bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-scale CRISPR–Cas9 screen reveals novel regulators of B7-H3 in tumor cells
Authors: Zhao Shasha , Wang Yuelong , Yang Nian , Mu Min , Wu Zhiguo , Li Hexian , Tang Xin , Zhong Kunhong , Zhang Zongliang , Huang Cheng , Cao Ting , Zheng Meijun , Wang Guoqing , Nie Chunlai , Yang Hui , Guo Gang , Zhou Liangxue , Zheng Xi , Tong Aiping 
Published: June 2022

BackgroundDespite advances in B7 homolog 3 protein (B7-H3) based immunotherapy, the development of drug resistance remains a major clinical concern. The heterogeneity and emerging loss of B7-H3 expression are the main causes of drug resistance and treatment failure in targeted therapies, which reveals an urgent need to elucidate the mechanism underlying the regulation of B7-H3 expression. In this study, we identified and explored the crucial role of the transcription factor SPT20 homolog (SP20H) in B7-H3 expression and tumor progression.MethodsHere, we performed CRISPR/Cas9-based genome scale loss-of-function screening to identify regulators of B7-H3 in human ovarian cancer cells. Signaling pathways altered by SP20H knockout were revealed by RNA sequencing. The regulatory role and mechanism of SP20H in B7-H3 expression were validated using loss-of-function and gain-of-function assays in vitro. The effects of inhibiting SP20H on tumor growth and efficacy of anti-B7-H3 treatment were evaluated in tumor-bearing mice.ResultsWe identified SUPT20H (SP20H) as negative and eIF4E as positive regulators of B7-H3 expression in various cancer cells. Furthermore, we provided evidence that either SP20H loss or TNF-α stimulation in tumor cells constitutively activates p38 MAPK-eIF4E signaling, thereby upregulating B7-H3 expression. Loss of SP20H upregulated B7-H3 expression both in vitro and in vivo. Additionally, deletion of SP20H significantly suppressed tumor growth and increased immune cells infiltration in tumor microenvironment. More importantly, antibody–drug conjugates targeting B7-H3 exhibited superior antitumor performance against SP20H-deficient tumors relative to control groups.ConclusionsActivation of p38 MAPK-eIF4E signaling serves as a key event in the transcription initiation and B7-H3 protein expression in tumor cells. Genetically targeting SP20H upregulates target antigen expression and sensitizes tumors to anti-B7-H3 treatment. Collectively, our findings provide new insight into the mechanisms underlying B7-H3 expression and introduce a potential synergistic target for existing antibody-based targeted therapy against B7-H3.
Lifetime exposure to rubber dusts, fumes and N-nitrosamines and cancer mortality in a cohort of British rubber workers with 49 years follow-up
Authors: Hidajat Mira , McElvenny Damien Martin , Ritchie Peter , Darnton Andrew , Mueller William , van Tongeren Martie , Agius Raymond M , Cherrie John W , de Vocht Frank 
Published: June 2022

ObjectivesTo quantitatively evaluate exposure-response associations between occupational exposures to rubber dust, fumes and N-nitrosamines and cancer mortality in the UK rubber industry.MethodsCompeting risk survival analyses were used to examine cancer mortality risk in a cohort of 36 441 males aged 35+ years employed in the British rubber industry in 1967, followed up to 2015 (94% mortality). Exposure measurements are based on a population-specific quantitative job-exposure matrix for rubber dust, rubber fumes and N-nitrosamines from the EU-EXASRUB project.ResultsExposure (lifetime cumulative (LCE))-response associations were found for N-nitrosomorphiline and all cancers (subdistribution HR (SHR) 1.48, 95% CI 1.39 to 1.57) and cancers of the bladder, stomach, multiple myeloma, oesophagus, prostate and pancreas, as well as for N-nitrosodimethylamine and all cancers (SHR 2.08, 95% CI 1.96 to 2.21) and cancers of the bladder, stomach, leukaemia, multiple myeloma, prostate and liver. LCE to the N-nitrosamines sum were associated with increased risks from all cancers (SHR 1.89, 95% CI 1.78 to 2.01) and cancers of the lung, non-Hodgkin’s lymphoma and brain. LCE to rubber dust and fumes are associated with increased mortality from all cancers (rubber dust SHR 1.67, 95% CI 1.58 to 1.78; rubber fumes SHR 1.91, 95% CI 1.80 to 2.03) and cancers of the bladder, lung, stomach, leukaemia, multiple myeloma, non-Hodgkin’s lymphoma, oesophagus, prostate, pancreas and liver.ConclusionsConsistent with previous studies, N-nitrosamines exposures are associated with mortality from cancers of the bladder, lung, stomach, leukaemia, multiple myeloma, oesophagus, prostate, pancreas and liver. The long follow-up with nearly complete mortality enabled estimations of lifetime cancer mortality risk from occupational exposures in the rubber industry.
Transfer of water and contaminants in the Chalk unsaturated zone – underground quarry of Saint-Martin-le-Nœud
Authors: Valdes Danièle , Chen Ningxin , Dumont Marc , Marlin Christelle , Blanchoud Hélène , Guérin Roger , Guillemoteau Julien , Alliot Fabrice , Nespoulet Romane , Aubry Emmanuel , Rouelle Maryse , Fauchard Cyrille , Gombert Philippe , Ribstein Pierre 
Published: June 2022

Abstract
The aim of this study is to understand the water and contaminant (nitrate and atrazine) transfer in the unsaturated zone (UZ) of Chalk. For this, the underground quarry of Saint-Martin-le-Nœud is an exceptional site because it permits entry to the aquifer at the limit between the UZ and the saturated zone (SZ). It provides direct access to the water table: underground lakes and the output of the UZ (percolation water at the ceiling). The thicknesses of the UZ and the clay-with-flints (CwF) layer that overlie the Chalk, vary along the 1200 m length of the quarry.

From 2012, the chemical evolution and the flow variability of groundwater are characterized for 16 sites with different UZ properties. Chalk groundwater has highly spatially variable hydrodynamic behaviour and geochemical properties. A peak of contaminants is observed in the UZ around 15–20 m depth, with differing behaviours of nitrate and atrazine. The downward matrix water velocity is estimated to be from 0.3 to over 0.72 m a
−1
, and the water table is mainly composed of ‘old’ water resulting from transfer through the matrix. A thick CwF layer modifies (1) the transfer processes: surface water is stored in a sort of ‘near-surface perched groundwater’, the infiltration is concentrated by preferential pathways; and (2) water quality: pesticides degradation processes occur in the perched groundwater.
Squalene Epoxidase Metabolic Dependency Is a Targetable Vulnerability in Castration-Resistant Prostate Cancer
Authors: Shangguan Xun , Ma Zehua , Yu Minghao , Ding Jie , Xue Wei , Qi Jun 
Published: June 2022

Abstract

Considering the dismal prognosis of castration-resistant prostate cancer (CRPC), it is critical to identify novel therapeutic targets in this disease. Malignant cells have metabolic dependencies distinct from their healthy counterparts, resulting in therapeutic vulnerabilities. Although PTEN and TP53 are the most frequently comutated or codeleted driver genes in lethal CRPC, the metabolic dependencies underlying PTEN/p53 deficiency-driven CRPC for therapeutic intervention remain largely elusive. In this study, PTEN/p53 deficient tumors were determined to be reliant on cholesterol metabolism. Moreover, PTEN/p53 deficiency transcriptionally upregulated squalene epoxidase (SQLE) via activation of sterol regulatory element-binding protein 2 (SREBP2). In addition, PTEN deficiency enhanced the protein stability of SQLE by inhibiting the PI3K/Akt/GSK3β-mediated proteasomal pathway. Consequently, SQLE increased cholesterol biosynthesis to facilitate tumor cell growth and survival. Pharmacologic blockade of SQLE with FR194738 profoundly suppressed the invasive program of CRPC. Collectively, these results demonstrate a synergistic relationship between SQLE and PTEN/p53 deficiency in CRPC development and progression. Therefore, pharmacologic interventions targeting SQLE may hold promise for the treatment of patients with CRPC.

Significance:
This study reveals PTEN and p53 deficiency confers a dependence on SQLE-mediated cholesterol metabolism, providing insights for new therapeutic strategies for treating castration-resistant prostate cancer.
Phase I Trial of a Novel Anti-HER2 Antibody–Drug Conjugate, ARX788, for the Treatment of HER2-Positive Metastatic Breast Cancer
Authors: Zhang Jian , Ji Dongmei , Shen Weina , Xiao Qin , Gu Yajia , O'Shaughnessy Joyce , Hu Xichun 
Published: June 2022

Abstract

Purpose:
ARX788 is a novel antibody–drug conjugate (ADC) comprised of an anti-HER2 mAb and a potent tubulin inhibitor payload AS269 that is site-specifically conjugated to the antibody via a nonnatural amino acid incorporated into the antibody. Herein, we present the results of a phase I study of the safety, pharmacokinetics, and antitumor activity of ARX788 in patients with HER2-positive metastatic breast cancer (MBC).

Patients and Methods:
Patients with HER2-positive MBC received ARX788 at doses of 0.33, 0.66, 0.88, 1.1, 1.3, or 1.5 mg/kg every 3 weeks, or 0.88, 1.1, or 1.3 mg/kg every 4 weeks. The dose-limiting toxicity (DLT) was assessed for 84 days for pulmonary toxicity and at a duration of one cycle (21 or 28 days) for other toxicities.

Results:
In total, 69 patients were enrolled. No DLT or drug-related deaths occurred. Most patients (67/69; 97.1%) experienced at least one treatment-related adverse event (TRAE). Common (≥ 30%) TRAEs included an increase in aspartate aminotransferase, an increase in alanine aminotransferase, corneal epitheliopathy, alopecia, hypokalemia, interstitial lung disease (ILD)/pneumonitis, and an increase in aldosterone. While 34.8% of participants experienced ILD/pneumonitis, only 2 had a severity of grade 3. At 1.5 mg/kg every 3 weeks, the recommended phase II dose, the objective response rate was 65.5% [19/29, 95% confidence interval (CI), 45.7–82.1], the disease control rate was 100% (95% CI, 81.2–100), and the median progression-free survival was 17.02 months (95% CI, 10.09–not reached).

Conclusions:
ARX788 demonstrated a manageable safety profile with promising preliminary signs of activity in patients with HER2-positive MBC who progressed on prior anti-HER2 therapies.
Systemic and Oligo-Acquired Resistance to PD-(L)1 Blockade in Lung Cancer
Authors: Schoenfeld Adam J. , Rizvi Hira A. , Memon Danish , Shaverdian Narek , Bott Matthew J. , Sauter Jennifer L. , Tsai C. Jillian , Lihm Jayon , Hoyos David , Plodkowski Andrew J. , Perez-Johnston Rocio , Sawan Peter , Egger Jacklynn V. , Greenbaum Benjamin D. , Rimner Andreas , Riely Gregory J. , Rudin Charles M. , Rusch Valerie W. , Gomez Daniel R. , Hellmann Matthew D. 
Published: June 2022

Abstract

Purpose:
Clinical patterns and the associated optimal management of acquired resistance to PD-(L)1 blockade are poorly understood.

Experimental Design:
All cases of metastatic lung cancer treated with PD-(L)1 blockade at Memorial Sloan Kettering were reviewed. In acquired resistance (complete/partial response per RECIST, followed by progression), clinical patterns were distinguished as oligo (OligoAR ≤ 3 lesions of disease progression) or systemic (sAR). We analyzed the relationships between patient characteristics, burden/location of disease, outcomes, and efficacy of therapeutic interventions.

Results:
Of 1,536 patients, 312 (20%) had an initial response and 143 developed AR (9% overall, 46% of responders). OligoAR was the most common pattern (80/143, 56%). Baseline tumor mutational burden, depth of response, and duration of response were significantly increased in oligoAR compared with sAR (P &lt; 0.001, P = 0.03, P = 0.04, respectively), whereas baseline PD-L1 and tumor burden were similar. Post-progression, oligoAR was associated with improved overall survival (median 28 months vs. 10 months, P &lt; 0.001) compared with sAR. Within oligoAR, post-progression survival was greater among patients treated with locally-directed therapy (e.g., radiation, surgery; HR, 0.41; P = 0.039). Fifty-eight percent of patients with oligoAR treated with locally-directed therapy alone are progression-free at last follow-up (median 16 months), including 13 patients who are progression-free more than 2 years after local therapy.

Conclusions:
OligoAR is a common and distinct pattern of acquired resistance to PD-(L)1 blockade compared with sAR. OligoAR is associated with improved post-progression survival and some cases can be effectively managed with local therapies with durable benefit.
Phase II Study of TQB2450, a Novel PD-L1 Antibody, in Combination with Anlotinib in Patients with Locally Advanced or Metastatic Soft Tissue Sarcoma
Authors: Liu Jiayong , Gao Tian , Tan Zhichao , Li Shu , Xu Jie , Bai Chujie , Xue Ruifeng , Xie Lu , Zhang Lu , Fan Zhengfu , Guo Wei 
Published: June 2022

Abstract

Purpose:
To explore the efficacy and safety of TQB2450 combined with anlotinib in patients with locally advanced or metastatic soft-tissue sarcoma (LA/M STS).

Patients and Methods:
This was a single arm phase II study (TQB2450-Ib-02 study) performed at two hospitals in China to assess the potency of TQB2450 combined with anlotinib in patients with LA/M STS. Patients were previously unresponsive to at least one chemotherapy regimen. Anlotinib (12 mg every day) was administered orally from day 1 to day 14 every 3 weeks. TQB2450 was administered by intravenous infusion at 1,200 mg on day 1 every 3 weeks. The primary endpoint was the objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety.

Results:
Between January 2019 and June 2020, 30 patients were enrolled. The ORR was 36.67% and the DCR was 76.67%. The median PFS was 7.85 months [95% confidence interval (CI), 2.89–23.06] and the median OS was not reached [95% CI, 10.58–not estimable (NE)]. Among the patients with alveolar soft part sarcoma (ASPS; 12/30, 40%), the ORR was 75% and the median PFS was 23.06 months (95% CI, 8.97–NE). The most common treatment related adverse events were hypothyroidism (76.67%), hypertriglyceridemia (63.33%), hypercholesterolemia (60.00%), and elevated blood lactate dehydrogenase (53.33%).

Conclusions:
The study showed the promising activity in patients with ASPS, also indicating the trend of treatment efficacy in other sarcomas. The toxicity was tolerable. More studies with larger sample size and controlled arm were warranted.
Comparison of Echocardiographic Changes Between Surgery and Medication Treatment in Patients With Primary Aldosteronism
Authors: Ueda Tomomi , Tsurutani Yuya , Osada Jun , Inoue Kosuke , Hoshino Yoshitomo , Ono Masato , Nakai Kazuki , Saito Jun , Yumoto Kazuhiko , Nishikawa Tetsuo 
Published: June 2022

Background
Primary aldosteronism can cause cardiac dysfunction, including left ventricular hypertrophy, left ventricular diastolic dysfunction, and left atrial enlargement. A few studies have compared the cardioprotective effects between surgery and medication for primary aldosteronism, although most have not adjusted for baseline disease status. In this study, we investigated the difference in cardiovascular outcomes between surgery and medication treatment for primary aldosteronism after adjusting for baseline clinical characteristics, including aldosterone level and pretreatment echocardiographic information.

Methods and Results

We retrospectively analyzed 220 patients diagnosed with primary aldosteronism who underwent adrenalectomy (n=144) or medication treatment (n=76) between 2009 and 2019. Echocardiographic changes were evaluated pretreatment and 1 year posttreatment. The surgery group had lower potassium, lower plasma renin activity, and higher plasma aldosterone concentration than the medication group, indicating a severe primary aldosteronism phenotype in the former. The decrease in left ventricular mass index after treatment was significantly greater in the surgery group than in the medication group (
P
=0.047). However, this relationship was not noted after multivariable regression analysis (standard β=−0.08,
P
=0.17). Additionally, decreased parameter values related to left ventricular diastolic dysfunction and left atrial enlargement were not different between the groups. Pretreatment echocardiographic values were most associated with changes in all echocardiographic parameters. The findings were consistent in the propensity score‐matched analysis.

Conclusions
This study's findings suggest that there is no difference in cardioprotective efficacy between surgical and medication treatment under similar disease severity; however, it should be considered that several study participants with severe hyperaldosteronism were managed surgically.
B‐Type Natriuretic Peptide and Long‐Term Cardiovascular Mortality in Patients With Coronary Heart Disease
Authors: Stewart Ralph A. H. , Kirby Adrienne , White Harvey D. , Marschner Simone L. , West Malcolm , Thompson Peter L. , Sullivan David , Janus Edward , Hunt David , Kritharides Leonard , Keech Anthony , Simes John , Tonkin Andrew M. 
Published: June 2022

Background
The plasma concentration of B‐type natriuretic peptide (BNP) is a strong predictor of adverse cardiovascular events. The aim of this study was to determine whether the association between plasma BNP concentration and cardiovascular mortality is sustained or diminishes with increasing time after BNP is measured.

Methods and Results

Six thousand seven hundred forty patients with a history of myocardial infarction or unstable angina who participated in the LIPID (Long‐Term Intervention with Pravastatin in Ischemic Disease) trial had plasma BNP concentration measured at baseline and after 1 year. Associations with cardiovascular mortality were evaluated in landmark analyses 1 to <5, 5 to <10, and 10 to 16 years after randomization. There were 1640 cardiovascular deaths. The cardiovascular mortality rate increased progressively from 10.2 to 19.1 to 26.3/1000 patient‐years from 1 to <5, 5 to <10, and 10 to 16 years after baseline, respectively. The average of baseline and 1‐year BNP concentration was more strongly associated with cardiovascular mortality compared with baseline or 1‐year BNP only. The hazard ratio (HR) for cardiovascular death associated with each doubling of average BNP concentration was similar during years 1 to <5 (HR, 1.53 [95% CI, 1.44–1.63]), years 5 to <10 (HR, 1.52 [95% CI, 1.44–1.60]), and years 10–16 (HR, 1.43 [95% CI, 1.36–1.50]),
P
<0.0001 for all.

Conclusions
BNP concentration remains an independent predictor of cardiovascular mortality more than a decade after it is measured. Because of random variation in plasma concentrations, the average of >1 BNP measurement improves long‐term risk prediction.
Bidirectional Longitudinal Relationships Between Arterial Stiffness and Hypertension Are Independent of Those Between Arterial Stiffness and Diabetes: A Large‐Scale Prospective Observational Study in Employees of a Japanese Company
Authors: Nakano Hiroki , Shiina Kazuki , Takahashi Takamichi , Fujii Masatsune , Iwasaki Yoichi , Matsumoto Chisa , Yamashina Akira , Chikamori Taishiro , Tomiyama Hirofumi 
Published: June 2022

Background
Hypertension and diabetes frequently coexist; however, it has not yet been clarified if the bidirectional longitudinal relationships between arterial stiffness and hypertension are independent of those between arterial stiffness and diabetes.

Methods and Results

In this 16‐year prospective observational study, 3960 middle‐aged employees of a Japanese company without hypertension/diabetes at the study baseline underwent annual repeated measurements of blood pressure, serum glycosylated hemoglobin A
1c
levels, and brachial‐ankle pulse wave velocity. By the end of the study period, 664, 779, 154, and 406 subjects developed hypertension, prehypertension, diabetes, and prediabetes, respectively. Increased brachial‐ankle pulse wave velocity at the baseline was associated with a significant odds ratio (per 1 SD increase) for new onset of prehypertension/hypertension with (2.45/3.28;
P
<0.001) or without (2.49/2.76;
P
<0.001) coexisting prediabetes/diabetes, but not for new onset of prediabetes/diabetes without coexisting hypertension. Analyses using the latent growth curve model confirmed the bidirectional relationships between brachial‐ankle pulse wave velocity and hypertension, but no such relationship was observed between brachial‐ankle pulse wave velocity and abnormal glucose metabolism.

Conclusions
In middle‐aged employees of a Japanese company, while bidirectional relationships were found to exist between increased arterial stiffness and hypertension, such a relationship was not found between increased arterial stiffness and diabetes. Therefore, it appears that increased arterial stiffness may be associated with the development of hypertension but not with that of diabetes.
Utility of Updated Japanese Circulation Society Guidelines to Diagnose Isolated Cardiac Sarcoidosis
Authors: Sato Kimi , Kawamatsu Naoto , Yamamoto Masayoshi , Machino‐Ohtsuka Tomoko , Ishizu Tomoko , Ieda Masaki 
Published: June 2022

Background
In the population with cardiac sarcoidosis (CS), approximately one third lacks extracardiac involvement and is considered to have isolated CS. Recently, the Japanese Circulation Society updated the diagnostic criteria for CS, providing a methodology for diagnosing isolated CS. We aimed to assess the characteristics of isolated CS diagnosed using a multimodal imaging approach according to the updated Japanese Circulation Society guidelines.

Methods and Results

We retrospectively identified 161 consecutive patients who underwent 18F‐fluorodeoxyglucose positron emission tomography for suspected CS between 2012 and 2019. According to the guidelines, patients were classified as having CS with extracardiac involvement, isolated CS, or no CS. We compared the characteristics of multimodality imaging and the prevalence of major adverse cardiovascular events. The Japanese Circulation Society criteria classified 28 patients (17%) as having CS with 4 (2%) with histological confirmation, 21 (13%) as isolated CS, and 112 (70%) as no CS. Compared with CS, isolated CS showed higher left ventricular volume and reduced left ventricular ejection fraction (
P
<0.01 for all). During the median follow‐up period of 522 days, 24 patients had major adverse cardiovascular events. Isolated CS (hazard ratio, 3.35; [95% CI, 1.08–10.39],
P
=0.036) was independently associated with major adverse cardiovascular events after adjusting for reduced left ventricular ejection fraction and steroid. In the subgroup of 41 patients with serial 18F‐fluorodeoxyglucose positron emission tomography evaluation, only updated CS criteria were associated with improvement in myocardial inflammation on 18F‐fluorodeoxyglucose positron emission tomography.

Conclusions
Isolated CS detected using the updated Japanese Circulation Society guidelines was associated with poor event‐free survival and should be managed with caution.