bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictable Clinical Benefits without Evidence of Synergy in Trials of Combination Therapies with Immune-Checkpoint Inhibitors
Authors: Palmer Adam C. , Izar Benjamin , Hwangbo Haeun , Sorger Peter K. 
Published: January 2022

Abstract

Purpose:
Combinations of immune-checkpoint inhibitors (ICI) with other cancer therapies have been approved for advanced cancers in multiple indications, and numerous trials are under way to test new combinations. However, the mechanisms that account for the superiority of approved ICI combinations relative to their constituent monotherapies remain unknown.

Experimental Design:
We analyzed 13 phase III clinical trials testing combinations of ICIs with each other or other drugs in patients with advanced melanoma and lung, breast, gastric, kidney, and head and neck cancers. The clinical activity of the individual constituent therapies, measured in the same or a closely matched trial cohort, was used to compute progression-free survival (PFS) curves expected under a model of independent drug action. To identify additive or synergistic efficacy, PFS expected under this null model was compared with observed PFS by Cox regression.

Results:
PFS elicited by approved combination therapies with ICIs could be accurately predicted from monotherapy data using the independent drug action model (Pearson r = 0.98, P &lt; 5 × 10−9, N = 4,173 patients, 8 types of cancer). We found no evidence of drug additivity or synergy except in one trial in which such interactions might have extended median PFS by 9 days.

Conclusions:
Combining ICIs with other cancer therapies affords predictable and clinically meaningful benefit by providing patients with multiple chances of response to a single agent. Conversely, there exists no evidence in phase III trials that other therapies interact with and enhance the activity of ICIs. These findings can inform the design and testing of new ICI combination therapies while emphasizing the importance of developing better predictors (biomarkers) of ICI response.
The Phase II MutHER Study of Neratinib Alone and in Combination with Fulvestrant in HER2-Mutated, Non-amplified Metastatic Breast Cancer
Authors: Ma Cynthia X. , Luo Jingqin , Freedman Rachel A. , Pluard Timothy J. , Nangia Julie R. , Lu Janice , Valdez-Albini Frances , Cobleigh Melody , Jones Jason M. , Lin Nancy U. , Winer Eric P. , Marcom P. Kelly , Thomas Shana , Anderson Jill , Haas Brittney , Bucheit Leslie , Bryce Richard , Lalani Alshad S. , Carey Lisa A. , Goetz Matthew P. , Gao Feng , Kimmick Gretchen , Pegram Mark D. , Ellis Matthew J. , Bose Ron 
Published: January 2022

AbstractPurpose:HER2 mutations (HER2mut) induce endocrine resistance in estrogen receptor–positive (ER+) breast cancer.Patients and Methods:In this single-arm multi-cohort phase II trial, we evaluated the efficacy of neratinib plus fulvestrant in patients with ER+/HER2mut, HER2 non-amplified metastatic breast cancer (MBC) in the fulvestrant-treated (n = 24) or fulvestrant-naïve cohort (n = 11). Patients with ER-negative (ER−)/HER2mut MBC received neratinib monotherapy in an exploratory ER− cohort (n = 5).Results:The clinical benefit rate [CBR (95% confidence interval)] was 38% (18%–62%), 30% (7%–65%), and 25% (1%–81%) in the fulvestrant-treated, fulvestrant-naïve, and ER− cohorts, respectively. Adding trastuzumab at progression in 5 patients resulted in three partial responses and one stable disease ≥24 weeks. CBR appeared positively associated with lobular histology and negatively associated with HER2 L755 alterations. Acquired HER2mut were detected in 5 of 23 patients at progression.Conclusions:Neratinib and fulvestrant are active for ER+/HER2mut MBC. Our data support further evaluation of dual HER2 blockade for the treatment of HER2mut MBC.
First-in-Human Dose-Escalation Study of Cyclin-Dependent Kinase 9 Inhibitor VIP152 in Patients with Advanced Malignancies Shows Early Signs of Clinical Efficacy
Authors: Diamond Jennifer R. , Boni Valentina , Lim Emerson , Nowakowski Grzegorz , Cordoba Raul , Morillo Daniel , Valencia Ray , Genvresse Isabelle , Merz Claudia , Boix Oliver , Frigault Melanie M. , Greer Joy M. , Hamdy Ahmed M. , Huang Xin , Izumi Raquel , Wong Harvey , Moreno Victor 
Published: January 2022

Abstract

Purpose:
To report on the first-in-human phase I study of VIP152 (NCT02635672), a potent and highly selective cyclin-dependent kinase 9 (CDK9) inhibitor.

Patients and Methods:
Adults with solid tumors or aggressive non–Hodgkin lymphoma who were refractory to or had exhausted all available therapies received VIP152 monotherapy as a 30-minute intravenous, once-weekly infusion, as escalating doses (5, 10, 15, 22.5, or 30 mg in 21-day cycles) until the MTD was determined.

Results:
Thirty-seven patients received ≥ 1 VIP152 dose, with 30 mg identified as the MTD based on dose-limiting toxicity of grade 3/4 neutropenia. The most common adverse events were nausea and vomiting (75.7% and 56.8%, respectively), all of grade 1/2 severity. Of the most common events, grade 3/4 events occurring in &gt; 1 patient were neutropenia (22%), anemia (11%), abdominal pain (8%), increased alkaline phosphatase (8%), and hyponatremia (8%). Day 1 exposure for the MTD exceeded the predicted minimum therapeutic exposure and reproducibly achieved maximal pathway modulation; no accumulation occurred after multiple doses. Seven of 30 patients with solid tumors had stable disease (including 9.5 and 16.8 months in individual patients with pancreatic cancer and salivary gland cancer, respectively), and 2 of 7 patients with high-grade B-cell lymphoma with MYC and BCL2/BCL6 translocations (HGL) achieved durable complete metabolic remission (ongoing at study discontinuation, after 3.7 and 2.3 years of treatment).

Conclusions:
VIP152 monotherapy, administered intravenously once weekly, demonstrated a favorable safety profile and evidence of clinical benefit in patients with advanced HGL and solid tumors.
SynPathy: Predicting Drug Synergy through Drug-Associated Pathways Using Deep Learning
Authors: Tang Yi-Ching , Gottlieb Assaf 
Published: January 2022

AbstractDrug combination therapy has become a promising therapeutic strategy for cancer treatment. While high-throughput drug combination screening is effective for identifying synergistic drug combinations, measuring all possible combinations is impractical due to the vast space of therapeutic agents and cell lines. In this study, we propose a biologically-motivated deep learning approach to identify pathway-level features from drug and cell lines' molecular data for predicting drug synergy and quantifying the interactions in synergistic drug pairs. This method obtained an MSE of 70.6 ± 6.4, significantly surpassing previous approaches while providing potential candidate pathways to explain the prediction. We further demonstrate that drug combinations tend to be more synergistic when their top contributing pathways are closer to each other on a protein interaction network, suggesting a potential strategy for combination therapy with topologically interacting pathways. Our computational approach can thus be utilized both for prescreening of potential drug combinations and for designing new combinations based on proximity of pathways associated with drug targets and cell lines.Implications:Our computational framework may be translated in the future to clinical scenarios where synergistic drugs are tailored to the patient and additionally, drug development could benefit from designing drugs that target topologically close pathways.
Identifikasi Industri Unggulan untuk Akselerasi Pemulihan Ekonomi di Sulawesi Selatan dan Dampaknya pada Wilayah Lain di Indonesia
Authors: Lestari Wahyu Puji , Ruslam  
Published: January 2022

Perencanaan pembangunan berdasarkan aspek kewilayahan membutuhkan tools untuk menentukan kebijakan kewilayahan. Data Inter Regional Input-Output (IRIO) dapat dimanfaatkan untuk mendukung kebijakan perekonomian suatu wilayah. Tabel IRIO mampu memberikan informasi mengenai struktur ketergantungan sektoral (sectoral interdependency) maupun ketergantungan antarwilayah (regional interdependency). Studi ini dilakukan untuk menganalisis keterkaitan antar industri di Sulawesi Selatan dan menganalisis perekonomian Sulawesi Selatan dan hubungannya dengan wilayah lainnya menggunakan tabel Inter Regional Input-Output (IRIO) 2016 yang telah diterbitkan oleh Badan Pusat Statistik pada tahun 2021 untuk mengidentifikasi industri unggulan dan dampaknya pada wilayah lainnya.Hasil analisis menunjukkan bahwa ada dua industri unggulan di Provinsi Sulawesi Selatan, yaitu Pengadaan Listrik dan Gas dan Industri Pengolahan. Selanjutnya, analisis antar wilayah menunjukkan bahwa shock permintaan akhir di Provinsi Sulawesi Selatan berdampak besar terhadap perekonomian provinsi-provinsi di Pulau Jawa, khususnya DKI Jakarta. Di sisi lain, perekonomian Sulawesi Selatan sangat dipengaruhi oleh shock permintaan akhir di Provinsi Sulawesi Barat. Sulawesi Selatan merupakan salah satu provinsi unggulan. Peluang untuk melakukan akselerasi pemulihan ekonomi dapat dilakukan pada industri unggulan seperti Industri Pengolahan.
Cost-Effectiveness of Coronary Artery Bypass Surgery Versus Medicine in Ischemic Cardiomyopathy: The STICH Randomized Clinical Trial
Authors: Chew Derek S. , Cowper Patricia A. , Al-Khalidi Hussein , Anstrom Kevin J. , Daniels Melanie R. , Davidson-Ray Linda , Li Yanhong , Michler Robert E. , Panza Julio A. , Piña Ileana L. , Rouleau Jean L. , Velazquez Eric J. , Mark Daniel B. ,   on behalf of the STICH Investigators
Published: January 2022

Background:
The STICH Randomized Clinical Trial (Surgical Treatment for Ischemic Heart Failure) demonstrated that coronary artery bypass grafting (CABG) reduced all-cause mortality rates out to 10 years compared with medical therapy alone (MED) in patients with ischemic cardiomyopathy and reduced left ventricular function (ejection fraction ≤35%). We examined the economic implications of these results.

Methods:
We used a decision-analytic patient-level simulation model to estimate the lifetime costs and benefits of CABG and MED using patient-level resource use and clinical data collected in the STICH trial. Patient-level costs were calculated by applying externally derived US cost weights to resource use counts during trial follow-up. A 3% discount rate was applied to both future costs and benefits. The primary outcome was the incremental cost-effectiveness ratio assessed from the US health care sector perspective.

Results:
For the CABG arm, we estimated 6.53 quality-adjusted life-years (95% CI, 5.70–7.53) and a lifetime cost of $140 059 (95% CI, $106 401 to $180 992). For the MED arm, the corresponding estimates were 5.52 (95% CI, 5.06–6.09) quality-adjusted life-years and $74 894 lifetime cost (95% CI, $58 372 to $93 541). The incremental cost-effectiveness ratio for CABG compared with MED was $63 989 per quality-adjusted life-year gained. At a societal willingness-to-pay threshold of $100 000 per quality-adjusted life-year gained, CABG was found to be economically favorable compared with MED in 87% of microsimulations.

Conclusions:
In the STICH trial, in patients with ischemic cardiomyopathy and reduced left ventricular function, CABG was economically attractive relative to MED at current benchmarks for value in the United States.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT00023595.
Perivascular Adipose Tissue Is a Major Source of Nitric Oxide in Saphenous Vein Grafts Harvested via the No‐Touch Technique
Authors: Saito Toshiro , Kurazumi Hiroshi , Suzuki Ryo , Matsunaga Kazumasa , Tsubone Sarii , Lv Bochao , Kobayashi Sei , Nagase Takashi , Mizoguchi Takahiro , Samura Makoto , Suehiro Kotaro , Harada Takasuke , Morikage Noriyasu , Mikamo Akihito , Hamano Kimikazu 
Published: January 2022

Background
Saphenous vein grafts (SVGs) are broadly used in coronary artery bypass grafting despite their inferior patency compared with arterial grafts. Recently, the no‐touch technique (NT), in which an SVG is harvested with a pedicle of perivascular adipose tissue (PVAT) without conduit distension, was shown to improve long‐term patency compared with conventional preparation (CV), wherein outer tissue is removed with distension. The NT was also reportedly associated with reduced atherosclerosis. Although endothelial damage provoked by conventional distension may underlie poor patency when CV is performed, the precise mechanisms underlying the salutary effects of the NT have been unclear.

Methods and Results

Residual SVGs prepared with CV (CV‐SVGs) or NT (NT‐SVGs) were obtained during coronary artery bypass grafting. Nitric oxide (NO
2
−
/NO
3
−
(NO
x
)) levels after 24 hours of tissue culture were quantified. The protein expression and localization were analyzed. The isometric force of SVG strips was measured. NT‐SVGs showed superior NO
x
production to CV‐SVGs. PVAT generated the majority of NO
x
in NT‐SVGs. PVAT highly expressed arginosuccinate synthase 1, a rate‐limiting enzyme in the molecular circuit for NO synthesis, thereby continuously providing the substrate for NO. A substantial level of endothelial NO synthase was also expressed in PVAT. Pharmacological inhibition of arginosuccinate synthase 1 or endothelial NO synthase significantly suppressed the NO
x
production in NT‐SVGs. PVAT induced vasorelaxation through NO production, even in the endothelium‐denuded SVG strips.

Conclusions

Preserving PVAT was predominantly involved in the superior NO
x
production in NT‐SVGs. Since NO plays crucial roles in suppressing atherosclerosis, this mechanism may greatly contribute to the excellent patency in NT‐SVGs.
Monthly Weather Review at 150 Years: Its History, Impact, and Legacy
Authors: Schultz David M. , Potter Sean 
Published: January 2022

Abstract
Monthly Weather Review, one of the oldest continuously published meteorological journals in the world, publishes its 150th volume this year. In January 1873, the U.S. War Department’s Army Signal Service began producing this monthly report summarizing weather across the United States. Its first issue consisted of a one-page narrative of weather conditions and storms and one chart depicting tracks of low pressure centers during that month. In 1891, Monthly Weather Review continued as a government publication with the transfer of the nation’s weather service from the military to the newly established U.S. Weather Bureau. Over time and sometimes erratically, it grew into a scientific journal. In 1974, Monthly Weather Review was transferred to the American Meteorological Society, who continues to publish it to this day (although a 2003 proposal might have ended it). This Historical Review discusses some of the journal’s history and impact, as well as its legacy. This review also compiles for the first time a complete list of Monthly Weather Review editors. The research published within Monthly Weather Review has included highly cited, ground-breaking articles on weather and climate phenomena (e.g., extratropical and tropical cyclones, El Niño–Southern Oscillation, Madden–Julian oscillation), general circulation modeling, and numerical weather prediction. The data published in the early issues have been used—and continue to be used to this day—for a variety of applied research and historical analysis purposes. The composition and content of Monthly Weather Review have changed over the past century and a half, continuing to evolve with the modern publishing landscape, with color figures at no additional cost, open-access articles, open data, and, in the near future, embedded figure animations.
The preservation of synovial fluid using dimethyl sulfoxide
Authors: Pavic Katrina , McGill Vicki , D’Souza Mario , McGill Neil 
Published: January 2022

Background The Royal College of Pathologists of Australasia Quality Assurance Programs runs a Quality Assurance Program for the assessment of synovial fluid crystals. It provides aliquots of synovial fluid to various laboratories. The quality of specimens can deteriorate prior to being examined. We aimed to assess whether the addition of dimethyl sulfoxide (DMSO) to synovial fluid specimens helps maintain cellular morphology. Methods Synovial fluid specimens were obtained from 15 patients. Each specimen was aliquoted into 24 samples, with half having DMSO added at a concentration of 10%. For each specimen, six samples containing DMSO and six samples not containing DMSO were stored at−80°C and room temperature. Samples from each group were examined at 1, 2, 3, 6, 7 and 8 weeks. Comparative Analysis: For each specimen, the final remaining aliquoted samples containing DMSO and not containing DMSO, which were stored at−80°C, were directly compared. Quantitative Analysis: A system for grading cellular morphology and assessing for artefacts and cellular clumping was applied by two independent assessors. Results Comparative Analysis: A significant difference was found between samples containing DMSO and not containing DMSO which were stored at −80°C ( p = .000), in favour of those containing DMSO. Quantitative Analysis: Regarding the combined findings of Assessors 1 and 2 and the grading of cellular morphology, a significant difference was found according to “groups” ( p = .000), in favour of those containing DMSO and stored at−80°C. Conclusions DMSO contributes to the maintenance of cellular morphology in synovial fluid when stored in frozen conditions.
Characteristics and risk factors of retinal vasculopathy in antiphospholipid syndrome
Authors: Xie Zhijuan , Li Hui , Qi Wanting , Li Jing , Wu Chanyuan , Hu Chaojun , Jiang Nan , Wang Qian , Tian Xinping , Li Mengtao , Zhao Jiuliang , Sui Ruifang , Zeng Xiaofeng 
Published: January 2022

Background Retinal vasculopathy including retinal artery occlusion (RAO) or retinal vein occlusion (RVO) was recently found to occur more frequently in antiphospholipid syndrome (APS) patients than non-APS patients. This study aims to investigate the clinical manifestation and risk factors of retinal vasculopathy among APS patients. Methods In this single-center prospective cohort study, we evaluated APS patients with or without retinal vasculopathy during 2018–2020 at Peking Union Medical College Hospital. Clinical variables were compared, and a logistical regression model was built to explore risk factors. Hierarchical cluster analysis using Euclidean distances was applied to identify clusters of variables. Results A total of 310 APS patients (67.4% female, mean age 38.1 years) were included, of whom 18 (5.8%) were diagnosed with retinal vasculopathy (9 with RVO and 9 with RAO). No significant differences were found among most demographic characteristics, clinical manifestations, or antibody profiles. APS-related heart valve disease (odds ratio OR 13.66, 95% confidence interval CI 4.55–40.98), APS nephropathy (OR 12.77, 95% CI 4.04–40.35), and thrombocytopenia (OR 2.63, 95% CI 1.01–6.89) were predictive of retinal vasculopathy. APS-related heart valve disease and nephropathy were also found to be statistically significant predictors in multivariate logistical regression analysis. Non-criteria manifestations were aggregated with retinal vasculopathy from a cluster analysis of variables. Conclusion Patients with APS-related heart valve disease and nephropathy suffered a higher risk of retinal vasculopathy. The underlying mechanisms of aPL-associated retinal vasculopathy may involve thrombotic microangiopathy, leading to poor prognosis and therapeutic changes.
Electroacupuncture alleviates anxiety and modulates amygdala CRH/CRHR1 signaling in single prolonged stress mice
Authors: Zhu Jing , Wang Chang , wang Yu , Guo Chunxia , Lu Pingping , Mou Fangfang , Shao Shuijin 
Published: January 2022

Background: Post-traumatic stress disorder (PTSD) is an anxiety-related psychiatric disorder, manifesting high comorbidity with anxiety disorders. Its underlying neurobiological mechanisms have been associated with hypothalamic–pituitary–adrenal (HPA) axis dysfunction and stress hormones. Corticotropin-releasing hormone (CRH) is a primary stress hormone, expressed in the hypothalamus and amygdala. Electroacupuncture (EA) can improve mood disorders, but its mechanisms have not been fully elucidated. The aim of this study was to observe the effect of EA on PTSD and explore the related mechanisms. Methods: We used single prolonged stress (SPS) mice to establish a PTSD model, and EA was performed after SPS or 7 days later for a week. Then we observed their fear and anxiety-like behavior through cue-induced fear condition tests, open field test and the elevated zero maze. CRH and CRH receptor 1 (CRHR1) protein levels in the amygdala were measured in SPS mice after EA intervention. Results: We found that EA at ST36 and GV20 improved fear and anxiety behavior in SPS mice. The amygdala CRH and CRHR1 protein levels increased in the SPS mice, and this effect was reversed by the EA intervention. CRHR1 inhibition by the CRHR1 antagonist NBI 27914 alleviated anxiety behavior in SPS mice. Conclusion: CRH/CRHR1 signaling in the amygdala may contribute to the anxiolytic effect of EA in SPS mice.
Parental Satisfaction from Telemedicine in the Follow-up of Children Operated for Craniosynostosis during COVID-19 Pandemic
Authors: Kilipiris Evangelos G. , Horn Frantisek , Kolnikova Miroslava , Ochoa Jose Vallejo , Matuskova Olga , Jelovac Drago , Stebel Adam 
Published: January 2022

Objective The current study aimed to evaluate the satisfaction level of parents from telemedicine use in the long-term follow-up of children operated for craniosynostosis during the COVID-19 pandemic. Design A cross-sectional 9-question survey analysis using Qualtrics survey software. Setting An institutional study carried out at a national, tertiary level academic center in the Slovak Republic. Patients All patients operated for non-syndromic and syndromic craniosynostosis in our department, who participated in the virtual postoperative follow-up consultations from March 23, 2020, through July 2, 2021, were included in our series. They were enrolled 498 patients, with the parents of 256 children being responding to the survey. Interventions The survey remained open until July 16, 2021, two weeks after the last virtual consultations. It was delivered to the parents by e-mail to generate closed 5-point Likert scale responses. Results Overall, 72.3% of parents were satisfied with the telemedicine program, and 67.2% found it convenient. Collectively, 89.1% reported that the received instructions were helpful to them. However, only 18.7% of them answered that they would prefer telemedicine consultations in the future. Conclusion The results of this study showed a high satisfaction from the parents during the virtual follow-up of children operated for craniosynostosis. However, despite their positive experience with telemedicine, the vast majority of parents stated that they would prefer in-person visits in the future.