tbuckley/cabot-search huggingface dataset:
Early integrated palliative care in patients newly diagnosed with cancer in Ethiopia: a randomised controlled trial and cost–consequence analysis
Authors: Eleanor Reid, Ephrem Abathun, Jilcha Diribi, Yoseph Mamo, Tigineh Wondemagegnhu, Peter Hall, Marie Fallon, Liz Grant
Journal: The Lancet Global Health (2022)

Deaths due to non-communicable diseases are rising worldwide, with low-income and middle- income countries (LMICs) particularly affected. Palliative care can reduce pain and suffering for patients with incurable disease. A gap in access to palliative care and research to support its implementation exists in LMICs, and cancer care is a particularly problematic area. We designed a pragmatic study to better understand the implementation of home-based palliative care, patient-reported outcomes, costs, and consequences in Addis Ababa, Ethiopia.A single-blind, single-site, randomised, controlled trial of standard cancer care versus standard cancer care plus early integrated palliative care in patients newly diagnosed with cancer was performed at the Black Lion Outpatient Oncology Clinic (Addis Ababa, Ethiopia). The palliative care intervention was home-based and delivered by Hospice Ethiopia nurses. Follow-up was done at 4-12 weeks and at 8-16 weeks at the discretion of the oncologist. Sample size was determined by ability to detect a change in mean African Palliative Care Association Palliative Outcome Score. A cost-consequence analysis was done for patients who completed all three study visits. Ethical approval was granted by Addis Ababa University and Yale University. All participants signed or thumb-printed written informed consent. The study is registered at ClinicalTrials.gov, NCT03712436.98 adults were enrolled. The mean age was 49·5 years and 66% of participants were women. 27 participants completed all three study visits. Significant improvements in patient-reported outcomes were seen (p=0·0025). Mean total health-care costs to the patient were Ethiopian birr (ETD) 40 430 (US$979); mean palliative care costs to Hospice Ethiopia were ETD 765 ($19) per patient. Those receiving standard cancer care reported higher out-of-pocket payments for medical care and increased lost wages of an informal caregiver. Out-of-pocket payments for medical care and lost wages were multiple times higher than an average yearly salary (ETD 5810 [$141] and ETD 74900 birr [$1814·9] respectively). By the end of study, health-care costs, health-use, and mortality had all increased.Delivery and integration of early, home-based, and low-cost palliative care into cancer care is possible in a LMIC setting. Widespread implementation of palliative care is likely to be a resource-sparing and poverty-reducing strategy in LMICs.Department of Emergency Medicine, Yale University.
CARDIAC COMPUTED TOMOGRAPHY ANGIOGRAPHY PLANNING FOR PRE-CLINICAL TRANSSEPTAL MITRAL VALVE REPLACEMENT WITH THE SATURN BIOPROSTHESIS IN A PORCINE MODEL
Authors: Lauren Sharan Ranard, Yanping Cheng, Geng-Hua Yi, Federica Sacco, Pietro Ghillani, Giovanni Righini, Torsten P. Vahl
Journal: Journal of the American College of Cardiology (2022)
Loss of Sam50 in hepatocytes induces cardiolipin‐dependent mitochondrial membrane remodeling to trigger mtDNA release and liver injury
Authors: Li Chen, Jun Dong, Siyang Liao, Siyou Wang, Zhida Wu, Meiling Zuo, Bing Liu, Chaojun Yan, Yong Chen, He He, Qingtao Meng, Zhiyin Song
Journal: Hepatology (2022)

Abstract Background and Aims Sam50, a key component of the sorting and assembly machinery (SAM) complex, is also involved in bridging mitochondrial outer‐membrane and inner‐membrane contacts. However, the physiological and pathological functions of Sam50 remain largely unknown. Approach and Results Here we show that Sam50 interacts with MICOS (mitochondrial contact site and cristae organizing system) and ATAD3 (ATPase family AAA domain‐containing protein 3) to form the Sam50‐MICOS‐ATAD3‐mtDNA axis, which maintains mtDNA stability. Loss of Sam50 causes mitochondrial DNA (mtDNA) aggregation. Furthermore, Sam50 cooperates with Mic60 to bind to cardiolipin, maintaining the integrity of mitochondrial membranes. Sam50 depletion leads to cardiolipin externalization, which causes mitochondrial outer‐membrane and inner‐membrane (including crista membrane) remodeling, triggering Bax mitochondrial recruitment, mtDNA aggregation, and release. Physiologically, acetaminophen (an effective antipyretic and analgesic)–caused Sam50 reduction or Sam50 liver‐specific knockout induces mtDNA release, leading to activation of the cGAS‐STING pathway and liver inflammation in mice. Moreover, exogenous expression of Sam50 remarkably attenuates APAP‐induced liver hepatoxicity. Conclusions Our findings uncover the critical role of Sam50 in maintaining mitochondrial membrane integrity and mtDNA stability in hepatocytes and reveal that Sam50 depletion–induced cardiolipin externalization is a signal of mtDNA release and controls mtDNA‐dependent innate immunity.
Therapeutic potential of CDK4/6 inhibitors in renal cell carcinoma
Authors: Rebecca A. Sager, Sarah J. Backe, Elham Ahanin, Garrett Smith, Imad Nsouli, Mark R. Woodford, Gennady Bratslavsky, Dimitra Bourboulia, Mehdi Mollapour
Journal: Nature Reviews Urology (2022)
SAFETY AND TOLERABILITY OF CAEL-101, AN ANTI-AMYLOID MONOCLONAL ANTIBODY, IN COMBINATION WITH PLASMA CELL DYSCRASIA THERAPY IN PATIENTS WITH LIGHT-CHAIN AMYLOIDOSIS: RESULTS FROM A PHASE 2 STUDY
Authors: Jason Valent, Michaela Liedtke, Jeffrey Zonder, John Silowsky, Michael Kurman, Eileen Daniel, Janet Jobes, Mark Harnett, Amit Bhattacharyya, Candida Cristina Quarta, Julia Catini, Jessica Raviwong, Michael Spector, Susan Sobolov
Journal: Journal of the American College of Cardiology (2022)
Abstract BS1-1: PR
Authors: C Hagan
Journal: Cancer Research (2022)

Abstract Much debate exists surrounding how progesterone receptor (PR) expression and activation by native progesterone affects hormone receptor (HR)-positive breast cancer cells. While its expression is conserved in the majority of HR+ breast cancers, studies have failed to identify a clear link between progesterone signaling and breast cancer proliferation, in contrast to what has been shown for ER signaling. Clinically, many studies have utilized PR expression as an indicator of ER signaling, with associations between PR expression demonstrating greater responsiveness to anti-estrogen therapies and outcomes. However, convincing clinical trial data have shown that women taking progestin (synthetic progesterone)-containing hormone replacement therapy (HRT) have a significantly increased risk of developing breast cancer. Likewise, other clinical studies have demonstrated that progestins contribute to the development of more invasive breast cancers and increase mortality. These clinical findings are supported by a variety of pre-clinical studies using animal models, which collectively suggest that PR signaling enhances the development of invasive breast cancer. Finally, our studies and those of others suggest that PR has a specific transcriptional impact that is distinct from ER signaling. Collectively, these studies have demonstrated a key role for PR in the progression and outcome of HR+ breast cancer, which is distinct from estrogen-mediated proliferation signaling. We believe the lack of clinically available PR-targeted therapies in breast cancer is due to a lack of knowledge about exactly how PR contributes to breast cancer progression, as studies have failed to define a conclusive role for PR signaling in tumor growth. However, our recent studies have unexpectedly revealed a significant immune modulatory role for PR. Specifically, our results have demonstrated a clear role for PR in suppressing local anti-tumor immunity, which may explain reduced T-cell infiltrates and responsiveness to immune checkpoint inhibition observed in HR+ breast cancer. This presentation will discuss the current controversial data regarding PR and progesterone in promoting breast cancer proliferation, as well as highlight new data suggesting that PR/progesterone promote immune shielding for developing breast cancers. Citation Format: C Hagan. PR [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr BS1-1.
In situ targeting nanoparticles-hydrogel hybrid system for combined chemo-immunotherapy of glioma
Authors: Xiaoqi Wang, Lu Ye, Weichong He, Chuanhui Teng, Shanbo Sun, Hongdan Lu, Shengnan Li, Lingyan Lv, Xiang Cao, Haoyuan Yin, Wei Lv, Hongliang Xin
Journal: Journal of Controlled Release (2022)
Aberrant Activation of Cell-Cycle–Related Kinases and the Potential Therapeutic Impact of PLK1 or CHEK1 Inhibition in Uterine Leiomyosarcoma
Authors: Kosuke Yoshida, Akira Yokoi, Tomofumi Yamamoto, Yusuke Hayashi, Jun Nakayama, Tsuyoshi Yokoi, Hiroshi Yoshida, Tomoyasu Kato, Hiroaki Kajiyama, Yusuke Yamamoto
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Uterine leiomyosarcoma is among the most aggressive gynecological malignancies. No effective treatment strategies have been established. This study aimed to identify novel therapeutic targets for uterine leiomyosarcoma based on transcriptome analysis and assess the preclinical efficacy of novel drug candidates. Experimental Design: Transcriptome analysis was performed using fresh-frozen samples of six uterine leiomyosarcomas and three myomas. The Ingenuity Pathway Analysis (IPA) was used to identify potential therapeutic target genes for uterine leiomyosarcoma. Afterward, our results were validated using three independent datasets, including 40 uterine leiomyosarcomas. Then, the inhibitory effects of several selective inhibitors for the candidate genes were examined using SK-UT-1, SK-LMS-1, and SKN cell lines. Results: We identified 512 considerably dysregulated genes in uterine leiomyosarcoma compared with myoma. The IPA revealed that the function of several genes, including CHEK1 and PLK1, were predicted to be activated in uterine leiomyosarcoma. Through an in vitro drug screening, PLK1 or CHEK1 inhibitors (BI-2536 or prexasertib) were found to exert a superior anticancer effect against cell lines at low nanomolar concentrations and induce cell-cycle arrest. In SK-UT-1 tumor-bearing mice, BI-2536 monotherapy remarkably suppressed tumorigenicity. Moreover, the prexasertib and cisplatin combination therapy inhibited tumor proliferation and prolonged the time to tumor progression. Conclusions: We identified upregulated expressions of PLK1 and CHEK1; their kinase activity was activated in uterine leiomyosarcoma. BI-2536 and prexasertib demonstrated a significant anticancer effect. Therefore, cell-cycle–related kinases may present a promising therapeutic strategy for the treatment of uterine leiomyosarcoma.
OUTCOME OF ST-ELEVATION MYOCARDIAL INFARCTION (STEMI) PATIENTS WITH BASELINE Q WAVES UNDERGOING PRIMARY PERCUTANEOUS CORONARY INTERVENTION (PPCI)
Authors: Eng-How Lim, Marie Houdmont, Vianne Lau, Siew-Pang Chan, Poay-Huan Loh, Gavin Ng, Saurabh Rastogi, Mark Chan, Adrian Low, Ronald Chi Hang Lee, Huay-Cheem Tan, Koo-Hui Chan
Journal: Journal of the American College of Cardiology (2022)
Moral Distress: What Are We Measuring?
Authors: Laura Kolbe, Inmaculada de Melo-Martin
Journal: The American Journal of Bioethics (2022)

While various definitions of moral distress have been proposed, some agreement exists that it results from illegitimate constraints in clinical practice affecting healthcare professionals’ moral agency. If we are to reduce moral distress, instruments measuring it should provide relevant information about such illegitimate constraints. Unfortunately, existing instruments fail to do so. We discuss here several shortcomings of major instruments in use: their inability to determine whether reports of moral distress involve an accurate assessment of the requisite clinical and logistical facts in play, whether the distress in question is aptly characterized as moral, and whether the moral distress reported is an appropriate target of elimination. Such failures seriously limit the ability of empirical work on moral distress to foster appropriate change.
PULMONARY ARTERY TO AORTA RATIO DERIVED FROM LUNG CANCER SCREENING CT IS ASSOCIATED WITH COPD HOSPITALIZATION
Authors: Hojune Chung, Dhairyasheel Ghosalkar, Alice Chu, Jacob R. Heath, Tiffany Ho, Wen-Chih Wu, Gaurav Choudhary, Alan Morrison
Journal: Journal of the American College of Cardiology (2022)
ESSENTIAL ROLE OF PRE AND POSTOPERATIVE CARDIAC CT FOR DECISION MAKING IN INFANTS WITH TOTAL ANOMALOUS PULMONARY VENOUS CONNECTION AND SINGLE VENTRICLE
Authors: Ana Vasquez Choy, Dilachew Achiko Adebo, Sheba John, Christopher E. Greenleaf, Jorge D. Salazar, Antonio F. Corno
Journal: Journal of the American College of Cardiology (2022)
TYPE 2 DIABETES AND CONGESTIVE HEART FAILURE ARE MUTUALLY INDEPENDENT PREDICTORS OF THE PRESENCE OF ALBUMINURIA
Authors: Maximilian Maechler, Alexander Vonbank, Barbara Larcher, Arthur Mader, Lukas Sprenger, Valentin Grabher, Andreas Leiherer, Axel Muendlein, Heinz Drexel, Christoph H. Saely
Journal: Journal of the American College of Cardiology (2022)
Abstract PD2-02: Combination CDK4/6 inhibition and AR agonism suppresses the growth of CDK4/6 inhibitor resistant breast cancers
Authors: Allegra Freelander, Geraldine Laven-Law, Leila Eshraghi, Kee Ming Chia, Marie Pickering, Aliza Yong, Ashleigh Wilkinson, Sarah Alexandrou, C. Elizabeth Caldon, Theresa E Hickey, Wayne D Tilley, Elgene Lim
Journal: Cancer Research (2022)

Abstract Resistance to standard-of care-therapies is a significant clinical challenge in estrogen receptor positive (ER+) breast cancer. Cyclin dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapies (ET) is the current standard-of-care for advanced metastatic ER+ breast cancer; however, resistance to this combination is considered inevitable, leading to disease progression. The androgen receptor (AR) is expressed in up to 90% of all ER+ breast cancers, and has been associated with better patient outcome. Compelling recent pre-clinical data demonstrates that selective androgen receptor AR modulators (SARMs) act to suppress ER-driven tumour growth of endocrine-sensitive and -resistant models of ER+ breast cancer. Furthermore, a recent clinical trial evaluating the efficacy of SARMs has shown clinical benefit in patients with ER+/AR+ metastatic breast cancer (NCT02463032). We hypothesise that the SARMS, either alone or in combination with a CDK4/6i, would be an effective treatment for tumours that are sensitive and resistant to ET and CDK4/6i. We report therapeutic efficacy of combination AR agonism + CDK4/6i in CDK4/6-naïve and -resistant pre-clinical models, including cell lines and patient derived xenograft (PDX) models. We demonstrate that combination SARM + CDK4/6i potently and durably inhibited in vitro and in vivo tumour growth. Additionally, we provide evidence that in vivo treatment with the CDK4/6i Palbociclib increased AR expression and signalling, highlighting an interaction of the two signalling pathways not previously described. In conclusion, our data provides a pre-clinical rationale for combination SARM + CDK4/6i in CDK4/6i resistant ER+ breast cancer. Citation Format: Allegra Freelander, Geraldine Laven-Law, Leila Eshraghi, Kee Ming Chia, Marie Pickering, Aliza Yong, Ashleigh Wilkinson, Sarah Alexandrou, C. Elizabeth Caldon, Theresa E Hickey, Wayne D Tilley, Elgene Lim. Combination CDK4/6 inhibition and AR agonism suppresses the growth of CDK4/6 inhibitor resistant breast cancers [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD2-02.
42P BAL0891: A novel, small molecule, dual TTK/PLK1 mitotic checkpoint inhibitor (MCI) with potent single agent activity
Authors: H.A. Lane, E. Zanini, N. Forster-Gross, K. Litherland, F. Bachmann, L. Bury, N. Willemsem-Seegers, J. De Man, D. Vu-Pham, W. Van Riel, G. Zaman, R. Buijsman, A. Groner, M. Roceri, K. Burger, P. McSheehy, L. Kellenberger
Journal: Annals of Oncology (2022)
Clinical considerations for the design of PROTACs in cancer
Authors: Cristina Nieto-Jiménez, Esther Cabañas Morafraile, Carlos Alonso-Moreno, Alberto Ocaña
Journal: Molecular Cancer (2022)

Abstract Degradation of targeted proteins using proteolysis targeting chimeras (PROTACs) has gained momentum. A PROTAC is a bifunctional molecule that consists of three parts: a ligand that interacts with the protein to be degraded, another ligand that binds to an E3 ubiquitin ligase and a linker that connects both. Identification of the right proteins as targets to be degraded and a ligase that is highly expressed in tumors compare with normal tissue is mandatory, as can augment efficacy reducing toxicity. In this article we review the current development stage of PROTACs in cancer to categorize the best PROTAC construction. Targets including BCL2, CDK4 and MCL1 were highly expressed in all tumors; MCL1 was significantly increased in breast cancer and lung adenocarcinoma and CDK4 in colon adenocarcinoma. Degradation of CDK9, AURKA or PLK1, followed by BCL2, MCL1, PTPN11, BRD4, PTK2, showed a high dependency. Most ligases evaluated were not highly present in tumors except for MDM2 in breast, lung, prostate and gastric cancer. In non-transformed tissue MDM2 was the most abundant ligase, followed by cIAP and CRBN, and those with low expression included XIAP and VHL. MDM2 ligase coupled with inhibitors of the targets BCL2, BRD4, CDK9, PLK1 and MCL1 in stomach tumor, and MDM2 with PIK3C3 inhibitors in breast cancer, seems to be the best therapeutic strategy. Our results suggest potential options for the design of PROTACS in specific medical indications.
Cancer pharmacomicrobiomics: targeting microbiota to optimise cancer therapy outcomes
Authors: Nick Lung-Ngai Ting, Harry Cheuk-Hay Lau, Jun Yu
Journal: Gut (2022)

Despite the promising advances in novel cancer therapy such as immune checkpoint inhibitors (ICIs), limitations including therapeutic resistance and toxicity remain. In recent years, the relationship between gut microbiota and cancer has been extensively studied. Accumulating evidence reveals the role of microbiota in defining cancer therapeutic efficacy and toxicity. Unlike host genetics, microbiota can be easily modified via multiple strategies, including faecal microbiota transplantation (FMT), probiotics and antibiotics. Preclinical studies have identified the mechanisms on how microbes influence cancer treatment outcomes. Clinical trials have also demonstrated the potential of microbiota modulation in cancer treatments. Herein, we review the mechanistic insights of gut microbial interactions with chemotherapy and ICIs, particularly focusing on the interplay between gut bacteria and the pharmacokinetics (eg, metabolism, enzymatic degradation) or pharmacodynamics (eg, immunomodulation) of cancer treatment. The translational potential of basic findings in clinical settings is then explored, including using microbes as predictive biomarkers and microbial modulation by antibiotics, probiotics, prebiotics, dietary modulations and FMT. We further discuss the current limitations of gut microbiota modulation in patients with cancer and suggest essential directions for future study. In the era of personalised medicine, it is crucial to understand the microbiota and its interactions with cancer. Manipulating the gut microbiota to augment cancer therapeutic responses can provide new insights into cancer treatment.
Efficacy of Losartan in Hospitalized Patients With COVID-19–Induced Lung Injury
Authors: Michael A. Puskarich, Nicholas E. Ingraham, Lisa H. Merck, Brian E. Driver, David A. Wacker, Lauren Page Black, Alan E. Jones, Courtney V. Fletcher, Andrew M. South, Thomas A. Murray, Christopher Lewandowski, Joseph Farhat, Justin L. Benoit, Michelle H. Biros, Kartik Cherabuddi, Jeffrey G. Chipman, Timothy W. Schacker, Faheem W. Guirgis, Helen T. Voelker, Joseph S. Koopmeiners, Christopher J. Tignanelli, Andrew C Nelson, Alex Hall, David Wright, Ronald A Reilkoff, Tyler Bold, Kenneth Beckman, Ryan Langlois, Matthew T Aliota, James Galbriath, Margaret Beyer, Chas Salmen, Dana Byrne, Brian Roberts, Nastasia James
Journal: JAMA Network Open (2022)

SARS-CoV-2 viral entry may disrupt angiotensin II (AII) homeostasis, contributing to COVID-19 induced lung injury. AII type 1 receptor blockade mitigates lung injury in preclinical models, although data in humans with COVID-19 remain mixed.To test the efficacy of losartan to reduce lung injury in hospitalized patients with COVID-19.This blinded, placebo-controlled randomized clinical trial was conducted in 13 hospitals in the United States from April 2020 to February 2021. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already using a renin-angiotensin-aldosterone system (RAAS) inhibitor were eligible for participation. Data were analyzed from April 19 to August 24, 2021.Losartan 50 mg orally twice daily vs equivalent placebo for 10 days or until hospital discharge.The primary outcome was the imputed arterial partial pressure of oxygen to fraction of inspired oxygen (Pao2:Fio2) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity; days without supplemental o2, ventilation, or vasopressors; and mortality. Losartan pharmacokinetics and RAAS components (AII, angiotensin-[1-7] and angiotensin-converting enzymes 1 and 2)] were measured in a subgroup of participants.A total of 205 participants (mean [SD] age, 55.2 [15.7] years; 123 [60.0%] men) were randomized, with 101 participants assigned to losartan and 104 participants assigned to placebo. Compared with placebo, losartan did not significantly affect Pao2:Fio2 ratio at 7 days (difference, -24.8 [95%, -55.6 to 6.1]; P = .12). Compared with placebo, losartan did not improve any secondary clinical outcomes and led to fewer vasopressor-free days than placebo (median [IQR], 9.4 [9.1-9.8] vasopressor-free days vs 8.7 [8.2-9.3] vasopressor-free days).This randomized clinical trial found that initiation of orally administered losartan to hospitalized patients with COVID-19 and acute lung injury did not improve Pao2:Fio2 ratio at 7 days. These data may have implications for ongoing clinical trials.ClinicalTrials.gov Identifier: NCT04312009.
Primaquine and <i>Plasmodium vivax</i> Malaria Recurrence in Brazil
Authors: Brian Greenwood, Chris Drakeley
Journal: New England Journal of Medicine (2022)

Attempts to control malaria have been making good progress in South America, and two countries, Paraguay and Argentina, have recently been certified by the World Health Organization (WHO) as having achieved elimination of malaria. Brazil has the highest incidence of malaria in South America,1 with 143,381 indigenous cases of malaria recorded in 2021, of which 84% were attributed to Plasmodium vivax. The elimination of P. vivax infection, which is critical to eliminating malaria, is challenging because of the ability of the parasite to persist in the liver as a quiescent hypnozoite and subsequently cause recrudescence months or years later.2,3 Until . . .
Association between social determinants of health and rates of liver transplantation in individuals with cirrhosis
Authors: Jennifer A. Flemming, Hala Muaddi, Maja Djerboua, Paula Neves, Gonzalo Sapisochin, Nazia Selzner
Journal: Hepatology (2022)

This study evaluated the association between neighborhood-level social determinants of health (SDOH) and liver transplantation (LT) among patients with cirrhosis who have universal access to health care.
MONITORED ANESTHESIA CARE VS GENERAL ANESTHESIA OUTCOMES IN TRANSCATHETER AORTIC VALVE IMPLANTATION-A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Hamza Hanif, Sanskriti Shrivastava, Raza Naseer, Muhammad Affan, Najam U. Saqib, Muhammad Siddique Pir, Arpit Sothwal
Journal: Journal of the American College of Cardiology (2022)