tbuckley/cabot-search huggingface dataset:
Circulating microRNA Analysis in a Prospective Co-clinical Trial Identifies MIR652–3p as a Response Biomarker and Driver of Regorafenib Resistance Mechanisms in Colorectal Cancer
Authors: Somaieh Hedayat, Luciano Cascione, David Cunningham, Marta Schirripa, Andrea Lampis, Jens C. Hahne, Nina Tunariu, Sung Pil Hong, Silvia Marchetti, Khurum Khan, Elisa Fontana, Valentina Angerilli, Mia Delrieux, Daniel Nava Rodrigues, Letizia Procaccio, Sheela Rao, David Watkins, Naureen Starling, Ian Chau, Chiara Braconi, Nicos Fotiadis, Ruwaida Begum, Naomy Guppy, Louise Howell, Melanie Valenti, Scott Cribbes, Bernadett Kolozsvari, Vladimir Kirkin, Sara Lonardi, Michele Ghidini, Rodolfo Passalacqua, Raghad Elghadi, Luca Magnani, David J. Pinato, Federica Di Maggio, Filippo Ghelardi, Elisa Sottotetti, Guglielmo Vetere, Paolo Ciracì, Georgios Vlachogiannis, Filippo Pietrantonio, Chiara Cremolini, Alessio Cortellini, Fotios Loupakis, Matteo Fassan, Nicola Valeri
Journal: Clinical Cancer Research (2024)

Abstract Purpose: The multi-kinase inhibitor (mKi) regorafenib has demonstrated efficacy in chemorefractory patients with metastatic colorectal cancer (mCRC). However, lack of predictive biomarkers and concerns over significant toxicities hamper the use of regorafenib in clinical practice. Experimental Design: Serial liquid biopsies were obtained at baseline and monthly until disease progression in chemorefractory patients with mCRC treated with regorafenib in a phase II clinical trial (PROSPECT-R n = 40; NCT03010722) and in a multicentric validation cohort (n = 241). Tissue biopsies collected at baseline, after 2 months and at progression in the PROSPECT-R trial were used to establish patient-derived organoids (PDO) and for molecular analyses. MicroRNA profiling was performed on baseline bloods using the NanoString nCounter platform and results were validated by digital-droplet PCR and/or ISH in paired liquid and tissue biopsies. PDOs co-cultures and PDO-xenotransplants were generated for functional analyses. Results: Large-scale microRNA expression analysis in longitudinal matched liquid and tissue biopsies from the PROSPECT-R trial identified MIR652–3p as a biomarker of clinical benefit to regorafenib. These findings were confirmed in an independent validation cohort and in a “control” group of 100 patients treated with lonsurf. Using ex vivo co-culture assays paired with single-cell RNA-sequencing of PDO established pre- and post-treatment, we modeled regorafenib response observed in vivo and in patients, and showed that MIR652–3p controls resistance to regorafenib by impairing regorafenib-induced lethal autophagy and by orchestrating the switch from neo-angiogenesis to vessel co-option. Conclusions: Our results identify MIR652–3p as a potential biomarker and as a driver of cell and non–cell-autonomous mechanisms of resistance to regorafenib.
Comparison of safety, efficacy, and patient satisfaction with thermal ablation versus endoscopic thyroidectomy for benign thyroid nodules in a propensity-matched cohort
Authors: Ting-Chun Kuo, Kuen-Yuan Chen, Chieh-Wen Lai, Yi-Chia Wang, Ming-Tsan Lin, Chin-Hao Chang, Ming-Hsun Wu
Journal: International Journal of Surgery (2024)

Background: Thyroid nodules (TNs) often require intervention due to symptomatic or cosmetic concerns. Radiofrequency ablation (RFA) has shown promise as a treatment option, offering potential advantages without neck scars. Recently, the scarless treatment alternative of transoral endoscopic thyroidectomy vestibular approach (TOETVA) has emerged. When surgery can be performed in a scarless manner, it remains unclear whether ablation is still the preferred treatment choice. This study aims to compare the safety, efficacy, and patient satisfaction of RFA and TOETVA. Study Design: A retrospective data analysis was conducted on patients treated with RFA or TOETVA for unilateral benign TNs between December 2016 and September 2021. Propensity score matching was employed to create comparable groups. Various clinicopathologic parameters, treatment outcomes, and costs were assessed. Results: Of the 2,814 nonfunctional thyroid nodules treated during this period, 642 were benign and unilateral. A total of 121 and 100 patients underwent thermal ablation and transoral endoscopic thyroidectomy, respectively. After matching, 84 patients were selected for each group. Both RFA and TOETVA demonstrated low complication rates, with unique complications associated with each procedure. Treatment time (30.8±13.6 minutes vs. 120.7±36.5 minutes, P &lt;0.0001) was shorter in the RFA group. Patient satisfaction (significant improvement: 89.3% vs. 61.9%, P &lt;0.0001) and cosmetic results (cosmetic score 1-2: 100.0% vs. 54.76%, P &lt;0.0001) favored TOETVA. RFA was found to be less costly for a single treatment, but the cost of retreatment should be considered. The histological diagnoses post-TOETVA revealed malignancies in 9 out of 84 cases, underscoring the significance of follow-up assessments. Conclusion: Scarless procedures, RFA and TOETVA, are effective for treating unilateral benign TNs, each with unique advantages and drawbacks. While RFA is cheaper for a single treatment, TOETVA offers superior cosmetic results and patient satisfaction. Further research is needed to evaluate long-term safety and cost-effectiveness. It is crucial to remain vigilant about the possibility of malignancy despite benign cytology pre-treatment.
Efficacy of surgical intervention over conservative management in intertrochanteric fractures among nonagenarians and centenarians: a prospective cohort study
Authors: Junfei Guo, Xin Xu, Qian Geng, Tao Wang, Ke Xu, Jinwen He, Yubin Long, Qi Zhang, Wensen Jing, Zheng Li, Ying Pan, Peng Xu, Zhiyong Hou
Journal: International Journal of Surgery (2024)

Background: Optimal treatment strategy for nonagenarians and centenarians with hip fractures (NCHF) remained unknown. We aimed to compare the outcomes of surgical and conservative management in NCHF. Methods: A prospective cohort study was conducted based on CPMHF database with NCHF patients hospitalized during 2014–2020. Comorbidities were evaluated by mECM score and restricted cubic spline was utilized to visually assess the dose-effect relationship between the mECM and outcomes. Propensity score matching was performed to balance baseline characteristics between non-surgical and surgical groups. Multivariate logistic regression, Cox proportional hazard analysis, and survival analysis were employed for unfavorable outcomes (UFO) evaluation. Competing risk of death were analyzed based on Fine and Gray’s hazard model and then constructed nomogram models for predicting survival rates. Subgroup analyses were used to determine potential population heterogeneity and sensitivity analyses were performed to test robustness of the results. Results: We found increasing trends for UFO with the increase in the mECM score, and that high mECM score (HMS, ≥3) was independently associated with a 2.42-fold (95%CI, 2.07-3.54; P =0.024) increased risk of UFO, which remained significant after considering the competing role of death and were more pronounced in non-surgical treatment, women, no insurance, and patients with spouse (all P for interaction&lt;0.05). Surgical intervention was identified to be significant protective factors for UFO (RR, 0.59; 95%CI, 0.46-0.75; P &lt;0.001) and severe complications (RR, 0.63; 95%CI, 0.41-0.96; P =0.033) after PSM, as well as survival (HR, 0.40, 95%CI, 0.28-0.58; P &lt;0.001), which remained significant after considering the competing role of death and in all sensitivity analyses and were more pronounced in HMS participants ( P for interaction=0.006). Subgroup analyses revealed surgical patients with HMS had a significantly higher UFO rate (excluding death, P &lt;0.001) while non-surgical patients with HMS had higher mortality rate as compared to the others ( P =0.005). Conclusion: Surgical treatment for NCHF yields better outcomes compared to conservative treatment.
Breast Cancer Index and Prediction of Extended Aromatase Inhibitor Therapy Benefit in Hormone Receptor-Positive Breast Cancer from the NRG Oncology/NSABP B-42 Trial
Authors: Eleftherios P. Mamounas, Hanna Bandos, Priya Rastogi, Yi Zhang, Kai Treuner, Peter C. Lucas, Charles E. Geyer, Louis Fehrenbacher, Stephen K. Chia, Adam M. Brufsky, Janice M. Walshe, Gamini S. Soori, Shaker Dakhil, Soonmyung Paik, Sandra M. Swain, Dennis C. Sgroi, Catherine A. Schnabel, Norman Wolmark
Journal: Clinical Cancer Research (2024)

Abstract Purpose: BCI (H/I) has been shown to predict extended endocrine therapy (EET) benefit. We examined BCI (H/I) for EET benefit prediction in NSABP B-42, which evaluated extended letrozole therapy (ELT) in patients with hormone receptor-positive breast cancer after 5 years of ET. Experimental Design: A stratified Cox model was used to analyze RFI as the primary endpoint, with DR, BCFI, and DFS as secondary endpoints. Because of a nonproportional effect of ELT on DR, time-dependent analyses were performed. Results: The translational cohort included 2,178 patients (45% BCI (H/I)-High, 55% BCI (H/I)-Low). ELT showed an absolute 10-year RFI benefit of 1.6% (P = 0.10), resulting in an underpowered primary analysis (50% power). ELT benefit and BCI (H/I) did not show a significant interaction for RFI (BCI (H/I)-Low: 10 years absolute benefit 1.1% [HR, 0.70; 95% confidence interval (CI), 0.43–1.12; P = 0.13]; BCI (H/I)-High: 2.4% [HR, 0.83; 95% CI, 0.55–1.26; P = 0.38]; Pinteraction = 0.56). Time-dependent DR analysis showed that after 4 years, BCI (H/I)-High patients had significant ELT benefit (HR = 0.29; 95% CI, 0.12–0.69; P &amp;lt; 0.01), whereas BCI (H/I)-Low patients were less likely to benefit (HR, 0.68; 95% CI, 0.33–1.39; P = 0.29; Pinteraction = 0.14). Prediction of ELT benefit by BCI (H/I) was more apparent in the HER2- subset after 4 years (ELT-by-BCI (H/I) Pinteraction = 0.04). Conclusions: BCI (H/I)-High versus BCI (H/I)-Low did not show a statistically significant difference in ELT benefit for the primary endpoint (RFI). However, in time-dependent DR analysis, BCI (H/I)-High patients experienced statistically significant benefit from ELT after 4 years, whereas (H/I)-Low patients did not. Because BCI (H/I) has been validated as a predictive marker of EET benefit in other trials, additional follow-up may enable further characterization of BCI's predictive ability.
Novel 3D morphological characteristics for congenital biliary dilatation diagnosis: A case-control study
Authors: Jiaqi Dou, Nan Jiang, Jianping Zeng, Siyuan Wang, Song Tian, Siqiao Shan, Yuze Li, Ziming Xu, Xiaoqi Lin, Shuo Jin, Jiahong Dong, Huijun Chen
Journal: International Journal of Surgery (2024)

Background: Congenital biliary dilatation (CBD) necessitates the timely removal of dilated bile ducts. Accurate differentiation between CBD and secondary biliary dilatation (SBD) is crucial for treatment decisions, and identification of CBD with intrahepatic involvement is vital for surgical planning and supportive care. This study aimed to develop quantitative models based on bile duct morphology to distinguish CBD from SBD and further identify CBD with intrahepatic involvement. Materials and Methods: The retrospective study included 131 CBD and 209 SBD patients between December 2014 and December 2021 for model development, internal validation and testing. A separate cohort of 15 CBD and 34 SBD patients between January 2022 and December 2022 was recruited for temporally-independent validation. Quantitative shape-based (Shape) and diameter-based (Diam) morphological characteristics of bile ducts were extracted to build a CBD diagnosis model to distinguish CBD from SBD and an intrahepatic involvement identification model to classify CBD with/without intrahepatic involvement. The diagnostic performance of the models was compared with that of experienced hepatobiliary surgeons. Results: The CBD diagnosis model using clinical, Shape, and Diam characteristics showed good performance with an AUROC of 0.942 [95% CI: 0.890-0.994], AUPRC of 0.917 [0.855-0.979], accuracy of 0.891, sensitivity of 0.950 and F1-score of 0.864. The model outperformed two experienced surgeons in accuracy, sensitivity, and F1-score. The intrahepatic involvement identification model using clinical, Shape, and Diam characteristics yielded outstanding performance with an AUROC of 0.944 [0.879-1.000], AUPRC of 0.982 [0.947-1.000], accuracy of 0.932, sensitivity of 0.971 and F1-score of 0.957. The models demonstrated generalizable performance on the temporally-independent validation cohort. Conclusions: This study developed two robust quantitative models for distinguishing CBD from SBD and identifying CBD with intrahepatic involvement, respectively, based on morphological characteristics of the bile ducts, showing great potential in risk stratification and surgical planning of CBD.
The HIV-1 reservoir landscape in persistent elite controllers and transient elite controllers
Authors: Carmen Gasca-Capote, Xiaodong Lian, Ce Gao, Isabelle C. Roseto, María Reyes Jiménez-León, Gregory Gladkov, María Inés Camacho-Sojo, Alberto Pérez-Gómez, Isabel Gallego, Luis E. Lopez-Cortes, Sara Bachiller, Joana Vitalle, Mohamed Rafii-El-Idrissi Benhnia, Francisco J. Ostos, Antonio R. Collado-Romacho, Jesús Santos, Rosario Palacios, Cristina Gomez-Ayerbe, Leopoldo Muñoz-Medina, Andrés Ruiz-Sancho, Mario Frias, Antonio Rivero-Juarez, Cristina Roca-Oporto, Carmen Hidalgo-Tenorio, Anna Rull, Julian Olalla, Miguel A. Lopez-Ruz, Francesc Vidal, Consuelo Viladés, Andrea Mastrangelo, Matthias Cavassini, Nuria Espinosa, Matthieu Perreau, Joaquin Peraire, Antonio Rivero, Luis F. López-Cortes, Mathias Lichterfeld, Xu G. Yu, Ezequiel Ruiz-Mateos
Journal: Journal of Clinical Investigation (2024)

Background: Persistent controllers (PC) maintain antiretroviral-free HIV-1 control indefinitely over time while transient controllers (TC) eventually lose virological control. It is essential to characterize the quality of the HIV reservoir of these phenotypes to identify the factors that lead to HIV progression and to open new avenues in HIV cure strategies. Methods: The characterization of HIV-1 reservoir, from peripheral blood mononuclear cells, was performed using next-generation sequencing techniques, such as full-length individual and matched integration site proviral sequencing (FLIP-seq; MIP-seq). Results: PC and TC before losing virological control, presented significantly lower total, intact and defective proviruses compared to participants on antiretroviral therapy (ART). No differences were found in total and defective proviruses between PC and TC. However, intact provirus levels were lower in PC compared to TC, being the intact/defective HIV-DNA ratio significantly higher in TC. Clonally expanded intact proviruses were found only in PC and located in centromeric satellite DNA or zinc-finger genes, both associated with heterochromatin features. In contrast, sampled intact proviruses were located in permissive genic euchromatic positions in TC. Conclusions: These results suggest the need for, and can give guidance to the design of, future research to identify a distinct proviral landscape that may be associated with the persistent control of HIV-1 without ART. Funding: Instituto de Salud Carlos III (FI17/00186, FI19/00083, MV20/00057 PI18/01532, PI19/01127 and PI22/01796), Consejería de Economía, Conocimiento, Empresas y Universidad, Junta de Andalucía (PI20/1276), Gilead Fellowships (GLD22/00147) and I+D+iFEDER Andalucía 2014-2020 (US-1380938).
Theorizing Pathways Between Eviction Filings and Increased Mortality Risk
Authors: Jack Tsai
Journal: JAMA (2024)

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Food Insecurity Among Graduate Students and Postdoctoral Trainees
Authors: Nour M. Hammad, Cindy W. Leung
Journal: JAMA Network Open (2024)

Importance Food insecurity on college campuses has emerged as an urgent public health priority; however, there has been a lack of studies focused on graduate students or postdoctoral trainees, particularly those enrolled at private academic institutions. Objective To estimate the prevalence of and factors associated with food insecurity among graduate students and postdoctoral trainees at a private academic university in Boston, Massachusetts. Design, Setting, and Participants In this cross-sectional survey study, a survey on food insecurity was sent to graduate students and postdoctoral trainees at 3 health-focused graduate schools at Harvard University during the end of the spring 2023 academic term (April to June). Participants were studying medicine, dental medicine, or public health. Data analysis was performed from July to September 2023. Exposure Sociodemographic characteristics of graduate students and postdoctoral trainees. Main Outcomes and Measures The primary outcome was food insecurity as assessed using the US Household Food Security Survey Module. Food insecurity also encompassed low and very low food security. Bidirectional stepwise logistic regression models were conducted to estimate the factors associated with food insecurity for graduate students and postdoctoral trainees. Results The analytic sample included 1745 participants (response rate, 55%): 1287 were graduate students and 458 were postdoctoral trainees. The median age of respondents was 29.0 (IQR, 7.0) years, and more than half (1073 [61.5%]) identified as female. A total of 694 respondents (39.8%) identified as Asian, 625 (35.8%) as White, and 426 (24.4%) as being of other race or ethnicity. The prevalence of food insecurity was 17.4% (224 of 1287) among graduate students and 12.7% (58 of 458) among postdoctoral trainees. Among graduate students, factors associated with food insecurity included being Asian (OR, 1.06 [95% CI, 1.01-1.11]) or of other race or ethnicity (OR, 1.07 [95% CI, 1.02-1.13]), receiving financial aid (OR, 1.09 [95% CI, 1.05-1.13]), and having housing instability (OR, 1.53 [95% CI, 1.45-1.61]). Among postdoctoral trainees, factors associated with food insecurity included receiving Supplemental Nutrition Assistance Program benefits (OR, 1.59 [95% CI, 1.28-1.97]), having housing instability (OR, 1.33 [95% CI, 1.22-1.45]), and not owning a car (OR, 1.11 [95% CI, 1.04-1.18]). Conclusions and Relevance In this study, a substantial proportion of graduate students and postdoctoral trainees at a private academic institution experienced food insecurity during the academic year. These findings underscore the need for national and institutional interventions to address the complex, structural factors related to food insecurity in these distinct populations.
Human Papillomavirus Vaccination Among Young Adults Before and During the COVID-19 Pandemic
Authors: Kalyani Sonawane, Ashvita Garg, Eric G. Meissner, Haluk Damgacioglu, Elizabeth Hill, Alan G. Nyitray, Ashish A. Deshmukh
Journal: JAMA Network Open (2024)

This cross-sectional survey study assesses the self-reported human papillomavirus vaccination rate by sociodemographic characteristics in adults aged 18 to 26 years from 2018 to 2022.
Disparities in All-Cause Mortality Beyond the Acute Phase of the COVID-19 Pandemic in the US
Authors: Kaitlyn M. Berry, Andrew C. Stokes, Keeley J. Morris, Rafeya V. Raquib, Elizabeth Wrigley-Field
Journal: JAMA Network Open (2024)

This cross-sectional study examines all-cause mortality in the US between March 2018 and May 2023 by sex, race and ethnicity, metropolitan status, and region.
Historical Redlining, Persistent Mortgage Discrimination, and Race in Breast Cancer Outcomes
Authors: Jasmine M. Miller-Kleinhenz, Lauren E. Barber, Maret L. Maliniak, Leah Moubadder, Maya Bliss, Micah J. Streiff, Jeffrey M. Switchenko, Kevin C. Ward, Lauren E. McCullough
Journal: JAMA Network Open (2024)

Importance Inequities created by historical and contemporary mortgage discriminatory policies have implications for health disparities. The role of persistent mortgage discrimination (PMD) in breast cancer (BC) outcomes has not been studied. Objective To estimate the race-specific association of historical redlining (HRL) with the development of BC subtypes and late-stage disease and a novel measure of PMD in BC mortality. Design, Setting, and Participants This population-based cohort study used Georgia Cancer Registry data. A total of 1764 non-Hispanic Black and White women with a BC diagnosis and residing in an area graded by the Home Owners’ Loan Corporation (HOLC) in Georgia were included. Patients were excluded if they did not have a known subtype or a derived American Joint Committee on Cancer stage or if diagnosed solely by death certificate or autopsy. Participants were diagnosed with a first primary BC between January 1, 2010, to December 31, 2017, and were followed through December 31, 2019. Data were analyzed between May 1, 2022, and August 31, 2023. Exposures Scores for HRL were examined dichotomously as less than 2.5 (ie, nonredlined) vs 2.5 or greater (ie, redlined). Contemporary mortgage discrimination (CMD) scores were calculated, and PMD index was created using the combination of HRL and CMD scores. Main Outcomes and Measures Estrogen receptor (ER) status, late stage at diagnosis, and BC-specific death. Results This study included 1764 women diagnosed with BC within census tracts that were HOLC graded in Georgia. Of these, 856 women (48.5%) were non-Hispanic Black and 908 (51.5%) were non-Hispanic White; 1148 (65.1%) were diagnosed at 55 years or older; 538 (30.5%) resided in tracts with HRL scores less than 2.5; and 1226 (69.5%) resided in tracts with HRL scores 2.5 or greater. Living in HRL areas with HRL scores 2.5 or greater was associated with a 62% increased odds of ER-negative BC among non-Hispanic Black women (odds ratio [OR], 1.62 [95% CI, 1.01-2.60]), a 97% increased odds of late-stage diagnosis among non-Hispanic White women (OR, 1.97 [95% CI, 1.15-3.36]), and a 60% increase in BC mortality overall (hazard ratio, 1.60 [95% CI, 1.17-2.18]). Similarly, PMD was associated with BC mortality among non-Hispanic White women but not among non-Hispanic Black women. Conclusions and Relevance The findings of this cohort study suggest that historical racist policies and persistent discrimination have modern-day implications for BC outcomes that differ by race. These findings emphasize the need for a more nuanced investigation of the social and structural drivers of disparate BC outcomes.