bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dissolving Fusion Oncoprotein Condensates to Reverse Aberrant Gene Expression
Authors: Shirnekhi Hazheen K. , Chandra Bappaditya , Kriwacki Richard W. 
Published: October 2023

Abstract
In a recent study, Wang and colleagues reported that a significant fraction of cancer-associated fusion proteins display a common structural topology, including an N-terminal phase separation-prone region (PS) from one parent protein and a C-terminal DNA-binding domain (DBD) from the other. This is reminiscent of the structural topology of transcription factors and led to the hypothesis that the PS-DBD fusions form aberrant transcriptional condensates through phase separation, which was supported through transcriptomic data analysis and cellular condensate assays. The authors developed a high-throughput screen based upon time-lapse, high-content imaging to identify 114 compounds that dissolved condensates formed by a chromatin-dissociated mutant of FUS::ERG (FUS::ERGmut). One of these compounds, LY2835219, was shown to dissolve FUS::ERGmut condensates by promoting lysosome formation and was also active against condensates formed by other PS-DBD fusions, including EWS::FLI1. Finally, condensate dissolution by LY2835219 was shown to reverse aberrant gene expression driven by EWS::FLI1, although how this compound specifically marshals lysosomes to target some PS-DBD fusions and not other condensate-forming proteins remains elusive. This work not only highlights likely roles for aberrant condensate formation in the oncogenic function of PS-DBD fusions, but also provides proof of principle for mechanistically unbiased screening to identify compounds that modulate fusion protein-driven condensates and their oncogenic functions.
A Population-Based Family Case–Control Study of Sun Exposure and Follicular Lymphoma Risk
Authors: Odutola Michael K. , van Leeuwen Marina T. , Bruinsma Fiona , Turner Jennifer , Hertzberg Mark , Seymour John F. , Prince H. Miles , Trotman Judith , Verner Emma , Roncolato Fernando , Opat Stephen , Lindeman Robert , Tiley Campbell , Milliken Samuel T. , Underhill Craig R. , Benke Geza , Giles Graham G. , Vajdic Claire M. 
Published: October 2023

Abstract

Background:
Epidemiologic evidence suggests an inverse association between sun exposure and follicular lymphoma risk.

Methods:
We conducted an Australian population-based family case–control study based on 666 cases and 459 controls (288 related, 171 unrelated). Participants completed a lifetime residence and work calendar and recalled outdoor hours on weekdays, weekends, and holidays in the warmer and cooler months at ages 10, 20, 30, and 40 years, and clothing types worn in the warmer months. We used a group-based trajectory modeling approach to identify outdoor hour trajectories over time and examined associations with follicular lymphoma risk using logistic regression.

Results:
We observed an inverse association between follicular lymphoma risk and several measures of high lifetime sun exposure, particularly intermittent exposure (weekends, holidays). Associations included reduced risk with increasing time outdoors on holidays in the warmer months [highest category OR = 0.56; 95% confidence interval (CI), 0.42–0.76; Ptrend &lt; 0.01], high outdoor hours on weekends in the warmer months (highest category OR = 0.71; 95% CI, 0.52–0.96), and increasing time outdoors in the warmer and cooler months combined (highest category OR = 0.66; 95% CI, 0.50–0.91; Ptrend 0.01). Risk was reduced for high outdoor hour maintainers in the warmer months across the decade years (OR = 0.71; 95% CI, 0.53–0.96).

Conclusions:
High total and intermittent sun exposure, particularly in the warmer months, may be protective against the development of follicular lymphoma.

Impact:
Although sun exposure is not recommended as a cancer control policy, confirming this association may provide insights regarding the future control of this intractable malignancy.
CD24hiCD27+ Bregs within Metastatic Lymph Nodes Promote Multidrug Resistance in Breast Cancer
Authors: Huang Huanhuan , Yao Yao , Shen Lesang , Jiang Jingxin , Zhang Ting , Xiong Jia , Li Jiaxin , Sun Shanshan , Zheng Siwei , Jia Fang , Zhou Jun , Yu Xiuyan , Chen Wuzhen , Shen Jun , Xia Wenjie , Shao Xuan , Wang Qingqing , Huang Jian , Ni Chao 
Published: October 2023

Abstract

Purpose:
Axillary lymph nodes (LN) are the primary and dominant metastatic sites in breast cancer. However, the interaction between tumor cells and immune cells within metastatic LNs (mLN) remains poorly understood. In our study, we explored the effect of CD24hiCD27+ regulatory B cells (Breg) within mLNs on orchestrating drug resistance of breast cancer cells.

Experimental Design:
We collected mLN samples from patients with breast cancer who had received standard neoadjuvant therapy (NAT) and analyzed the spatial features of CD24hiCD27+ Bregs through multicolor immunofluorescence staining. The effect of CD24hiCD27+ Bregs on drug resistance of breast cancer cells was evaluated via in vitro experiments. A mouse model with mLNs was used to evaluate the strategies with blocking the interactions between Bregs and breast cancer for improving tumor regression within mLNs.

Results:
In patients with breast cancer who had received NAT, there is a close spatial correlation between activated CD24hiCD27+ Bregs and residual tumor cells within mLNs. Mechanistically, CD24hiCD27+ Bregs greatly enhance the acquisition of multidrug resistance and stem-like features of breast cancer cells by secreting IL6 and TNFα. More importantly, breast cancer cells further promote the activation of CD24hiCD27+ Bregs via CD40L-dependent and PD-L1–dependent proximal signals, forming a positive feedback pattern. PD-L1 blockade significantly attenuates the drug resistance of breast cancer cells induced by CD24hiCD27+ Bregs, and addition of anti-PD-L1 antibody to chemotherapy improves tumor cell remission in mLNs.

Conclusions:
Our study reveals the pivotal role of CD24hiCD27+ Bregs in promoting drug resistance by interacting with breast cancer cells in mLNs, providing novel evidence for an improved strategy of chemoimmunotherapy combination for patients with breast cancer with mLNs.
Sex-dependent Prognosis of Patients with Advanced Soft Tissue Sarcoma
Authors: Pan Minggui , Zhou Maggie Yuxi , Jiang Chen , Zhang Zheyang , Bui Nam Q. , Bien Jeffrey , Siy Amanda , Achacoso Ninah , Solorzano Aleyda V. , Tse Pamela , Chung Elaine , Thomas Sachdev , Habel Laurel A. , Ganjoo Kristen N. 
Published: October 2023

AbstractPurpose:To examine whether overall survival (OS) differs for male and female patients with advanced soft-tissue sarcoma (STS).Experimental Design:The study included patients from Kaiser Permanente Northern California and Stanford Cancer Center with grade 2 and 3 locally advanced or metastatic STS whose tumor underwent next-generation sequencing. We used Cox regression modeling to examine association of sex and OS adjusting for other important factors.Results:Among 388 eligible patients, 174 had leiomyosarcoma (LMS), 136 had undifferentiated pleomorphic sarcoma (UPS), and 78 had liposarcoma. OS for male versus female patients appeared to be slightly better among the full cohort [HR = 0.89; 95% confidence interval (CI), 0.66–1.20]; this association appeared to be stronger among the subsets of patients with LMS (HR = 0.76; 95% CI, 0.39–1.49) or liposarcoma (HR = 0.74; 95% CI, 0.32–1.70). Better OS for male versus female patients was also observed among all molecular subgroups except mutRB1 and mutATRX, especially among patients whose tumor retained wtTP53 (HR = 0.73; 95% CI, 0.44–1.18), wtCDKN2A (HR = 0.85; 95% CI, 0.59–1.23), wtRB1 (HR = 0.73; 95% CI, 0.51–1.04), and among patients whose tumor had mutPTEN (HR = 0.37; 95% CI, 0.09–1.62). OS also appeared to be better for males in the MSK-IMPACT and TCGA datasets.Conclusions:A fairly consistent pattern of apparent better OS for males across histologic and molecular subgroups of STS was observed. If confirmed, our results could have implications for clinical practice for prognostic stratification and possibly treatment tailoring as well as for future clinical trials design.
A Small Molecule with Big Impact: MRTX1133 Targets the KRASG12D Mutation in Pancreatic Cancer
Authors: Wei Daoyan , Wang Liang , Zuo Xiangsheng , Maitra Anirban , Bresalier Robert S. 
Published: October 2023

Abstract
KRAS mutations drive oncogenic alterations in numerous cancers, particularly in human pancreatic ductal adenocarcinoma (PDAC). About 93% of PDACs have KRAS mutations, with G12D (∼42% of cases) and G12V (∼32% of cases) being the most common. The recent approval of sotorasib (AMG510), a small-molecule, covalent, and selective KRASG12C inhibitor, for treating patients with non–small cell lung cancer represents a breakthrough in KRAS targeted therapy. However, there is a need to develop other much-needed KRAS-mutant inhibitors for PDAC therapy. Notably, Mirati Therapeutics recently developed MRTX1133, a small-molecule, noncovalent, and selective KRASG12D inhibitor through extensive structure-based drug design. MRTX1133 has demonstrated potent in vitro and in vivo antitumor efficacy against KRASG12D-mutant cancer cells, especially in PDAC, leading to its recent initiation of a phase I/II clinical trial. Here, we provide a summary of the recent advancements related to the use of MRTX1133 for treating KRASG12D-mutant PDAC, focusing on its efficacy and underlying mechanistic actions. In addition, we discuss potential challenges and future directions for MRTX1133 therapy for PDAC, including overcoming intrinsic and acquired drug resistance, developing effective combination therapies, and improving MRTX1133’s oral bioavailability and target spectrum. The promising results obtained from preclinical studies suggest that MRTX1133 could revolutionize the treatment of PDAC, bringing about a paradigm shift in its management.
An Antibody–Drug Conjugate Directed to Tissue Factor Shows Preclinical Antitumor Activity in Head and Neck Cancer as a Single Agent and in Combination with Chemoradiotherapy
Authors: Bakema Jantine E. , Stigter-van Walsum Marijke , Harris Jeffrey R. , Ganzevles Sonja H. , Muthuswamy Anantharaman , Houtkamp Mischa , Plantinga Theo S. , Bloemena Elisabeth , Brakenhoff Ruud H. , Breij Esther C.W. , van de Ven Rieneke 
Published: October 2023

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a solid tumor type that arises in the squamous epithelial cells lining the mucosal surfaces of the upper aerodigestive tract. Long-term survival of patients with advanced disease stage remains disappointing with current treatment options. We show that tissue factor is abundantly expressed on patient-derived HNSCC cell lines, xenograft tumor material, and tumor biopsies from patients with HNSCC. Tisotumab vedotin (TV) is an antibody–drug conjugate (ADC) directed to tissue factor, a protein expressed in many solid tumors. HNSCC cells and xenograft tumors were efficiently eliminated in vitro and in vivo with TV-monotherapy compared with treatment with a control antibody conjugated to monomethyl auristatin E (MMAE). Antitumor activity of TV was also tested in vivo in combination with chemoradiotherapy, standard of care for patients with advanced stage HNSCC tumors outside the oral cavity. Preclinical studies showed that by adding TV to chemoradiotherapy, survival was markedly improved, and TV, not radiotherapy or chemotherapy, was the main driver of antitumor activity. Interestingly, TV-induced cell death in xenograft tumors showed an influx of macrophages indicative of a potential immune-mediated mode-of-action. In conclusion, on the basis of these preclinical data, TV may be a novel treatment modality for patients suffering from head and neck cancer and is hypothesized to improve efficacy of chemoradiotherapy.

Significance:
This work shows preclinical in vitro and in vivo antitumor activity of the antibody–drug conjugate Tisotumab vedotin in head and neck cancer models, and enhanced activity in combination with chemoradiotherapy, supporting further clinical development for this cancer type.
Dual CAR-T Cells Targeting CD19 and CD37 Are Effective in Target Antigen Loss B-cell Tumor Models
Authors: Imai Kanae , Takeuchi Yuki , Terakura Seitaro , Okuno Shingo , Adachi Yoshitaka , Osaki Masahide , Umemura Koji , Hanajiri Ryo , Shimada Kazuyuki , Murata Makoto , Kiyoi Hitoshi 
Published: October 2023

Abstract

Chimeric antigen receptor T (CAR-T) cells targeting multiple antigens (Ag), may reduce the risk of immune escape following the loss of the target Ag and further increase the efficacy of treatment. We developed dual-targeting CAR-T cells that target CD19 and CD37 Ags and evaluated their antitumor effects. CD19/CD37 dual CAR-T cells were generated using cotransduction and simultaneous gene transfer of two types of lentiviral vectors transferring CD19CAR or CD37CAR genes, including the intracellular domains of CD28 and CD3ζ signaling domains. These dual CAR-T cells contained three fractions: CD19/CD37 bispecific CAR-T cells, single CD19CAR-T cells, and single CD37CAR-T cells. In the functional evaluation of CAR-T cells in vitro, CD19/CD37 dual CAR-T cells showed adequate proliferation and cytokine production in response to CD19 and CD37 antigen stimulation alone or in combination. Evaluation of intracellular signaling revealed that dual CAR-T cell–mediated signals were comparable with single CAR-T cells in response to CD19- and CD37-positive B-cell tumors. Although the cytotoxicity of CD19/CD37 dual CAR-T cells in both CD19- and CD37-positive B-cell tumors was similar to that of single CD19 and CD37CAR-T cells, against CD19 and CD37 Ag-heterogeneous tumor, dual CAR-T cells demonstrated significantly superior tumor lysis compared with single CAR-T cells. Furthermore, CD19/CD37 dual CAR-T cells effectively suppressed Ag-heterogeneous Raji cells in a xenograft mouse model. Collectively, these results suggest that CD19/CD37 dual CAR-T cells may be effective target-Ag-loss B-cell tumor models in vitro and in vivo, which represents a promising treatment for patients with relapsed/refractory B-cell malignancies.
Effects of Synchronizing Foot Strike and Cardiac Phase on Exercise Hemodynamics in Patients With Cardiac Resynchronization Therapy: A Within-Subjects Pilot Study to Fine-Tune Cardio-Locomotor Coupling for Heart Failure
Authors: Wakeham Denis J. , Ivey Erika , Saland Sophie A. , Lewis Joshua S. , Palmer Dean , Morris Margot , Bleich Jeffery L. , Weyand Peter G. , Brazile Tiffany L. , Hearon Christopher M. , Sarma Satyam , MacNamara James P. , Hieda Michinari , Levine Benjamin D. 
Published: October 2023

BACKGROUND:
Despite advances in medical and cardiac resynchronization therapy (CRT), individuals with chronic congestive heart failure (CHF) have persistent symptoms, including exercise intolerance. Optimizing cardio-locomotor coupling may increase stroke volume and skeletal muscle perfusion as previously shown in healthy runners. Therefore, we tested the hypothesis that exercise stroke volume and cardiac output would be higher during fixed-paced walking when steps were synchronized with the diastolic compared with systolic portion of the cardiac cycle in patients with CHF and CRT.

METHODS:

Ten participants (58±17 years of age; 40% female) with CHF and previously implanted CRT pacemakers completed 5-minute bouts of walking on a treadmill (range, 1.5–3 mph). Participants were randomly assigned to first walking to an auditory tone to synchronize their foot strike to either the systolic (0% or 100±15% of the R-R interval) or diastolic phase (45±15% of the R-R interval) of their cardiac cycle and underwent assessments of oxygen uptake (V̇
o
2
; indirect calorimetry) and cardiac output (acetylene rebreathing). Data were compared through paired-samples
t
tests.

RESULTS:

V̇
o
2
was similar between conditions (diastolic 1.02±0.44 versus systolic 1.05±0.42 L/min;
P
=0.299). Compared with systolic walking, stroke volume (diastolic 80±28 versus systolic 74±26 mL;
P
=0.003) and cardiac output (8.3±3.5 versus 7.9±3.4 L/min;
P
=0.004) were higher during diastolic walking; heart rate (paced) was not different between conditions. Mean arterial pressure was significantly lower during diastolic walking (85±12 versus 98±20 mm Hg;
P
=0.007).

CONCLUSIONS:
In patients with CHF who have received CRT, diastolic stepping increases stroke volume and oxygen delivery and decreases afterload. We speculate that, if added to pacemakers, this cardio-locomotor coupling technology may maximize CRT efficiency and increase exercise participation and quality of life in patients with CHF.
Association of Real‐Time Feedback and Cardiopulmonary‐Resuscitation Quality Delivered by Ambulance Personnel for Out‐of‐Hospital Cardiac Arrest
Authors: Lyngby Rasmus Meyer , Quinn Tom , Oelrich Roselil Maria , Nikoletou Dimitra , Gregers Mads Christian Tofte , Kjølbye Julie Samsøe , Ersbøll Annette Kjær , Folke Fredrik 
Published: October 2023

Background
High‐quality cardiopulmonary resuscitation (CPR) is associated with improved survival from out‐of‐hospital cardiac arrest and includes chest compression depth, chest compression rate, and chest compression fraction within international guideline recommendations. Previous studies have demonstrated divergent results of real‐time feedback on CPR performance and patient outcomes. This study investigated the association between emergency medical service CPR quality and real‐time CPR feedback for out‐of‐hospital cardiac arrest.

Methods and Results

This study collected out‐of‐hospital cardiac arrest data within the Capital Region of Denmark and compared CPR quality delivered by ambulance personnel. Data were collected in 2 consecutive phases from October 2018 to February 2020. Median chest compression depth was 6.0 cm (no feedback) and 5.9 cm (real‐time feedback) (
P
=0.852). Corresponding proportion of guideline‐compliant chest compressions for depth was 16.6% and 28.7%, respectively (
P
<0.001). Median chest compression rate per minute was 111 and 109 (
P
<0.001), respectively. Corresponding guideline adherence proportion for compression rate was 65.4% compared with 80.4% (
P
<0.001), respectively. Chest compression fraction was 78.9% compared with 81.9% (
P
<0.001), respectively. The combination of guideline‐compliant chest compression depth and chest compression rate simultaneously was 8.5% (no feedback) versus 18.8% (feedback) (
P
<0.001). Improvements were not significant for return of spontaneous circulation (odds ratio [OR], 1.08 [95% CI, 0.84–1.39]), sustained return of spontaneous circulation (OR, 1.00 [95% CI, 0.77–1.31]), or survival to hospital discharge (OR, 0.91 [95% CI, 0.64–1.30]).

Conclusions
Real‐time feedback was associated with improved guideline compliance for chest compression depth, rate, and fraction but not return of spontaneous circulation, sustained return of spontaneous circulation, or survival to hospital discharge.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT04152252.
Aspirin Dosing for Secondary Prevention of Atherosclerotic Cardiovascular Disease in Patients Treated With P2Y12 Inhibitors
Authors: Girotra Saket , Stebbins Amanda , Wruck Lisa , Marquis‐Gravel Guillaume , Gupta Kamal , Farrehi Peter , Benziger Catherine P. , Effron Mark B. , Whittle Jeffrey , Muñoz Daniel , Kripalani Sunil , Anderson R. David , Jain Sandeep K. , Polonsky Tamar S. , Ahmad Faraz S. , Roe Matthew T. , Rothman Russell L. , Harrington Robert A. , Hernandez Adrian F. , Jones W. Schuyler 
Published: October 2023

Background
The ADAPTABLE (Aspirin Dosing: A Patient‐Centric Trial Assessing Benefits and Long‐Term Effectiveness) was a large, pragmatic, randomized controlled trial that found no difference between high‐ versus low‐dose aspirin for secondary prevention of atherosclerotic cardiovascular disease. Whether concomitant P2Y12 inhibitor therapy modifies the effect of aspirin dose on clinical events remains unclear.

Methods and Results
Participants in ADAPTABLE were stratified according to baseline use of clopidogrel or prasugrel (P2Y12 group). The primary effectiveness end point was a composite of death, myocardial infarction, or stroke; and the primary safety end point was major bleeding requiring blood transfusions. We used multivariable Cox regression to compare the relative effectiveness and safety of aspirin dose within P2Y12 and non‐P2Y12 groups. Of 13 815 (91.6%) participants with available data, 3051 (22.1%) were receiving clopidogrel (2849 [93.4%]) or prasugrel (203 [6.7%]) at baseline. P2Y12 inhibitor use was associated with higher risk of the primary effectiveness end point (10.86% versus 6.31%; adjusted hazard ratio [HR], 1.40 [95% CI, 1.22–1.62]) but was not associated with bleeding (0.95% versus 0.53%; adjusted HR, 1.42 [95% CI, 0.91–2.22]). We found no interaction in the relative effectiveness and safety of high‐ versus low‐dose aspirin by P2Y12 inhibitor use. Overall, dose switching or discontinuation was more common in the high‐dose compared with low‐dose aspirin group, but the pattern was not modified by P2Y12 inhibitor use.

Conclusions
In this prespecified analysis of ADAPTABLE, we found that the relative effectiveness and safety of high‐ versus low‐dose aspirin was not modified by baseline P2Y12 inhibitor use.

Registration

https://www.clinical.trials.gov
. Unique identifier: NCT02697916.
Association of SARS‐CoV‐2 Infection and Cardiopulmonary Long COVID With Exercise Capacity and Chronotropic Incompetence Among People With HIV
Authors: Durstenfeld Matthew S. , Peluso Michael J. , Spinelli Matthew A. , Li Danny , Hoh Rebecca , Chenna Ahmed , Yee Brandon , Winslow John , Petropoulos Christos , Gandhi Monica , Henrich Timothy J. , Aras Mandar A. , Long Carlin S. , Deeks Steven G. , Hsue Priscilla Y. 
Published: October 2023

Background
Postacute sequelae of COVID‐19 (PASC) and HIV are both associated with reduced exercise capacity, but whether SARS‐CoV‐2 or PASC are associated with exercise capacity among people with HIV (PWH) is unknown. We hypothesized that PWH with PASC would have reduced exercise capacity from chronotropic incompetence.

Methods and Results

We conducted cross‐sectional cardiopulmonary exercise testing within a COVID recovery cohort that included PWH with and without prior SARS‐CoV‐2 infection and people without HIV with prior SARS‐CoV‐2 infection (controls). We evaluated associations of HIV, SARS‐CoV‐2, and PASC with exercise capacity (peak oxygen consumption) and chronotropy (adjusted heart rate reserve). We included 83 participants (median age, 54 years; 35% women; 37 PWH): 23 out of 37 (62%) PWH and all 46 controls had prior SARS‐CoV‐2 infection, and 11 out of 23 (48%) PWH and 28 out of 46 (61%) without HIV had PASC. Peak oxygen consumption was reduced among PWH versus controls (80% predicted versus 99%,
P
=0.005), a difference of 5.5 mL/kg per minute (95% CI, 2.7–8.2;
P
<0.001). Chronotropic incompetence was more prevalent among PWH (38% versus 11%,
P
=0.002), with lower adjusted heart rate reserve (60% versus 83%,
P
<0.0001) versus controls. Among PWH, SARS‐CoV‐2 coinfection and PASC were not associated with exercise capacity. Chronotropic incompetence was more common among PWH with PASC: 7 out of 11 (64%) with PASC versus 7 out of 26 (27%) without PASC (
P
=0.04).

Conclusions
Exercise capacity and chronotropy are lower among PWH compared with individuals with SARS‐CoV‐2 infection without HIV. Among PWH, SARS‐CoV‐2 infection and PASC were not strongly associated with reduced exercise capacity. Chronotropic incompetence may be a common underrecognized mechanism of exercise intolerance among PWH, especially those with cardiopulmonary PASC.