bluuebunny/crossref_metadata_2025_split huggingface dataset:
Application of Artificial Intelligence in Radiotherapy of Nasopharyngeal Carcinoma with Magnetic Resonance Imaging
Authors: Zhao Wanlu , Zhang Desheng , Mao Xinjian 
Published: February 2022

The value of automatic organ-at-risk outlining software for radiotherapy is based on artificial intelligence technology in clinical applications. The accuracy of automatic segmentation of organs at risk (OARs) in radiotherapy for nasopharyngeal carcinoma was investigated. In the automatic segmentation model which is proposed in this paper, after CT scans and manual segmentation by physicians, CT images of 147 nasopharyngeal cancer patients and their corresponding outlined OARs structures were selected and grouped into a training set (115 cases), a validation set (12 cases), and a test set (20 cases) by complete randomization. Adaptive histogram equalization is used to preprocess the CT images. End-to-end training is utilized to improve modeling efficiency and an improved network based on 3D Unet (AUnet) is implemented to introduce organ size as prior knowledge into the convolutional kernel size design to enable the network to adaptively extract features from organs of different sizes, thus improving the performance of the model. The DSC (Dice Similarity Coefficient) coefficients and Hausdorff (HD) distances of automatic and manual segmentation are compared to verify the effectiveness of the AUnet network. The mean DSC and HD of the test set were 0.86 ± 0.02 and 4.0 ± 2.0 mm, respectively. Except for optic nerve and optic cross, there was no statistical difference between AUnet and manual segmentation results (

P

> 0.05). With the introduction of the adaptive mechanism, AUnet can achieve automatic segmentation of the endangered organs of nasopharyngeal carcinoma based on CT images more accurately, which can substantially improve the efficiency and consistency of segmentation of doctors in clinical applications.
Targeting the P53 Protein for Cancer Therapies: The Translational Impact of P53 Research
Authors: Levine Arnold J. 
Published: February 2022

Abstract
It is only recently that drugs targeting K-RAS and Tp53 missense mutations have been developed, and along with the allele specific nature of some of these drugs comes the possibility of combining them with the immunologic therapies for cancers. It has taken about 40 years since their discoveries to understand the pathways they command, how they function, and how they interact with the environment of the cells they control. This communication focuses on the transfer of some of the hard won information about the p53 protein, its mutations, structures, and activities learned in the basic science laboratory and translated to the clinic.
Genetic Polymorphisms and Correlation with Treatment-Induced Cardiotoxicity and Prognosis in Patients with Breast Cancer
Authors: Peddi Parvin F. , Fasching Peter A. , Liu Duan , Quinaux Emmanuel , Robert Nicholas J. , Valero Vicente , Crown John , Falkson Carla , Brufsky Adam , Cunningham Julie M. , Weinshilboum Richard M. , Pienkowski Tadeusz , Eiermann Wolfgang , Martín Miguel , Bee Valerie , Wang Xiaoyan , Wang Liewei , Yang Eric , Slamon Dennis J. , Hurvitz Sara A. 
Published: February 2022

AbstractPurpose:Cardiac toxicity is a serious potential complication of HER2-directed therapies and anthracyclines. HER2 codon 655 and SLC28A3 gene polymorphisms have been reported to be associated with cardiac toxicity from anti-HER2 and anthracycline therapy, respectively. Association of the polymorphism at HER2 codon 655 with prognosis has also been reported.Experimental Design:Whole blood samples from patients treated on a randomized adjuvant breast cancer trial (BCIRG-006) that compared chemotherapy with or without trastuzumab plus either anthracycline or nonanthracycline chemotherapy were tested for genetic polymorphisms in HER2 codon 655 and SLC28A3. Genotypes were correlated with cardiac function and disease-free survival (DFS) outcomes.Results:Of 3,222 patients enrolled in BCIRG-006, 662 patient samples were successfully genotyped for the rs1136201 allele in HER2 (codon 655): 424 (64%) were AA, 30 (4.5%) were GG, and 208 (31%) were AG genotype. In addition, 665 patient samples were successfully genotyped for the rs7853758 allele in the SLC28A3 gene: 19 (3%) were AA, 475 (71%) were GG, and 171 (26%) were AG genotype. Follow-up time was 10 years. No correlation between DFS, cardiac event rate, or mean left ventricular ejection fraction (LVEF) and rs1136201 genotype was seen in the trastuzumab-treated or non–trastuzumab-treated patients. Moreover, mean LVEF and cardiac event rates were similar in all rs7853758 genotype groups treated with anthracycline-based therapy.Conclusions:In the largest study to date to evaluate whether two polymorphisms are associated with DFS and/or cardiac toxicity in HER2-positive breast cancer treated with trastuzumab and/or anthracyclines, we observed no correlation.
Phase Ib Trial of the Combination of Imatinib and Binimetinib in Patients with Advanced Gastrointestinal Stromal Tumors
Authors: Chi Ping , Qin Li-Xuan , Camacho Niedzica , Kelly Ciara M. , D'Angelo Sandra P. , Dickson Mark A. , Gounder Mrinal M. , Keohan Mary L. , Movva Sujana , Nacev Benjamin A. , Rosenbaum Evan , Thornton Katherine A. , Crago Aimee M. , Francis Jasmine H. , Martindale Moriah , Phelan Haley T. , Biniakewitz Matthew D. , Lee Cindy J. , Singer Samuel , Hwang Sinchun , Berger Michael F. , Chen Yu , Antonescu Cristina R. , Tap William D. 
Published: February 2022

Abstract

Purpose:
This phase Ib trial was designed to evaluate the safety and early efficacy signal of the combination of imatinib and binimetinib in patients with imatinib-resistant advanced gastrointestinal stromal tumors (GISTs).

Patients and Methods:
This trial used a standard 3 + 3 design to determine the recommended phase II dose (RP2D). Additional patients were enrolled on an expansion cohort at the RP2D enriching for succinate dehydrogenase (SDH)-deficient GISTs to explore potential efficacy.

Results:
The trial enrolled nine patients in the dose-escalation cohort and 14 in the dose-expansion cohort including six with SDH-deficient GISTs. Imatinib 400 mg daily with binimetinib 45 mg twice daily was established as the RP2D. Dose-limiting toxicity (DLT) was asymptomatic grade 4 creatinine phosphokinase (CPK) elevation. The most common non-DLT grade 3/4 toxicity was asymptomatic CPK elevation (69.6%). Other common ≥grade 2 toxicities included peripheral edema (17.4%), acneiform rash (21.7%), anemia (30.4%), hypophosphatemia (39.1%), and aspartate aminotransferase (AST) increase (17.4%). Two serious adverse events occurred (grade 2 dropped head syndrome and grade 3 central retinal vein occlusion). No unexpected toxicities were observed. Limited clinical activity was observed in KIT-mutant GIST. For SDH-deficient GISTs, one of five had confirmed RECIST1.1 partial response (PR). The median progression-free survival (mPFS) in patients with SDH-deficient GIST was 45.1 months [95% confidence interval (CI), 15.8–not estimable (NE)]; the median overall survival (mOS) was not reached (95% CI, 31.6 months–NE). One patient with a refractory metastatic SDH-deficient GIST had an exceptional pathologic response and durable clinical benefit.

Conclusions:
The combination of imatinib and binimetinib is safe with manageable toxicity and has encouraging activity in SDH-deficient but not imatinib-refractory KIT/PDGFRA-mutant GISTs. The observed clinical benefits provide a motivation for a larger trial of the combination strategy in SDH-deficient GISTs.
Phase I/II Trial of Enzalutamide and Mifepristone, a Glucocorticoid Receptor Antagonist, for Metastatic Castration-Resistant Prostate Cancer
Authors: Serritella Anthony V. , Shevrin Daniel , Heath Elisabeth I. , Wade James L. , Martinez Elia , Anderson Amanda , Schonhoft Joseph , Chu Yen-Lin , Karrison Theodore , Stadler Walter M. , Szmulewitz Russell Z. 
Published: February 2022

AbstractPurpose:Although androgen deprivation therapy (ADT) and androgen receptor (AR) signaling inhibitors are effective in metastatic prostate cancer, resistance occurs in most patients. This phase I/II trial assessed the safety, pharmacokinetic impact, and efficacy of the glucocorticoid receptor (GR) antagonist mifepristone in combination with enzalutamide for castration-resistant prostate cancer (CRPC).Patients and Methods:One hundred and six patients with CRPC were accrued. Phase I subjects were treated with enzalutamide monotherapy at 160 mg per day for 28 days to allow steady-state accumulation. Patients then entered the dose escalation combination portion of the study. In phase II, patients were randomized 1:1 to either receive enzalutamide alone or enzalutamide plus mifepristone. The primary endpoint was PSA progression-free survival (PFS), with radiographic PFS, and PSA response rate (RR) as key secondary endpoints. Circulating tumor cells were collected before randomization for exploratory translational biomarker studies.Results:We determined a 25% dose reduction in enzalutamide, when added to mifepristone, resulted in equivalent drug levels compared with full-dose enzalutamide and was well tolerated. However, the addition of mifepristone to enzalutamide following a 12-week enzalutamide lead-in did not delay time to PSA, radiographic or clinical PFS. The trial was terminated early due to futility.Conclusions:This is the first prospective trial of dual AR–GR antagonism in CRPC. Enzalutamide combined with mifepristone was safe and well tolerated but did not meet its primary endpoint. The development of more specific GR antagonists combined with AR antagonists, potentially studied in an earlier disease state, should be explored.
Efficacy and Safety of Chinese Herbal Medicine Compared With Losartan for Mild Essential Hypertension: A Randomized, Multicenter, Double-Blind, Noninferiority Trial
Authors: Lai Xinxing , Dong Zhenyu , Wu Shengxian , Zhou Xiaohua , Zhang Genming , Xiong Shangquan , Wu Wei , Cao Rui , Wang Xiaolong , Hua Qi , Du Jinhang , Fan Jinying , Mao Jingyuan , Jiang Weimin , Yuan Huishu , Chen Yushan , Xu Yong , Li Zhanquan , Zhang Jun , Dong Guiying , Zhen Hui , Ding Ru , Wu Zonggui , Gao Ying 
Published: February 2022

Background:
Hypertension is one of the most challenging public health problems worldwide. Previous studies suggested that the Songling Xuemaikang capsule (SXC)—a Chinese herbal formula—was effective for essential hypertension. However, the efficacy of SXC monotherapy for hypertension remains unclear. We aimed to compare the blood pressure (BP)–lowering efficacy and safety of SXC versus losartan in patients with essential hypertension.

Methods:
In this multicenter, randomized, double-blind, noninferiority trial in China, patients 18 to 65 years of age with mild essential hypertension were randomly allocated to receive either SXC or losartan for 8 weeks. The primary outcome was the change in sitting diastolic BP from baseline to 8 weeks, with a predefined noninferiority margin of −2.5 mm Hg.

Results:

Of the 755 patients who entered a 2-week run-in period, 628 patients (327 women and 301 men; mean [SD] age, 52.6 [9.2] years) were randomly assigned to the SXC (n=314) or losartan (n=314) group. The primary analysis based on the intention-to-treat principle showed that the change in diastolic BP from baseline to 8 weeks was similar between the SXC and losartan groups (−7.9 [8.0] versus −8.1 [7.9]). The lower boundary of 95% CI (mean difference, −0.24 [95% CI, −1.51 to 1.03]) was above the margin of −2.5 mm Hg, showing noninferiority. Results were consistent with per-protocol analysis. SXC produced greater improvements in total hypertension symptom score (−5.7 [4.2] versus −5.0 [4.0];
P
=0.020) and total cholesterol (−0.1 [1.0] versus 0.1 [1.2];
P
=0.025). There were no differences between groups in the other BP and patient-reported outcomes. Incidence and severity of adverse events were similar between groups.

Conclusions:
SXC was well tolerated and demonstrated noninferior to losartan in BP lowering in patients with mild hypertension. SXC might be an alternative for mild hypertension, particularly for patients with a preference for natural medicine.

Registration:

URL:
www.chictr.org.cn
; Unique identifier: ChiCTR-IPR-16008108.
Familial Mortality Risks in Patients With Ischemic Stroke: A Swedish Sibling Study
Authors: Zöller Bengt , Pirouzifard MirNabi , Lindgren Magnus P. , Sundquist Jan , Sundquist Kristina 
Published: February 2022

Background:
The influence of familial factors on the prognosis of ischemic stroke (IS) is unknown. This nationwide follow-up study evaluated familial mortality risks of IS among Swedish sibling pairs hospitalized for IS.

Methods:
We linked Swedish nationwide registers for the identification of 1380 Swedish born sibling pairs (2760 cases), where both siblings were hospitalized for first-time IS between 1991 and 2010. Median age was 62 years (range, 26–78 years). Sibling pairs with cancer were excluded. Familial hazard ratios (FHRs) for mortality after first IS hospitalization were determined with Cox regression. The influence of proband survival after IS was categorized as short sibling survival (<1, 2, 3, 4, or 5 years) or long sibling survival (≥1, 2, 3, 4, or 5 years) after IS. FHRs were adjusted for age at onset, sex, education, county, year of diagnosis, days of hospitalization, and comorbidities.

Results:
Short sibling survival (ie, <3 or <4 years) after IS was associated with an adjusted FHR of 1.29 (95% CI, 1.05–1.58) and 1.24 (95% CI, 1.02–1.51), respectively, for overall mortality after IS. Stratified analysis showed that short sibling survival (ie, <2—<5 years) was stronger and significant only among younger individuals (<62 years) and males. Highest FHR for short sibling survival (ie, <4 years) was 1.42 (95% CI, 1.08–1.88) for younger individuals and 1.50 (95% CI, 1.21–1.87) for males. For young male subjects, FHR was 1.80 (95% CI, 1.33–2.46). In the adjusted model, mortality was also associated with sex, education, age at onset, year of diagnosis, days of hospitalization, coronary heart disease, diabetes, dementia, heart failure, obesity, alcoholism, and hyperlipidemia.

Conclusions:
Our results suggest that family history of short survival in siblings after IS is associated with mortality after IS for younger male subjects. Additional studies are needed to characterize possible genetic and nongenetic familial environmental causes of this association.
‘Market Substitution’ in the Context of Climate Litigation
Authors: Dwyer Guy 
Published: February 2022

Abstract
In several countries where climate litigation has challenged the authorization of fossil-fuel extraction developments, resource companies have presented courts with a ‘market substitution’ argument (msa) in support of authorization. In these contexts msa is premised on the notion that if the fossil-fuel development in question is not approved, another one (or, broadly, increased production) elsewhere leading to similar amounts of greenhouse gas emissions will be approved to meet market demand. Some courts have accepted msa. Others have rejected it. In several cases, and in the academic literature, the argument has been rejected on one or more of four grounds: logic or law; evidence; economics; and jurisprudence. These rejections are all questionable. I argue that msa is not illogical or flawed in law, and therefore that it cannot be dismissed on a priori logical or legal grounds. I further argue that it is capable of being made out on evidence and does not suffer from economic or jurisprudential flaws. Courts and academic commentators should not be too quick to dismiss it.
Adaptation to Climate Change Risks and Regulation Through Insurance: The Case of China
Authors: He Qihao , Faure Michael 
Published: February 2022

Abstract
Insurance transfers and spreads risk, including climate change risk. It can provide direct financial protection to those affected by climate change. It has received attention for its regulatory function in influencing policyholder behaviour. This is sometimes called ‘insurance as governance’, a form of private contractual regulation. This article examines the functions and limits of insurance in climate-related compensation and in governing complex climate-related risks by describing the variable performance of such insurance schemes in China. We show that insurance can perform a useful regulatory function in adaptation to climate change. However, we equally make clear that insurance can play this role only if an appropriate regulatory framework is provided. The case of China illustrates how the very lack of such a regulatory framework limits the role that insurers can play in climate change adaptation.
Medical Missionaries and the Invention of the “Serai Hospital” in North-western British India
Authors: Honarmand Ebrahimi Sara 
Published: February 2022

Abstract
This article sets out to challenge the assumption that the pavilion plan hospital became an international standard by the late nineteenth century. This assumption is based on evidence of just a few, mainly British, state and military hospitals. Hospitals constructed by non-British European empires and those by North Americans in the colonised world have been excluded. Moreover, indigenous people in many parts of colonial territories encountered so-called Western biomedical services for the first time in Protestant mission hospitals rather than in state or military hospitals. The article examines several case hospitals built by the Church Missionary Society (cms) in north-western British India and offers a framework for analysing the architecture of Protestant mission hospitals that goes “beyond” a postcolonial approach. Drawing on conceptual tools offered by the field of the history of emotions, the article argues that the missionaries remade the pavilion plan and invented a new form, namely the Serai hospital, to gain local people’s “trust” and “affection”. This strategy was less about “pacifying” the patients and more about increasing their numbers. Indeed, medical missions were “emotional set-ups” that served to change the sensory relationship between missionaries and local people.
Destructive Interference of ENSO on North Pacific SST and North American Precipitation Associated with Aleutian Low Variability
Authors: Larson Sarah M. , Okumura Yuko , Bellomo Katinka , Breeden Melissa L. 
Published: February 2022

Abstract
Identifying the origins of wintertime climate variations in the Northern Hemisphere requires careful attribution of the role of El Niño–Southern Oscillation (ENSO). For example, Aleutian low variability arises from internal atmospheric dynamics and is remotely forced mainly via ENSO. How ENSO modifies the local sea surface temperature (SST) and North American precipitation responses to Aleutian low variability remains unclear, as teasing out the ENSO signal is difficult. This study utilizes carefully designed coupled model experiments to address this issue. In the absence of ENSO, a deeper Aleutian low drives a positive Pacific decadal oscillation (PDO)-like SST response. However, unlike the observed PDO pattern, a coherent zonal band of turbulent heat flux–driven warm SST anomalies develops throughout the subtropical North Pacific. Furthermore, non-ENSO Aleutian low variability is associated with a large-scale atmospheric circulation pattern confined over the North Pacific and North America and dry precipitation anomalies across the southeastern United States. When ENSO is included in the forcing of Aleutian low variability in the experiments, the ENSO teleconnection modulates the turbulent heat fluxes and damps the subtropical SST anomalies induced by non-ENSO Aleutian low variability. Inclusion of ENSO forcing results in wet precipitation anomalies across the southeastern United States, unlike when the Aleutian low is driven by non-ENSO sources. Hence, we find that the ENSO teleconnection acts to destructively interfere with the subtropical North Pacific SST and southeastern United States precipitation signals associated with non-ENSO Aleutian low variability.
Decadal Background for Active Extreme Drought Episodes in the Decade of 2010–19 over Southeastern Mainland Asia
Authors: Wang Lin , Huang Gang , Chen Wen , Wang Ting , Chotamonsak Chakrit , Limsakul Atsamon 
Published: February 2022

AbstractSevere and extreme drought in southeastern mainland Asia (SEMA) worsened drastically in 2010–19, occurring more than twice as frequently as in the preceding decade. It is found that the spring rainfall has undergone a concordant positive-to-negative transition with the turning point at 2010, and can explain 43% of the overall regime shift toward exaggerated severely dry condition. Associated with the decadal precipitation change, the anomalous northeasterlies prevail over SEMA, resulting in weakened eastward moisture propagation from the Indian Ocean as well as enhanced divergence. Meanwhile, there is downward motion over SEMA. This circulation pattern is remotely forced by a teleconnection from the tropical western Indian Ocean (TWI) SST. TWI SST is negatively correlated with SEMA precipitation and highlights a regime shift around 2010, after which the TWI has persistent warm SST helping to maintain deficient SEMA precipitation. In terms of the physical mechanism, the heating in the TWI warms the troposphere aloft and emanates wedge-shaped Kelvin waves with their northeast flank traversing SEMA, where friction-driven northeasterly low-level wind and divergence emerge to block moisture penetration from the Indian Ocean. The low-level divergence is followed by descending motion in SEMA, suppressing convection and rainfall. Further, the simulated structure forced by TWI SST alone bears a close resemblance to the observed evidence, confirming the critical role of the TWI. Finally, it is shown that ENSO and its diversity have a modulating effect on SEMA precipitation as well as on the coupling between TWI SST and SEMA precipitation, during both the previous winter and the concurrent spring.Significance StatementIn the last decade, a sequence of extreme droughts has swept southeastern mainland Asia (SEMA), resulting in tremendous losses. Instead of examining individual extreme cases, this study aims to advance the understanding of how the active extreme drought episodes can be modulated by the decadal background and to reveal the underlying physical mechanisms. The results suggest that decadal change can explain 43% of the overall regime shift toward more extreme dry conditions, and that the sea surface temperature in the tropical west Indian Ocean has a profound impact. The knowledge obtained here has benefits for estimation of overall risks to extreme drought hazards and highlights the future work direction that skillful decadal prediction is crucial for robust planning in an uncertain climate.