tbuckley/cabot-search huggingface dataset:
Macula Densa NOS1β Modulates Renal Hemodynamics and Blood Pressure during Pregnancy: Role in Gestational Hypertension
Authors: Jin Wei, Jie Zhang, Shan Jiang, Lan Xu, Larry Qu, Bo Pang, Kun Jiang, Lei Wang, Suttira Intapad, Jacentha Buggs, Feng Cheng, Shyam Mohapatra, Luis A. Juncos, Jeffrey L. Osborn, Joey P. Granger, Ruisheng Liu
Journal: Journal of the American Society of Nephrology (2021)

Regulation of renal hemodynamics and BP via tubuloglomerular feedback (TGF) may be an important adaptive mechanism during pregnancy. Because the β-splice variant of nitric oxide synthase 1 (NOS1β) in the macula densa is a primary modulator of TGF, we evaluated its role in normal pregnancy and gestational hypertension in a mouse model. We hypothesized that pregnancy upregulates NOS1β in the macula densa, thus blunting TGF, allowing the GFR to increase and BP to decrease.We used sophisticated techniques, including microperfusion of juxtaglomerular apparatus in vitro, micropuncture of renal tubules in vivo, clearance kinetics of plasma FITC-sinistrin, and radiotelemetry BP monitoring, to determine the effects of normal pregnancy or reduced uterine perfusion pressure (RUPP) on macula densa NOS1β/NO levels, TGF responsiveness, GFR, and BP in wild-type and macula densa-specific NOS1 knockout (MD-NOS1KO) mice.Macula densa NOS1β was upregulated during pregnancy, resulting in blunted TGF, increased GFR, and decreased BP. These pregnancy-induced changes in TGF and GFR were largely diminished, with a significant rise in BP, in MD-NOS1KO mice. In addition, RUPP resulted in a downregulation in macula densa NOS1β, enhanced TGF, decreased GFR, and hypertension. The superimposition of RUPP into MD-NOS1KO mice only caused a modest further alteration in TGF and its associated changes in GFR and BP. Finally, in African green monkeys, renal cortical NOS1β expression increased in normotensive pregnancies, but decreased in spontaneous gestational hypertensive pregnancies.Macula densa NOS1β plays a critical role in the control of renal hemodynamics and BP during pregnancy.
Characterization of findings on prostate cancer tumor sequencing that should prompt consideration for germline testing.
Authors: Hong Truong, Kelsey Breen, Yelena Kemel, Andrew Thomas Lenis, Peter Reisz, Nicole Benfante, Behfar Ehdaie, Karim A. Touijer, Vincent Paul Laudone, Peter T. Scardino, James Andrew Eastham, Vijai Joseph, Ozge Birsoy, Diana Mandelker, Zsofia Kinga Stadler, Kenneth Offit, Michael J. Morris, Wassim Abida, Mark E. Robson, Maria Isabel Carlo
Journal: Journal of Clinical Oncology (2021)

5022 Background: Tumor sequencing is increasingly used for therapeutic selection in men with advanced prostate cancer (PC). If tumor-only sequencing is performed without matched germline, identified mutations could be of somatic or germline origin. Germline mutations could confer additional risk for other cancers to the patient and at-risk family members. The objective of this study is to determine the overall and gene-specific probability of pathogenic/likely pathogenic germline mutations based on tumor-only sequencing. Methods: We investigated mutations found in a cohort of men with PC who underwent targeted next generation sequencing of PC tumor and matched peripheral blood using the MSK-IMPACT assay between 01/2015 and 01/2020. A germline probability for each gene was determined by dividing the number of germline mutations by the total number of somatic and germline mutations. Cancer susceptibility genes commonly sequenced on tumor-based tests for PC were assessed, including ATM, BRCA1/ 2, BRIP1, CHEK2, HOXB13, MLH1, MSH2, MSH6, NBN, PALB2, PMS2 (henceforth referred to as PC genes). Results: A total of 1883 men with PC were included, with median age of diagnosis of 62.0 ± 8.8 years. 84% had high risk PC, 52% had metastasis, 38% had family history of PC. A total of 364 (19%) men had at least one mutation (either somatic or germline) in PC genes. Overall, 189 (10%) men had at least one germline mutation that would not have been reported as germline without matched normal. The average germline probability of PC genes was 40% (range: 0% in MLH1 to 83% in CHEK2). The number of total mutations, germline mutations, and germline probability of genes found in &gt; 0.5% of the study cohort are summarized in Table. All these genes are moderate/high penetrance autosomal dominant genes with established guidelines for cascade testing, enhanced cancer screening, or potential risk-reducing surgery. Conclusions: In this study, an average of 40% of mutations found in cancer susceptibility genes on PC tumor sequencing were germline mutations. Men undergoing tumor-only sequencing should be counseled on the possibility of uncovering a germline mutation. In addition to BRCA1/ 2, mutations in certain genes, such as CHEK2 and PALB2, have a high probability of being germline and should prompt referral for genetic counseling and germline testing.[Table: see text]
New approaches to moderate CRISPR-Cas9 activity: Addressing issues of cellular uptake and endosomal escape
Authors: Maja van Hees, Sofie Slott, Anders Højgaard Hansen, Heon Seok Kim, Hanlee P. Ji, Kira Astakhova
Journal: Molecular Therapy (2021)

CRISPR-Cas9 is rapidly entering molecular biology and biomedicine as a promising gene-editing tool. A unique feature of CRISPR-Cas9 is a single-guide RNA directing a Cas9 nuclease toward its genomic target. Herein, we highlight new approaches for improving cellular uptake and endosomal escape of CRISPR-Cas9. As opposed to other recently published works, this review is focused on non-viral carriers as a means to facilitate the cellular uptake of CRISPR-Cas9 through endocytosis. The majority of non-viral carriers, such as gold nanoparticles, polymer nanoparticles, lipid nanoparticles, and nanoscale zeolitic imidazole frameworks, is developed with a focus toward optimizing the endosomal escape of CRISPR-Cas9 by taking advantage of the acidic environment in the late endosomes. Among the most broadly used methods for in vitro and ex vivo ribonucleotide protein transfection are electroporation and microinjection. Thus, other delivery formats are warranted for in vivo delivery of CRISPR-Cas9. Herein, we specifically revise the use of peptide and nanoparticle-based systems as platforms for CRISPR-Cas9 delivery in vivo. Finally, we highlight future perspectives of the CRISPR-Cas9 gene-editing tool and the prospects of using non-viral vectors to improve its bioavailability and therapeutic potential.
Randomized Phase III Postoperative Trial of Platinum-Based Chemotherapy Versus Capecitabine in Patients With Residual Triple-Negative Breast Cancer Following Neoadjuvant Chemotherapy: ECOG-ACRIN EA1131
Authors: Ingrid A. Mayer, Fengmin Zhao, Carlos L. Arteaga, William F. Symmans, Ben H. Park, Brian L. Burnette, Amye J. Tevaarwerk, Sofia F. Garcia, Karen L. Smith, Della F. Makower, Margaret Block, Kimberly A. Morley, Chirag R. Jani, Craig Mescher, Shabana J. Dewani, Bernard Tawfik, Lisa E. Flaum, Erica L. Mayer, William M. Sikov, Eve T. Rodler, Lynne I. Wagner, Angela M. DeMichele, Joseph A. Sparano, Antonio C. Wolff, Kathy D. Miller
Journal: Journal of Clinical Oncology (2021)

Patients with triple-negative breast cancer (TNBC) and residual invasive disease (RD) after completion of neoadjuvant chemotherapy (NAC) have a high-risk for recurrence, which is reduced by adjuvant capecitabine. Preclinical models support the use of platinum agents in the TNBC basal subtype. The EA1131 trial hypothesized that invasive disease-free survival (iDFS) would not be inferior but improved in patients with basal subtype TNBC treated with adjuvant platinum compared with capecitabine.
Identifying androgen receptor (AR) and genomic characteristics that define populations of patients with mHSPC who benefit from early PARP inhibition therapy with talazoparib.
Authors: Saro Kasparian, Leanne Burnham, Rick Kittles, Zj Sun, Fornati Bedell, Justin Tran, Min Li, Tanya B. Dorff
Journal: Journal of Clinical Oncology (2021)

TPS5097 Background: A minority of men with mCRPC, those with DNA repair mutations, can benefit from PARP inhibitor therapy. In addition to DNA repair, PARP is used by cancer cells to interact with other cellular mechanisms including androgen receptors (AR). The next generation PARP inhibitor talazoparib can, in addition to inhibiting DNA repair, trap PARP, preventing it from carrying out its other functions. As progression in mHSPC is based on AR escape mechanisms, we predict that early exposure to PARP inhibition will delay progression. In addition, AR characteristics and function vary by ethnic populations. AR expression is inversely related with the number of polymorphic CAG repeats. As African American (AfrAm) men commonly have shorter CAG repeats in their AR, they may experience different response duration, but have been under-represented in clinical trials. Furthermore, CAG repeats may be associated with greater signaling through pathways such as wnt and Myc, which is associated with aggressive disease. Thus, studying intensified up-front therapy in a diverse prostate cancer population is a critical unmet need. Methods: 70 subjects will be treated with ADT + abiraterone + talazoparib. Outreach by our Division of Health Equities and accrual at community satellites located near diverse populations will be enlisted to accrue a target of 30% African American. Talazoparib will be dosed at 1mg daily (0.75 mg in renal insufficiency). LHRH and abiraterone formulations will be left to physician’s choice. PSA and safety labs will be checked every 4 weeks for the first 12 weeks. Imaging will be performed every 12 weeks for the first year then every 24 weeks if PSA is decreasing, or 12 weeks if rising. Data safety monitoring for toxicity after every 10 subjects have been accrued. Diversity of accrual will be evaluated after 30 subjects are enrolled; amendments will be made if the diversity goal is not achieved. Tissue genomics and ctDNA will be measured at baseline; ctDNA will be repeated after 4 weeks and at castration resistance. Endpoints: Primary: PSA nadir at 7 months has been found to be associated with overall survival and is achieved by 55% of men with mHSPC with ADT + abiraterone. With 70 subjects there is 97% power to confirm improved nadir rate of 75%, and 83% power to determine a nadir rate &gt;70%. Secondary endpoints include objective response by RECIST 1.1 for subjects with measurable disease. radiographic progression free survival. Correlative objectives include comparing outcomes in subsets of men with high vs low number of AR CAG repeats, men with genomic alterations, and the change in ctDNA alteration fractions from baseline to 4 weeks and at progression. Progress: The trial is open to accrual as of Feb 2021. Sponsor: Pfizer/ Prostate Cancer Foundation RFP Clinical trial information: NCT04734730.
TNF-alpha immunosuppressive use and future malignancy risk.
Authors: Conor Driscoll, Kaitlyn O'Shea, Hui Zhang, Jordan Rich, Christopher Yang, Dylan Isaacson, Eric Li, Mohammad Siddiqui, Roopal Kundu, Edward M. Schaeffer, Shilajit Kundu
Journal: Journal of Clinical Oncology (2021)

10558 Background: Tumor Necrosis Factor Alpha (TNF-a) inhibitors suppress the immune system in patients with systemic inflammatory conditions. Long term data assessing future cancer risk for these patients is not known. We assessed long term risk of malignancy in patients with Rheumatoid Arthritis [RA], Inflammatory Bowel Disease [IBD], Psoriasis [PS], and Ankylosing Spondylitis [AS], who were or were not exposed to a TNF-a inhibitor. Methods: This was a retrospective, cohort study conducted using electronic medical record data for patients with complete demographic and treatment data at Northwestern Medicine from years 1998 to 2020 (RA: n = 10763; IBD: n = 12106; PS: n = 1920; AS: n = 5103). Inverse Probability of Treatment Weighting (IPTW) was used to balance the distributions of age, race, gender, smoking status, and follow-up time across exposure groups within each inflammatory condition type. Relative risk (RR) of malignancy based on TNF-a exposure was assessed using logistic regression. Results: 2583 (24.0%) of RA, 2185 (18.0%) of IBD, 1811 (94.3%) of PS, 572 (11.2%) of AS patients had TNF-a exposure. Median follow-up for patients was 43 months. The RR for any cancer was higher for patients exposed to a TNF-a agent with rheumatoid arthritis (RR 1.121 (95% CI 1.02-1.23, p = 0.015) and psoriasis (RR 1.763 (95% CI 1.32-2.37, p &lt; 0.001). The relative risk of any cancer was lower in patients exposed to a TNF-a agent with IBD (RR 0.858 (95% CI 0.78-0.94, p = 0.001). No significant difference in relative risk associated with TNF-a exposure was detected with ankylosing spondylitis (RR 0.929 (95% CI 0.8-1.08, p = 0.344). Conclusions: Patients with RA or PS and TNF-a exposure had higher RR of overall malignancy. Patients with IBD and TNF-a exposure had lower risk of overall malignancy. TNF-a immunosuppression may alter cancer risk differently based on the disease states for which it is being used. This information is critical when counseling patients on long term risk and screening strategies when considering TNF-a inhibition.
Comparison of tongue cancer survival among White and Black cancer patients: An exploratory analysis of the SEER database.
Authors: Jaffer Shah, Asghar Shah, Aarati Shah, Hani Aiash
Journal: Journal of Clinical Oncology (2021)

e18053 Background: Despite the relatively rare incidence of tongue cancer in the United States, 2,830 people were estimated to have died from it in 2020. Research has indicated disparities in oral cancer screenings among minority and low-income patients. The aim of the present study is to characterize the incidence of tongue cancer across in the US population and to determine mediators of survival months. Methods: SEER 18 regions database (November 2019 submission) was queried to obtain data on tongue cancer incidence, patient demographics, and clinical variables for patients (n=51,622) from 2000-2017 using SEER*Stat 8.3.8. Data analysis were performed using R and RStudio version 4.02, and 1.3.1073, respectively. For comparison between groups, Chi-squared test for independence, Fisher’s exact test, and Wilcoxon signed-rank test were applied where applicable. Univariate and multivariate regression models characterized the relationship between survival months and sex, race, primary site, and additional patient characteristics. Results: Several significant group differences were determined in the incidence of tongue cancer. Patient sex was significantly associated (P&lt;0.001), with survival months in White patients, with median survival months 33 (IQR 11,85) and 35 (IQR 12,82) for females and males respectively. Regression analysis found multiple patient level characteristics significantly mediating survival months. The odds ratio (OR) for reported patient race of Black were OR 0.78 (95% CI 0.68, 0.89; P&lt;.001) and OR 0.75 (95% CI 0.66, 0.86; P&lt;.001) for univariate and multivariate regression, respectively. Conclusions: The study indicates that health disparities vis-à-vis social determinants of health play a role in mediating differences in tongue cancer survival months for patients in the US. Further research should characterize and address persisting health inequities and potential solutions in oral cancer incidence and mortality.[Table: see text]
First-in-human phase 1/1b expansion of PMD-026, an oral RSK inhibitor, in patients with metastatic triple-negative breast cancer.
Authors: Muralidhar Beeram, Pavani Chalasani, Judy S. Wang, Lida A. Mina, Rebecca Arielle Shatsky, Meghna S. Trivedi, Robert Wesolowski, Sara A. Hurvitz, Hyo S. Han, Amita Patnaik, Mary Rose Pambid, Aarthi Jayanthan, My-my Huynh, Gerrit Los, Sandra Elaine Dunn, Andrew Dorr
Journal: Journal of Clinical Oncology (2021)

e13043 Background: P90 ribosomal S6 kinase (RSK) is an actionable molecular target against metastatic triple negative breast cancer (mTNBC). RSK is a major convergence point in the integral TNBC signaling pathways, MAPK and PDK-1. PMD-026 is a first-in-class oral RSK inhibitor with high selectivity. The dose escalation portion of this study established the RP2D of PMD-026 as 200 mg Q12. PMD-026 demonstrated good plasma exposure following oral dosing, with a T 1/2 of ̃ 6 h (range 4-8 h), and achieved the targeted preclinical efficacious concentrations using a Q12h dosing schedule. PMD-026 also demonstrated a tolerable safety profile and initial signs of efficacy in patients with metastatic breast cancer. The intensity of RSK2 activation ranged from an H Score of 110-268 based on a CLIA companion immunohistochemistry assay. We present initial data from the expansion cohort. Methods: The primary aim of this single-arm, open-label, first-in-human phase 1/1b study is to evaluate the safety of single agent PMD-026 in patients with mTNBC. Secondary endpoints are clinical activity, pharmacokinetics, and correlative biomarker expression on tumor specimens. Patients are dosed at 200 mg twice daily in 21-day cycles. Eligible patients have measurable disease as per RECIST v1.1 and have had disease progression on or after standard of care treatment. Tumor tissue is assessed to retrospectively correlate RSK2 activity by immunohistochemistry (IHC) with clinical outcomes. Pharmacokinetics are assessed along with a food effect (sub-study with n=12). In addition, a pharmacodynamic marker, YB-1 phosphorylation, is being explored in peripheral blood mononuclear cells before and during treatment. Results: As of February 16, 2021, 7 patients with mTNBC (median age 62 years, range 33-74) have been enrolled in the phase 1b Expansion (median of 7 prior lines of therapy). Notable prior therapies in the phase 1b include sacituzumab govitecan (n=4) and atezolizumab/nab-paclitaxel (n=1). Patients in escalation and expansion treated with the RP2D had median progression free survival of 30 vs 99 days for low vs high RSK2 expression, respectively. This cut-off will be further evaluated in the expansion phase of the study. Conclusions: Updated safety, clinical activity, pharmacokinetic, and biomarker analyses will be presented. Target accrual for phase 1b Expansion is a minimum of 20 patients with mTNBC. Clinical trial information: NCT04115306.
The clinicopathological characteristics, gene mutation characteristics and survival analysis of carcinoma of unknown primary origin.
Authors: Yanzhi Cui, Da Jiang, Ran Hou, Xue Zhang, Wenya Song, Xinliang Zhou, Zexian Hu
Journal: Journal of Clinical Oncology (2021)

e15098 Background: Analyze the characteristics of CUPS clinicopathology and gene mutation spectrum, and discuss CUPS drug treatment strategies. Methods: A retrospective analysis of the data of 30 patients with metastatic cancer of CUP admitted to our department from April 2015 to April 2020. Including clinicopathological characteristics, treatment process and methods, gene molecular information, follow-up survival period. The follow-up was until February 1, 2021 or the patient died. Results: The pathological types of these cases were adenocarcinoma (14/30,46.7%), squamous cell carcinoma (5/30, 16.7%), neuroendocrine carcinoma (3/30,10%), small cell carcinoma (2/30,6.7%), sarcomatoid carcinoma (2/30,6.7%), large cell carcinoma (1/30,3.3%), lymphoepithelial carcinoma (1/30,3.3%), and poorly differentiated carcinoma (2/30,6.7%) . The most predilection site was lymph nodes, accounting for 70%. Primary lesions were not found in 23 cases in the course of diagnosis and treatment. They were head and neck in 1 case, lung in 1 case, mammary gland in 1 case, digestive tract in 3 cases and thymus in 1 case. 23 patients received chemotherapy alone or combined with antiangiogenic therapy, 2 patients received molecular targeted agents, 1 patient received ICI combined with antiangiogenic therapy, and the remaining 4 patients died without antitumor therapy or gave up treatment. The survival time of 26 patients was between 1 to 143 months, and the median survival time was 8.6 months. The 1-year, 2-year, 3-year and 5-year OS rate were 40%, 20%, 6.7% and 3.3%, respectively. Mean survival time was significantly longer among patients without visceral metastasis vs. with visceral metastasis (15.6m vs. 7.3m, P = 0.023). OS rate were 70% vs. 25%, 30% vs. 15%, 20% vs. 0% and 10% vs. 0%, respectively. The median survival time were 18.3m (with targeted therapy), 8.8m (without targeted therapy), 23.2m (with primary lesion), 8.4m (without primary lesion), The 1-year, 2-year, 3-year and 5-year OS were 53.3% vs. 26.7%, 40% vs. 0%, 23.3% vs. 0% and 6.7% vs. 0% for patients with targeted therapy vs. without targeted therapy, respectively. The 1-year, 2-year, 3-year and 5-year OS were 85.7% vs. 261%, 42.9% vs. 13%, 28.6% vs. 0% and 14.3% vs. 0% for patients with primary lesion vs. without primary lesion, respectively. 20 patients were interrogated genes using NGS of ctDNA. 80% of patients exhibited ctDNA alterations; TP53-associated genes were most commonly altered (13/20,65%) followed by genes involved in the MAPK pathway (20%), PI3K signaling (10%) and the cell cycle machinery (5%). The genomic profiles help guide treatment in 4 cases. Conclusions: CUPS has a poor prognosis. The pathological type is mostly adenocarcinoma, and lymph node metastasis is the first diagnosis. Chemotherapy is still the main treatment method. Molecular detection is helpful for individualized treatment.
The tumor microenvironment (TME) and atezolizumab + <i>nab</i>-paclitaxel (A+nP) activity in metastatic triple-negative breast cancer (mTNBC): IMpassion130.
Authors: Leisha A. Emens, Leonard D Goldstein, Peter Schmid, Hope S. Rugo, Sylvia Adams, Carlos H. Barrios, Andreas Schneeweiss, Veronique Dieras, Hiroji Iwata, Ching-Wei Chang, Hartmut Koeppen, Stephen Y. Chui, Sherene Loi, Luciana Molinero
Journal: Journal of Clinical Oncology (2021)

1006 Background: IMpassion130 was the first randomized phase 3 study to show clinical benefit of cancer immunotherapy (CIT) in untreated PD-L1+ mTNBC. Enhanced A + nP efficacy vs placebo (P) + nP was seen in pts with a richer immune TME but was confined to PD-L1 IC+ pts (PD-L1–expressing immune cells on ≥1% of tumor area; Emens JNCI 2021). While TNBC molecular subtyping and CD8 localization are prognostic in early TNBC, it is unknown whether these features are associated with CIT benefit in mTNBC. This exploratory analysis aimed to identify TME components associated with A + nP efficacy in IMpassion130. Methods: IHC was used to assess PD-L1 status (VENTANA SP142) and immune phenotypes (inflamed/excluded/desert per CD8 stromal/intratumoral localization; Mariathasan Nature 2018). RNA-seq was used for molecular subtyping (Burstein CCR 2015) and pathway analyses (MSigDB Hallmark). Cox regression was used to compare PFS/OS between A + nP vs P + nP, adjusted for prior taxanes, liver mets. Results: Sample classification and PD-L1 distribution are shown (Table). Improved PFS with A + nP vs P + nP was seen in PD-L1 IC+ inflamed and excluded tumors, but improved OS was limited to PD-L1 IC+ inflamed tumors. PD-L1 IC+ basal-like immune activated (BLIA) and immune suppressed (BLIS) subgroups derived PFS benefit, but OS benefit was limited to PD-L1 IC+ BLIA subgroups. In PD-L1 IC+ pts, pathway analysis identified proliferation/DNA damage repair (basal-like tumor features) and angiogenesis/ER response (higher in luminal androgen receptor [LAR]/ mesenchymal [MES] tumors) were associated with improved and reduced PFS, respectively. Conclusions: PD-L1 IC+ immune-inflamed tumors and PD-L1 IC+ BLIA tumors show highest CIT sensitivity, and LAR tumors may be resistant to CIT. These data warrant further study and validation. Clinical trial information: NCT02425891 .[Table: see text]