bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-in-Maintenance Therapy for Localized High-Grade Osteosarcoma: An Open-Label Phase I/II Trial of the Anti–PD-L1 Antibody ZKAB001
Authors: Zhou Yan , Yang Qingcheng , Dong Yang , Ji Tong , Zhang Bing , Yang Cheng , Zheng Shuier , Tang Lina , Zhou Chenliang , Qian Guowei , Huang Yujing , Yu Wenxi , Li Hongtao , Wang Yonggang , He Aina , Shen Zan , Bao Qiyuan , Hua Yingqi , Bai Hongyu , Zhao Jiayi , Li Xiaoyi , Dai Xiangrong , Zhang Jianjun , Hu Haiyan , Yao Yang 
Published: December 2022

AbstractPurpose:We investigated the safety and preliminary efficacy of anti–PD-L1 antibody (ZKAB001) as maintenance therapy for localized patients with high-grade osteosarcoma to reduce the risk of recurrence and metastasis.Patients and Methods:This open-label Phase I/II study was divided into dose-escalation Phase I and expansion Phase II. Phase I used a 3+3 design with ZKAB001 at three escalating doses ranging: 5, 10, 15 mg/kg every 2 weeks in 9 patients with localized high-grade osteosarcoma and Phase II tested 10 mg/kg in 12 patients for up to 24 cycles. Primary endpoints were safety and tolerability assessed using CTCAE4.0.3.Results:Between October 2018 and 2019, 21 eligible patients were enrolled and accepted ZKAB001 treatment: 9 in the dose-escalation phase, and 12 in expansion phase. Six patients with disease progression withdrew from this study and follow-up is ongoing. The MTD was not defined in Phase I. All doses had a manageable safety profile. The recommended dose in Phase II was set at 10 mg/kg. Most frequent immune-related adverse events were thyroiditis (76.2%) and dermatitis (42.9%). Only 1 (4.8%) of 21 patients had a Grade 3 skin rash. The median 3-year event-free survival (EFS) and overall survival (OS) were not established; however, 24-month EFS was 71.4% (95% confidence interval, 47.2–86.0) and 2-year OS was 100%. Preliminary efficacy data showed EFS benefits in patients with PD-L1 positive or an MSI-H sub-population.Conclusions:Switching to maintenance using ZKAB001 showed an acceptable safety profile and provided preliminary evidence of clinical activity in localized patients with osteosarcoma.
FDA Approval Summary: Lutetium Lu 177 Vipivotide Tetraxetan for Patients with Metastatic Castration-Resistant Prostate Cancer
Authors: Fallah Jaleh , Agrawal Sundeep , Gittleman Haley , Fiero Mallorie H. , Subramaniam Sriram , John Christy , Chen Wei , Ricks Tiffany K. , Niu Gang , Fotenos Anthony , Wang Min , Chiang Kelly , Pierce William F. , Suzman Daniel L. , Tang Shenghui , Pazdur Richard , Amiri-Kordestani Laleh , Ibrahim Amna , Kluetz Paul G. 
Published: December 2022

Abstract
On March 23, 2022, the FDA approved Pluvicto (lutetium Lu 177 vipivotide tetraxetan, also known as 177Lu-PSMA-617) for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The recommended 177Lu-PSMA-617 dose is 7.4 gigabecquerels (GBq; 200 mCi) intravenously every 6 weeks for up to six doses, or until disease progression or unacceptable toxicity. The FDA granted traditional approval based on VISION (NCT03511664), which was a randomized (2:1), multicenter, open-label trial that assessed the efficacy and safety of 177Lu-PSMA-617 plus best standard of care (BSoC; n = 551) or BSoC alone (n = 280) in men with progressive, PSMA-positive mCRPC. Patients were required to have received ≥1 androgen receptor pathway inhibitor, and one or two prior taxane-based chemotherapy regimens. There was a statistically significant and clinically meaningful improvement in overall survival (OS), with a median OS of 15.3 months in the 177Lu-PSMA-617 plus BSoC arm and 11.3 months in the BSoC arm, respectively (HR: 0.62; 95% confidence interval: 0.52–0.74; P &lt; 0.001). The most common adverse reactions (≥20%) occurring at a higher incidence in patients receiving 177Lu-PSMA-617 were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥30% of patients receiving 177Lu-PSMA-617 were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium. This article summarizes the FDA review of data supporting traditional approval of 177Lu-PSMA-617 for this indication.
ATM Regulation of the Cohesin Complex Is Required for Repression of DNA Replication and Transcription in the Vicinity of DNA Double-Strand Breaks
Authors: Bass Thomas E. , Fleenor Donald E. , Burrell Paige E. , Kastan Michael B. 
Published: December 2022

AbstractAtaxia-telangiectasia mutated (ATM) is an apical regulator of responses to DNA double-strand breaks (DSB). Using two complementary unbiased proteomic screens, we identified the cohesin complex proteins PDS5A, PDS5B, RAD21, NIPBL, and WAPL as apparent novel ATM interactors and substrates. ATM-dependent phosphorylation of PDS5A on Ser1278 following treatment with ionizing radiation is required for optimal cell survival, cell-cycle checkpoint activation, and chromosomal stability. Using a system that introduces site-specific DNA breaks, we found that ATM phosphorylation of cohesin proteins SMC1A, SMC3, and PDS5A are all required for repression of both RNA transcription and DNA replication within the vicinity of a DSB, the latter insight based on development of a novel localized S-phase cell-cycle checkpoint assay. These findings highlight the significance of interactions between ATM and cohesin in the regulation of DNA metabolic processes by altering the chromatin environment surrounding a DSB.Implications:Multiple members of the cohesin complex are involved in the regulation of DNA replication and transcription in the vicinity of DNA double-strand breaks and their role(s) are regulated by the ATM kinase.
In VivoModeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities
Authors: ten Hacken Elisa , Sewastianik Tomasz , Yin Shanye , Hoffmann Gabriela Brunsting , Gruber Michaela , Clement Kendell , Penter Livius , Redd Robert A. , Ruthen Neil , Hergalant Sébastien , Sholokhova Alanna , Fell Geoffrey , Parry Erin M. , Broséus Julien , Guieze Romain , Lucas Fabienne , Hernández-Sánchez María , Baranowski Kaitlyn , Southard Jackson , Joyal Heather , Billington Leah , Regis Fara Faye D. , Witten Elizabeth , Uduman Mohamed , Knisbacher Binyamin A. , Li Shuqiang , Lyu Haoxiang , Vaisitti Tiziana , Deaglio Silvia , Inghirami Giorgio , Feugier Pierre , Stilgenbauer Stephan , Tausch Eugen , Davids Matthew S. , Getz Gad , Livak Kenneth J. , Bozic Ivana , Neuberg Donna S. , Carrasco Ruben D. , Wu Catherine J. 
Published: December 2022

AbstractTransformation to aggressive disease histologies generates formidable clinical challenges across cancers, but biological insights remain few. We modeled the genetic heterogeneity of chronic lymphocytic leukemia (CLL) through multiplexed in vivo CRISPR-Cas9 B-cell editing of recurrent CLL loss-of-function drivers in mice and recapitulated the process of transformation from indolent CLL into large cell lymphoma [i.e., Richter syndrome (RS)]. Evolutionary trajectories of 64 mice carrying diverse combinatorial gene assortments revealed coselection of mutations in Trp53, Mga, and Chd2 and the dual impact of clonal Mga/Chd2 mutations on E2F/MYC and interferon signaling dysregulation. Comparative human and murine RS analyses demonstrated tonic PI3K signaling as a key feature of transformed disease, with constitutive activation of the AKT and S6 kinases, downmodulation of the PTEN phosphatase, and convergent activation of MYC/PI3K transcriptional programs underlying enhanced sensitivity to MYC/mTOR/PI3K inhibition. This robust experimental system presents a unique framework to study lymphoid biology and therapy.Significance:Mouse models reflective of the genetic complexity and heterogeneity of human tumors remain few, including those able to recapitulate transformation to aggressive disease histologies. Herein, we model CLL transformation into RS through multiplexed in vivo gene editing, providing key insight into the pathophysiology and therapeutic vulnerabilities of transformed disease.This article is highlighted in the In This Issue feature, p. 101
Multiple Intelligence and Career Preference: A Basis for Senior High School Career Guidance Orientation
Authors: Parojenog Robin C. , Parojenog Anna-Louise Precila R. , Atup Ma. Delilah C. 
Published: December 2022

This study aimed to determine the multiple intelligence and career preferences of Grade XII students of Biabas Trade High School as the basis for career guidance orientation. The respondents of the study are the 179 grade 12 students from different tracks. A descriptive survey method type of research was used in conducting the research using an adapted multiple intelligence test survey, multiple intelligence checklist, and an adapted and modified inventory of occupational interest checklist from National Career Assessment Examination (NCAE). The results were analyzed using analysis of variance and Pearson r to determine the significant difference and significant correlation respectively. The results showed that there is no significant relationship between the multiple intelligence and career preferences of the students. This implies that students have different multiple intelligences without any regard to their career preference. It was observed that among the nine multiple intelligences, the Existential and the Kinesthetic strength are most dominant among the Grade 12 Senior High School students. On the other hand, students who fall under the Logical strength are the least dominant. In terms of career preferences, the careers that fall under the Interpersonal strength are most dominant. The least dominant preferred careers are the ones that belongs to the Existential strength. Based on the given result, it is recommended that it must be disseminated to all senior high school teachers, career guidance advocates, and school heads through conference, in-service trainings, or during LAC sessions to communicate the importance of developing multiple intelligence and career guidance orientation among senior high school students.
Efforts to Improve Students’ Critical Thinking Skills in Primary Education Fundamental Class through Group Investigation Model
Authors: Chairunnisa Connie 
Published: December 2022

This study aimed to describe the application of Group Investigation Model (GIM) to improve students’ comprehension of subject concepts and their critical thinking skills and to understand the challenges faced by lecturers while practicing GIM in the classroom. The research approach used was a qualitative method of description involving 21 students who took the course of the Foundation of Education in the Education Administration study program at Muhammadiyah University of Prof.Dr.Hamka (Uhamka), Jakarta , Indonesia, in the odd semester 2019/2020. Data were collected through tests, observations, interviews, questionnaires, and documents. The application of GIM in the Education Foundation class can improve students’ critical thinking skills. The study findings suggested that the average student’s grades improved on formative tests.
In using GIM there are several challenges that include aspects of learning and outside learning. This study suggests: (1) prior to implementing this model, careful preparation is needed, especially in the learning process so as to encourage students to actively think and ask questions. 2) In implementing this GIM, it is necessary to have guidance and motivation from the lecturer. (3) The implementation of this GIM can be successful if the stages one and two have been agreed and determined.
Subsurface Anticyclonic Eddy Transited from Kuroshio Shedding Eddy in the Northern South China Sea
Authors: Wang Xiangpeng , Du Yan , Zhang Yuhong , Wang Tianyu , Wang Minyang , Jing Zhiyou 
Published: December 2022

Abstract
Subsurface eddies are a special type of oceanic eddy that display the maximum velocity in the subsurface layer. Based on field observations, a lens-shaped subsurface anticyclonic eddy (SAE) was detected in the northern South China Sea (SCS) in May 2021. The SAE was located between 20 and 200 m, with a shoaling of the seasonal thermocline and deepening of the main thermocline. Satellite images showed that the SAE exhibited positive sea level anomaly (SLA) and negative sea surface temperature (SST) anomaly. Eddy track indicated that this SAE originated from the Luzon Strait and was generated in the Kuroshio Loop Current (KLC) last winter. The evolution of the SAE was related to the anomalous water properties inside the eddy and the seasonal change of sea surface heat flux. In winter, the continuous surface cooling and Kuroshio intrusion led to a cold, salty core in the upper part of the anticyclonic eddy, which resulted in a subsurface-intensified structure through geostrophic adjustment. As the season changed from winter to spring, sea surface temperature increased. The lens-shaped structure was formed when the seasonal thermocline appeared near the surface that capped the winter well-mixed water inside the eddy. From 1993 to 2021, nearly half of the winter KLC shedding eddies (12/25) survived to late spring and evolved into subsurface lens-shaped structures. This result indicates that the transition of KLC shedding eddy to SAE is a common phenomenon in the northern SCS, which is potentially important for local air–sea interaction, heat–salt balance, and biogeochemical processes.

Significance Statement
Subsurface eddies are lens-shaped eddies with anomalous water properties in the subsurface layer. While such eddies have been reported in many regions of the World Ocean, they are poorly investigated in the SCS, especially the periodic subsurface eddies that appear in a fixed time frame with similar patterns and trajectories. This study reported a subsurface anticyclonic eddy (SAE) in the northern SCS and elucidated its generation and evolution processes. Statistical results confirm that this is a periodic SAE, which occurs nearly annually in late spring and evolves from the Kuroshio shedding eddy with seasonal changes. This study provides a new perspective on the evolution of subsurface eddies in the SCS and will benefit targeted observations in the future.
The effect of Del Nido versus custodiol cardioplegia on clinical outcomes and troponin-I changes among pediatrics with tetralogy of fallot undergoing cardiopulmonary bypass
Authors: Gholampour Dehaki Maziar , Gorjipour Farhad , Gorjipour Fazel , Mahdavi Mohammad , Kachoueian Naser , Heidarynia Saeid 
Published: December 2022

Background Myocardial protection during operations with cardiopulmonary bypass (CPB) and aortic cross clamping is vital. For this purpose, Del Nido (DN) and Custodiol cardioplegia (CC) solutions are used for single-dose cardioplegia in cardiac surgical procedures with CPB. Present study aimed to compare the effects of DN and CC on peri-operative clinical outcomes in pediatrics with Tetralogy of Fallot (TF) undergoing cardiopulmonary bypass. Methods Present randomized clinical trial was performed in two trial groups with parallel design. One group received DN and another group received CC. We assessed circulatory Troponin-I (cTnI) and coronary sinus lactate level as primary outcomes. Secondary outcomes were ventilation time, electrolytes levels, pump time, cross-clamp time and other clinical parameters. Results Duration of CPB and cross-clamp were the same in both groups. There were no significant differences in hemodynamic parameters, left ventricular ejection fraction after the surgery and discharge time between the two trial groups. Ventilation time (8.5 vs. 18; p = 0.001), ICU stay, Troponin-I in ICU admission and Coronary sinus lactate level ( p = 0.001) were significantly higher among patients of Custodiol group compared to other trial group. Electrolytes Na, Cl and K levels, during CPB, were significantly less in Custodiol group. Conclusion When used for inducing cardiac arrest during CPB, DN solution offers better maintenance of the electrolyte balance during CPB, and is associated with less circulatory cTnI and coronary sinus lactate level compared with the CC.
The Expression of Hypoxia-Related Biomarkers: A Significance of HIF-1α C1772T Polymorphism as Predictor of Laryngeal Carcinoma Relapse
Authors: Folic Miljan M. , Banko Ana V. , Todorovic Vera N. , Puskas Nela S. , Milovanovic Jovica P. , Krejovic Sanja B. , Dragicevic-Babic Neda Z. , Bukumiric Zoran M. , Milicic Biljana R. , Jotic Ana D. , Djukic Vojko B. 
Published: December 2022

Introduction The association between the expression of HIF-1α in the laryngeal carcinoma and the prognosis of disease is quite well documented, but the significance of HIF-1α C1772T polymorphism and its relation to disease phenotype have to be clarified. The aim of this study was to investigate the influence of C1772T polymorphism on the clinical-pathological characteristics and disease-free survival after initial surgical treatment of patients with laryngeal carcinoma. Materials and methods The prospective cohort study included 65 patients with laryngeal carcinoma. Two representative tumor tissue specimens were taken in each patient during surgery; 1 specimen was used to asses HIF-1α C1772T polymorphism and the other 1 to determine the immunohistochemical expression of HIF-1α, VEGF, as well as CD 34 proteins. The comparison of polymorphism frequency between study and control population was conducted by collecting a 5 mL of peripheral venous blood samples in each subject. Results Clinicopathological characteristics of laryngeal carcinoma didn’t affect the expression of hypoxia-related biomarkers, such as HIF-1α, VEGF or MVD. The statistically significant association between HIF-1α and VEGF expression was found ( P = .034), but not between HIF-1α expression and MVD value ( P = .696). The expression of HIF-1α was significantly higher among CT heterozygotes ( P = .029). We found a significantly more recurrence among CT heterozygotes compared with patients with CC homozygous alleles (57.10% and 24.30%, respectively; P = .007). Patients with C1772T polymorphic variants had significantly worse disease-free survival compared with patients without polymorphism (Log-rank test, P = .007). Conclusion HIF-1α C1772T polymorphism was significantly associated with worse disease-free survival which nominates it as a predictor of laryngeal carcinoma relapse. The preoperative assessment of hypoxia-related biomarkers should be used in everyday practice in order to determine the treatment modalities for laryngeal carcinoma.
Multimodal imaging in differential diagnosis between papilledema and choroidal neovascularization associated with morning glory syndrome
Authors: Cennamo Gilda , Montorio Daniela , Brescia Morra Vincenzo , Costagliola Ciro 
Published: December 2022

Purpose To describe the role of optical coherence tomography angiography (OCTA) to help in differential diagnosis between papilledema and a rare case of choroidal neovascularization (CNV) associated with Morning Glory Syndrome (MGS). Methods Observational case report. Results A 22-year old man was referred to Eye clinic from Neurological unit with a diagnosis of papilledema in right eye. OCTA scans on the optic disc revealed a dense radial peripapillary vascular network while two polypoidal choroidal vasculopathy (PCV) were present in peripapillary region at the edge of staphyloma in corrispondence of choriocapillary layer. Therefore, the patient underwent three-monthly intravitreal injections of anti-vascular endothelial growth factor. One and six months after loading phase, the PCVs showed no clinical activity at structural spectral domain-OCT and OCTA. Conclusion This case revealed the crucial role of OCTA as an efficace diagnostic technique in discriminating papilledema from MGS complicated by CNV, allowing to make differential diagnosis, useful in ophthalmological and neurological clinical practice.
“Band-Aids on Bullet Holes”: Experiences of pediatric hospital social workers after 1 year of the COVID-19 pandemic
Authors: McKenna John L , Ross Abigail M , Boskey Elizabeth R 
Published: December 2022

COVID-19 has continued to bring devastation to children and families, even 1 year into the pandemic. The rise of the Black Lives Matter movement has also led to renewed attention to systemic racism in the United States and awareness of how the pandemic has further exacerbated health inequities that disproportionately affect communities of color. Pediatric hospital social workers have played a key role since the beginning of the pandemic in responding to the resulting behavioral health crisis and helping to address social disparities. There is a need to understand how the roles and experiences of pediatric social workers have evolved during the first year of the pandemic. In this qualitative study, a series of practice-setting based focus groups were conducted with social workers to capture (a) what has changed or stayed the same since the beginning of COVID-19, (b) thoughts and experiences on diversity, equity, and inclusion with particular attention to race and racism, and (c) perspectives about the long-term implications of COVID-19 on the profession of social work. The Framework Method was used to analyze data, from which six superordinate themes emerged: burnout/coping; the impact of patient acuity; awareness of racial inequity in patient care; awareness of social determinants of health; social worker inclusion in hospital decision-making and policy reform; and grief/racial inequity. An overview of what has stayed the same, what has changed, and what the future may hold for pediatric hospital social workers is reviewed.
Modified Mayo score versus Mayo score for evaluation of treatment efficacy in patients with ulcerative colitis: data from the tofacitinib OCTAVE program
Authors: Sandborn William J. , Sands Bruce E. , Vermeire Séverine , Leung Yvette , Guo Xiang , Modesto Irene , Su Chinyu , Wang Wenjin , Panés Julian 
Published: December 2022

Objectives: The subjectivity of the Physician Global Assessment (PGA) is a limitation of the Mayo score in assessing severity of ulcerative colitis (UC). We compared treatment efficacy using endpoint definitions based on modified Mayo (mMayo) score, versus those based on Mayo score, using data from the tofacitinib OCTAVE program. Design: This post hoc analysis included data from two 8-week induction studies (OCTAVE Induction 1 and 2) and a 52-week maintenance study (OCTAVE Sustain). Methods: Remission and clinical response [with nonresponder imputation (NRI)] were assessed using mMayo (without PGA) and Mayo scores, and further stratified by prior tumor necrosis factor inhibitor (TNFi) failure status. Results: At week 8 of OCTAVE Induction 1 and 2, remission rates with placebo and tofacitinib 10 mg twice daily (BID), respectively, were 7.7% and 24.8% (mMayo) and 6.0% and 17.6% (Mayo). At week 52 of OCTAVE Sustain, remission rates with placebo, tofacitinib 5 and 10 mg BID, respectively, were 12.1%, 35.9%, and 42.1% (mMayo) and 11.1%, 34.3%, and 40.6% (Mayo). A statistically significant ( p < 0.05) treatment effect of tofacitinib versus placebo was observed for remission and clinical response at all time points, regardless of scoring definition or prior TNFi failure status. Conclusions: A significant effect of tofacitinib versus placebo was demonstrated across efficacy endpoints using mMayo score, consistent with previously reported data using Mayo score. Treatment effect sizes were generally similar regardless of scoring definition. This observation may help contextualize tofacitinib therapy outcomes with those of new UC therapies and support the use of Mayo score-based endpoints in UC clinical trials. Trail registration: ClinicalTrials.gov identifiers: NCT01465763; NCT01458951; NCT01458574.