tbuckley/cabot-search huggingface dataset:
Clinical outcomes in patients with metastatic renal cell carcinoma and brain metastasis treated with ipilimumab and nivolumab
Authors: Landon C. Brown, Kunal Desai, Wei Wei, Emily N. Kinsey, Chester Kao, Daniel J. George, Brian I. Rini, Moshe C. Ornstein, Tian Zhang
Journal: Journal for ImmunoTherapy of Cancer (2021)

The combination of ipilimumab plus nivolumab (I+N) has greatly improved outcomes in patients with intermediate or poor-risk untreated metastatic renal cell carcinoma (mRCC). However, little is known about the outcomes of patients with brain metastasis (BrM) treated with I+N. A search was performed to retrospectively identify all patients with mRCC treated with I+N in the Duke Cancer Institute and the Cleveland Clinic Taussig Cancer Center, followed by a chart review. Patients were included if they had BrM at the time of I+N initiation. Cohort characteristics are summarized with descriptive statistics. Kaplan-Meier method was used to estimate overall survival (OS) and global, intracranial, and extracranial progression-free survival (PFS) for the cohort and log rank test was used to compare OS and PFS between patient groups. Radiographic response was categorized by RECIST. Fisher’s exact test was used to correlate patient factors with radiographic response. From October 2017 to December 2020, 19 patients with BrM received I+N for mRCC with a median follow-up time of 27.1 months (range 15.0–35.6). By International Metastatic RCC Database Consortium (IMDC) risk criteria, 16% had favorable, 58% had intermediate, and 26% had poor-risk disease. 68% were systemic therapy naïve, and 77% of patients had clear cell histology. 95% had received local CNS directed therapy with surgery, radiotherapy, or both. The objective response rate was 44% (0% complete response) with three of six patients treated in the second line or greater setting experiencing a partial response. The median PFS was 7.6 months (95% CI 5.6 to 14.9). The median extracranial PFS was 8.5 months (95% CI 5.6 to 19.7), and median intracranial PFS was 14.7 months (95% CI 7.2 to not reached). No variables assessed were significantly associated with radiographic response (gender, IMDC risk, presence of bone metastasis, line of therapy, or presence of immune related adverse events). In our retrospective cohort of patients with mRCC with BrM, I+N, in combination with CNS-directed local therapy, appears to have clinical efficacy as previously described with responses seen beyond the first-line setting. Further investigation is warranted in this population given exclusion from prior clinical trials.
Requirement of RORα for maintenance and antitumor immunity of liver‐resident natural killer cells/ILC1s
Authors: Jiaxi Song, Hao Song, Haiming Wei, Rui Sun, Zhigang Tian, Hui Peng
Journal: Hepatology (2021)

Abstract Backgroud and Aims Liver type 1 innate lymphoid cells (ILC1s), also known as liver‐resident natural killer (LrNK) cells, comprise a high proportion of total hepatic ILCs. However, factors regulating their maintenance and function remain unclear. Approach and Results In this study, we found high expression of retinoid‐related orphan nuclear receptor alpha (RORα) in LrNK cells/ILC1s. Mice with conditional ablation of retinoid‐related orphan nuclear receptor alpha ( Rorα ) in LrNK cells/ILC1s and conventional natural killer (cNK) cells had decreased LrNK cells/ILC1s but normal numbers of cNK cells. RORα‐deficient LrNK cells/ILC1s displayed increased apoptosis and significantly altered transcriptional profile. Using a murine model of colorectal cancer liver metastasis, we found that RORα conditional deficiency resulted in more aggressive liver tumor progression and impaired effector molecule expression in LrNK cells/ILC1s. Consequently, treatment with the RORα agonist efficiently limited liver metastases and promoted effector molecule expression of LrNK cells/ILC1s. Conclusions This study reveals a role of RORα in LrNK cell/ILC1 maintenance and function, providing insights into the harnessing of LrNK cell/ILC1 activity in the treatment of liver cancer.
KCNQ Potassium Channels as Targets of Botanical Folk Medicines
Authors: Kaitlyn E. Redford, Geoffrey W. Abbott
Journal: The Annual Review of Pharmacology and Toxicology (2021)

Since prehistory, human species have depended on plants for both food and medicine. Even in countries with ready access to modern medicines, alternative treatments are still highly regarded and commonly used. Unlike modern pharmaceuticals, many botanical medicines are in widespread use despite a lack of safety and efficacy data derived from controlled clinical trials and often unclear mechanisms of action. Contributing to this are the complex and undefined composition and likely multifactorial mechanisms of action and multiple targets of many botanical medicines. Here, we review the newfound importance of the ubiquitous KCNQ subfamily of voltage-gated potassium channels as targets for botanical medicines, including basil, capers, cilantro, lavender, fennel, chamomile, ginger, and
Measuring Pharmacogene Variant Function at Scale Using Multiplexed Assays
Authors: Renee C. Geck, Gabriel Boyle, Clara J. Amorosi, Douglas M. Fowler, Maitreya J. Dunham
Journal: The Annual Review of Pharmacology and Toxicology (2021)

As costs of next-generation sequencing decrease, identification of genetic variants has far outpaced our ability to understand their functional consequences. This lack of understanding is a central challenge to a key promise of pharmacogenomics: using genetic information to guide drug selection and dosing. Recently developed multiplexed assays of variant effect enable experimental measurement of the function of thousands of variants simultaneously. Here, we describe multiplexed assays that have been performed on nearly 25,000 variants in eight key pharmacogenes ( ADRB2, CYP2C9, CYP2C19, NUDT15, SLCO1B1, TMPT, VKORC1, and the LDLR promoter), discuss advances in experimental design, and explore key challenges that must be overcome to maximize the utility of multiplexed functional data.
Care at the end of life during the COVID-19 pandemic: A CancerLinQ Discovery (CLQD) analysis.
Authors: Gabrielle Betty Rocque, Mark Riffon, Electra D. Paskett, Abdul-Rahman Jazieh, Jennifer C. King, Danielle M. Potter
Journal: Journal of Clinical Oncology (2021)

310 Background: For patients with cancer approaching end-of-life (EOL) during the COVID-19 pandemic, the changes in service availability and transition to telehealth may impact care delivery. Little is known about how the COVID-19 pandemic impacted EOL encounters with the healthcare system, particularly for vulnerable patient populations. Methods: This retrospective cohort study included patients with cancer who died from 1/2019-9/2020 in the CLQD electronic health record-based dataset. Descriptive statistics were generated for demographic characteristics and for clinical encounters (telehealth/in person/no encounter) in the last 3 months of life (EOL) among patients deceased in the year. Results were stratified by age, race, ethnicity, and geographic region. Results: Among the 49,688 deceased patients, 27% were under 65, 29% were 65-74, and 44% were 75+. The majority were Non-Hispanic White, with 5% Hispanic, 12% Black. In 2020, patients who were age 75+, White, Non-Hispanic, and/or living in the Midwest or Northeast had lower rates of in person encounters and higher rates of no encounter at EOL than those &lt;65, Black, Hispanic, and/or living in the South (Table). Telehealth use at EOL increased from 2019 to 2020, with highest use amongst those in the West and Hispanic patients (Table). Conclusions: During the pandemic, telehealth use was limited at EOL compared to the 14% reported use for all cancer patients (data not shown). Black and Hispanic patients had slightly higher provider encounters at EOL, which may be due to differences in intensity of EOL care or death capture within the database. Further research is needed to evaluate the quality of EOL care and to assess opportunities to leverage telehealth where patients are unable to access outpatient services.[Table: see text]
mRNA vaccine effectiveness against COVID-19-related hospitalisations and deaths in older adults: a cohort study based on data linkage of national health registries in Portugal, February to August 2021
Authors: Baltazar Nunes, Ana Paula Rodrigues, Irina Kislaya, Camila Cruz, André Peralta-Santos, João Lima, Pedro Pinto Leite, Duarte Sequeira, Carlos Matias Dias, Ausenda Machado
Journal: Eurosurveillance (2021)

Through deterministic data linkage of health registries, mRNA vaccine effectiveness (VE) against COVID-19-related hospitalisations and deaths was measured in 1,880,351 older adults. VE against hospitalisations was 94% (95% confidence interval (CI): 88-97) and 82% (95% CI: 72-89) for those 65-79 and ≥ 80 years old, with no evidence of waning 98 days after dose two. VE against mortality was 96% (95% CI: 92-98) and 81% (95% CI: 74-87) in these two age groups.
Optical Coherence Tomography of Coronary Plaque Progression and Destabilization
Authors: Tom Adriaenssens, Marc P. Allard-Ratick, Vikas Thondapu, Tomoyo Sugiyama, O. Christopher Raffel, Peter Barlis, Eric K.W. Poon, Makoto Araki, Akihiro Nakajima, Yoshiyasu Minami, Masamichi Takano, Osamu Kurihara, Valentin Fuster, Tsunekazu Kakuta, Ik-Kyung Jang
Journal: Journal of the American College of Cardiology (2021)
Abstract 15930: Circulating Levels of Proprotein Convertase Subtilisin/kexin Type 9 (pcsk9) are Associated With Monocyte Subsets in Patients With Stable Coronary Artery Disease
Authors: Konstantin Krychtiuk, Max Lenz, Philipp Hohensinner, Klaus Distelmaier, Lore Schrutka, Stefan Kastl, Stefan Pfaffenberger, Kurt Huber, Christian Hengstenberg, Johann Wojta, Walter S Speidl
Journal: Circulation (2020)

Introduction: Proprotein convertase subtilisin/kexin type-9 (PCSK9) is an enzyme promoting the degradation of low-density lipoprotein receptors (LDL-R) in hepatocytes. Inhibition of PCSK9 has emerged as a novel target for lipid-lowering therapy. Monocytes are crucially involved in the pathogenesis of atherosclerosis. Circulating monocytes can be divided into three subsets. The aim of this study was to examine whether circulating levels of PCSK9 are associated with monocyte subsets. Methods: We included 69 patients with stable coronary artery disease. PCSK9 levels were measured and monocyte subsets were assessed by flow cytometry and divided into classical monocytes (CD14++CD16-; CM), intermediate monocytes (CD14++CD16+; IM) and non-classical monocytes (CD14+CD16++; NCM). Results: Mean age was 64 years and 80% of patients were male. Patients on statin treatment (n=55) showed higher PCSK9-levels (245.4 (206.0-305.5) ng/mL) as opposed to those without statin treatment (186.1 (162.3-275.4) ng/mL; p=0.05). In patients on statin treatment, CM correlated with circulating PCSK9 levels (R=0.29; p=0.04), while NCM showed an inverse correlation with PCSK9 levels (R=-0.33; p=0.02). Patients with PCSK9 levels above the median showed a significantly higher proportion of CM as compared to patients with PCSK-9 below the median (83.5 IQR 79.2-86.7 vs. 80.4, IQR 76.5-85.2%; p=0.05). Conversely, patients with PCSK9 levels &gt;median were associated with a significantly lower proportion of NCM as compared to those with PCSK9 &lt;median (10.2, IQR 7.3-14.6 vs. 14.3, IQR 10.9-18.7%; p=0.02). In contrast, IM showed no association with PCSK-9 levels. Conclusions: We hereby provide a novel link between PCSK9 regulation, innate immunity and atherosclerotic disease in statin-treated patients.
Stem/Proliferative and Differentiated Cells within Primary Murine Colonic Epithelium Display Distinct Intracellular Free Ca<sup>2+</sup> Signal Codes
Authors: Sebastian Mestril, Raehyun Kim, Samuel S. Hinman, Shawn M. Gomez, Nancy L. Allbritton
Journal: Advanced Healthcare Materials (2021)

The second messenger, intracellular free calcium (Ca
Therapeutic targeting of the inflammasome in myeloid malignancies
Authors: Samarpana Chakraborty, Lauren C. Shapiro, Sofia de Oliveira, Bianca Rivera-Pena, Amit Verma, Aditi Shastri
Journal: Blood Cancer Journal (2021)

Abstract Even though genetic perturbations and mutations are important for the development of myeloid malignancies, the effects of an inflammatory microenvironment are a critical modulator of carcinogenesis. Activation of the innate immune system through various ligands and signaling pathways is an important driver of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The DAMPs, or alarmins, which activate the inflammasome pathway via the TLR4/NLR signaling cascade causes the lytic cell death of hematopoietic stem and progenitor cells (HSPCs), ineffective hematopoiesis, and β-catenin-induced proliferation of cancer cells, leading to the development of MDS/AML phenotype. It is also associated with other myeloid malignancies and involved in the pathogenesis of associated cytopenias. Ongoing research suggests the interplay of inflammasome mediators with immune modulators and transcription factors to have a significant role in the development of myeloid diseases, and possibly therapy resistance. This review discusses the role and importance of inflammasomes and immune pathways in myeloid malignancies, particularly MDS/AML, to better understand the disease pathophysiology and decipher the scope of therapeutic interventions.
Patient and clinician perceptions of a digital patient monitoring program in the community oncology setting: Findings from the Texas Two-Step Study.
Authors: Debra A. Patt, Amila Patel, Lalan S. Wilfong, Holly Books, Lance Ortega, Max Franklin, Sarah Croft, Angela M. Stover, Rhonda Boren, Ethan M. Basch
Journal: Journal of Clinical Oncology (2021)

189 Background: Digital monitoring strategies that include electronic patient reported outcomes (ePRO) measures to monitor symptoms among cancer patients have been shown to be effective in improving patient outcomes in a large academic setting and across several smaller multi-center trials. However, demonstration of clinical utility in the real-world setting must incorporate patient and provider perspectives of ePRO programs to ensure successful implementation. We sought to understand perceptions among patients and clinicians in ePRO digital symptom monitoring program. Methods: Texas Two-Step is an ongoing hybrid implementation-effectiveness study of Navigating Cancer’s ePRO digital monitoring program at Texas Oncology. Patients initiating new systemic therapy for their cancer diagnosis were introduced to the program by their oncologist and enrolled in the program by nursing staff for weekly reporting of symptoms based on a modified version of NCI’s PRO-CTCAE instrument. Feedback surveys were administered to both patients and clinic staff after 6 months of implementation of the program to evaluate the overall experience with the program. Results: 1040 (23.5%) patients and 215 (12.4%) clinicians completed the feedback survey. Of the patient responders, 90% found the program very or somewhat easy for reporting symptoms, 85% moderately-extremely beneficial for having symptoms addressed, and 84% moderately-extremely interested in utilizing the program for future treatments. Of the clinician responders, 73% indicated that that they had a good understanding of the benefit of the program; 70.6% felt confident in their ability to interpret patients’ ePRO responses; 80.3% felt confident in their ability to discuss the program with patients; 71.2% confident in their ability to counsel patients based on ePRO responses; and 55.3% felt the program enhanced communication with patients. Additionally, 59% of clinicians felt the program was beneficial for patients. Conclusions: Patients have a more favorable perception of the benefit of the ePRO program than clinicians. Methods to reduce staff burden and reinforcement of program benefits during training and implementation are imperative to improve clinical utility and will be studied further as the program is optimized. As implementation occurred during the COVID-19 pandemic, this may impact perceptions regarding the tool.
Africa’s COVID-19 Experience—A Window of Opportunity to Act
Authors: Igho Ofotokun, Anandi N. Sheth
Journal: JAMA Network Open (2021)

Berthe Amélie Iroungou, PhD; Laurette Guignali Mangouka, MD; Berthold Bivigou-Mboumba, PhD; Pamela Moussavou-Boundzanga, PhD; Judicaël Obame-Nkoghe, PhD; Farrel Nzigou Boucka, MSc; Augustin Mouinga-Ondeme, PhD; Avelin Fobang Aghokeng, PhD; Romain Tchoua, MD; Pascal Pineau, PhD; Jean Raymond Nzenze, MD
Interaction with patients of color or ethnic minority (PCEM): Oncologist perceptions of racial anxiety and/or implicit bias (RA/IB).
Authors: Alexandrina Balanean, Yolaine Jeune-Smith, Bruce A. Feinberg, Ajeet Gajra
Journal: Journal of Clinical Oncology (2021)

141 Background: Oncologists interacting with PCEM may be unaware of RA/IB, yet data show lower-quality care. Helping oncologists recognize this may improve quality of patient-provider interaction, care, and outcomes. We conducted a descriptive study of medical/hematologic oncologists to assess perceptions of RA/IB impact on PCEM interaction. Methods: From February to April 2021, U.S.-based medical/hematologic oncologists participated in an online survey of perceptions on cancer care and outcomes in PCEM (part of broader survey of various clinical and practice-related concerns). Questions used a modified 5-point Likert scale with an option of declining to answer, and respondents were aware data would be anonymized and aggregated. Results: Among 369 physicians surveyed, median years in practice were 17 (range 2-49). Most (72.4%) were in community settings; 64.0% were age 40 to 59 years; 20.6% identified as female, 70.5% male, and 8.7% declined to disclose. Racial distribution was 32.0% White, 33.1% Asian, 7.0% Black, 4.1% Hispanic/Latinx, and 18.7% declined to disclose. When asked the degree of RA/IB White providers had toward PCEM, 39.6% chose low/none, 33.3% moderate, 14.9% high/very high, and 12.2% declined. When asked whether RA/IB among White providers adversely affects PCEM, 37.1% somewhat/strongly agreed, 29.3% somewhat/strongly disagreed, 23.6% neither agreed nor disagreed, and 10.0% declined. Also, 7.9% declined to estimate percent of non-White patients managed. Perceived frequency of scenarios involving RA/IB impacting PCEM interaction at their practices was also assessed (Table). Notably, 12.0% to 14.0% declined to answer regarding their own practices. Although most oncologists (76.4%) perceived RA/IB among White providers toward PCEM, only 37.1% agreed it had adverse effects. Conclusions: Discrepancy in perception of RA/IB among White providers and its effect on PCEM suggests a need to show causality, and declining to respond suggests mistrust/apprehension in expressing true views. Findings suggest oncologists may benefit from improved education and awareness regarding RA/IB in PCEM interaction, treatment, and outcomes. Provider responses (N=369).[Table: see text]
Impact of Nonadherence to NCCN Adjuvant Radiotherapy Initiation Guidelines in Head and Neck Squamous Cell Carcinoma in an Underserved Urban Population
Authors: Anusha Ponduri, David Z. Liao, Nicolas F. Schlecht, Gregory Rosenblatt, Michael B. Prystowsky, Rafi Kabarriti, Madhur Garg, Thomas J. Ow, Bradley A. Schiff, Richard V. Smith, Vikas Mehta
Journal: Journal of the National Comprehensive Cancer Network (2021)

Background: Nonadherence to NCCN Guidelines during time from surgery to postoperative radiotherapy (S-PORT) can alter survival outcomes in head and neck squamous cell carcinomna (HNSCC). There is a need to validate this impact in an underserved urban population and to understand risk factors and reasons for delay. We sought to investigate the impact of delayed PORT with outcomes of overall survival (OS) in HNSCC, to analyze predictive factors of delayed PORT, and to identify reasons for delay. Methods: We conducted a retrospective cohort study in an urban, community-based academic center. A total of 184 patients with primary HNSCC were identified through the Montefiore Medical Center cancer registry who had been treated between March 1, 2005, and March 8, 2017, and met the inclusion and exclusion criteria. The primary exposure was S-PORT. OS, recurrence, and risk factors and reasons for treatment delay were the main outcomes and measures. Results: Among 184 patients with HNSCC treated with PORT, the median S-PORT was 48.5 days (interquartile range, 41–67 days). The S-PORT threshold that optimally differentiated worse OS outcomes was &gt;50 days (46.7% of our cohort; n=86). Independent of other relevant factors, patients with HNSCC and S-PORT &gt;50 days had worse OS (hazard ratio, 2.30; 95% CI, 1.34–3.95) and greater recurrence (odds ratio, 3.51; 95% CI, 1.31–9.39). Predictors of delayed S-PORT included being underweight or obese, prolonged postoperative length of stay, and age &gt;70 years. The most frequent reasons for PORT delay were complications related to surgery (22.09%), unrelated medical comorbidities (18.60%), and nonadherence/missed appointments (6.98%). Conclusions: Delayed PORT beyond 50 days after surgery was associated with decreased OS and greater recurrence. Identification of predictive factors and reasons for treatment delay helps to target at-risk patients and facilitates interventions in underserved populations.
Evaluation of Community-Level Vulnerability and Racial Disparities in Living Donor Kidney Transplant
Authors: A. Cozette Killian, Brittany Shelton, Paul MacLennan, M. Chandler McLeod, Alexis Carter, Rhiannon Reed, Haiyan Qu, Babak Orandi, Vineeta Kumar, Deirdre Sawinski, Jayme E. Locke
Journal: JAMA Surgery (2021)

Living donor kidney transplant (LDKT) is the ideal treatment for end-stage kidney disease, but racial disparities in LDKT have increased over the last 2 decades. Recipient clinical and social factors do not account for LDKT racial inequities, although comprehensive measures of community-level vulnerability have not been assessed.
DAAB‐V2: Updated database of allergy and asthma biomarkers
Authors: Sreyashi Majumdar, Sudipto Bhattacharjee, Tanmoy Jana, Sudipto Saha
Journal: Allergy (2021)

Supporting figures and tables are included in Supplementary Material. Data are available at http://bicresources.jcbose.ac.in/ssaha4/daab-v2. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Sleep, circadian rhythm and gut microbiota: alterations in Alzheimer’s disease and their potential links in the pathogenesis
Authors: Yi Li, Lingzhan Shao, Yang Mou, Yan Zhang, Yong Ping
Journal: Gut Microbes (2021)

ABSTRATCIn recent years, emerging studies have observed gut microbiota (GM) alterations in Alzheimer's disease (AD), even in individuals with mild cognitive impairment (MCI). Further, impaired sleep and circadian patterns are common symptoms of AD, while sleep and circadian rhythm disruption (SCRD) is associated with greater β-amyloid (Aβ) burden and AD risk, sometimes years before the clinical onset of AD. Moreover, reports have demonstrated that GM and its metabolites exhibit diurnal rhythmicity and the role of SCRD in dampening the GM rhythmicity and eubiosis. This review will provide an evaluation of clinical and animal studies describing GM alterations in distinct conditions, including AD, sleep and circadian disruption. It aims to identify the overlapping and distinctive GM alterations in these conditions and their contributions to pathophysiology. Although most studies are observational and use different methodologies, data indicate partial commonalities in GM alterations and unanimity at functional level. Finally, we discuss the possible interactions between SCRD and GM in AD pathogenesis, as well as several methodological improvements that are necessary for future research.