tbuckley/cabot-search huggingface dataset:
NF- B/HDAC1/SREBP1c pathway mediates the inflammation signal in progression of hepatic steatosis
Authors: Yunwei Guo, Xiaoying Zhang, Zhiyun Zhao, Hongyun Lu, Bilun Ke, Xin Ye, Bin Wu, Jianping Ye
Journal: Acta Pharmaceutica Sinica B (2020)

The transcription factor nuclear factor kappa B (NF-κB) is activated in hepatocytes in the pathogenesis of hepatic steatosis. However, the action mechanism of NF-κB remains to be established in the hepatic steatosis. In this study, the P50 subunit of NF-κB was found to promote the hepatic steatosis through regulation of histone deacetylase 1 (HDAC1) in hepatocytes. The activity was supported by the phenotypes of P50 knockout (P50-KO) mice and P65 knockout (P65-KO) mice. Hepatic steatosis was reduced in the P50-KO mice, but not in the P65-KO mice. The reduction was a result of inhibition of HDAC1 activity in the P50-KO cells. Knockdown of Hdac1 gene led to suppression of hepatocyte steatosis in HepG2 cells. A decrease in sterol-regulatory element binding protein 1c (SREBP1c) protein was observed in the liver of P50-KO mice and in cell with Hdac1 knockdown. The decrease was associated with an increase in succinylation of SREBP1c protein. The study suggests that P50 stabilizes HDAC1 to support the SREBP1c activity in hepatic steatosis in the pathophysiological condition. Interruption of this novel pathway in the P50-KO, but not the P65-KO mice, may account for the difference in hepatic phenotypes in the two lines of transgenic mice.
Mechanical Activation of ADGRE2 Causes Calcium-dependent Activation of PI3K and MAPK Pathways Driving Mast Cell Degranulation and PGD2 Production
Authors: Hirsh Komarow, Andrea Naranjo, Margery Smelkinson, Yun Bai, Araceli Tobio, Steven Boyden, Dean Metcalfe, Ana Olivera
Journal: Journal of Allergy and Clinical Immunology (2020)
Combination of dual immune checkpoint inhibition (ICI) with stereotactic radiation (SBRT) in metastatic renal cell carcinoma (mRCC) (RADVAX RCC).
Authors: Hans J. Hammers, Dendra Vonmerveldt, Chul Ahn, Rosa Maria Nadal, Charles G. Drake, Michael Ryan Folkert, Aaron Michael Laine, Kevin Dale Courtney, James Brugarolas, Daniel Y. Song, Raquibul Hannan, Michael Anthony Carducci
Journal: Journal of Clinical Oncology (2020)

614 Background: Dual ICI with nivolumab/ipilimumab (N/I) has become a standard of care (SOC) for patients (pts) with mRCC. Since the failure to respond to ICI may be due to a lack of immune recognition, novel vaccination approaches and stimulation of the innate immune system (e.g. stimulator of interferon genes (STING) agonists) are being pursued in clinical trials. Because preclinical studies using SBRT have demonstrated the a.) release of tumor antigens, b.) STING pathway activation and c.) synergy with ICI, we have conducted a study to explore the safety and efficacy of this approach in mRCC pts. Methods: Pts with clear cell mRCC were screened and enrolled at two sites (UT Southwestern and Johns Hopkins). Prior treatment with tyrosine kinase inhibitors (TKI) and IL2 were allowed. Enrolled pts received standard of care dosing with Nivolumab (3 mg/kg) and Ipilimumab (1mg/kg) IV q3weeks followed by nivolumab monotherapy. SBRT was administered to 1-2 disease sites with a dose of 50 Gy in 5 fractions between the first and the second dose of N/I. The primary goals of this exploratory study were to determine the safety and tolerability as well as the objective response rate (ORR) by RECIST 1.1 of non-irradiated lesions. Results: A total of 29 pts were screened and 25 pts were enrolled. 11 (44%) of pts received at least one prior systemic therapy: 4 (16%) pts received IL2 and 7 (28%) TKI therapy. The cohort was primarily intermediate and poor risk pts (favorable risk n = 2 (8%), intermediate risk n = 20 (80%), poor risk n = 3 (12%)). 10 (40%) pts required immune suppressive therapy with prednisone for classic immune related adverse events as seen with dual ICI. Radiation pneumonitis limited to the radiation field (grade 2) was seen in 2 pts and responded promptly to oral steroids. At the time of analysis, partial responses (PR) were observed in 14/25 patients with an ORR of 56%. Additional analyses including duration of response, progression free survival and overall survival will be presented. Conclusions: Dual ICI with SBRT showed an acceptable safety and encouraging antitumor activity in mRCC warranting further investigations. Clinical trial information: NCT03065179.
Skin Barrier Dysfunction In Patients With Peanut Allergy Without Eczema
Authors: Donald Leung, Elena Goleva, Bryce Hoffman, Anna Sofia Bronoff, John Jung, Shannon Garcia, Marco Ramirez-Gama, Shifaa Alkotob, Kari Nadeau, Christine Cho, Irina Bronova, Evgeny Berdyshev
Journal: Journal of Allergy and Clinical Immunology (2020)
A Randomised Phase II Study of Cetuximab (C) in Combination with Two Cisplatin-Based Concurrent Chemoradiotherapy Regimens in Patients (PTS) with Stage III Non-Small Cell Lung Cancer (NSCLC). Final Results of the GFPC 08-03 Trial
Authors: L. Greillier, I. Martel-Lafay, D. Arpin, N. Pourel, S. Chabaud, R. Lamy, A. Madroszyk, P. Fournel
Journal: Annals of Oncology (2012)
MHCI and FOXP3 predicting outcome to neoadjuvant atezolizumab in sequential urothelial cancer tissue.
Authors: Bernadett Szabados, Mark Kockx, Pieter-Jan Van Dam, Alejo Rodriguez-Vida, Ignacio Duran, Simon J. Crabb, Michiel Simon Van Der Heijden, Albert Font, Gwenaelle Gravis, Aaron Prendergast, Maurizio Perdicchio, Diana Stanoeva, Sofie Daelemans, Sanjeev Mariathasan, Joy S. Tea, Kelly Mousa, Romain Banchereau, Daniel Castellano, Thomas Powles
Journal: Journal of Clinical Oncology (2020)

541 Background: Biomarker analysis predicting outcome with neoadjuvant atezolizumab in muscle invasive bladder cancer (MIBC) was performed. This includes previously unreported findings with FOXP3 and MHC1. Methods: Sequential tissue obtained from 95 patients in the ABACUSstudy (NCT02662309) which investigated two cycles of atezolizumab prior to cystectomy in MIBC patients. Multiplex immunohistochemistry staining, Foundation One analysis and RNA sequencing was performed on paired pre- and post- treatment samples. CD8+ T cells, fibroblast activation protein (FAP), granzyme – B (GZMB), FOXP3, MHC1, PD-L1 expressions were analyzed and correlated with outcome. Results: After a median follow up of 13.1 months, 31% had a pathological complete response (pCR) and 18% have relapsed. 40% were PD-L1 positive at baseline and 73%, 19% and 8%had inflamed, excluded and desert phenotype respectively. CD8/GZMB and CD8/MHC1 expression prior to therapy was significantly associated with response in inflamed tumors. CD8, PDL1, GZMB and MHC1 expression all increased with treatment in this group of patients. Immune desert phenotype at baseline, showed low and static expression of immune biomarker. TGFb correlated with relapse in excluded phenotypes. Treatment was associated with increase in cell cycle genes and FAP, both of which were associated with relapse. FOXP3 expression correlated with CD8 and increased with therapy in responding tumors. Combining FAP (high) to CD8 (low) and MHC1 (low) increased the positive predictive value for relapse. TMB did not correlate with outcome or increase with therapy. FGF DNA alterations were associated with response. Conclusions: MIBCs have high T effector immune expression, which may account for high pCR rates. Biomarkers at baseline and after treatment can predict outcome. Assessment of multiple biomarker within algorithms improves accuracy in predicting outcome. FOXP3 expression correlates with activated T cell expression, potentially accounting for the counterintuitive findings. Clinical trial information: NCT02662309.
Identifying the low-risk population for metachronous colorectal neoplasia: a first step towards personalized surveillance
Authors: Jae Gon Lee, Dong Soo Han
Journal: Endoscopy (2020)

Colorectal cancer (CRC) is the third most common cancer, and it is a major cause of cancer-related deaths worldwide [1]. Surgery remains the standard method for curative treatment of CRC. However, after patients with CRC undergo surgical resection, their risk of developing metachronous CRC in the remaining colorectum is higher than that of the average-risk population. The cumulative incidence of metachronous CRC is reported to be approximately 0.3 % per year [2]. Postoperative surveillance colonoscopy plays a pivotal role in the early detection of recurrent CRC at a curable stage, as well as in the detection and removal of metachronous precursor lesions, which may contribute to reducing the incidence of and death from metachronous CRC [3].
Update: Public Health Response to the Coronavirus Disease 2019 Outbreak — United States, February 24, 2020
Authors: Daniel B. Jernigan
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

An outbreak of coronavirus disease 2019 (COVID-19) caused by the 2019 novel coronavirus (SARS-CoV-2) began in Wuhan, Hubei Province, China in December 2019, and has spread throughout China and to 31 other countries and territories, including the United States (1). As of February 23, 2020, there were 76,936 reported cases in mainland China and 1,875 cases in locations outside mainland China (1). There have been 2,462 associated deaths worldwide; no deaths have been reported in the United States. Fourteen cases have been diagnosed in the United States, and an additional 39 cases have occurred among repatriated persons from high-risk settings, for a current total of 53 cases within the United States. This report summarizes the aggressive measures (2,3) that CDC, state and local health departments, multiple other federal agencies, and other partners are implementing to slow and try to contain transmission of COVID-19 in the United States. These measures require the identification of cases and contacts of persons with COVID-19 in the United States and the recommended assessment, monitoring, and care of travelers arriving from areas with substantial COVID-19 transmission. Although these measures might not prevent widespread transmission of the virus in the United States, they are being implemented to 1) slow the spread of illness; 2) provide time to better prepare state and local health departments, health care systems, businesses, educational organizations, and the general public in the event that widespread transmission occurs; and 3) better characterize COVID-19 to guide public health recommendations and the development and deployment of medical countermeasures, including diagnostics, therapeutics, and vaccines. U.S. public health authorities are monitoring the situation closely, and CDC is coordinating efforts with the World Health Organization (WHO) and other global partners. Interim guidance is available at https://www.cdc.gov/coronavirus/index.html. As more is learned about this novel virus and this outbreak, CDC will rapidly incorporate new knowledge into guidance for action by CDC, state and local health departments, health care providers, and communities.
Adaptive genetic algorithms combined with high sensitivity single cell-based technology derived urine-based score to differentiate between high-grade and low-grade transitional cell carcinoma of the bladder.
Authors: Shaheen Riadh Alanee, Zade Roumayah, Musatafa Deebajah, James O. Peabody, Rodrigo Mora, Jose Guevara, Brian Francisco, Bruce Kendrick Patterson
Journal: Journal of Clinical Oncology (2020)

572 Background: We previously showed that adaptive genetic algorithms (AGA), in combination with single-cell flow cytometry technology, can be used to develop a noninvasive urine-based score to detect bladder cancer with high accuracy. Our aim in this analysis was to investigate if that same score can differentiate between high grade (HG) and low grade (LG) transitional cell carcinoma of the bladder (BC). Methods: We collected urine samples from cystoscopy confirmed HG and LG superficial bladder cancer patients and healthy donors in an optimized urine collection media. We then examined these samples using an assay developed from AGA in combination with single-cell flow cytometry technology. Results: We examined 50 BC and 15 healthy donor urine samples. Patients were majorly White (59.2%), males (61.2%), and had HG BC (66.7%). AGA derived score of 1.1 differentiated between BCa and healthy patients with high precision (AUC 0.92). The median score was 2.8 for LG BC and 6 for LG BC. Mann-Whitney Rank Sum Test indicated that the difference between the median score of HG and LG BC was significant at P value = 0.003. The score performed well independent of patients’ sex or smoking history. Conclusions: Using single-cell technology and machine learning, we developed a new urine-based score that can potentially differentiate between HG and LG bladder cancer. Future studies are planned to validate this score.
Association of very small nuclear circulating tumor cell (vsnCTC) with clinical outcomes in metastatic castration-resistant prostate cancer.
Authors: Jasmine Jiemei Wang, Pai-Chi Teng, Yu Jen Jan, Jie-Fu Chen, Galen Cook-Wiens, Nu Yao, Gina Chia-Yi Chu, Pin-Jung Chen, Hao Ho, Yingying Yang, Yi-Te Lee, Jiaoti Huang, Leland WK Chung, Sungyong You, Yazhen Zhu, Michael Freeman, Andre Rogatko, Ju Dong Yang, Hsian-Rong Tseng, Edwin M. Posadas
Journal: Journal of Clinical Oncology (2020)

168 Background: Circulating tumor cells (CTCs) have arisen as contemporary noninvasive prognostic biomarkers for prostate cancer (PC). Previously, a subgroup of PC CTCs, with particularly small nuclei (&lt;8.5 μm), were found to be correlated with the presence of visceral metastases. This subgroup was named very-small-nuclear CTCs (vsnCTCs). We proposed vsnCTCs as a putative biomarker of a lethal subtype in metastatic castration resistant PC (mCRPC). Methods: In this study, 76 patients with mCRPC were recruited for overall survival (OS) analysis. Of the 76 patients, 47 had available pre-treatment blood specimens prior to the initiation of androgen receptor signaling inhibitor (ARSI, e.g. abiraterone and enzalutamide) or taxane therapy. Using the NanoVelcro CTC Assay, CTCs were captured and subjected to immunofluorescence staining. CTCs were identified as DAPI+/CK+/CD45- with a round or oval nucleus. Additionally, CTC nuclear size was measured and defined as the square root of the product of the long axis and the short axis. Kaplan-Meier analysis and Cox proportional hazards model were conducted. Results: Patients with vsnCTC (i.e., vsnCTC+) had a significantly shortened OS compared with patients without vsnCTC (i.e., vsnCTC-). The median OS was 34 (vsnCTC+, n=49) vs. 149 (vsnCTC-, n=27) weeks (log-rank HR=2.6 with 95% CI 1.5 to 4.5, p=0.0006). Progression free survival (PFS) analysis was performed for the 47 patients with pre-treatment blood samples. The median PFS was 14 (vsnCTC+, n=29) vs. 26 (vsnCTC-, n=18) weeks (log-rank HR=2.2 with 95% CI 1.2 to 3.9, p=0.0069). We also found that the hazard ratio of overall survival increased significantly as the CTC nuclear size decreased using the p spline plot. Conclusions: Our study showed that nuclear size reduction has importance in CTCs in a fashion similar to its utility in tissue. This study points toward the importance of the vsnCTC in patients with mCRPC, as vsnCTC+ patients represented a group at risk for faster clinical progression who are at the highest risk for morality. We posit that the vsnCTC represents a new hallmark of an aggressive subtype of mCRPC. This has potential importance in optimizing therapeutic choices.
Cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICI) or targeted therapy (TT): A propensity score-based analysis.
Authors: Ziad Bakouny, Wanling Xie, Shaan Dudani, Connor Wells, Chun Loo Gan, Frede Donskov, Julia Shapiro, Ian D. Davis, Francis Parnis, Praful Ravi, John A. Steinharter, Neeraj Agarwal, Ajjai Shivaram Alva, Lori Wood, Anil Kapoor, Jose Manuel Ruiz Morales, Christian K. Kollmannsberger, Benoit Beuselinck, Daniel Yick Chin Heng, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2020)

608 Background: The role of CN for mRCC treated with ICI is not well defined. Our aim was to evaluate the role of CN for mRCC treated by ICI or TT using a propensity score-based analysis. Methods: We retrospectively assessed patients who were diagnosed with de novo mRCC and who had started first line systemic therapy (ICI or TT) between 2009 and 2019 using the International Metastatic RCC Database Consortium (IMDC). Overall Survival (OS) was compared between patients receiving CN and those treated by systemic therapies alone, using the Kaplan-Meier method and Cox regressions, in the TT and ICI arms separately. In order to account for treatment selection bias, inverse probability of treatment weighting (IPTW) of propensity scores, based on 14 confounding variables, was used and variables were considered balanced if standardized mean difference (SMD) &lt; 0.1. For variables with SMD≥0.1, residual confounding was adjusted for using multivariable models. Results: 3856 patients had been treated by TT (2470 CN+ &amp; 1386 CN-) and 198 by ICI (143 CN+ &amp; 55 CN-). Median follow-up was 38.5 months. After IPTW, baseline characteristics were largely balanced between the CN+ and CN- arms, in the TT and ICI groups (14/14 and 12/14 with SMD &lt; 0.1, respectively). CN was associated with significantly improved OS in both the ICI (Hazard Ratio [HR] = 0.39 [0.19-0.83]) and TT (HR = 0.56 [0.51-0.62]) groups. The interaction term between CN and therapy type (ICI vs TT) was not statistically significant (p = 0.43). The point estimates of the HRs were consistent in sensitivity analyses using multivariable models. Conclusions: In a propensity score-based analysis, CN was found to be associated with a significant OS benefit in patients treated by either ICI or TT. While this study is not a substitute for randomized controlled trials (e.g. CARMENA), the results suggest that CN may still play a role in selected patients in the ICI era.[Table: see text]
Erratum: Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies (Nature Medicine (2009) 15 (528-536))
Authors: M Pellegrini, T Calzascia, AR Elford, A Shahinian, Ae Lin, D Dissanayake, S Dhanji, LT Nguyen, MA Gronski, M Morre, B Assouline, K Lahl, T Sparwasser, PS Ohashi, TW Mak
Journal: Nature Medicine (2009)
Risk of secondary sarcoma after abdominopelvic cancer treatment: Results from a contemporary cohort.
Authors: Amanda Elizabeth Hird, Rano Matta, Diana E. Magee, Girish S. Kulkarni, Ronald Kodama, Sender Herschorn, Robert Nam
Journal: Journal of Clinical Oncology (2020)

317 Background: Our objective was to explore the risk of sarcoma in a large cohort of patients with localized abdominopelvic cancer treated with radiotherapy (RT) compared to surgery. The risk of other secondary non-sarcoma solid organ tumors was also explored. Methods: This is a population-based retrospective cohort study examining the risk of sarcoma in patients with localized prostate, bladder, colorectal, cervical, uterine, and testis cancer between January 1, 2002-December 31, 2016. Multivariable Cox proportional hazard analysis was used to compare time from primary treatment (radical surgery or RT) to second cancer, adjusting for age, comorbidity, income quintile, and rurality, accounting for death as a competing risk. The standardized incidence rate (SIR) was calculated as the ratio of the observed divided by the age- and sex-stratified expected number of sarcoma cases from the Ontario population. Results: 173,580 patients were included (79,662 underwent surgery and 93,918 underwent RT). Most patients had genitourinary (51.4%) or colorectal cancer (39.9%) and 24.4% received chemotherapy. Overall, 332 sarcomas developed over a median 5.7 years (IQR: 2.2-8.9) and were more common in the RT group (239/93918 [0.3%]) compared to the surgery group (93/79662 [0.1%], p&lt;0.001). RT exposure (unadjusted HR=2.67, 95%CI:2.10-3.40, p&lt;0.001, adjusted HR=2.59, 95%CI:2.03-3.31, p&lt;0.001) and perioperative chemotherapy use (HR=1.31, 95%CI:1.03-1.69, p=0.038) were associated with an increased relative rate of sarcoma. Patients who received RT had an increased risk of sarcoma compared to the general population (SIR=1.46, 95%CI:1.12-1.90, p=0.005). For our secondary outcome, patients who received RT had an increased hazard of developing a second non-sarcoma solid malignancy compared to patients who underwent surgery (HR=1.16, 95%CI:1.10-1.22, p&lt;0.001). Conclusions: This is the largest cohort investigating sarcoma in patients with abdominopelvic cancer. Patients treated with RT have a markedly increased risk of sarcoma compared to the general population. RT was an independent risk factor for sarcoma and non-sarcoma second malignancy.
Your results may vary: the imprecision of medical measurements
Authors: James P McCormack, Daniel T Holmes
Journal: BMJ (2020)

### What you need to know

Clinicians and patients need to interpret a multitude of medical measurements. These are often central to monitoring health and informed decision making. Has the serum cholesterol concentration come down since starting a statin? Have vitamin D levels gone up? Is the dose of thyroid medication correct? An understanding of the imprecision of medical measurements is essential to answer any of these questions. Even when laboratory and industry scientists have optimised their diagnostic testing processes to minimise inaccuracies, there always remains an error in any clinical measurement due to unavoidable, naturally occurring variability.

This practice pointer explains the nature of measurement errors and offers a practical guide to both estimating the confidence interval of a single result and deciding if changes between serial laboratory tests reflect true changes or simply fluctuations based on analytical or biological variation.

### How this article was made

This article was based on a review of the available biological variation data for select routine clinical chemistry measurements as collated by the European Federation of Clinical Chemistry and Laboratory Medicine (https://biologicalvariation.eu/) and in select cases identified by …