clinical strategy for AMC.
Extent of lymph node resection and effect on pancreatic cancer overall survival.
Authors: Brian Cox, Nicholas Manguso, Humair Quadri, Jessica Crystal, Katelyn Mae Atkins, Jaewon Lee, Andrew Eugene Hendifar, Mitchell Kamrava, Richard Tuli, Jun Gong, Alexandra Gangi
Journal: Journal of Clinical Oncology (2020)

682 Background: Lymph node (LN) metastases affect overall survival (OS) in pancreatic cancer (PC). However, a LN sampling threshold does not exist. We examined the impact of nodal sampling on overall survival (OS). Methods: Patients with Stage I-III PC ≥55 years old who underwent curative resection from 2004-2016 were identified from the National Cancer Database (NCDB). After adjusting for age, gender, grade, stage, and Charlson-Deyo score, multiple binomial logistic regression analyses assessed the impact of the LN ratio (LNR) on OS. LNR was defined as the number of positive LN over the number of LN examined. Regression analyses, a Cox-Regression, and a Kaplan-Meier survival curve assessed how many LN should be sampled. Results: A total of 13,673 patients, median age 69 years (55-90), were included. Most were Caucasian (86.6%) males with Charlson-Deyo scores ≤ 1 (90.3%) and moderately to poorly differentiated PC (90.1%). Median number of LN examined was 15 (1-75) with a median of 1 positive LN (0-35). As expected, increased number of positive LNs was associated with reduced OS, p &lt; 0.001. After data normalization, an increasing LNR was associated with a 12-fold likelihood of death [OR: 11.9, p &lt; 0.001 (CI 6.0, 23.7)]. Subsequent regression models established evaluation of ≥ 16 LNs as the greatest predictor of OS. A regression model evaluating &lt; or ≥ 16 lymph nodes was performed to ascertain the effects of age, gender, ethnicity, grade, stage, and LN examined on OS. The logistic regression model correctly classified 74.5% of cases with a specificity of 99.6% (p &lt; 0.001). Examination of &lt; 16 LN, Caucasian race, grade, stage, and higher Charlson-Deyo scores were significantly associated with decreased OS. If ≥ 16 LNs were examined, patients had a 1.5-fold likelihood of better OS, p &lt; 0.001 (CI 1.4, 1.6). An adjusted Cox Regression showed increased HR of 1.2, p &lt; 0.001 (CI 1.1, 1.2) and an unadjusted Kaplan Meier survival curve predicted ≥ 16 LN examined are associated with an increase in OS of 2.8 months [log-rank: 32.0, p &lt; 0.001]. Conclusions: Patients undergoing curative intent resection for PC should have adequate nodal sampling. Stratification of patients by LNR may provide useful information of OS. Examination of ≥ 16 LNs impacts OS in patients with Stage I-III PC.