bluuebunny/crossref_metadata_2025 huggingface dataset:
Ponatinib (PON) in patients (pts) with chronic-phase chronic myeloid leukemia (CP-CML) and the T315I mutation (mut): 4-year results from OPTIC.
Authors: Deininger Michael , Apperley Jane , Arthur Christopher Kevin , Chuah Charles , Hochhaus Andreas , de Lavallade Hugues , Lipton Jeffrey Howard , Lomaia Elza , McCloskey James K. , Maness Lori J. , Mauro Michael J. , Moiraghi Beatriz , Pavlovsky Carolina , Rosti Gianantonio , Rousselot Philippe , Undurraga Sutton Maria , Ren Xiaowei , Vorog Alexander , Kantarjian Hagop M. , Cortes Jorge E.
Published: June 2024

6501

Background: PON, an approved BCR::ABL1 TKI, potently inhibits native BCR::ABL1 and all reported single-resistance muts, including T315I. In the primary analysis of the phase 2 OPTIC study (NCT02467270) at 12 mo, pts with CP-CML and the T315I mut had robust responses to PON. We present 4-year results from the OPTIC trial in pts with the T315I mut. Methods: Pts with CP-CML resistant to ≥2 TKIs or with the BCR::ABL1 T315I mut were randomized 1:1:1 to PON starting doses of 45, 30, or 15 mg QD, with dose reduction to 15 mg upon achievement of ≤1% BCR::ABL1IS in the 45-mg and 30-mg cohorts. This subgroup analysis evaluated 48-mo ≤1% BCR::ABL1IS, PFS and OS rates and safety outcomes in pts with the T315I mut. Results: Overall, 283 pts received PON (45 mg/30 mg/15 mg: n=94/95/94); 23.8% had the T315I mut (n=25/21/21). At the data cutoff for the 4-year analysis (May 8, 2023), median follow-up in the 45-, 30-, and 15-mg cohorts was 60.6, 63.5, and 60.7 mo, respectively. The proportion of pts with the T315I mut achieving ≤1% BCR::ABL1IS by 48 mo was highest in the 45-mg cohort (64%; Table). Median time to response (mo) and estimated median duration of response (mo) were 6.0 and 16.7 in the 45-mg cohort, 3.1 and 12.0 in the 30-mg cohort, and 6.0 and not reached (NR) in the 15-mg cohort. In the 45- and 30-mg cohorts, 15 and 5 pts had dose reduction to 15 mg after achieving ≤1% BCR::ABL1IS, of which 7 and 2 maintained response; of pts not maintaining response, 6 and 1 regained response after dose re-escalation. Median PFS was NR, 28.4 mo, and 45.6 mo in the 45-, 30-, and 15-mg cohorts, respectively, and median OS was NR in all groups. The 45-mg cohort had the highest 4-year survival rates (OS: T315I 86%; overall 88%; Table). Grade ≥3 TEAE rates in the 45-, 30-, and 15-mg cohorts were 60%, 38%, and 38%, with TEAEs leading to discontinuation in 8%, 14%, and 5%, respectively. Arterial occlusive events (AOEs) occurred in 8%, 14%, and 5% of pts in the 45-, 30-, and 15-mg cohorts; exposure-adjusted AOE rates were 2.4%, 7.3%, and 2.8%, respectively. Conclusions: PON demonstrated robust long-term efficacy and manageable safety in this 4-year update in pts with the T315I mut. A PON starting dose of 45 mg with reduction to 15 mg upon achievement of ≤1% BCR::ABL1IS provided the optimal benefit:risk ratio. Clinical trial information: NCT02467270 . [Table: see text]
Efficacy of GCN2 inhibition by a novel small molecule AP030 in acute leukemia.
Authors: Clemo Nadine , Roman-Trufero Monica , Auner Holger , Butt Richard , Zebisch Armin , Chaida Panagiota , Herzog Sereina , Fuchter Matthew
Published: June 2024

6532

Background: GCN2 is an evolutionarily conserved kinase and a pivotal regulator of the Integrated Stress Response (ISR) that is activated in response to amino acid scarcity. Active GCN2 phosphorylates translation initiation factor eIF2α resulting in the attenuation of global protein synthesis. ISR signaling primarily promotes cell survival but may trigger cell death, dependent on the cellular context. In hematological tumors GCN2 promotes tumor cell survival under conditions of nutrient scarcity. Several GCN2 inhibitors are in clinical development for treatment of both solid and hematological tumors. Here, we describe the preclinical results of a novel, selective ATP-competitive inhibitor of GCN2. Methods: GCN2 inhibition by AP030 was determined using a biochemical Lanthascreen assay and a cell based HTRF assay measuring eIF2a phosphorylation following stimulation with Borrelidin. Kinase selectivity was determined using KinomeScan, and bespoke biochemical and cell-based assays. Interaction of AP030 with GCN2 was determined using X-ray crystallography. AP030 activity in disease-relevant tumor cell lines was determined using cell viability, caspase activation, protein expression and qPCR gene expression endpoints. Inhibition of hematological tumor growth and induction of cell death was investigated in patient samples, and ALL and AML in vivo animal models. Results: Potent inhibition of GCN2 in the Lanthascreen assay was demonstrated with AP030 (Ki of 4.4nM). Following stimulation with Borrelidin, AP030 inhibited eIF2a phosphorylation with an IC50 of 50.8nM and inhibited downstream targets CHAC1 and DDIT3 measured by qPCR. X-ray crystallography confirmed that AP030 binds to the ATP-binding site of GCN2. The KinomeScan confirmed that AP030 was highly selective against the human kinome. AP030 led to partial or complete reduction of AML cell line viability as a single agent and acted synergistically with asparaginase in ALL cell lines. Caspase 3/7 induction was observed in the AML and ALL cell lines evaluated and AP030 increased the proportion of cells undergoing apoptosis in AML patient primary samples. In the CCRF-CEM ALL systemic in vivo tumor model AP030 inhibited tumor growth in combination with asparaginase (TGI 79.33%). Treatment with 0.5-5mg/kg (q.d.) of AP030 resulted in dose-dependent tumor growth inhibition and regression of the MOLM-16 AML in vivo model (TGI 97.37% 5mg/kg). RNA sequencing of residual tumor cells revealed disruption of amino acid and protein metabolism, consistent with GCN2 inhibition. Conclusions: Targeting hematological tumor reliance on the GCN2 arm of the ISR during nutrient scarcity is a novel approach to preventing tumor cell survival. AP030 a novel, potent, selective, ATP-competitive kinase inhibitor has been shown to lead to impressive efficacy in acute leukemia. Based on these preclinical results, a phase 1/2 study has been initiated in AML.
Safety and efficacy of lisaftoclax, a novel BCL-2 inhibitor, in combination with azacitidine in patients with treatment-naïve or relapsed or refractory acute myeloid leukemia.
Authors: Wang Huafeng , Wei Xudong , Liang Yang , Jiang Qian , He Wenjuan , Li Qiubai , Weng Jianyu , Chen Suning , Chang Chunkang , Ma Hongbing , Xu Yajing , He Qun , Chen Zi , Liu Lihui , Men Lichuang , Cong Danhua , Zhang Zhang , Yang Dajun , Zhai Yifan , Jin Jie
Published: June 2024

6541

Background: Investigational agent lisaftoclax (Lisa) was shown in preclinical findings to synergistically induce apoptosis in acute myeloid leukemia (AML). Here, we present follow up safety and efficacy data from a phase 1b/2 study evaluating Lisa + azacitidine (AZA) in adults with AML. Methods: Elderly (≥ 75 years)/unfit treatment-naïve (TN) and relapsed or refractory (R/R) AML (≥ 18 years) patients (pts) were enrolled. Lisa (400/600/800 mg) was administered orally once daily in 28-day cycles (a daily ramp up schedule was used for Lisa to prevent tumor lysis syndrome, TLS) combined with AZA (75 mg/m2/day on D1-7). Results: As of January 25, 2024, 76 AML pts were enrolled (R/R [n = 37]; elderly/unfit TN [n = 39]). The median (range) age was 66 (20-81) years and 61.8% of pts were male. All pts treated with Lisa + AZA reported TEAEs, with 89.5% Grade 3/4 AEs; and 43.4% SAEs. Common TEAEs (≥ 30%) included neutropenia (60.5%), thrombocytopenia (60.5%), diarrhea (42.1%), hypokalemia (40.8%), pyrexia (35.5%), and vomiting (30.3%). Grade ≥ 3 TEAEs reported in ≥ 10% of pts were neutropenia (57.9%), thrombocytopenia (50.0%), anemia (27.6%), pneumonia (17.1%), and febrile neutropenia (10.5%). No TLS was reported, and the 30-/60-day mortality rates were 1.3% and 3.9%, respectively. In pts with R/R AML treated with Lisa + AZA, the overall response ([ORR] = CR + CRi + morphologic leukemia-free state [MLFS] + PR) and composite complete remission (CRc = CR + CRi) rates were 72.7% and 45.5%, respectively. In the 600 mg cohort (n = 30), ORR and CRc were 76.7% and 50.0%; the median (range) duration of treatment (mDoT), 3.8 (0.8‒15.4) month (mo); median time to CRc (mTTCRc), 2.5 (95% CI, 1.5-6.1) mo; median PFS was 10.2 (95% CI, 6.5-NR) mo; and median OS was 14.7 (95% CI, 7.8-NR) mo. Among 39 pts with TN AML treated with Lisa + AZA, ORR and CRc were 64.1% and 51.3%, respectively (Table). In the 600 mg cohort (n = 29), mDoT was 3.3 (1.0- 9.9) mo; mTTCRc was 1.9 (95% CI, 1.2-3.3) mo; median PFS was not reached (3.5, NR). 600 mg of Lisa + AZA was established as the recommended phase 2 dose. Conclusions: Our data support an emerging role for this new BCL-2 inhibitor Lisa combined with AZA for the treatment of elderly/unfit TN and R/R AML pts, especially with low early mortality and promising mPFS. A phase 3, randomized, double-blind clinical study is in progress to determine whether Lisa + AZA improves OS in elderly/unfit pts with AML. *HW, XW, and YL are co-first authors. Clinical trial information: NCT04501120 . [Table: see text]
Improved overall survival in acute myeloid leukemia over the last 15 years.
Authors: Dhakal Prajwal , Loeffler Bradley T. , Ravindra Aditya , Acharya Luna , Pyakuryal Avantika , Bhatt Vijaya Raj
Published: June 2024

6543

Background: Overall survival (OS) for acute myeloid leukemia (AML) has remained dismal over the past decades. In the last five years, 11 drugs have been approved for newly diagnosed and relapsed/refractory AML. We, therefore, hypothesized that OS has increased significantly in recent years. Methods: We identified 78,092 pts diagnosed with AML between 2004 and 2019 from the National Cancer Database and divided them into 2 cohorts based on year of diagnosis, 2004-2010 and 2011-2019. The Kaplan-Meier method was used to estimate OS probabilities. Cox regression was used to evaluate the association of patient and disease characteristics with OS and differences in these associations between the two cohorts. Results: Sixty-one percent of patients were ≥60 years old, 46% were female, 85% were white, and 90% had Charlson comorbidity index of 0-1. Forty-five percent were diagnosed in 2004-2010, and the rest were diagnosed in 2011-2019. Chemotherapy use increased over the years, with 81% of patients receiving chemotherapy in 2019 compared to 73% in 2004. Similarly, 12.2% of patients in 2012 received hematopoietic cell transplant (HCT) compared to 6.5% in 2004. One-year, 3-year, and 5-year OS for patients diagnosed in 2011-2019 were 48%, 31%, and 28% compared to 42%, 25%, and 22%, respectively, for patients diagnosed in 2004-2010. On multivariable analysis, OS differed significantly over the years based on race, AML subtype, receipt of chemotherapy, and HCT use. OS for white people was better compared to black in 2004-2010 but similar in 2011-2019. Both white and black people had worse OS compared to other race types in 2004-2010 and 2011-2019. Acute promyelocytic leukemia had the best OS compared to core-binding factor, therapy-related, and other AML types; OS improved the most in acute promyelocytic leukemia and core-binding factor AML over the years. Compared to 2004-2010, OS increased significantly in 2011- 2019 with the receipt of chemotherapy and HCT. Older age, male sex, lower income, no insurance, higher Charlson comorbidity index, and lower educational attainment were associated with worse OS with no significant change in recent years. Conclusions: In one of the largest studies, we identified improved OS in patients with AML in recent years. Improvement in OS is likely multifactorial, including recent drug approvals, increased use of chemotherapy and HCT, and better supportive care. Despite a meaningful improvement in OS, only one out of four patients with AML were alive after five years, highlighting a continued need for further drug development and the importance of HCT.
Mutation patterns and prognostic implications in acute myeloid leukemia with chromosomal 7 deletions.
Authors: Kugler Eitan , Dasdemir Enes , Wang Bofei , Bataller Alex , Dinardo Courtney Denton , Daver Naval Guastad , Yilmaz Musa , Short Nicholas James , Kadia Tapan M. , Sasaki Koji , Bazinet Alexandre , Pierce Sherry , Reville Patrick Kevin , Ravandi-Kashani Farhad , Abbas Hussein
Published: June 2024

6547

Background: Chromosomal 7 deletions (del7/7q) are the most common adverse cytogenetic event in acute myeloid leukemia and are associated with high rate of relapse. We analyzed gene mutation profiles in del7/7q AML patients who relapsed after initial remission to identify molecular patterns associated with clinical outcomes. Methods: Out of 351 newly diagnosed AML patients with del7/7q, 115 (32%) achieved complete remission after first-line treatment between 2012-2023. Of the 115 patients, 77 (67%) patients relapsed during the study follow-up. Kaplan-Meier and Cox regression were used to analyze survival outcomes. Next-generation sequencing was performed on a targeted panel of 81 genes for 59 patients who relapsed on bone marrow samples at diagnosis and relapse for paired analysis. Results: The median age of the 115 patients at diagnosis was 74 (41-93). Thirty-four patients (30%) received intensive treatment. With 30.8-month median follow-up, the median overall survival (OS) was 10.4 months, with improved survival in patients without TP53 mutation (13.04 vs. 8.6 months, p=0.005) or complex karyotype (12.4 vs. 8.6 months, p=0.03). The median duration of response for the 77 patients who relapsed was 5 months (2-7). Allo-HSCT significantly improved median OS (not reached vs. 8.5 months, P=6e-06), and was identified as the key variable impacting survival in multivariate analysis. TP53 was the most commonly mutated gene at diagnosis (67%) and relapse (71%). Mutations in CBLC and KDM6A were cleared after induction therapy, while BCOR and BCORL1 were commonly acquired at relapse (Table). At diagnosis, a lower co-mutation burden was observed in TP53 mutant patients as compared with wild type (average 1.84 vs. 3.65 respectively, p=0.0001). Patients with mutated TP53 and coexisting mutations in GATA2, NF1, BCORL1, or RUNX1 at diagnosis had shorter relapse free survival (RFS, 2 vs. 5 months, p=0.01) and OS (7.2 vs. 10.4 months, p=0.01) compared to patients with solely mutated TP53 (HR 2.2; 95% CI 1.2-4; P = 0.004). Allo-HSCT significantly improved the OS in patients with mutated TP53 (13 vs. 8 months, p=0.01). Conclusions: Mutated TP53 clones persist from diagnosis to relapse in patients with del7/7q AML. In patients with mutated TP53, co-occurring mutations in GATA2, NF1, BCORL1or RUNX1 at diagnosis were linked to a shorter RFS and indicate a particularly high-risk subgroup that require proceeding to allo-HSCT in CR1 without delay. [Table: see text]
Depletion of histone H3K27 demethylase exerts anti-tumor activity as a monotherapy and in combination therapy with ceralasertib in non-small cell lung carcinoma.
Authors: Lee Pony Yu-Ling , Lin Kun-Yuan , Chang Chao-Di , Cheng Shan-Yun , Hung Ya-Wen , Yang Chih-Chieh , Chang Yu-Hsien , Shen Chien-Chang , Yeh Lin-Wen , Aberin Marvin Angelo Esteban , Wang Shu-Ping
Published: June 2024

e20035

Background: Lung cancer is one of the most frequently diagnosed cancers and is the leading cause of cancer-related death worldwide. Non-small cell lung carcinoma (NSCLC) represents 85% of lung cancers and is the most common type with poor prognosis. The lysine-specific demethylase UTX (gene name KDM6A) demethylates H3K27me2/3 at genes and enhancers and have been shown to support oncogenic transcription factors. We hypothesize that UTX is a highly pleiotropic factor in tumorigenesis and may plays a critical role in controlling DNA replication-associated gene activation as well as in replication stress-related DNA damage repair. Methods: To evaluate the role of UTX in tumorigenesis, shRNA-mediated UTX knockdown was employed in NCI-H1975 cells followed by cell cycle and cell proliferation assays. In the UTX-knocked down NCI-H1975 cells, target genes involved in DNA replication and DNA damage repair were discovered by RNA sequencing and further validated with RT-qPCR. Effects of UTX depletion on DNA replication and radiation-induced DNA repair were analyzed by immunofluorescence. Effects of UTX depletion on cell cycle arrest and the ATR–CHK1 checkpoint signaling pathway were analyzed by flow cytometry and immunoblotting. In vivo response to UTX inhibition monotherapy (UTX knockdown) and combination therapy of UTX knockdown with ceralasertib, a selective ATR kinase inhibitor, was evaluated in dox-inducible UTX knockdown NCI-H1975 xenografts. Results: Induction of UTX knockdown significantly reduced the NCI-H1975 tumor volume compared to the control group, showing anti-tumor activity. Furthermore, loss of UTX induced hyperactivation of ATR–CHK1 checkpoint signaling pathway, suggesting the UTX-depleted tumor cells attempt to alleviate replication stress to escape from apoptosis. To inhibit the UTX-depletion induced ATR–CHK1 pathway, ceralasertib (formerly AZD6738), an oral potent selective inhibitor of ATR, was combined with UTX-knockdown for in vitro and in vivo evaluation. Consistent with in vitro cell-based assay, combination therapy of ceralasertib with UTX depletion showed enhanced tumor growth inhibition and regression in the NCI-H1975 xenograft model. Conclusions: Our findings provide new insights into a pro-oncogenic role of UTX in supporting tumor maintenance via engaging DNA replication and repair pathway. Depletion of UTX alone may serve as a new therapeutic target in non-small cell lung carcinoma; and further combination with ceralasertib enhances the anti-tumor activity of UTX knockdown by inhibiting the ATR–CHK1 checkpoint signaling pathway.
Predicting spread through air space and immune status in lung adenocarcinoma by CT-based deep learning model.
Authors: Zhou HaiYu , Li Qiaxuan , Cai Linghan , Xie Daipeng , Yao Lintong , Lei Yu , Cai Canjia , Zhang Qi
Published: June 2024

e20043

Background: Tumor spread through air space (STAS) is a novel histologic pattern of invasion related to high recurrence and poor prognosis. Meanwhile, there is a potential relationship between STAS status and the tumor immune microenvironment. The aim of this study was to predict STAS status in lung adenocarcinoma (LUAD) using a CT-based 3D-CNN deep learning model and explore the tumor immune microenvironment in the GSE58661 cohort. Methods: We retrospectively collected data from 368 patients with lung adenocarcinoma and STAS status from Guangdong Province General Hospital between 2021 and 2023. We performed propensity score matching (PSM) based on gender, year, BMI, and smoking status to obtain a cohort of 368 patients without STAS status. A 3D-Resnet-Resnetearning model was developed to identify the STAS status of lung adenocarcinoma, and the performance of the models was evaluated using the area under the curve (AUC), accuracy, sensitivity, and specificity. Meanwhile, bule RNA sequencing and baseline CT of LUAD from 41 patients in the GSE58661 cohort and the TCIA dataset were used to investigate the potential biological mechanism in the patients with STAS status. Results: We included 584 and 152 patients in the training and testing sets, respectively. The 3D-Resnet algorithm was used in the 3D patch with voxel sizes of 128*128*128, 96*96*96, and 64*64*64 to construct the DL-STAS model. With the training set's AUC of 0.899, the results showed that the model achieved an AUC, sensitivity, specificity, and accuracy of 0.884, 0.831, 0.838, and 0.835 in the testing cohort, respectively. According to our model, we divided the patients in GSE58661 into STAS and non-STAS. By identifying and analyzing the differentially expressed genes between the STAS and non-STAS groups, we found that several immune-related pathways, such as the T cell receptor signaling pathway, the PD-1/PD-L1 expression pathway, the natural killer cell-mediated cytotoxicity pathway, and the macrophage activation pathway, were enriched in the group with STAS status. Conclusions: The DL-STAS model we developed has great potential for accurately predicting STAS status in lung adenocarcinoma. In the meanwhile, the prognosis of patients with STAS status may be impacted by their particular tumor immune microenvironment.
Association of tissue microbiota with cancer stages in lung adenocarcinoma.
Authors: Su Yanfang , Li Shiyu , Sang Die , Zhang Yurong
Published: June 2024

e20061

Background: There has been a lack of comprehensive investigation into changes in the tissue microbial environment at various stages of lung adenocarcinoma (LUAD). This study aims to identify and analyze microbial markers that show significant differences at different stages of LUAD and to assess their impact on the tumor microenvironment. Methods: Microbiome data, gene expression, and clinical information from LUAD patient tissues were retrieved by reanalyzing the sample sequencing data from the Cancer Genome Atlas (TCGA) database, as conducted by Rob Knight’s group. The samples, categorized into early (pathological stage I) and late (stages II-IV) following the initial diagnosis, were subjected to comparative analyses. Firstly, microbial alpha diversity metrics, such as the Shannon index, were computed for each sample. Subsequently, Principal Coordinate Analysis (PCoA) and the Wilcoxon rank sum test were employed to assess differences in microbial communities between the two groups. Furthermore, the study delved into the associations between microbes and host gene expressions using Spearman rank correlation to construct a heterogeneous network encompassing microbial interaction networks at the genus level, microbe-gene interaction network, and gene co-expression network. Various network features, including the clustering coefficient, were examined. Finally, diverse machine learning algorithms were employed to develop a diagnostic model for cancer stage based on microbial and gene expression data. Results: A total of 491 samples, including 267 in the early group and 224 in the late group, were matched with microbial data, mRNA expression, and clinical information. Our findings revealed distinct differences in the microbiome of patients with LUAD at various stages, particularly in the tissues of advanced patients, where in the co-abundance network exhibited a significantly higher level of complexity. Furthermore, we identified five bacterial biomarkers (Pseudoalteromonas, Luteibacter, Caldicellulosiruptor, Loktanella, and Serratia) that were associated with the LUAD stage. Notably, Pseudoalteromonas, Luteibacter, Caldicellulosiruptor, and Serratia were significantly overexpressed in advanced patients. Utilizing the random forest model, we determined that microbial markers possess predictive capabilities for the stage of lung adenocarcinoma and can compensate for deficiencies in other omics data for determining tumor stage. Integration of the mRNA and intratumor microbe biomarkers yielded a prediction area under the Receiver Operating Characteristic curve of 0.70. Conclusions: Our study unveiled the microbial profile of LUAD patients, elucidating the intrinsic pathogenic mechanisms linking the microbiome and the disease. Additionally, we developed a multi-omics model for determining the tumor stage of LUAD.
A phase II trial of monalizumab in combination with durvalumab (MEDI4736) plus platinum-based chemotherapy for first-line treatment of extensive stage small cell lung cancer (MOZART): Hoosier Cancer Research Network LUN21-530 study.
Authors: Mamdani Hirva , Kim Seongho , Gentzler Ryan D. , Shields Misty Dawn , Furqan Muhammad , Pizana Kristen , Abid Qura , Jalal Shadia Ibrahim
Published: June 2024

TPS8129

Background: Chemoimmunotherapy consisting of platinum, etoposide, and PD-L1 inhibitor remains the standard of care first-line treatment for extensive stage small cell lung cancer (SCLC) yielding median overall survival (OS) of slightly over a year. NKG2A/CD94 is an immune checkpoint that is selectively expressed on natural killer (NK) cells and CD8+ T cells in the tumor microenvironment. When engaging with its ligand, HLA-E, NKG2A transduces inhibitory signals that suppress immune-mediated cytotoxicity. Thus, NKG2A blockade enhances anti-tumor immunity by promoting both, NK and CD8+ T cell, effector functions. Monalizumab, a monoclonal antibody targeting NKG2A, enhances NK cell activity against tumor cells and rescues CD8+ T cell function in combination with PD-(L)1 axis blockade. Pre-clinical data have demonstrated that the absence of NK cells substantially enhances metastatic dissemination of SCLC tumor cells in vivo. NK cell function is modulated in response to cytotoxic chemotherapy, especially platinum. Post-chemotherapy NK cells display an induced expression of NKG2A compared with pre-chemotherapy patients and is associated with a reduced NK cell mediated anti-tumor activity. Hyperactivation of NK cell activity ameliorates SCLC metastases, an effect that is enhanced when combined with anti PD-(L)1 therapy. Altogether, these data suggest that addition of monalizumab to standard of care first-line treatment may be associated with improved efficacy in patients with SCLC. Methods: Patients with extensive-stage SCLC with ECOG performance status of 0-2 and adequate organ function are eligible for enrollment on this single-arm phase II study with an initial safety lead-in cohort. Patients may have received one prior cycle of platinum doublet with or without durvalumab and may have treated or untreated asymptomatic brain metastasis. Patients will receive platinum (cis or carbo), etoposide, durvalumab, and monalizumab every 3 weeks for 4 cycles followed by durvalumab and monalizumab every 4 weeks until disease progression or unacceptable toxicity. Primary endpoints include 1-year progression-free survival, safety, and tolerability. Secondary endpoints include objective response rate, 1-year overall survival, and intracranial progression-free survival. Exploratory objectives include analyzing association of treatment efficacy with minimal residual disease status, blood- and tissue-based genomic and transcriptomic signatures, tumor infiltrating immune cells, and peripheral blood NK cell and CD8+ T cell activity. Five of the planned 30 patients have been enrolled to date. Clinical trial information: NCT05903092 .
Dose and Time Effects of Renin–Angiotensin Inhibitors on Patients With Advanced Stages 4 to 5 of Diabetic Kidney Disease
Authors: Chen Yi-Chun , Tung Chien-Hsueh , Yu Ben-Hui
Published: June 2024

Context

Limited evidence exists regarding the cumulative dosing and duration impact of renin–angiotensin system inhibitors (RASis) on cardiorenal and mortality outcomes in patients with advanced stages (predominantly in stage 5 and a minority in stage 4) of diabetic kidney disease (DKD).

Objective

To retrospectively investigate whether there are dose- and time-dependent relationships between RASis and cardiorenal and mortality outcomes in this population.

Methods

Using Taiwan's national health insurance data in 2000-2017, we analyzed 2196 RASi users and 2196 propensity-matched nonusers among 8738 patients living with diabetes and newly diagnosed with advanced chronic kidney disease (23% stage 4, 77% stage 5). Cox proportional hazards regression models were used to estimate adjusted hazard ratios (aHRs) and 95% CI.

Results

RASi use was significantly associated with reduced risks of all-cause mortality (aHR, 0.53; 95% CI 0.47-0.60) and cardiovascular mortality (0.68; 0.56-0.83) with the degree of benefit depending on therapeutic dosage and duration, despite a nonsignificant increase in acute kidney injury risk (1.16; 0.98-1.38) and a significant increase in hyperkalemia risk (1.45; 1.19-1.77). Significant differences in proteinuria risk (1.32; 1.21-1.43) were observed, while there were no significant differences in end-stage renal disease risk (1.01; 0.88-1.15) and no dose– or time–response relationships for either end-stage renal disease or proteinuria risks. Sensitivity analyses confirmed cardiovascular and survival benefits, even in patients with stage 5 DKD.

Conclusion

This real-world study suggests that RASi use in advanced stages 4 to 5 DKD may provide dose- and time-dependent cardioprotection and improved survival, without excess renal harms.
Η Διδασκαλία των Φυσικών Επιστημών στην Προσχολική Εκπαίδευση μέσω της Εκπαίδευσης Βασισμένη στον Τόπο
Authors: Φιλιππάκη Αμαλία , Καλαϊτζιδάκη Μαριάννα
Published: June 2024

Σύμφωνα με τη σύγχρονη βιβλιογραφία το αστικό περιβάλλον μπορεί να αξιοποιηθεί ως πεδίο διδασκαλίας των Φυσικών Επιστημών, αφού οι πόλεις ως κοινωνικά και οικολογικά πεδία προσφέρουν πολλές δυνατότητες για διδασκαλία σχετικά με το περιβάλλον. Με βάση αυτή την παραδοχή επιχειρήθηκε σε ένα αστικό σχολείο της Ελλάδας (όπου λειτουργούσαν και δύο τμήματα Προσχολικής Εκπαίδευσης) να αξιοποιηθεί ως πεδίο διδασκαλίας το αστικό περιβάλλον. Έτσι εφαρμόσαμε ως παιδαγωγική προσέγγιση την “Εκπαίδευση βασισμένη στον τόπο”, στο πλαίσιο της οποίας υλοποιήθηκαν ποικίλες βιωματικές δράσεις. Σε κάποιες από αυτές συμμετείχαν και μαθητές Προσχολικής Εκπαίδευσης. Μέσα από τις παρατηρήσεις των εκπαιδευτικών που συμμετείχαν φάνηκε πως το πεδίο αυτό της μάθησης ήταν πολύ ενδιαφέρον για τους μαθητές προσχολικής εκπαίδευσης. Μία από τις προτάσεις μας είναι οι ίδιοι οι εκπαιδευτικοί να συμβάλουν στην δημιουργία φυσικών οικοσυστημάτων στο προαύλιο των σχολείων τους ή να αξιοποιήσουν χώρους με στοιχεία φυσικών οικοσυστημάτων κοντά στο σχολείο τους, για τη διδασκαλία διαφόρων γνωστικών αντικειμένων και κυρίως των Φυσικών Επιστημών.
Association of LEP rs2167270 and LEPR rs1137100 genetic variants with obesity in the Jordanian population cohort
Authors: Jarrar Manal , Hasan Maen , Haddad Moawiya , Obeidat Maher , Al-Qerem Ahmad , Estêvão M. Dulce , Palma Mateus Maria
Published: June 2024

Background Previous Genome Wide Association Studies (GWAS) of obesity susceptibility genes in different populations have confirmed the association of some variants with obesity, body mass index (BMI), and some related metabolic traits. To our knowledge, the current study is the first to investigate the genetic basis of obesity in the Jordanian population. The aim of our study is to investigate the occurrence and frequency of obesity-related genes in Jordanian individuals and any possible relationship between SNP genetic markers and phenotypic characteristics of studied individuals. Methods A total of 150 Jordanian unrelated adults, including 83 obese, 26 overweight, and 41 normal-weight subjects, were genotyped using the high resolution melt analysis (HRMA) and tested for the association of single nucleotide polymorphisms (SNPs), rs2167270 in LEP gene and rs1137100 in LEPR gene, with obesity risk, obesity/overweight risk, BMI, weight, height, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and blood level glucose. Results A significant association between obesity risk and the rs2167270 mutation in LEP gene was observed under a dominant model (odds ratio (OR) = 2.5147, 95% CI =1.0629 to 5.9494, p = 0.0358). A marginal (not significant) association between BMI and the rs2167270 mutation in LEP gene (p = 0.075), was also detected. Moreover, an association between rs2167270 mutation in LEP gene and glucose blood level was observed (p = 0.038). Total cholesterol and LDL-cholesterol also presented a weak association with the rs1137100 mutation in LEPR gene, with p = 0.071 and p = 0.078, respectively. Additionally, no significant association between LDL-cholesterol and the rs2167270 mutation in LEP gene was observed (p = 0.091). By contrast, there was no association between weight or height and the SNPs mutation evaluated in this study (p > 0.05). Conclusions These results suggest that some SNPs in some obesity-related genes may contribute to obesity risk and its related anthropometric and metabolic traits in Jordanian population. To confirm these results, further studies on a larger Jordanian cohort should be carried out.
Evaluating the Malay version of NIOSH WellBQ: A study on reliability and construct validity for enhanced workplace well-being assessment
Authors: Omar Aswandi , Guan Ng Yee , Nair Mohan Sindhu , Mokhtar Siti Aisah , Poh Ying Lim
Published: June 2024

This study aimed to validate the Worker Well-Being Questionnaire, originally developed by the US National Institute for Occupational Safety and Health, in the Malay language. The translation process involved an initial independent translation by a professional translator, followed by a comparison of translations to synthesize a unified version, which was subsequently back-translated. The back-translations were then reviewed by an expert committee to create a finalized questionnaire version. The results of this validation study indicate a high level of satisfaction, demonstrating an excellent fit with confirmatory factor analysis (CFI and TLI values ranging from 0.96 to 0.99) and a low root mean square error of approximation (RMSEA values ranging from 0.03 to 0.07). Moreover, the questionnaire exhibits sound internal consistency, with Cronbach’s alpha values exceeding 0.7, and the factor structures align with theoretical expectations. In conclusion, the Malay version of the questionnaire faithfully reproduces the original instrument, enabling a robust and efficient assessment of workers’ well.
Vaccination against hepatitis B virus in hemodialysis patients: trends in dialysis centers of Northern Pakistan
Authors: Nadeem Muhammad , Shah Syed Asim Ali , Arshad Naveed , Riaz Faiza , Kiani Rizwan Saeed , Quddus Muhammad Abdul
Published: June 2024

Background Chronic kidney disease (CKD) patients, especially those on hemodialysis, are at increased risk of developing hepatitis B virus (HBV) infection. Guidelines suggest that all patients with CKD should be vaccinated against HBV, but these guidelines are usually not followed. We conducted this study to know the status of vaccination against HBV in CKD patients on regular hemodialysis. Methods This observational descriptive study was conducted at the Department of Medicine, Sheikh Khalifa Bin Zayed Teaching Hospital, Poonch Medical College Rawalakot , and POF Teaching Hospital, Wah Medical College Wah Cantt, from March to July 2019. Patients reporting to the dialysis center of both hospitals on regular dialysis were included in the study. Patient information (HBV vaccination status, age, gender, education, socioeconomic status, duration of CKD and duration of dialysis) were collected on a specially designed questionnaire. The statistical analysis of data was done in SPSS for Windows, version 20. Results A total 149 patients were included in the study, 63.1% were male and 36.9% were female. Out of these 24.2% were uneducated, 33.6% had 1–10 years school education, 38.2% had 10–14 years education, and 4% had more than 14 years education. About 35% patients were from low socioeconomic class, 54% from middle and 11% from higher class. Only 45.6% (n=68) of patients were vaccinated and 54.4% (n=81) were not vaccinated against HBV. Vaccination status was significantly associated with education (p=0.004) and socioeconomic status (p=0.008). Conclusion The HBV status of patients on regular hemodialysis is not satisfactory at the two centers observed. It is associated with education and socioeconomic status of the patient.
Overview of multimorbidity research in India: a scoping review
Authors: Puri Parul , Girotra Siaa , Ghosh Arpita
Published: June 2024

Background Due to demographic and epidemiological shifts, people are living until older ages with more morbidities. These morbidities often have shared pathophysiology, which leads to a rise in coexisting health issues known as 'multimorbidity'. Primary care studies and disease burden surveys have multiplied, unveiling varied aspects of multimorbidity, yet with inconsistent definitions and methods. This protocol aims to guide an in-depth and comprehensive exploration of multimorbidity research in India through a scoping review, to understand the extent, range, and nature of research on multimorbidity in India. Methods This study will comprehensively search the PubMed/Medline, Cochrane, and Embase databases employing a well-defined strategy. All studies published in English will be considered, provided the focus is multimorbidity and there is information specifically from India. Two reviewers will independently screen the search outcomes, and data extraction will include multimorbidity definitions, data and methods, patterns, risk factors and outcomes. The research will follow the Joanna Briggs Institute framework and adhere to PRISMA-P 2015 guidelines for reporting. Descriptive statistics and narrative synthesis will be used to summarize findings. Conclusions The findings from this review will provide crucial insights for healthcare planning, evidence-based decisions, and policy shaping in India's evolving health landscape.
The genome sequence of the willow leaf beetle, Lochmaea capreae Linnaeus, 1758
Authors: Barclay Maxwell V. L. , Vassiliades Danaë , Bayfield-Farrell Will , Cristóvão Joana , Matsumoto Keita , Geiser Michael ,   Natural History Museum Genome Acquisition Lab,   Darwin Tree of Life Barcoding collective,   Wellcome Sanger Institute Tree of Life Management, Samples and Laboratory team,   Wellcome Sanger Institute Scientific Operations: Sequencing Operations,   Wellcome Sanger Institute Tree of Life Core Informatics team,   Tree of Life Core Informatics collective,   Darwin Tree of Life Consortium
Published: June 2024

We present a genome assembly from an individual female Lochmaea capreae (the willow leaf beetle; Arthropoda; Insecta; Coleoptera; Chrysomelidae). The genome sequence is 534.7 megabases in span. Most of the assembly is scaffolded into 17 chromosomal pseudomolecules. The mitochondrial genome has also been assembled and is 18.85 kilobases in length. Gene annotation of this assembly on Ensembl identified 12,254 protein coding genes.
Universal Classification of Business Models in the Digital Economy
Authors: Ryabihina A. , Slepenkova E.
Published: June 2024

The article considers the main approaches to the definition of the term business model, identifies the peculiarities of business model formation in the field of digital economy and e-commerce. As a result of analytical study of existing approaches to the classification of business models, their universal classification is compiled. The practical significance lies in simplifying the process of selecting and adapting the existing business model of the organization in conditions of economic uncertainty.
Human Resource Management in the Context of the Formation of a Green Economy
Authors: Gretchenko A. , Garnov Andrey , Gretchenko A.
Published: June 2024

n the context of the transition of Russian organizations to the active use of green technologies, special requirements are imposed on the managers and employees of these organizations for their professional qualifications, mastering new green competencies. The proposed article examines the processes of transformation of the human resource management system during the transition of enterprises to a green economy. The authors substantiate the expediency of integrating innovative green technologies into the practice of human resource management of an organization, contributing to increase their competitiveness in both domestic and foreign markets.

The results obtained are of practical value for the heads of domestic organizations making managerial decisions during the formation and transition to a green economy.
Case report of a preserved male corpse: estimation of post-mortem interval based on four Dipteran species of four different families
Authors: Botteon Victor Wilson , Gaedke Anderson , Alves Victor Michelon
Published: June 2024

Case reports are extremely valuable in forensic entomology and very rare in Brazil. In this report we describe a case of multiple colonization of a preserved male cadaver found indoors in Santa Catarina State, southern Brazil, by four dipterans species of four different families: Fannia canicularis (Linnaeus, 1761) (Diptera: Fanniidae), Microcerella halli (Engel, 1931) (Diptera: Sarcophagidae), Muscina stabulans (Fallén, 1817) (Diptera: Muscidae) and Sarconesia chlorogaster (Wiedemann, 1830) (Diptera: Calliphoridae). The development time data of the species were used to estimate the minimum postmortem interval (PMI). Considering the methodology applied in this study and the values calculated for the species development, it was possible to estimate a minimum PMI of 24 days. Besides the diversity of dipteran species colonizing a single human body in an indoor environment, this case report reinforces the importance of these species as forensically indicator to estimate the time of death.
Gry i zabawy w świetle frazematyki polskich gwar
Authors: Wysoczański Włodzimierz
Published: June 2024

The article describes the phenomenon of games and plays recorded in the phrasematics of Polish dialects. It presents games and plays which differ in character and participants’ age – adult and child ones. Distinguished types of games and plays show the scope of interests in activities and actions undertaken in free time in specific conditions and space.
La propiedad de la tierra en el distrito de Manizales. Algunos aspectos de la conformación de su mercado (1850 – 1871).
Authors: Tolosa Castañeda Maria Alejandra , Monsalvo Mendoza Edwin
Published: June 2024

En este documento se analiza la conformación del mercado y los precios de la tierra en el distrito de Manizales entre 1850 y 1871. La hipótesis sugiere una participación más amplia de agentes de lo inicialmente considerado, argumentando que estos utilizaron la legislación nacional como fundamento jurídico para legitimar el proceso de titulación de la propiedad en un distrito recientemente colonizado. La metodología involucró la recopilación de datos de las escrituras de compraventas asentadas en la notaría única de Manizales, identificando 2,080 transacciones en 11 tomos. Buscando arrojar nuevas luces sobre el proceso de colonización, el resultado esperado es una visión más completa y matizada de la evolución económica de la propiedad de la tierra en el periodo.
Conservative management in kidney disease
Authors: Federation National Kidney
Published: June 2024

The National Kidney Federation (NKF) are a primary resource if your patients are seeking additional renal information and support, in this issue the NKF share their information leaflet on conservative management in kidney disease
Mental capacity: legal considerations
Authors: Ellis Peter
Published: June 2024

In this paper, Peter Ellis discusses the topic of mental capacity. What does it mean to lack capacity?
Masculinidade Tóxica e Saúde Mental na tragédia “Héracles” de Eurípides
Authors: Gabriel Santana Silva  , Brian Gordon Lutalo Kibuuka
Published: June 2024

O presente trabalho analisou a tragédia Héracles de Eurípides, enfocando as masculinidades subalterna, tóxica e hegemônica. Na Grécia antiga, a masculinidade se relacionava com a andreía, um termo que representava o máximo do masculino.
Francesco D’Adamo’s Ordinary Moral Heroes
Authors: Truglio Maria Rosa
Published: June 2024

Abstract: Building on the inspirational “monthly stories” in Edmondo De Amicis’s Cuore , Francesco D’Adamo’s novels present rich resources for youth navigating through the increasingly dehumanized world. His eighteen children’s books narrate compelling and imaginative stories of heroism while avoiding the paternalistic didacticism for which De Amicis and his imitators are often critiqued. D’Adamo won the Premio Andersen Best Writer Award for children’s literature in 2023.
A Funny Thing Happened on the Way to the Third Heaven: Reading the Secret Book of James (NHC I,2) with a Parodic Imagination
Authors: McBrien Kimberly Bauser
Published: June 2024

Abstract: From its appearance of the risen Lord to its heavenly ascent the Secret Book of James (NHC I,2; Ap. Jas .) is imitative of other early Christian revelatory literature. Scholarship has attended to these points of similarity to situate this text in relation to others and has found it to be the product of an educationally elite community. Its imitation, however, is marked with critical twists that point to essential difference as well as similarity. Parody, an intertextual mode marked by this type of imitation with critical difference, was well known in literary circles of the first several centuries. The works of Lucian in particular demonstrate how parody could be used as a vehicle for displays of educational bravado as well as social commentary, both of which might also characterize Ap. Jas . Reading through a lens of parody, or with a parodic imagination, brings into focus new interpretive possibilities for Ap. Jas ., along with its elite author and audience, and their posture toward the diverse landscape of early Christianity around them. Correspondingly, it stands to expand our historical imagination concerning the means and modes of discourse accessible to early Christian groups carving out identities for themselves within that landscape.
Fraught with Tension: The Question of the Unity of the Corpus Dionysiacum
Authors: Stock Wiebke-Marie
Published: June 2024

Abstract: There is debate about whether the Corpus Dionysiacum consists of two parts or offers a coherent position. One group of scholars presents a divisionist position, distinguishing one group of treatises dominated by the idea of hierarchical mediation from a second concentrating on the idea of individual and mystical knowledge of God. The second scholarly interpretation supports a holistic view and underlines the unity of the Corpus . I argue that the Corpus is a unity fraught with tension. Dionysius presents, I argue, a comprehensive view of human beings and their place in the world that offers different—and maybe at times competing—paths to understanding and to the ascent to the divine. The mystical, metaphysical, and meditative path and the sacramental path are not merely parallel ways, one for monks and the other for the bishops and laity. They are connected through the communal theological work presented in the fiction of a theological correspondence between the author and various members of the hierarchy.
Simultaneous removal of noise and correction of motion warping in neuron calcium imaging using a pipeline structure of self-supervised deep learning models
Authors: Zhang Hongdong , Xu Zhiqiang , Chen Ningbo , Ma Fei , Zheng Wei , Liu Chengbo , Meng Jing
Published: June 2024

Calcium imaging is susceptible to motion distortions and background noises, particularly for monitoring active animals under low-dose laser irradiation, and hence unavoidably hinder the critical analysis of neural functions. Current research efforts tend to focus on either denoising or dewarping and do not provide effective methods for videos distorted by both noises and motion artifacts simultaneously. We found that when a self-supervised denoising model of DeepCAD [Nat. Methods 18, 1359 (2021)10.1038/s41592-021-01225-0] is used on the calcium imaging contaminated by noise and motion warping, it can remove the motion artifacts effectively but with regenerated noises. To address this issue, we develop a two-level deep-learning (DL) pipeline to dewarp and denoise the calcium imaging video sequentially. The pipeline consists of two 3D self-supervised DL models that do not require warp-free and high signal-to-noise ratio (SNR) observations for network optimization. Specifically, a high-frequency enhancement block is presented in the denoising network to restore more structure information in the denoising process; a hierarchical perception module and a multi-scale attention module are designed in the dewarping network to tackle distortions of various sizes. Experiments conducted on seven videos from two-photon and confocal imaging systems demonstrate that our two-level DL pipeline can restore high-clarity neuron images distorted by both motion warping and background noises. Compared to typical DeepCAD, our denoising model achieves a significant improvement of approximately 30% in image resolution and up to 28% in signal-to-noise ratio; compared to traditional dewarping and denoising methods, our proposed pipeline network recovers more neurons, enhancing signal fidelity and improving data correlation among frames by 35% and 60% respectively. This work may provide an attractive method for long-term neural activity monitoring in awake animals and also facilitate functional analysis of neural circuits.