tbuckley/cabot-search huggingface dataset:
A multicenter retrospective analysis examining the effect of dipeptidyl protease 4 (DPP4) inhibitors on progression-free survival in patients with prostate cancer.
Authors: Kelsey Pan, William Paul Skelton, Mohammed Elzeneini, Thu-Cuc Nguyen, Aaron J Franke, azka ali, Sandip Patel, Rohit Bishnoi, Chintan Shah, Long H. Dang, Nam H. Dang, Julie Ann Kish
Journal: Journal of Clinical Oncology (2021)

109 Background: Dipeptidyl peptidase IV (DPP4), also known as Cluster of differentiation 26 (CD26) is a commonly expressed cell surface protein found in many cell types that can function as a tumor suppressor or activator, depending on the cancer type its interactions with the tumor microenvironment. DPP4 has been studied as a tumor biomarker due to its expression in various primary tumors and metastases. Recent literature established benefits of DPP4 inhibitors on progression free survival (PFS) of diabetic patients with advanced colorectal and airway cancers. In this study, we examine the effect of DPP4 inhibitors on PFS in diabetic patients (pts) with advanced-stage prostate cancer. Methods: We performed a multi-center retrospective analysis at Moffitt Cancer Center and the University of Florida of diabetic pts with advanced stage (III or IV) prostate cancer. All pts were on anti-hyperglycemic therapy and received either surgery, radiation therapy, or both for their prostate cancer. The control group included pts on metformin and a sulfonylurea, and the study group included pts on a DPP4 inhibitor and metformin. PFS was calculated for both groups, and Cox proportional hazards regression was used to determine statistical significance. Kaplan-Meier survival analysis was done to predict the effect of DPP4 inhibition and radiation therapy on PFS. Results: Our study population consisted of 161 pts, with 120 pts in the control group and 41 in the study group. No significant difference in progression of prostate cancer was found between those on DPP4 inhibitor vs. Metformin. Specifically, 24 of 41 (59%) of patients on DPP4 inhibitors progressed, while 73 of 120 (61%) of patients on Metformin had progression of prostate cancer (HR 1.01, 95% CI 0.64 to 1.61, p= 0.955). Median time to progression was 3.3 years in the DPP4 group versus 3.5 years in the Metformin group. However, radiation therapy was associated with improved PFS (HR 0.56, 95% CI 0.37 to 0.84, p= 0.0006). Conclusions: Contrary to what has been shown in pts with diabetes and advanced colorectal or airway cancers, exposure to DPP4 inhibitors did not lead to statistically significant improvement in PFS in pts with advanced stage prostate cancer. Recent data suggests that DPP4 may act as a tumor suppressor gene to the androgen receptor (AR) pathway, and that DPP4 inhibition can result in emergence of resistance to androgen deprivation therapy (ADT). Further analysis with larger sample sizes is necessary to elucidate if this is applicable to prostate cancer as a whole, or if this effect is specific to castrate-sensitive prostate cancer (CSPC) vs. castrate-resistant prostate cancer (CRPC).
Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared with adult and pediatric COVID-19
Authors: Laura A. Vella, Josephine R. Giles, Amy E. Baxter, Derek A. Oldridge, Caroline Diorio, Leticia Kuri-Cervantes, Cécile Alanio, Maria Betina Pampena, Jennifer E. Wu, Zeyu Chen, Yinghui Jane Huang, Elizabeth M. Anderson, Sigrid Gouma, Kevin O. McNerney, Julie Chase, Chakkapong Burudpakdee, Jessica H. Lee, Sokratis A. Apostolidis, Alexander C. Huang, Divij Mathew, Oliva Kuthuru, Eileen C. Goodwin, Madison E. Weirick, Marcus J. Bolton, Claudia P. Arevalo, Andre Ramos, C. J. Jasen, Peyton E. Conrey, Samir Sayed, Heather M. Giannini, Kurt D’Andrea, Nuala J. Meyer, Edward M. Behrens, Hamid Bassiri, Scott E. Hensley, Sarah E. Henrickson, David T. Teachey, Michael R. Betts, E. John Wherry, Sharon Adamski, Zahidul Alam, Mary M. Addison, Katelyn T. Byrne, Aditi Chandra, Hélène C. Descamps, Nicholas Han, Yaroslav Kaminskiy, Shane C. Kammerman, Justin Kim, Allison R. Greenplate, Jacob T. Hamilton, Nune Markosyan, Julia Han Noll, Dalia K. Omran, Ajinkya Pattekar, Eric Perkey, Elizabeth M. Prager, Dana Pueschl, Austin Rennels, Jennifer B. Shah, Jake S. Shilan, Nils Wellhausen, Ashley N. Vanderbeck
Journal: Science Immunology (2021)

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8+ T cells that correlated with the use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct from one another and implicate CD8+ T cells in the clinical presentation and trajectory of MIS-C.
Abstract 14209: High Sensitivity Troponin T and NT-proBNP in Heart Failure Risk Prediction: an Analysis from the Atherosclerosis Risk in Communities (ARIC) Sudy
Authors: Vijay Nambi, Xiaoxi Liu, Lloyd Chambless, James A De Lemos, Sunil Agarwal, Salim S Virani, David Aguilar, Pothur Srinivas, Anita Deswal, Thomas Mosley, Eric Boerwinkle, Ron C Hoogeveen, Joe Coresh, Aaron R Folsom, Gerardo Heiss, Christie M Ballantyne
Journal: Circulation (2012)

Objectives: We evaluated whether scores incorporating troponin T (TnT), measured with a high sensitivity assay and NT-pro B type natriuretic peptide (NTproBNP) improve heart failure (HF) risk predi...
총회구연 : 성남지역의 급성 바이러스간염: 전향적, 다기관 연구
Authors: 정숙향, 정연무, 김정심, 이지혜, 이상협, 김진욱, 박상종, 박영민, 황성규, 임규성, 강숙경, 이현석, 윤혜선, 지영미, 김종현, 배근량
Journal: Clinical and Molecular Hepatology (2009)
High IGF1R Expression Is Associated with Worse Prognosis in CLL and Impacts Response to PI3K-δ Inhibitor Treatment
Authors: Annika Scheffold, Billy Michael Chelliah Jebaraj, Johannes Bloehdorn, Eugen Tausch, Jasmin Bahlo, Sandra Robrecht, Kirsten Fischer, Michael Hallek, Hartmut Döhner, Daniel Mertens, Stephan Stilgenbauer
Journal: Blood (2017)
The ABCs of ovarian cancer immunology: IgA, B cells, and CTLs
Authors: Andrew Lichtman
Journal: Science Immunology (2021)

Intratumoral B cells in ovarian cancers produce IgA, which binds tumor antigens and inhibit tumor growth through myeloid cell-dependent mechanisms or by neutralization of secreted factors, and by antigen-nonspecific binding to poly-Ig receptor on cancer cells leading to transcytosis, which sensitizes the cells for CTL killing.
SARS-CoV-2 mutations in MHC-I-restricted epitopes evade CD8 <sup>+</sup> T cell responses
Authors: Benedikt Agerer, Maximilian Koblischke, Venugopal Gudipati, Luis Fernando Montaño-Gutierrez, Mark Smyth, Alexandra Popa, Jakob-Wendelin Genger, Lukas Endler, David M. Florian, Vanessa Mühlgrabner, Marianne Graninger, Stephan W. Aberle, Anna-Maria Husa, Lisa Ellen Shaw, Alexander Lercher, Pia Gattinger, Ricard Torralba-Gombau, Doris Trapin, Thomas Penz, Daniele Barreca, Ingrid Fae, Sabine Wenda, Marianna Traugott, Gernot Walder, Winfried F. Pickl, Volker Thiel, Franz Allerberger, Hannes Stockinger, Elisabeth Puchhammer-Stöckl, Wolfgang Weninger, Gottfried Fischer, Wolfgang Hoepler, Erich Pawelka, Alexander Zoufaly, Rudolf Valenta, Christoph Bock, Wolfgang Paster, René Geyeregger, Matthias Farlik, Florian Halbritter, Johannes B. Huppa, Judith H. Aberle, Andreas Bergthaler
Journal: Science Immunology (2021)

CD8+ T cell immunity to SARS-CoV-2 has been implicated in COVID-19 severity and virus control. Here, we identified nonsynonymous mutations in MHC-I-restricted CD8+ T cell epitopes after deep sequencing of 747 SARS-CoV-2 virus isolates. Mutant peptides exhibited diminished or abrogated MHC-I binding in a cell-free in vitro assay. Reduced MHC-I binding of mutant peptides was associated with decreased proliferation, IFN-γ production and cytotoxic activity of CD8+ T cells isolated from HLA-matched COVID-19 patients. Single cell RNA sequencing of ex vivo expanded, tetramer-sorted CD8+ T cells from COVID-19 patients further revealed qualitative differences in the transcriptional response to mutant peptides. Our findings highlight the capacity of SARS-CoV-2 to subvert CD8+ T cell surveillance through point mutations in MHC-I-restricted viral epitopes.
In vivo testing of mucus-permeating nanoparticles for oral insulin delivery using Caenorhabditis elegans as a model under hyperglycemic conditions
Authors: Ana L. Martínez-López, Carlos J. González-Navarro, Paula Aranaz, José L. Vizmanos, Juan M. Irache
Journal: Acta Pharmaceutica Sinica B (2021)

The aim was to evaluate the potential of mucus-permeating nanoparticles for the oral administration of insulin. These nanocarriers, based on the coating of zein nanoparticles with a polymer conjugate containing PEG, displayed a size of 260 nm with a negative surface charge and an insulin payload of 77 μg/mg. In intestinal pig mucus, the diffusivity of these nanoparticles (PPA-NPs) was found to be 20-fold higher than bare nanoparticles (NPs). These results were in line with the biodistribution study in rats, in which NPs remained trapped in the mucus, whereas PPA-NPs were able to cross this layer and reach the epithelium surface. The therapeutic efficacy was evaluated in Caenorhabditis elegans grown under high glucose conditions. In this model, worms treated with insulin-loaded in PPA-NPs displayed a longer lifespan than those treated with insulin free or nanoencapsulated in NPs. This finding was associated with a significant reduction in the formation of reactive oxygen species (ROS) as well as an important decrease in the glucose and fat content in worms. These effects would be related with the mucus-permeating ability of PPA-NPs that would facilitate the passage through the intestinal peritrophic-like dense layer of worms (similar to mucus) and, thus, the absorption of insulin.
Sociodemographic Factors Associated With Rapid Relapse in Triple-Negative Breast Cancer: A Multi-Institution Study
Authors: Sarah Asad, Carlos H. Barcenas, Richard J. Bleicher, Adam L. Cohen, Sara H. Javid, Ellis G. Levine, Nancy U. Lin, Beverly Moy, Joyce Niland, Antonio C. Wolff, Michael J. Hassett, Daniel G. Stover
Journal: Journal of the National Comprehensive Cancer Network (2021)

Triple-negative breast cancer (TNBC) accounts for disproportionately poor outcomes in breast cancer, driven by a subset of rapid-relapse TNBC (rrTNBC) with marked chemoresistance, rapid metastatic spread, and poor survival. Our objective was to evaluate clinicopathologic and sociodemographic features associated with rrTNBC.We included patients diagnosed with stage I-III TNBC in 1996 through 2012 who received chemotherapy at 1 of 10 academic cancer centers. rrTNBC was defined as a distant metastatic recurrence event or death ≤24 months after diagnosis. Features associated with rrTNBC were included in a multivariable logistic model upon which backward elimination was performed with a P<.10 criterion, with a final multivariable model applied to training (70%) and independent validation (30%) cohorts.Among all patients with breast cancer treated at these centers, 3,016 fit the inclusion criteria. Training cohort (n=2,112) bivariable analyses identified disease stage, insurance type, age, body mass index, race, and income as being associated with rrTNBC (P<.10). In the final multivariable model, rrTNBC was significantly associated with higher disease stage (adjusted odds ratio for stage III vs I, 16.0; 95% CI, 9.8-26.2; P<.0001), Medicaid/indigent insurance, lower income (by 2000 US Census tract), and younger age at diagnosis. Model performance was consistent between the training and validation cohorts. In sensitivity analyses, insurance type, low income, and young age were associated with rrTNBC among patients with stage I/II but not stage III disease. When comparing rrTNBC versus late relapse (>24 months), we found that insurance type and young age remained significant.Timing of relapse in TNBC is associated with stage of disease and distinct sociodemographic features, including insurance type, income, and age at diagnosis.
Preliminary results from a phase II trial of docetaxel before castration with degarelix in men with newly diagnosed metastatic prostate cancer.
Authors: Theodore Stewart Gourdin, Michael B. Lilly, Arif Hussain, Stephen Savage, Harry S Clarke, Amy Marie Sion, Robert Grubb, David Sellman, Toros Dincman, Jennifer Mikoll, Pooja Patel, David T. Marshall, Hong Li, Thomas E. Keane
Journal: Journal of Clinical Oncology (2021)

116 Background: Randomized trials have demonstrated a survival advantage to administering docetaxel (D) shortly after initiation of androgen deprivation therapy (ADT) in men with newly diagnosed hormone sensitive metastatic prostate cancer (hsMPC). Clinical trials in breast cancer, research in prostate cancer cell lines, and pharmacokinetic analyses of D clearance in the castrate state, suggest increased efficacy of chemotherapy administered separately from hormone suppression. We proposed that treatment with D before ADT might improve outcomes in newly diagnosed hsMPC. Methods: In an ongoing phase II study (NCT03069937), men with newly diagnosed hsMPC were treated with 4 cycles of D (75mg/m2) every 21 days without ADT followed by 2 cycles of D concurrent with the LHRH antagonist degarelix (Deg) administered every 4 weeks. The Deg alone was continued for a total of 7 injections. Men were trial eligible with high or low volume disease by CHAARTED criteria. Bicalutamide was allowed for &lt; 30 days before trial entry, but LHRH directed therapy was not permitted. The primary endpoint for this trial is percentage of men obtaining PSA &lt; 0.2 ng/ml. Pre-specified secondary endpoints examined here after 4 cycles of docetaxel alone are safety, and efficacy defined by PSA (decrease by &gt; 50%) and radiographic responses. Results: At time of this abstract, 50 patients have been enrolled to trial. Two patients withdrew after 1 cycle of D, and 4 patients have not yet completed 4 cycles. Of the 50 patients evaluable for safety, 6 (12%) had Grade 3 toxicities related to D. No Grade 4/5 toxicities were reported. Of patients who completed 4 cycles of D, 24/44 (55%) had a PSA response and 34/44 (77%) had PSA decline from baseline. All but two patients with declining PSA had stable or improved radiographic imaging. Six of the 44 patients (14%) had PSA progression (&gt;25% increase) with D therapy, 3 of whom also had radiographic progression. Every patient with PSA response after 4 cycles D had PSA decline after 2 cycles. No patient with PSA decline after 2 cycles had PSA progression after 4 cycles. PSA response rate was stratified by baseline variables in table below. Conclusions: In hsMPC patients, 4 cycles D without ADT appears to be a safe and active therapy. Treatment with bicalutamide prior to the start of D predicts poorer PSA response. This result strengthens our hypothesis that sensitivity of hsMPC to taxane therapy may be enhanced if ADT is postponed. Baseline genomics will be analyzed, and we hope to correlate responses to D alone with later primary efficacy outcomes. Clinical trial information: NCT03069937. [Table: see text]
Reconstruction of the Origin of a Neo-Y Sex Chromosome and Its Evolution in the Spotted Knifejaw,<i>Oplegnathus punctatus</i>
Authors: Ming Li, Rui Zhang, Guangyi Fan, Wenteng Xu, Qian Zhou, Lei Wang, Wensheng Li, Zunfang Pang, Mengjun Yu, Qun Liu, Xin Liu, Manfred Schartl, Songlin Chen
Journal: Molecular Biology and Evolution (2021)

Abstract Sex chromosomes are a peculiar constituent of the genome because the evolutionary forces that fix the primary sex-determining gene cause genic degeneration and accumulation of junk DNA in the heterogametic partner. One of the most spectacular phenomena in sex chromosome evolution is the occurrence of neo-Y chromosomes, which lead to X1X2Y sex-determining systems. Such neo-sex chromosomes are critical for understanding the processes of sex chromosome evolution because they rejuvenate their total gene content. We assembled the male and female genomes at the chromosome level of the spotted knifejaw (Oplegnathus punctatus), which has a cytogenetically recognized neo-Y chromosome. The full assembly and annotation of all three sex chromosomes allowed us to reconstruct their evolutionary history. Contrary to other neo-Y chromosomes, the fusion to X2 is quite ancient, estimated at 48 Ma. Despite its old age and being even older in the X1 homologous region which carries a huge inversion that occurred as early as 55–48 Ma, genetic degeneration of the neo-Y appears to be only moderate. Transcriptomic analysis showed that sex chromosomes harbor 87 genes, which may serve important functions in the testis. The accumulation of such male-beneficial genes, a large inversion on the X1 homologous region and fusion to X2 appear to be the main drivers of neo-Y evolution in the spotted knifejaw. The availability of high-quality assemblies of the neo-Y and both X chromosomes make this fish an ideal model for a better understanding of the variability of sex determination mechanisms and of sex chromosome evolution.
An open-label, multicenter, phase IIIb study of patients with urinary tract carcinoma (UTC) (STRONG): Final analysis for fixed-dose durvalumab monotherapy (module A).
Authors: Guru Sonpavde, Aurelien Marabelle, Yohann Loriot, Cora N. Sternberg, Jae-Lyun Lee, Aude Flechon, Guilhem Roubaud, Damien Pouessel, Vittorina Zagonel, Fabio Calabro, Giuseppe L. Banna, Sang Joon Shin, Francisco Emilio Vera Badillo, Thomas Powles, Eva Hellmis, Paulo Andre Palhares de Miranda, Ana Rita Lima, William Sawyer, Sebastien J. Hotte
Journal: Journal of Clinical Oncology (2021)

429 Background: Patients (pts) with advanced UTC who fail first-line therapy have poor prognoses. Durvalumab (D; anti-PD-L1) 10 mg/kg every 2 weeks is approved for treatment of metastatic urothelial carcinoma (mUC) after progression on platinum-based chemotherapy (CT). Further understanding of long-term safety and efficacy of D in platinum and non-platinum pretreated pts, using a fixed dose every 4 weeks (Q4W), is of value. Methods: Module A of the phase IIIb STRONG study (NCT03084471) investigated the safety of fixed-dose D (1500 mg, Q4W) in pts with urothelial and nonurothelial UTC who progressed on or after platinum/non-platinum CT. The primary endpoint was the number of pts with adverse events of special interest (AESIs) – events with an inflammatory or immune-mediated mechanism that may require interventions (eg, steroids/immunosuppressants), including immune-mediated adverse events (imAE). AEs with onset date on or after the date of first dose and up to 90 days after study discontinuation were included. Secondary endpoints included serious AEs and overall survival (OS). Exploratory endpoints included objective response rate (ORR) and disease control rate (DCR) (investigator assessed per RECIST 1.1). Results: A total of 867 pts received D monotherapy. Median age was 68.1 yr and 80.0% were male; 87.1% had an ECOG PS 0-1 and 12.7% had ECOG PS 2. Most (96.3%) had urothelial UTC, including urothelial variants. Tumor PD-L1 expression was high (≥25%) in 239/577 (41.4%) pts with available data. Median treatment and follow-up duration were 12.1 wk (range 1-128) and 13.8 mo (range 0.0-28.8), respectively. Safety data are reported in the table. Deaths related to study treatment occurred in 9 pts (1.0%). At data cutoff (March 31, 2020), 30.8% of pts were in survival follow-up. Median OS was 7.0 mo (95% CI: 6.4-8.2); OS rate at 1 and 2 yr was 35.8% (95% CI: 32.5-39.2) and 20.2% (95% CI: 16.5-24.1), respectively. ORR was 17.7% with complete responses in 5.1% of pts. DCR at 6 mo was 33.0%. Median OS of subgroups: PD-L1 high or low: 9.3 mo (95% CI: 6.7-12.7) and 6.5 mo (95% CI: 5.8-8.1); ECOG PS 0-1 or 2: 8.4 mo (95% CI: 7.2–9.8) and 3 mo (95% CI: 2.0-4.1); urothelial and nonurothelial UTC: 7.0 mo (95% CI: 6.4-8.2) and 7.0 mo (95% CI: 2.7-10.2), respectively. Conclusions: Fixed-dose D monotherapy Q4W is convenient with an acceptable safety profile in previously treated pts for UTC. Long-term safety and efficacy data reported are consistent with published studies of D and other IO agents in this setting. Clinical trial information: NCT03084471 . [Table: see text]
Association Between Sex and Immune-Related Adverse Events During Immune Checkpoint Inhibitor Therapy
Authors: Ying Jing, Yongchang Zhang, Jing Wang, Kunyan Li, Xue Chen, Jianfu Heng, Qian Gao, Youqiong Ye, Zhao Zhang, Yaoming Liu, Yanyan Lou, Steven H Lin, Lixia Diao, Hong Liu, Xiang Chen, Gordon B Mills, Leng Han
Journal: JNCI Journal of the National Cancer Institute (2021)

Abstract Background Accumulated evidence supports the existence of sex-associated differences in immune systems. Understanding the role of sex in immune-related adverse events (irAEs) is important for management of irAE in patients receiving immunotherapy. Methods We performed meta-analysis on published clinical study data and multivariable logistic regression on pharmacovigilance data and applied a propensity algorithm to The Cancer Genome Atlas omics data. We further validated our observations in 2 independent in-house cohorts of 179 and 767 cancer patients treated with immune checkpoint inhibitors. Results A meta-analysis using 13 clinical studies that reported on 1096 female patients (36.8%, 95% confidence interval [CI] = 35.0% to 38.5%) and 1886 male patients (63.2%, 95% CI = 61.5% to 65.0%) demonstrated no statistically significant irAE risk difference between the sexes (odds ratio [OR] = 1.19, 95% CI = 0.91 to 1.54, 2-sided P = .21). Multivariable logistic regression analysis of 12 225 patients from the Food and drug administration Adverse Event Reporting System (FAERS) and 10 979 patients from VigiBase showed no statistically significant difference in irAEs by sex. A propensity score algorithm used on multi-omics data for 6019 patients from The Cancer Genome Atlas found no statistically significant difference by sex for irAE-related factors or pathways. The retrospective analysis of 2 in-house patient cohorts validated these results (OR = 1.55, 95% CI = 0.98 to 2.47, false discovery rate = 0.13, for cohort 1; OR = 1.16, 95% CI = 0.86 to 1.57, false discovery rate = 0.39, for cohort 2). Conclusions We observed minimal sex-associated differences in irAEs among cancer patients who received immune checkpoint inhibitor therapy. It may be unnecessary to consider sex effects for irAE management in clinical practice.