tbuckley/cabot-search huggingface dataset:
Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations
Authors: Azadeh C. Bashi, Elizabeth A. Coker, Krishna C. Bulusu, Patricia Jaaks, Claire Crafter, Howard Lightfoot, Marta Milo, Katrina McCarten, David F. Jenkins, Dieudonne van der Meer, James T. Lynch, Syd Barthorpe, Courtney L. Andersen, Simon T. Barry, Alexandra Beck, Justin Cidado, Jacob A. Gordon, Caitlin Hall, James Hall, Iman Mali, Tatiana Mironenko, Kevin Mongeon, James Morris, Laura Richardson, Paul D. Smith, Omid Tavana, Charlotte Tolley, Frances Thomas, Brandon S. Willis, Wanjuan Yang, Mark J. O'Connor, Ultan McDermott, Susan E. Critchlow, Lisa Drew, Stephen E. Fawell, Jerome T. Mettetal, Mathew J. Garnett
Journal: Cancer Discovery (2024)

Abstract Oncology drug combinations can improve therapeutic responses and increase treatment options for patients. The number of possible combinations is vast and responses can be context-specific. Systematic screens can identify clinically relevant, actionable combinations in defined patient subtypes. We present data for 109 anticancer drug combinations from AstraZeneca's oncology small molecule portfolio screened in 755 pan-cancer cell lines. Combinations were screened in a 7 × 7 concentration matrix, with more than 4 million measurements of sensitivity, producing an exceptionally data-rich resource. We implement a new approach using combination Emax (viability effect) and highest single agent (HSA) to assess combination benefit. We designed a clinical translatability workflow to identify combinations with clearly defined patient populations, rationale for tolerability based on tumor type and combination-specific “emergent” biomarkers, and exposures relevant to clinical doses. We describe three actionable combinations in defined cancer types, confirmed in vitro and in vivo, with a focus on hematologic cancers and apoptotic targets. Significance: We present the largest cancer drug combination screen published to date with 7 × 7 concentration response matrices for 109 combinations in more than 750 cell lines, complemented by multi-omics predictors of response and identification of “emergent” combination biomarkers. We prioritize hits to optimize clinical translatability, and experimentally validate novel combination hypotheses. This article is featured in Selected Articles from This Issue, p. 695
From euphoria to wellbeing: Correlates of gender euphoria and its association with mental wellbeing among transgender adults
Authors: Ruby Grant, Natalie Amos, Teddy Cook, Ashleigh Lin, Adam Hill, Marina Carman, Adam Bourne
Journal: International Journal of Transgender Health (2024)

Purpose There is a growing body of literature focusing on the importance of gender euphoria for transgender (hereafter 'trans') people. This article aims to explore factors that are associated with experiencing gender euphoria among trans adults in Australia, as well as identifying any correlation between gender euphoria and mental health within this population.
Axicabtagene ciloleucel treatment is more effective in primary mediastinal large B-cell lymphomas than in diffuse large B-cell lymphomas: the Italian CART-SIE study
Authors: Annalisa Chiappella, Beatrice Casadei, Patrizia Chiusolo, Alice Di Rocco, Silva Ljevar, Martina Magni, Piera Angelillo, Anna Maria Barbui, Ilaria Cutini, Anna Dodero, Francesca Bonifazi, Maria Chiara Tisi, Stefania Bramanti, Maurizio Musso, Mirko Farina, Massimo Martino, Mattia Novo, Giovanni Grillo, Francesca Patriarca, Giulia Zacchi, Mauro Krampera, Martina Pennisi, Eugenio Galli, Maurizio Martelli, Andrés J M Ferreri, Silvia Ferrari, Riccardo Saccardi, Anisa Bermema, Anna Guidetti, Rosalba Miceli, Pier Luigi Zinzani, Paolo Corradini
Journal: Leukemia (2024)

Axicabtagene ciloleucel showed efficacy for relapsed/refractory large B-cell lymphomas (LBCL), including primary mediastinal B-cell lymphomas (PMBCL); however, only few PMBCLs were reported. Aim was to evaluate efficacy and safety of axicabtagene ciloleucel in patients with PMBCL compared to those with other LBCL, enrolled in the Italian prospective observational CART-SIE study. PMBCLs (n = 70) were younger, with higher percentage of bulky and refractory disease, compared to other LBCLs (n = 190). Median follow-up time for infused patients was 12.17 months (IQR 5.53,22.73). The overall (complete + partial) response rate (ORR,CR + PR) after bridging was 41% for PMBCL and 28% for other LBCL, p = 0.0102. Thirty days ORR was 78% (53/68) with 50% (34) CR in PMBCL, and 75% (141/187) with 53% (100) CR in other LBCL, p = 0.5457. Ninety days ORR was 69% (45/65) with 65% (42) CR in PMBCL, and 54% (87/162) with 47% (76) CR in other LBCL; progressive disease was 21% in PMBCL and 45% in other LBCL, p = 0.0336. Twelve months progression-free survival was 62% (95% CI: 51-75) in PMBCL versus 48% (95% CI: 41-57) in other LBCL, p = 0.0386. Twelve months overall survival was 86% (95% CI: 78-95) in PMBCL versus 71% (95% CI: 64-79) in other LBCL, p = 0.0034. All grade cytokine release syndrome was 88% (228/260); all grade neurotoxicity was 34% (88/260), with 6% of fatal events in PMBCL. Non-relapse mortality was 3%. In conclusion, PMBCLs achieved significantly better response and survival rates than other LBCLs.
Reversing malnutrition and low muscle strength with targeted enteral feeding in patients awaiting liver transplant: A randomized controlled trial
Authors: Brooke Chapman, Darren Wong, Marie Sinclair, Penelope Hey, Ryma Terbah, Paul Gow, Avik Majumdar, Adam Testro
Journal: Hepatology (2024)

Background and Aims: Most patients with decompensated cirrhosis fail to meet their nutrition targets. The impact of nasogastric feeding (NGF) on malnutrition in cirrhosis remains unknown. This study aims to assess the impact of pretransplant NGF on pre–liver transplant and post–liver transplant outcomes. Approach and Results: This single-center, prospective randomized controlled trial of 55 patients with severe malnutrition and low handgrip strength (HGS) compared a standard high-energy high-protein diet to diet plus supplemental nocturnal NGF while awaiting transplant. The primary outcome was a change in HGS. The median age was 58.5 years (IQR: 51.1–64), median MELD was 24 (20–28.5), and 32 (58%) patients were male. The median duration of NGF was 63.0 days (34.5–127), following which time the median between-group difference in HGS was 3.6 kg (95% CI: 1.7–5.2, p &lt;0.001), an increase of 20% from baseline. Mid–upper-arm circumference, triceps skinfold, and immune function all increased significantly with NGF. Muscle and nutritional parameters continued to improve with increasing duration of feeding. NGF significantly increased daily energy intake between groups by 1285 kcal (95% CI: 860–1677) and protein intake by 51 g (95% CI: 32–71) (both p &lt;0.001). All NGF patients met &gt;100% of their measured nutritional requirements. Posttransplant clinical outcomes were similar between groups. Conclusions: Targeted enteral feeding before liver transplant improves HGS, anthropometry, and immune function in severely malnourished patients with cirrhosis. These findings provide a strong rationale for early consideration of NGF to reverse malnutrition and improve muscle strength. Appropriately powered studies should explore whether NGF can also impact clinically relevant outcomes including pretransplant and posttransplant mortality.
Ex vivo activation of the GCN2 pathway metabolically reprograms T cells, leading to enhanced adoptive cell therapy
Authors: Michael St. Paul, Samuel D. Saibil, Meghan Kates, SeongJun Han, Scott C. Lien, Rob C. Laister, Kebria Hezaveh, Andreas Kloetgen, Susanne Penny, Tingxi Guo, Carlos Garcia-Batres, Logan K. Smith, Douglas C. Chung, Alisha R. Elford, Azin Sayad, Devanand Pinto, Tak W. Mak, Naoto Hirano, Tracy McGaha, Pamela S. Ohashi
Journal: Cell Reports Medicine (2024)

The manipulation of T cell metabolism to enhance anti-tumor activity is an area of active investigation. Here, we report that activating the amino acid starvation response in effector CD8+ T cells ex vivo using the general control non-depressible 2 (GCN2) agonist halofuginone (halo) enhances oxidative metabolism and effector function. Mechanistically, we identified autophagy coupled with the CD98-mTOR axis as key downstream mediators of the phenotype induced by halo treatment. The adoptive transfer of halo-treated CD8+ T cells into tumor-bearing mice led to robust tumor control and curative responses. Halo-treated T cells synergized in vivo with a 4-1BB agonistic antibody to control tumor growth in a mouse model resistant to immunotherapy. Importantly, treatment of human CD8+ T cells with halo resulted in similar metabolic and functional reprogramming. These findings demonstrate that activating the amino acid starvation response with the GCN2 agonist halo can enhance T cell metabolism and anti-tumor activity.
Exposure-response associations between chronic exposure to fine particulate matter and risks of hospital admission for major cardiovascular diseases: population based cohort study
Journal: BMJ (2024)

Exposure-response associations between chronic exposure to fine particulate matter and risks of hospital admission for major cardiovascular diseases: population based cohort studyIn this paper by Wei and colleagues (BMJ 2024;384:e076939, doi:) the colour coding in the key to figure 6 was unintentionally switched.The blue lines represent female Medicare beneficiaries, and the orange lines represent male Medicare beneficiaries.The figure has been amended.
Folic Acid–Fortified Iodized Salt and Serum Folate Levels in Reproductive-Aged Women of Rural India
Authors: Jogi V. Pattisapu, Vijayasekhar V. Manda, Madhu Narayana Rao Kottakki, Phani Madhavi Kajana, Vijaya Kancherla, Hayagriva Rao Bhaganagarapu, Vigneshwar Veerappan, Achuith Ediga, Venkatesh Mannar, Levente Diosady, Godfrey P. Oakley
Journal: JAMA Network Open (2024)

Importance India has a disproportionately high prevalence of neural tube defects, including spina bifida and anencephaly (SBA), causing a high number of stillbirths, elective pregnancy terminations, and child mortality; India contributes a large proportion of the global burden of SBA. Thirty years after folic acid was shown to be effective in reducing SBA prevalence, only about one-quarter of such births are prevented globally through cereal grain fortification. Objective To determine the association of folic acid–fortified iodized salt with serum folate concentrations among nonpregnant and nonlactating women of reproductive age. Design, Setting, and Participants This nonrandomized controlled trial using a preintervention and postintervention design was conducted in 4 rural villages in Southern India from July 1 to November 30, 2022. All households in the villages agreed to participate in the study. Preintervention and postintervention serum folate levels were analyzed among study participants at baseline and after 4 months, respectively. Intervention Consumption of approximately 300 µg/d of folic acid using double fortified salt (folic acid plus iodine). Median serum folate concentrations were assessed at baseline and 4 months. Main Outcomes and Measures Change in median serum folate levels between baseline and study end point as the primary outcome of the study. Results A total of 83 nonpregnant nonlactating women aged 20 to 44 years (mean [SD] age, 30.9 [5.1] years) were eligible for the study and provided serum samples for analysis at baseline and the end point of the intervention. The median serum folate concentration increased from 14.6 (IQR, 11.2-20.6) nmol/L at baseline to 54.4 (IQR, 43.5-54.4) nmol/L at end of study, a 3.7-fold increase from baseline to study end point. Two-tailed Wilcoxon signed rank test showed the median difference in preintervention and postintervention serum folate concentrations to be highly significant ( P &amp;amp;lt; .001). The participants found the salt acceptable in color and taste. Conclusions and Relevance Use of folic acid–fortified iodized salt was associated with increased serum folate concentrations in women of reproductive age. This novel evidence can inform public health policy to accelerate SBA prevention. Trial Registration ClinicalTrials.gov Identifier: NCT06174883
The Search for the Causes of Common Hyperandrogenism, 1965 to Circa 2015
Authors: Robert L Rosenfield
Journal: Endocrine Reviews (2024)

Abstract From 1965 to 2015, immense strides were made into understanding the mechanisms underlying the common androgen excess disorders, premature adrenarche and polycystic ovary syndrome (PCOS). The author reviews the critical discoveries of this era from his perspective investigating these disorders, commencing with his early discoveries of the unique pattern of plasma androgens in premature adrenarche and the elevation of an index of the plasma free testosterone concentration in most hirsute women. The molecular genetic basis, though not the developmental biologic basis, for adrenarche is now known and 11-oxytestosterones shown to be major bioactive adrenal androgens. The evolution of the lines of research into the pathogenesis of PCOS is historically traced: research milestones are cited in the areas of neuroendocrinology, insulin resistance, hyperinsulinism, type 2 diabetes mellitus, folliculogenesis, androgen secretion, obesity, phenotyping, prenatal androgenization, epigenetics, and complex genetics. Large-scale genome-wide association studies led to the 2014 discovery of an unsuspected steroidogenic regulator DENND1A (differentially expressed in normal and neoplastic development). The splice variant DENND1A.V2 is constitutively overexpressed in PCOS theca cells in long-term culture and accounts for their PCOS-like phenotype. The genetics are complex, however: DENND1A intronic variant copy number is related to phenotype severity, and recent data indicate that rare variants in a DENND1A regulatory network and other genes are related to PCOS. Obesity exacerbates PCOS manifestations via insulin resistance and proinflammatory cytokine excess; excess adipose tissue also forms testosterone. Polycystic ovaries in 40 percent of apparently normal women lie on the PCOS functional spectrum. Much remains to be learned.
A Phase II Open-Label Randomized Clinical Trial of Preoperative Durvalumab or Durvalumab plus Tremelimumab in Resectable Head and Neck Squamous Cell Carcinoma
Authors: Chang Gon Kim, Min Hee Hong, Dahee Kim, Brian Hyohyoung Lee, Hyunwook Kim, Chan-Young Ock, Geoffrey Kelly, Yoon Ji Bang, Gamin Kim, Jung Eun Lee, Chaeyeon Kim, Se-Heon Kim, Hyun Jun Hong, Young Min Park, Nam Suk Sim, Heejung Park, Jin Woo Park, Chang Geol Lee, Kyung Hwan Kim, Goeun Park, Inkyung Jung, Dawoon Han, Jong Hoon Kim, Junha Cha, Insuk Lee, Mingu Kang, Heon Song, Chiyoon Oum, Seulki Kim, Sukjun Kim, Yoojoo Lim, Seunghee Kim-Schulze, Miriam Merad, Sun Och Yoon, Hyun Je Kim, Yoon Woo Koh, Hye Ryun Kim
Journal: Clinical Cancer Research (2024)

Clinical implications of neoadjuvant immunotherapy in patients with locally advanced but resectable head and neck squamous cell carcinoma (HNSCC) remain largely unexplored.
Correction:<i>What should all health professionals know about movement behaviour change? An international Delphi-based consensus statement</i>
Journal: British Journal of Sports Medicine (2024)

In the third line of the results, it reads 'In total, 63 of the 40 participants completed the second survey (90% response rate) and 34 completed the third survey (85% response rate).'It should read: 'In total, 36 of the 40 participants completed the second survey (90% response rate) and 34 completed the third survey (85% response rate).'
Predictive Tool Use and Willingness for Surgery in Patients With Knee Osteoarthritis
Authors: Yushy Zhou, Lauren Patten, Tim Spelman, Samantha Bunzli, Peter F. M. Choong, Michelle M. Dowsey, Chris Schilling
Journal: JAMA Network Open (2024)

Importance Despite the increasing number of tools available to predict the outcomes of total knee arthroplasty (TKA), the effect of these predictive tools on patient decision-making remains uncertain. Objective To assess the effect of an online predictive tool on patient-reported willingness to undergo TKA. Design, Setting, and Participants This parallel, double-masked, 2-arm randomized clinical trial compared predictive tool use with treatment as usual (TAU). The study was conducted between June 30, 2022, and July 31, 2023. Participants were followed up for 6 months after enrollment. Participants were recruited from a major Australian private health insurance company and from the surgical waiting list for publicly funded TKA at a tertiary hospital. Eligible participants had unilateral knee osteoarthritis, were contemplating TKA, and had previously tried nonsurgical interventions, such as lifestyle modifications, physiotherapy, and pain medications. Intervention The intervention group was provided access to an online predictive tool at the beginning of the study. This tool offered information regarding the likelihood of improvement in quality of life if patients chose to undergo TKA. The predictions were based on the patient’s age, sex, and baseline symptoms. Conversely, the control group received TAU without access to the predictive tool. Main Outcomes and Measures The primary outcome measure was the reduction in participants’ willingness to undergo surgery at 6 months after tool use as measured by binomial logistic regression. Secondary outcome measures included participant treatment preference and the quality of their decision-making process as measured by the Knee Decision Quality Instrument. Results Of 211 randomized participants (mean [SD] age, 65.8 [8.3] years; 118 female [55.9%]), 105 were allocated to the predictive tool group and 106 to the TAU group. After adjusting for baseline differences in willingness for surgery, the predictive tool did not significantly reduce the primary outcome of willingness for surgery at 6 months (adjusted odds ratio, 0.85; 95% CI, 0.42-1.71; P = .64). Conclusions and Relevance Despite the absence of treatment effect on willingness for TKA, predictive tools might still enhance health outcomes of patients with knee osteoarthritis. Additional research is needed to optimize the design and implementation of predictive tools, address limitations, and fully understand their effect on the decision-making process in TKA. Trial Registration ANZCTR.org.au Identifier: ACTRN12622000072718
Community Emergency Care Use by Veterans in an Era of Expanding Choice
Authors: Anita A. Vashi, Tracy Urech, Siqi Wu, Linda D. Tran
Journal: JAMA Network Open (2024)

Importance Recently passed legislation aimed at improving access to care has considerably expanded options for veterans to receive emergency care in community, or non–Veterans Affairs (VA) settings. However, national trends in community emergency department (ED) use by veterans are unknown. Objective To examine national, temporal trends in the frequencies and types of ED visits provided in community settings and explore the association between facilities’ purchase of community care with facility and regional characteristics. Design, Setting, and Participants Retrospective, observational cross-sectional study of ED visits over fiscal years (FY) 2016 to 2022. VA and community ED encounter data were obtained from the VA Corporate Data Warehouse and the Office of Integrated Veteran Care. Participants were veterans receiving ED care at VA facilities or paid for by the VA in the community. Data were analyzed from June to September 2023. Main Outcomes and Measures The primary outcome measures included community ED visit volume, disposition, and payments over time. Also, the most common and costly ED visits were assessed. Negative binomial regression analysis examined associations between facility and regional characteristics and the rate of ED visits purchased in community settings relative to all ED visits. Results There were 19 787 056 ED visits, predominantly at VA facilities (14 532 261 visits [73.4%]), made by 3 972 503 unique veterans from FY 2016 to 2022. The majority of ED users were male (3 576 120 individuals [90.0%]), and the median (IQR) age was 63 (48-73) years. The proportion of community ED visits increased in absolute terms from 18% in FY 2016 to 37% in FY 2022. Total community ED payments, adjusted to 2021 dollars, were $1.18 billion in FY 2016 and over $6.14 billion in FY 2022. The most common reasons for ED visits in the community were for nonspecific chest pain (305 082 visits [6%]), abdominal pain (174 836 visits [3%]), and septicemia (149 968 visits [3%]). The average proportion of ED visits purchased by a VA facility increased from 14% in FY 2016 to 32% by FY 2022. In multivariable analyses, facilities with greater ED volume and low-complexity facilities had higher expected rates of community emergency care than lower volume and high-complexity facilities, respectively. Conclusions and Relevance As veterans increasingly use community EDs for acute, unscheduled needs, attention to factors associated with veterans’ use of acute care services in different settings are important to identify access barriers and to ensure veterans’ health care needs are met.
COVID-19 Pandemic–Related Changes in Rates of Neonatal Abstinence Syndrome
Authors: Sarka Lisonkova, Jeffrey N. Bone, Qi Wen, Giulia M. Muraca, Joseph Y. Ting, Neda Razaz, K. S. Joseph
Journal: JAMA Network Open (2024)

This cross-sectional study examines COVID-19 pandemic–related changes in rates of neonatal abstinence syndrome (NAS) and whether infants in urban or rural areas and those with low socioeconomic status were disproportionately affected.
Magnetic Soft Microrobot Design for Cell Grasping and Transportation
Authors: Fanghao Wang, Youchao Zhang, Daoyuan Jin, Zhongliang Jiang, Yaqian Liu, Alois Knoll, Huanyu Jiang, Yibin Ying, Mingchuan Zhou
Journal: Cyborg and Bionic Systems (2024)

Manipulating cells at a small scale is widely acknowledged as a complex and challenging task, especially when it comes to cell grasping and transportation. Various precise methods have been developed to remotely control the movement of microrobots. However, the manipulation of micro-objects necessitates the use of end-effectors. This paper presents a study on the control of movement and grasping operations of a magnetic microrobot, utilizing only 3 pairs of electromagnetic coils. A specially designed microgripper is employed on the microrobot for efficient cell grasping and transportation. To ensure precise grasping, a bending deformation model of the microgripper is formulated and subsequently validated. To achieve precise and reliable transportation of cells to specific positions, an approach that combines an extended Kalman filter with a model predictive control method is adopted to accomplish the trajectory tracking task. Through experiments, we observe that by applying the proposed control strategy, the mean absolute error of path tracking is found to be less than 0.155 mm. Remarkably, this value accounts for only 1.55% of the microrobot’s size, demonstrating the efficacy and accuracy of our control strategy. Furthermore, an experiment involving the grasping and transportation of a zebrafish embryonic cell (diameter: 800 μm) is successfully conducted. The results of this experiment not only validate the precision and effectiveness of the proposed microrobot and its associated models but also highlight its tremendous potential for cell manipulation in vitro and in vivo.