tbuckley/cabot-search huggingface dataset:
T cells expressing NKG2D chimeric antigen receptors efficiently eliminate glioblastoma and cancer stem cells
Authors: Dong Yang, Bin Sun, Hongjiu Dai, Wenxuan Li, Lan Shi, Peixian Zhang, Shirong Li, Xudong Zhao
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Traditional therapies fail to cure most glioblastoma patients and the 5-year survival rate is less than 10%, highlighting need for new therapeutic approaches. The natural killer group 2 member D ligands (NKG2DLs) are highly expressed in glioblastomas and are considered promising targets for chimeric antigen receptor (CAR) T-cell therapy. The aim of this study was to investigate the effect of NKG2D-expressing CAR-T cells on glioblastomas and glioblastoma stem cells. <h3>Methods</h3> The expression of NKG2DLs was analyzed by flow cytometry and immunohistochemistry. NKG2D-BBz CAR, containing the extracellular domain of NKG2D, was constructed and delivered into T cells by lentiviral particles. In vitro cytotoxicity of the CAR-T cells was assessed by flow cytometry. Release of cytokine, perforin and granzyme B was quantified using enzyme-linked immunosorbent assay kits. The therapeutic efficacy of NKG2D-BBz CAR-T cells in vivo was evaluated using subcutaneous tumor models. The safety of the CAR was analyzed by investigating the effects on proliferation, apoptosis, and karyotype. <h3>Results</h3> Our data confirmed the high expression of NKG2DLs in human glioblastoma cells, cancer stem cells, and tumor samples. Further, the NKG2D-BBz CAR-T cells efficiently lysed glioblastoma cells and cancer stem cells in vitro and produced high levels of cytokines, perforin, and granzyme B. The CAR-T cells markedly eliminated xenograft tumors in vivo and did not exhibit significant treatment-related toxicity in the treated mice. The CAR expression also did not exert any obvious effects on cell proliferation, apoptosis, and genomic stability. <h3>Conclusion</h3> Our findings demonstrated that NKG2D CAR-T cells targeted glioblastoma cells and cancer stem cells in an NKG2D-dependent manner, supporting the use of CAR-T therapy in glioblastoma therapeutic strategies.
COPD Exacerbations — A Target for Antibiotic Stewardship
Authors: Allan S. Brett, Majdi N. Al-Hasan
Journal: New England Journal of Medicine (2019)

Patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) in whom outpatient treatment fails are at risk for serious decompensation and hospitalization. Thus, when outpatients with COPD present with acutely worsening symptoms, clinicians are tempted to err on the side of doing more, which usually entails prescribing both oral glucocorticoids and antibiotics. However, not all acute exacerbations are provoked by respiratory tract infection, and of those that are, it is difficult to distinguish whether viruses or bacteria are responsible. The dilemma is to identify patients who are most likely to benefit from antibiotics while avoiding unnecessary antibiotic use. Antibiotic . . .
Impact of Treatment on B-Cell Regeneration By Next Generation Flow Cytometry in Patients with Multiple Myeloma
Authors: Robéria Pontes, Juan Flores-Montero, Luzalba Sanoja-Flores, Noemi Puig, Roberto José Pessoa Magalhães, Alba Corral Mateos, Anna Beatriz Salgado, Angelo Maiolino, Maria-Victoria Mateos, Bruno Paiva, Elaine Sobral da Costa, Jacques JM van Dongen, Alberto Orfao
Journal: Blood (2018)
Anti-PD-1 antibody cetrelimab (JNJ-63723283) in patients with advanced cancers: Updated phase I/II study results.
Authors: Piotr Rutkowski, Enriqueta Felip, Victor Moreno, Jose Manuel Trigo Perez, Aitana Calvo, Dariusz Kowalski, Diego Cortinovis, James J. Lee, George Manikhas, Elizabeth Ruth Plummer, Michele Maio, Paolo Antonio Ascierto, Vladimir Ivanovich Vladimirov, Dana Gaffney, Lilian Y. Li, Kyounghwa Bae, James G. Greger, Chu Ri Shin, Hong Xie, Emiliano Calvo
Journal: Journal of Clinical Oncology (2019)

31 Background: Cetrelimab (JNJ-63723283) is an IgG4, anti-programmed cell death protein-1 (PD-1) antibody. Here we present updated results from an ongoing phase 1/2 study of cetrelimab in patients (pts) with advanced or refractory solid cancers. Methods: Part 2 of the study evaluated safety and efficacy of cetrelimab at 240 mg Q2W, a recommended phase 2 dose selected in Part 1 (Calvo JCO 2018; 36 suppl 5:58). Tumor types for Part 2 included non-small cell lung cancer (NSCLC), melanoma (MEL), bladder, renal cell, small cell lung cancer (SCLC), microsatellite-high (MSI-H)/DNA mismatch repair deficient (dMMR; locally or centrally tested) colorectal cancer (CRC) and gastric/esophageal cancer (GCA/EC). Tumor response was assessed by the investigator following RECIST v1.1. Results: As of 3 Sep 2018, 192 pts have been treated with cetrelimab from 80–800 mg Q2W and 480 mg Q4W. Median age was 60 years (23–86), and median prior regimens was 2 (1–12). Median duration of treatment was 85 days (1–561); 82 pts remain on treatment. Full receptor occupancy was maintained throughout dosing interval. Most common adverse events (AEs) were asthenia (19%), fatigue (19%), dyspnea (16%) and diarrhea (16%). Grade ≥3 AEs, regardless of causality, were reported in 45% of pts; most common were anemia (6%), dyspnea (4%), increased ALT (3%) and increased AST (3%). Observed serious AEs were dyspnea (4%), pleural effusion and intestinal obstruction (3% each). All grade and grade ≥3 immune-related AEs were reported in 30% and 7% of pts, respectively. Among response-evaluable pts (n = 156) from Parts 1 and 2, overall response rate (ORR) was 15%, with 2 complete and 22 partial responses. Half of pts had stable disease or better. ORR was 26% (7/27) in NSCLC (42% [5/12] in PD-L1+ NSCLC [≥50% by IHC]), 25% (12/49) in MEL (28% [12/43] in non-uveal MEL), 50% (1/2) in renal cancer, 8% (2/26) in MSI-H/dMMR CRC (recruited later per amendment) and 14% (2/14) in GCA/EC. No responses were observed in bladder cancer (n = 4) or SCLC (n = 10). Conclusions: The safety profile and preliminary activity of cetrelimab in immune-sensitive advanced cancers is consistent with known PD-1 inhibitors. The study is ongoing and analysis by PD-L1 status will be reported later. Clinical trial information: NCT02908906.
Mortality of acute promyelocytic leukemia in a rural tertiary care center.
Authors: Joseph Vadakara, Prakash Kharel, Prianka Bhattacharya, Erin Vanenkevort, Jesse Manikowski
Journal: Journal of Clinical Oncology (2019)

e18529 Background: Acute promyelocytic leukemia (APL) has a very good prognosis when diagnosed and treated promptly. Despite the excellent prognosis, early mortality remains high, ranging 17-40%. Geisinger Health System (GHS) has provided treatment for a significant number of APL patients, but mortality of APL at GHS has not been studied. We conducted a study to assess early mortality related to APL in GHS. Methods: Retrospective analysis was performed of patients diagnosed with APL from January 1988 to February 2019, determining the number of patients diagnosed and treated for APL in GHS, overall 30-day mortality rate, stratified by risk group (low, intermediate, high based on presenting white blood cell and platelet counts) and age above or below 55. Results: A total of 61 patients with APL were identified. Average age at diagnosis was 44.77 years (SD = 19.12). The death rates in patients in whom risk data was available was 7%, 9.3% and 11.6% respectively in the low, intermediate and high risk groups respectively. There was no statistically significant difference in the frequency distribution between risk categories for survival, χ 2 = 1.03, p = .60. Between age groups, 8.3% of patients under age 55 died, whereas 18.3% of those 55 or older died. Survival between the two age groups was statistically significant, χ 2 = 10.92, p = .001. Estimated 30-day overall mortality in the studied population was 16.39%; and 7.69%, 5.56% and 38.46% for the low, intermediate, high-risk patients respectively. Conclusions: Among patients diagnosed with APL in the GHS over the past 30 years, the early mortality rate has been comparable to reported mortality rates in centers around the world. Our study showed a statistically significant higher mortality rate in patients 55 years or older. Further study is planned to assess factors contributing to mortality and outcomes.
Preclinical CAR-T cell target safety, biodistribution, and tumor infiltration analysis using in situ hybridization technology.
Authors: Helly Pimentel, Helen Jarnagin, Hailing Zong, Courtney Todorov, Courtney M. Anderson, Bingqing Zhang, Christopher Bunker, Xiao-Jun Ma
Journal: Journal of Clinical Oncology (2019)

112 Background: Chimeric antigen receptor (CAR) T cell therapy is highly effective in treating hematologic malignancies, and major efforts are being made to achieve similar efficacy in solid tumors. The greater potency of CAR-T cells compared to antibody therapeutics demands a more stringent CAR-T target safety assessment to avoid adverse events resulting from “on-target/off-tumor” activity. Furthermore, it is critical to track and monitor CAR+ T cells within intact tissue and tumor to understand the mechanisms underlying off-tumor toxicity and efficacy in tumor killing. Methods: We employed the RNAscope in situ hybridization (ISH) technology to assess target expression specificity and to track CAR-T cell distribution and activation in xenograft and host tissues using the RPMI-8226 xenograft mouse model. Results: For the CAR-T target candidates, Target X and Target Y, RNA ISH revealed that Target X was only expressed in the xenograft tumor and in no mouse organs, while Target Y was found to be expressed at low levels in mouse lung and liver, as well as in the xenograft tumor. Duplex RNA ISH assays with probes targeting the CAR 3’ UTR and either IFNG or GZMB allowed for highly sensitive and specific detection of CAR-T cells and their activation state in both tumor and normal tissues from vehicle, Target X CAR-T cell, or Target Y CAR-T cell treated mice. Activated Target X CAR-T cells expressing GZMB and IFNG were found only in the xenograft tumor, where Target X was expressed. In contrast, activated Target Y CAR-T cells were found almost exclusively in mouse lung and liver, with very few Target Y CAR-T cells being found in the xenograft tumor. Lastly, a multiplex ISH-IHC approach confirmed the presence of activated Target X CAR-T cells in the xenograft tumor through simultaneous detection of the Target X CAR 3’ UTR, IFNG, GZMB, and CD3. Conclusions: These data demonstrate how the RNAscope assay can be utilized for CAR-T cell efficacy and safety/toxicity assessment in preclinical models by detecting very low levels of target antigen expression in off-tumor tissues and monitoring CAR-T cell pharmacodynamics and activation in tumor models and can also be applied for assessing TCR-T cell activity in tumors.
Relationship between tumor burden to growth rate and treatment outcomes of nivolumab for patients with head and neck squamous carcinoma.
Authors: Chiaki Suzuki, Naomi Kiyota, Yoshinori Imamura, Junpei Rikitake, Satoshi Sai, Taiji Koyama, Yasuko Hyogo, Yoshiaki Nagatani, Yohei Funakoshi, Masanori Toyoda, Naoki Otsuki, Ken-ichi Nibu, Hironobu Minami
Journal: Journal of Clinical Oncology (2019)

68 Background: Nivolumab improved overall survival (OS) in the treatment of platinum-refractory recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC) in a phase III clinical trial. However, Kaplan-Meier OS and progression-free survival (PFS) curves for the nivolumab and cytotoxic agent arms crossed at 3-6 months, suggesting that patients with initial resistance to immunotherapy may have better outcomes with cytotoxic treatment. Here, we explored suitable conditions and candidates of predictive factors for nivolumab for R/M HNSCC. Methods: We retrospectively reviewed the clinical records of 28 consecutive patients with HNSCC from 2014-2018. Tumor size was evaluated by computed tomography according to RECIST ver.1.1. Tumor growth rate (Gr) was defined as 3Log (Dt/D0)/t, where D 0 and D t are the sum of the longest diameters of the target lesions (SumTLs) at baseline and pre-baseline, and t is time, with 1 t defined as the 4-week interval between tumor evaluations. Results: After exclusion of 2 patients with unevaluable responses, 26 patients were included in the study. Median follow-up time for survivors was 9.5 months. Median SumTLs at baseline was 43.2 mm (range, 10.1-135.3). Median Gr was 0.22 (range, 0.05-0.76). Median OS and PFS was 7.9 months (95% CI, 5.8 to 34.5) and 3.7 months (95% CI, 2.1 to 12.9), respectively. Patients with progression within 3 months showed significantly worse survival (HR 6.33, 95% CI 2.08-21.67, p=0.001). Moreover, higher Gr and bigger SumTLs appeared to be associated with poorer outcomes. We therefore explored the association between prognosis and the ratio of SumTLs to Gr (SumTLs/Gr). The cut off value of SumTLs/Gr was calculated by ROC analysis. Pre-treatment SumTLs/Gr &gt; 212 was associated with significantly worse OS (HR 8.87, 95% CI 2.33-58.29, p&lt;0.001) and PFS (HR 2.86, 95% CI 1.10-8.33, p=0.03). Conclusions: Although retrospective with a small sample size, these results suggest that pre-treatment SumTLs/Gr &gt; 212 was significantly associated with inferior OS and PFS in R/M HNSCC patients treated with nivolumab. R/M HNSCC patients with pre-treatment SumTLs/Gr &gt; 212 might be unsuitable for treatment with nivolumab.
Association of Hidradenitis Suppurativa With Inflammatory Bowel Disease
Authors: Wei-Ti Chen, Ching-Chi Chi
Journal: JAMA Dermatology (2019)

Hidradenitis suppurativa (HS) and inflammatory bowel disease (IBD) are inflammatory diseases that share common genetic susceptibility and immunologic features. However, the link between HS and IBD has been largely unclear.To conduct a meta-analysis to investigate the association between HS and IBD.A search of the MEDLINE, Cochrane Central Register of Controlled Trials, and Embase databases yielded 397 relevant studies from inception to June 10, 2018. Two additional studies were supplied by one of the investigators.Case-control, cross-sectional, or cohort studies that examined the odds or risk of IBD in patients with HS were included. No geographic or language limitations were imposed.The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. The Newcastle-Ottawa Scale was used to assess the risk of bias of included studies. Crohn disease and ulcerative colitis were analyzed separately, and a random-effects model meta-analysis was conducted.The odds ratios (ORs) and hazard ratios (HRs) of IBD, Crohn disease, and ulcerative colitis in association with HS.Five case-control studies, 2 cross-sectional studies, and 1 cohort study with a total of 93 601 unique participants were included. The meta-analysis of case-control and cross-sectional studies showed significant associations of HS with Crohn disease (pooled OR, 2.12; 95% CI, 1.46-3.08) and ulcerative colitis (pooled OR, 1.51; 95% CI, 1.25-1.82). Two case-control studies found significant association of HS with IBD (ORs, 2.16 [95% CI, 1.40-3.34] and 10.00 [95% CI, 1.94-51.50]). One cohort study found an increased risk of IBD in patients with HS (HR, 5.6; 95% CI not reported; P < .002).The evidence to date supports an association of HS with IBD. These results suggest that consultation with gastroenterologists should be sought when patients with HS present with recurrent abdominal pain, chronic diarrhea, bloody stool, and body weight loss.
Nonalcoholic Steatohepatitis Is Associated With Liver‐Related Outcomes and All‐Cause Mortality in Chronic Hepatitis B
Authors: Hannah S.J. Choi, Willem P. Brouwer, Wayel M.R. Zanjir, Robert A. de Man, Jordan J. Feld, Bettina E. Hansen, Harry L.A. Janssen, Keyur Patel
Journal: Hepatology (2019)

Chronic hepatitis B (CHB) and nonalcoholic fatty liver disease are increasingly observed together in clinical practice, and development of nonalcoholic steatohepatitis (NASH) represents another leading cause of liver-related morbidity and mortality. Our aims were to determine whether biopsy-proven NASH impacts clinical outcomes in CHB patients and assess prognostic risk factors.CHB patients attending two tertiary centers in North America and Europe over 13 years with available clinical and biopsy data were included. Patients were categorized as no-NASH or probable/definite NASH based on standardized histological assessment. Clinical events (death, decompensation, transplant, and hepatoma) were evaluated, and Kaplan-Meier survival estimates and Cox proportional hazards regression were used to analyze the incidence of events. There were 1,089 CHB patients, classified as no-NASH (n = 904, 83%) or NASH (n = 185, 17%), with 52 (6%) versus 27 (15%) experiencing outcome events during follow-up, respectively. In the multivariable analysis adjusting for age, sex, hepatitis B e antigen serostatus, and diabetes, the presence of NASH and concomitant advanced fibrosis (AF) was significantly associated with clinical outcomes (hazard ratio [95% confidence interval], 4.8 [2.6-9.0], P < 0.01) when compared to absence of NASH and AF (reference). NASH and AF were associated with a greater risk of outcomes compared to AF (P = 0.01) or NASH alone (P < 0.01). Of the three histological determinants of NASH, ballooning and inflammation, but not steatosis, were independently associated with clinical outcomes (P < 0.05) in place of NASH. NASH was significantly associated with increased risk of hepatocellular carcinoma and death (P < 0.01) but not decompensation (P = 0.33).In our large combined tertiary center cohort, patients with concomitant NASH and CHB had more AF and shorter time to development of liver-related outcomes or death compared to patients with CHB alone. Among patients with AF, superimposed NASH predicted poorer clinical outcomes.
Abstract 15039: Oral Carbon Absorbent, AST-120, Protects the Progression of Atherosclerosis in a Chronic Renal Failure Model of Mice via Preserving sFlt-1 Expression Level
Authors: Yasuki Nakada, Kenji Onoue, Takuya Kumazawa, Satomi Ishihara, Tomoya Nakano, Hitoshi Nakagawa, Masaru Matsui, Hiroyuki Okura, Yoshihiko Saito
Journal: Circulation (2017)

Background: We reported that expression of soluble Flt-1 (sFlt-1), an endogenous antagonist against the proatherogenic cytokine placental growth factor, is decreased in chronic kidney disease (CKD)...
Reply
Authors: Mayank Sharma, Douglas A. Simonettos
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. We thank Gin‐Ho Lo for taking interest in our study and for the comments.1 Dr. Lo raises important points comparing the different adverse effect profiles of nonselective beta‐blockers (NSBBs) and variceal band ligation (VBL). Current guidelines still recommend the use of either NSBBs or VBL for the primary prevention of esophageal variceal bleeding, and the debate is likely to continue.2 In our systematic review and network meta‐analysis, when compared with VBL, NSBBs were associated with a higher rate of overall adverse events, resulting in treatment discontinuation. On the other hand, VBL was associated with 3 times greater number of serious adverse events.1 Therefore, NSBBs still represent a less invasive prophylactic measure with additional benefits beyond prevention of variceal bleeding in patients with cirrhosis. As opposed to VBL, NSBBs reduce portal pressure, as demonstrated by hepatic venous pressure gradient (HVPG) assessment. The hemodynamic effects of NSBBs are likely responsible for the additional survival benefit observed in our meta‐analysis and previous studies.3 A recently published randomized controlled trial showed that NSBBs also reduce the incidence of ascites and may increase decompensation‐free survival.4 Unfortunately, some patients do not adequately respond to NSBBs, and routine HVPG assessment is invasive and not feasible in clinical practice. However, a recent study has suggested that splenic stiffness, measured noninvasively through acoustic radiation force impulse assess elastography, may be beneficial in predicting the hemodynamic response to carvedilol therapy as primary prophylaxis in patients with cirrhosis and high‐risk esophageal varices.5 We agree that the choice of therapy should still be a decision made jointly by the patient and the medical team. However, not only the risk of adverse effects needs to be discussed with the patient but also the potential additional benefits of NSBBs, including decreased incidence of ascites and mortality.
The Effect of Fine Particulate Matter on the Inflammatory Responses in Human Upper Airway Mucosa
Authors: Hui Qing, Xiangdong Wang, Nan Zhang, Kaili Zheng, Kun Du, Ming Zheng, Ying Li, Yu Chang, Luo Zhang, Claus Bachert
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Particulate matter with an aerodynamic diameter equal or less than 2.5 µm (PM2.5) represents a main constituent of polluted air with a potential detrimental impact on human health. Objec...
The case for uric acid-lowering treatment in patients with hyperuricaemia and CKD
Authors: Yuka Sato, Daniel I. Feig, Austin G. Stack, Duk-Hee Kang, Miguel A. Lanaspa, A. Ahsan Ejaz, L. Gabriela Sánchez-Lozada, Masanari Kuwabara, Claudio Borghi, Richard J. Johnson
Journal: Nature Reviews Nephrology (2019)
Monitoring Cell-Type–Specific Gene Expression Using Ribosome Profiling In Vivo During Cardiac Hemodynamic Stress
Authors: Shirin Doroudgar, Christoph Hofmann, Etienne Boileau, Brandon Malone, Eva Riechert, Agnieszka A. Gorska, Tobias Jakobi, Clara Sandmann, Lonny Jürgensen, Vivien Kmietczyk, Ellen Malovrh, Jana Burghaus, Mandy Rettel, Frank Stein, Fereshteh Younesi, Ulrike A. Friedrich, Victoria Mauz, Johannes Backs, Günter Kramer, Hugo A. Katus, Christoph Dieterich, Mirko Völkers
Journal: Circulation Research (2019)

Rationale: Gene expression profiles have been mainly determined by analysis of transcript abundance. However, these analyses cannot capture posttranscriptional gene expression control at the level of translation, which is a key step in the regulation of gene expression, as evidenced by the fact that transcript levels often poorly correlate with protein levels. Furthermore, genome-wide transcript profiling of distinct cell types is challenging due to the fact that lysates from tissues always represent a mixture of cells. Objectives: This study aimed to develop a new experimental method that overcomes both limitations and to apply this method to perform a genome-wide analysis of gene expression on the translational level in response to pressure overload. Methods and Results: By combining ribosome profiling (Ribo-seq) with a ribosome-tagging approach (Ribo-tag), it was possible to determine the translated transcriptome in specific cell types from the heart. After pressure overload, we monitored the cardiac myocyte translatome by purifying tagged cardiac myocyte ribosomes from cardiac lysates and subjecting the ribosome-protected mRNA fragments to deep sequencing. We identified subsets of mRNAs that are regulated at the translational level and found that translational control determines early changes in gene expression in response to cardiac stress in cardiac myocytes. Translationally controlled transcripts are associated with specific biological processes related to translation, protein quality control, and metabolism. Mechanistically, Ribo-seq allowed for the identification of upstream open reading frames in transcripts, which we predict to be important regulators of translation. Conclusions: This method has the potential to (1) provide a new tool for studying cell-specific gene expression at the level of translation in tissues, (2) reveal new therapeutic targets to prevent cellular remodeling, and (3) trigger follow-up studies that address both, the molecular mechanisms involved in the posttranscriptional control of gene expression in cardiac cells, and the protective functions of proteins expressed in response to cellular stress.