bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from The BRD4–NUT Fusion Alone Drives Malignant Transformation of NUT Carcinoma
Authors: Durall R. Taylor , Huang Julianna , Wojenski Luke , Huang Yeying , Gokhale Prafulla C. , Leeper Brittaney A. , Nash Joshua O. , Ballester Pedro L. , Davidson Scott , Shlien Adam , Sotirakis Emmanuel , Bertaux Fabien , Dubus Vincent , Luo Jia , Wu Catherine J. , Keskin Derin B. , Eagen Kyle P. , Shapiro Geoffrey I. , French Christopher A.
Published: December 2023

Abstract
NUT carcinoma (NC) is an aggressive squamous carcinoma defined by the BRD4–NUT fusion oncoprotein. Routinely effective systemic treatments are unavailable for most NC patients. The lack of an adequate animal model precludes identifying and leveraging cell-extrinsic factors therapeutically in NC. Here, we created a genetically engineered mouse model (GEMM) of NC that forms a Brd4::NUTM1 fusion gene upon tamoxifen induction of Sox2-driven Cre. The model displayed complete disease penetrance, with tumors arising from the squamous epithelium weeks after induction and all mice succumbing to the disease shortly thereafter. Closely resembling human NC (hNC), GEMM tumors (mNC) were poorly differentiated squamous carcinomas with high expression of MYC that metastasized to solid organs and regional lymph nodes. Two GEMM-derived cell lines were developed whose transcriptomic and epigenetic landscapes harbored key features of primary GEMM tumors. Importantly, GEMM tumor and cell line transcriptomes co-classified with those of human NC. BRD4–NUT also blocked differentiation and maintained the growth of mNC as in hNC. Mechanistically, GEMM primary tumors and cell lines formed large histone H3K27ac-enriched domains, termed megadomains, that were invariably associated with the expression of key NC-defining proto-oncogenes, Myc and Trp63. Small-molecule BET bromodomain inhibition (BETi) of mNC induced differentiation and growth arrest and prolonged survival of NC GEMMs, as it does in hNC models. Overall, tumor formation in the NC GEMM is definitive evidence that BRD4–NUT alone can potently drive the malignant transformation of squamous progenitor cells into NC.
Significance:
The development of an immunocompetent model of NUT carcinoma that closely mimics the human disease provides a valuable global resource for mechanistic and preclinical studies to improve treatment of this incurable disease.
Data from Combinatorial Treatment with PARP and MAPK Inhibitors Overcomes Phenotype Switch-Driven Drug Resistance in Advanced Melanoma
Authors: Ferretti Lorenza P. , Böhi Flurina , Leslie Pedrioli Deena M. , Cheng Phil F. , Ferrari Elena , Baumgaertner Petra , Alvarado-Diaz Abdiel , Sella Federica , Cereghetti Alessandra , Turko Patrick , Wright Roni H. , De Bock Katrien , Speiser Daniel E. , Ferrari Roberto , Levesque Mitchell P. , Hottiger Michael O.
Published: December 2023

Abstract
Metastatic melanoma is either intrinsically resistant or rapidly acquires resistance to targeted therapy treatments, such as MAPK inhibitors (MAPKi). A leading cause of resistance to targeted therapy is a dynamic transition of melanoma cells from a proliferative to a highly invasive state, a phenomenon called phenotype switching. Mechanisms regulating phenotype switching represent potential targets for improving treatment of patients with melanoma. Using a drug screen targeting chromatin regulators in patient-derived three-dimensional MAPKi-resistant melanoma cell cultures, we discovered that PARP inhibitors (PARPi) restore sensitivity to MAPKis, independent of DNA damage repair pathways. Integrated transcriptomic, proteomic, and epigenomic analyses demonstrated that PARPis induce lysosomal autophagic cell death, accompanied by enhanced mitochondrial lipid metabolism that ultimately increases antigen presentation and sensitivity to T-cell cytotoxicity. Moreover, transcriptomic and epigenetic rearrangements induced by PARP inhibition reversed epithelial–mesenchymal transition-like phenotype switching, which redirected melanoma cells toward a proliferative and MAPKi-sensitive state. The combination of PARP and MAPKis synergistically induced cancer cell death both in vitro and in vivo in patient-derived xenograft models. Therefore, this study provides a scientific rationale for treating patients with melanoma with PARPis in combination with MAPKis to abrogate acquired therapy resistance.
Significance:
PARP inhibitors can overcome resistance to MAPK inhibitors by activating autophagic cell death and reversing phenotype switching, suggesting that this synergistic combination could help improve the prognosis of patients with melanoma.
Adipose Triglyceride Lipase Is a Therapeutic Target in Advanced Prostate Cancer That Promotes Metabolic Plasticity
Authors: Awad Dominik , Cao Pham Hong Anh , Pulliam Thomas L. , Spradlin Meredith , Subramani Elavarasan , Tellman Tristen V. , Ribeiro Caroline F. , Muzzioli Riccardo , Jewell Brittany E. , Pakula Hubert , Ackroyd Jeffrey J. , Murray Mollianne M. , Han Jenny J. , Leng Mei , Jain Antrix , Piyarathna Badrajee , Liu Jingjing , Song Xingzhi , Zhang Jianhua , Klekers Albert R. , Drake Justin M. , Ittmann Michael M. , Coarfa Cristian , Piwnica-Worms David , Farach-Carson Mary C. , Loda Massimo , Eberlin Livia S. , Frigo Daniel E.
Published: December 2023

Lipid metabolism plays a central role in prostate cancer. To date, the major focus has centered on de novo lipogenesis and lipid uptake in prostate cancer, but inhibitors of these processes have not benefited patients. A better understanding of how cancer cells access lipids once they are created or taken up and stored could uncover more effective strategies to perturb lipid metabolism and treat patients. Here, we identified that expression of adipose triglyceride lipase (ATGL), an enzyme that controls lipid droplet homeostasis and a previously suspected tumor suppressor, correlates with worse overall survival in men with advanced, castration-resistant prostate cancer (CRPC). Molecular, genetic, or pharmacologic inhibition of ATGL impaired human and murine prostate cancer growth in vivo and in cell culture or organoids under conditions mimicking the tumor microenvironment. Mass spectrometry imaging demonstrated that ATGL profoundly regulates lipid metabolism in vivo, remodeling membrane composition. ATGL inhibition induced metabolic plasticity, causing a glycolytic shift that could be exploited therapeutically by cotargeting both metabolic pathways. Patient-derived phosphoproteomics identified ATGL serine 404 as a target of CAMKK2–AMPK signaling in CRPC cells. Mutation of serine 404 did not alter the lipolytic activity of ATGL but did decrease CRPC growth, migration, and invasion, indicating that noncanonical ATGL activity also contributes to disease progression. Unbiased immunoprecipitation/mass spectrometry suggested that mutation of serine 404 not only disrupts existing ATGL protein interactions but also leads to new protein–protein interactions. Together, these data nominate ATGL as a therapeutic target for CRPC and provide insights for future drug development and combination therapies.

Significance:

ATGL promotes prostate cancer metabolic plasticity and progression through both lipase-dependent and lipase-independent activity, informing strategies to target ATGL and lipid metabolism for cancer treatment.
Serial Circulating Tumor DNA Analysis with a Tumor-Naïve Next-Generation Sequencing Panel Detects Minimal Residual Disease and Predicts Outcome in Ovarian Cancer
Authors: Heo Jinho , Kim Yoo-Na , Shin Saeam , Lee Kyunglim , Lee Ji-Hyun , Lee Yong Jae , Choi Zisun , Park Jihyang , Min Seungki , Kim Sang Wun , Choi Jong Rak , Kim Sunghoon , Lee Seung-Tae , Lee Jung-Yun
Published: December 2023

Circulating tumor DNA (ctDNA) may aid in personalizing ovarian cancer therapeutic options. Here, we aimed to assess the clinical utility of serial ctDNA testing using tumor-naïve, small-sized next-generation sequencing (NGS) panels. A total of 296 patients, including 201 with ovarian cancer and 95 with benign or borderline disease, were enrolled. Samples were collected at baseline (initial diagnosis or surgery) and every 3 months after that, resulting in a total of 811 blood samples. Patients received adjuvant therapy based on the current standard of care. Cell-free DNA was extracted and sequenced using an NGS panel of 9 genes: TP53, BRCA1, BRCA2, ARID1A, CCNE1, KRAS, MYC, PIK3CA, and PTEN. Pathogenic somatic mutations were identified in 69.2% (139/201) of patients with ovarian cancer at baseline but not in those with benign or borderline disease. Detection of ctDNA at baseline and/or at 6 months follow-up was predictive of progression-free survival (PFS). PFS was significantly poorer in patients with detectable pathogenic mutations at baseline that persisted at follow-up than in patients that converted from having detectable ctDNA at baseline to being undetectable at follow-up; survival did not differ between patients without pathogenic ctDNA mutations in baseline or follow-up samples and those that converted from ctDNA positive to negative. Disease recurrence was also detected earlier with ctDNA than with conventional radiologic assessment or CA125 monitoring. These findings demonstrate that serial ctDNA testing could effectively monitor patients and detect minimal residual disease, facilitating early detection of disease progression and tailoring of adjuvant therapies for ovarian cancer treatment.

Significance:

In ovarian cancer, serial circulating tumor DNA testing is a highly predictive marker of patient survival, with a significantly improved recurrence detection lead time compared with conventional monitoring tools.
Table S8 from Cancer Prevalence Projections in Japan and Decomposition Analysis of Changes in Cancer Burden, 2020–2050: A Statistical Modeling Study
Authors: Nguyen Phuong The , Hori Megumi , Matsuda Tomohiro , Katanoda Kota
Published: December 2023

Site-specific projections of 5-year prevalence count in 2020, 2030, 2040 and 2050
Table S2 from Cancer Incidence and Mortality Estimates in Arab Countries in 2018: A GLOBOCAN Data Analysis
Authors: Al-Muftah Mariam , Al-Ejeh Fares
Published: December 2023

Table S2: Pivot table which can be queried for cancer incidence and mortality across different age groups in Arab countries and the data for the world, the USA and Europe. The table also includes different subregions in the Arab region. The table is based on the data extracted from the GLOBOCAN 2018 web database supplied in Table S1 in this study.
Table S4 from Genome-Wide Association and Two-Sample Mendelian Randomization Analyses of Plasma Ghrelin and Gastrointestinal Cancer Risk
Authors: Larsson Susanna C. , Höijer Jonas , Sun Jing , Li Xue , Burgess Stephen , Michaëlsson Karl
Published: December 2023

Colocalization analysis results for plasma ghrelin and gastrointestinal cancer in the UK Biobank at the GHRL locus
Table S2 from Genome-Wide Association and Two-Sample Mendelian Randomization Analyses of Plasma Ghrelin and Gastrointestinal Cancer Risk
Authors: Larsson Susanna C. , Höijer Jonas , Sun Jing , Li Xue , Burgess Stephen , Michaëlsson Karl
Published: December 2023

Power calculations
Supplementary Table S1 from Efficacy of Nivolumab in Pediatric Cancers with High Mutation Burden and Mismatch Repair Deficiency
Authors: Das Anirban , Tabori Uri , Sambira Nahum Lauren C. , Collins Natalie B. , Deyell Rebecca , Dvir Rina , Faure-Conter Cecile , Hassall Timothy E. , Minturn Jane E. , Edwards Melissa , Brookes Elissa , Bianchi Vanessa , Levine Adrian , Stone Simone C. , Sudhaman Sumedha , Sanchez Ramirez Santiago , Ercan Ayse B. , Stengs Lucie , Chung Jill , Negm Logine , Getz Gad , Maruvka Yosef E. , Ertl-Wagner Birgit , Ohashi Pamela S. , Pugh Trevor , Hawkins Cynthia , Bouffet Eric , Morgenstern Daniel A.
Published: December 2023

Representativeness of Study Participants
Supplementary Table S2 from Comparative Genomic Analysis and Clinical Outcomes of BRAF-mutated Advanced Biliary Tract Cancers
Authors: Tang Tin-Yun , Nichetti Federico , Kaplan Ben , Lonardi Sara , Pietrantonio Filippo , Salvatore Lisa , Vivaldi Caterina , Rimassa Lorenza , de Braud Filippo , Rizzato Mario Domenico , Pavlick Dean , Chu Randy , Danner De Armas Anaemy , Sharaf Radwa , Sokol Ethan , Rodon Ahnert Jordi , Ross Jeffrey S. , Javle Milind , Niger Monica
Published: December 2023

Supplemental Table S2: Categorical Variables Used for the Comparative Genomics Analyses
Supp Table 5 from ATM Mutations Associate with Distinct Co-Mutational Patterns and Therapeutic Vulnerabilities in NSCLC
Authors: Vokes Natalie I. , Galan Cobo Ana , Fernandez-Chas Margarita , Molkentine David , Treviño Santiago , Druker Vitaly , Qian Yu , Patel Sonia , Schmidt Stephanie , Hong Lingzhi , Lewis Jeff , Rinsurongkawong Waree , Rinsurongkawong Vadeerat , Lee J. Jack , Negrao Marcelo V. , Gibbons Don L. , Vaporciyan Ara , Le Xiuning , Wu Jia , Zhang Jianjun , Rigney Una , Iyer Sonia , Dean Emma , Heymach John V.
Published: December 2023

Supp Table 5. Flatiron Health-Foundation Medicine Clinicogenomic Database (FH-FMI CGDB) cohort characteristics, overall and stratified by treatment with chemotherapy along (Chemo), immune checkpoint inhibitor monotherapy (ICI), or combination ICI with chemotherapy (ICI-chemo)
Supplementary Figure S2 from C-X-C Motif Chemokine Ligand 9 Correlates with Favorable Prognosis in Triple-Negative Breast Cancer by Promoting Immune Cell Infiltration
Authors: Cao Xi , Song Yu , Wu Huanwen , Ren Xinyu , Sun Qiang , Liang Zhiyong
Published: December 2023

Supplementary Figure S2 shows the Kaplan-Meier survival of (A) Disease-free survival (DFS) and (B) Overall survival (OS) according to CXCL9 mRNA expression level in basal-like subtype of TCGA BRCA cohort (n=138).
Supplementary Figure 4 from Microtubule-Targeting Combined with HDAC Inhibition Is a Novel Therapeutic Strategy for Diffuse Intrinsic Pontine Gliomas
Authors: Ehteda Anahid , Khan Aaminah , Rajakumar Gayathiri , Vanniasinghe Anne S. , Gopalakrishnan Anjana , Liu Jie , Tsoli Maria , Ziegler David S.
Published: December 2023

SAHA significantly affects alpha acetyl tubulin and HDAC6
levels in DIPG.
Abstract B095: Sacituzumab govitecan-based drug combinations overcome platinum/PARP inhibitor resistance in ovarian cancer models
Authors: Conlon Neil T , Möhrle Elena , Stockmann Luna , Crown John
Published: December 2023

Background: Ovarian cancer causes more deaths than any other gynaecological cancer per year in the USA. Sacituzumab govitecan (SG) is a TROP2-targeted antibody-drug conjugate, approved for the treatment of triple-negative and hormone receptor-positive breast cancers. TROP2 is commonly overexpressed in ovarian cancer and represents an attractive, potential therapeutic target in ovarian cancer. This study investigated the in vitro activity of SG alone and in combination with targeted therapies/chemotherapies in ovarian cancer cell line models.

Methods: This study utilized the PEO1 and PEO4 cell lines, which were derived from the same patient, with PEO4 acquiring a secondary restorative BRCA2 mutation to confer platinum resistance. Olaparib-resistant PEO1 (PEO1-Ola) cells were generated through continuous exposure to olaparib, to a maximum 13 μM, for four months. The anti-proliferative effects of SG, talazoparib, olaparib, carboplatin, and paclitaxel were tested in PEO1, PEO1-Ola, and PEO4 cell lines. Synergism was assessed using Combenefit software with the Loewe additivity model. Induction of caspase 3/7 activation, a marker of apoptosis, was tested with single agents and combinations using kinetic, fluorescent microscopy with the Incucyte S3 imaging system.

Results: Olaparib and carboplatin resistance did not result in their cross-resistance. PEO1-Ola showed similar sensitivity to carboplatin as PEO1 parental cells, while carboplatin-resistant PEO4 cells displayed clinically achievable sensitivity to olaparib and talazoparib. SG was highly effective in all models tested. SG in combination with carboplatin or talazoparib was synergistic across all cell lines and resulted in induction of apoptosis.

Conclusions: This pre-clinical study showed that TROP2-targeting ADC-based drug combinations warrant further investigation for the treatment of ovarian cancer.

Citation Format: Neil T Conlon, Elena Möhrle, Luna Stockmann, John Crown. Sacituzumab govitecan-based drug combinations overcome platinum/PARP inhibitor resistance in ovarian cancer models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B095.
Abstract LB_C14: EAI-432: A mutant-selective allosteric EGFR inhibitor for L858R-mutant non-small cell lung cancer
Authors: Eck Michael J. , Scott David A. , Janne Pasi , Beyett Tyler S. , Jiang Jie , Gokhale Praful , Gero Thomas W.
Published: December 2023

While osimertinib is highly efficacious in lung cancers with sensitizing mutations in EGFR, there is a major unmet need for agents that overcome resistance to it and other covalent third-generation EGFR TKIs due to the C797S mutation. Furthermore, osimertinib extends overall survival in patients with exon19 deletions but offers little improvement in overall survival in patients with the L858R mutation relative to the first-generation inhibitors. We are developing EAI-432 with the goal of improving outcomes for patients with EGFRL858R+ lung cancer. EAI-432 is a mutant-selective allosteric inhibitor that is effective against L858R and its common resistance variants, L858R/T790M, L858R/C797S, and L858R/T790M/C797S while sparing WT EGFR. The compound induces tumor regressions in a L858R/T790M/C797S mouse xenograft model at low doses (5 mg/kg). In the H1975 (L858R/T790M) xenograft model, EAI-432 induced marked tumor regressions in both subcutaneous and intracranial implants. EAI-432 co-binds with osimertinib, allowing double-drugging of the mutant receptor. The distinct binding site and allosteric mechanism of EAI-432 are expected to confer exquisite kinome-wide selectivity and orthogonal resistance mechanisms as compared with osimertinib and other ATP-competitive TKIs, properties that are highly desirable in a combination agent. The compound has efficacy, mutant-selectivity, and pharmacokinetic properties including brain-penetrance that support its further development as a therapeutic agent for EGFRL858R+ lung cancer alone or in combination with osimertinib.

Citation Format: Michael J. Eck, David A. Scott, Pasi Janne, Tyler S. Beyett, Jie Jiang, Praful Gokhale, Thomas W. Gero. EAI-432: A mutant-selective allosteric EGFR inhibitor for L858R-mutant non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C14.
Supplementary Figure 8 from Competing Engagement of β-arrestin Isoforms Balances IGF1R/p53 Signaling and Controls Melanoma Cell Chemotherapeutic Responsiveness
Authors: Cismas Sonia , Pasca Sylvya , Crudden Caitrin , Trocoli Drakensjo Iara , Suleymanova Naida , Zhang Simin , Gebhard Benjamin , Song Dawei , Neo Shiyong , Shibano Takashi , Smith Terry J. , Calin George A. , Girnita Ada , Girnita Leonard
Published: December 2023

Effect of β-arrestin isoform imbalance on survival of patients with metastatic melanoma.
Supplementary Figure 5 from Competing Engagement of β-arrestin Isoforms Balances IGF1R/p53 Signaling and Controls Melanoma Cell Chemotherapeutic Responsiveness
Authors: Cismas Sonia , Pasca Sylvya , Crudden Caitrin , Trocoli Drakensjo Iara , Suleymanova Naida , Zhang Simin , Gebhard Benjamin , Song Dawei , Neo Shiyong , Shibano Takashi , Smith Terry J. , Calin George A. , Girnita Ada , Girnita Leonard
Published: December 2023

Rescue-validation of β-arrestin imbalance effects on MDM2-dependent IGF1R expression.
Figure S1 from BACH1 Loss Exerts Antitumor Effects on Mantle Cell Lymphoma Cells via Inducing a Tumor-Intrinsic Innate Immune Response and Cell-Cycle Arrest
Authors: Li Guilan , Feng Min , Zhang Ziting , Liu Jiangyuan , Zhang Han
Published: December 2023

Figure S1 shows the cell apoptosis of the overexpressed MCL cells at day 2.
Supplementary Methods from Interleukin-6 Facilitates Acute Myeloid Leukemia Chemoresistance via Mitofusin 1–Mediated Mitochondrial Fusion
Authors: Hou Diyu , Zheng Xiaoming , Cai Danni , You Ruolan , Liu Jingru , Wang Xiaoting , Liao Xinai , Tan Maoqing , Lin Liyan , Wang Jin , Zhang Shuxia , Huang Huifang
Published: December 2023

Lentivirus-mediated STAT3 knockout and MFN1 overexpression
Supplementary Table S1 from Effective Antitumor Immunity Can Be Triggered by Targeting VISTA in Combination with a TLR3-Specific Adjuvant
Authors: Wang Bo , Ou Ziwei , Zhong Wenlong , Huang Lin , Liao Wenjian , Sheng Yiyu , Guo Zhixing , Chen Junyu , Yang Wenjuan , Chen Ke , Huang Xiaodong , Yang Tenghao , Lin Tianxin , Huang Jian
Published: December 2023

Clinicopathological characteristics of Cohort Ⅰ patients with urothelial cell carcinoma of the bladder
Supplementary Figure S2 from Effective Antitumor Immunity Can Be Triggered by Targeting VISTA in Combination with a TLR3-Specific Adjuvant
Authors: Wang Bo , Ou Ziwei , Zhong Wenlong , Huang Lin , Liao Wenjian , Sheng Yiyu , Guo Zhixing , Chen Junyu , Yang Wenjuan , Chen Ke , Huang Xiaodong , Yang Tenghao , Lin Tianxin , Huang Jian
Published: December 2023

Overall survival (OS) was analyzed with the Kaplan-Meier method stratifying 144 Cohort II UCB patients according to high or low levels of VISTA+ endothelial cells (ECs, A), or tumor cells (TCs, B)
Figure S6 from Tumor-Reactive CD8+ T Cells Enter a TCF1+PD-1− Dysfunctional State
Authors: Roetman Jessica J. , Erwin Megan M. , Rudloff Michael W. , Favret Natalie R. , Detrés Román Carlos R. , Apostolova Minna K.I. , Murray Kristen A. , Lee Ting-Fang , Lee Youngmin A. , Philip Mary
Published: December 2023

SST persisting in non-tumor bearing mice are memory-like but lack effector function.
Figure S3 from Tumor-Reactive CD8+ T Cells Enter a TCF1+PD-1− Dysfunctional State
Authors: Roetman Jessica J. , Erwin Megan M. , Rudloff Michael W. , Favret Natalie R. , Detrés Román Carlos R. , Apostolova Minna K.I. , Murray Kristen A. , Lee Ting-Fang , Lee Youngmin A. , Philip Mary
Published: December 2023

SST in ASTxGAG mice with premalignant liver lesions lose effector function.
Figure S2 from Tumor-Reactive CD8+ T Cells Enter a TCF1+PD-1− Dysfunctional State
Authors: Roetman Jessica J. , Erwin Megan M. , Rudloff Michael W. , Favret Natalie R. , Detrés Román Carlos R. , Apostolova Minna K.I. , Murray Kristen A. , Lee Ting-Fang , Lee Youngmin A. , Philip Mary
Published: December 2023

SST and TST upregulate CD69 upon co-culture with ASTxGAG hepatocytes.
Figure S1 from A Metabolic Gene Survey Pinpoints Fucosylation as a Key Pathway Underlying the Suppressive Function of Regulatory T Cells in Cancer
Authors: Pinioti Sotiria , Sharma Himal , Flerin Nina C. , Yu Qian , Tzoumpa Amalia , Trusso Cafarello Sarah , De Bousser Elien , Callewaert Nico , Oldenhove Guillaume , Schlenner Susan , Thienpont Bernard , Garg Abhishek D. , Di Matteo Mario , Mazzone Massimiliano
Published: December 2023

Gating strategy and quality controls of the CRISPR/Cas9 screen. Related to Figure 1. (A) Sorting strategy of the screening. (B) Sorted populations 1, 2, 3 and 4 were analyzed by NGS and the pooled populations 1+2 = Foxp3high and 3+4 = Foxp3low were analyzed bioinformatically. The screening was repeated twice and the data represent the pool of the data from the 2 replicates. QCs for each sample from the first replication (NGS1) and from the second replication (NGS2). (C) Number of reads per sample for both repetitions of the screening mentioned as NGS1 and NGS. (D) Log10 of missed gRNAs per sample for both repetitions of the screening mentioned as NGS1 and NGS. (E) Gini index for each sample measuring inequality between read counts. (F) Distribution of normalized read counts for each sample.
Data from Antigen Priming Induces Functional Reprogramming in iNKT Cells via Metabolic and Epigenetic Regulation: An Insight into iNKT Cell-Based Antitumor Immunotherapy
Authors: Zhang Huimin , Chen Sanwei , Zhang Yuwei , Tian Chenxi , Pan Jun , Wang Yu , Bai Shiyu , Wu Qielan , Su Miya , Xie Di , Fu Sicheng , Li Shuhang , Zhang Jing , Chen Yusheng , Zhu Shasha , Qian Yeben , Bai Li
Published: December 2023

Abstract
Dysfunction of intratumoral invariant natural killer T (iNKT) cells hinders their antitumor efficacy, but the underlying mechanisms and the relationship with endogenous antigen priming remain to be explored. Here, we report that antigen priming leads to metabolic reprogramming and epigenetic remodeling, which causes functional reprogramming in iNKT cells, characterized by limited cytokine responses upon restimulation but constitutive high cytotoxicity. Mechanistically, impaired oxidative phosphorylation (OXPHOS) in antigen-primed iNKT cells inhibited T-cell receptor signaling, as well as elevation of glycolysis, upon restimulation via reducing mTORC1 activation, and thus led to impaired cytokine production. However, the metabolic reprogramming in antigen-primed iNKT cells was uncoupled with their enhanced cytotoxicity; instead, epigenetic remodeling explained their high expression of granzymes. Notably, intratumoral iNKT cells shared similar metabolic reprogramming and functional reprogramming with antigen-primed iNKT cells due to endogenous antigen priming in tumors, and thus recovery of OXPHOS in intratumoral iNKT cells by ZLN005 successfully enhanced their antitumor responses. Our study deciphers the influences of antigen priming-induced metabolic reprogramming and epigenetic remodeling on functionality of intratumoral iNKT cells, and proposes a way to enhance efficacy of iNKT cell-based antitumor immunotherapy by targeting cellular metabolism.
Supplementary Figure 18 from CAR T-cell Design-dependent Remodeling of the Brain Tumor Immune Microenvironment Modulates Tumor-associated Macrophages and Anti-glioma Activity
Authors: Haydar Dalia , Ibañez-Vega Jorge , Crawford Jeremy Chase , Chou Ching-Heng , Guy Clifford S. , Meehl Michaela , Yi Zhongzhen , Perry Scott , Laxton Jonathan , Cunningham Trevor , Langfitt Deanna , Vogel Peter , DeRenzo Christopher , Gottschalk Stephen , Roussel Martine F. , Thomas Paul G. , Krenciute Giedre
Published: December 2023

Supplementary Figure S18 shows BLZ945 effect on CAR T cells in media and in co-culture with GL261-KO cells.
Total Hydrocortisone Dosage in the Neonatal Period May Be Related to Low Developmental Quotient in Extremely Low Birth Weight Infants: A Retrospective Cohort Study
Authors: Taniguchi Akinobu , Nishida Kazuki , Suzuki Toshihiko , Kataoka Erina , Fujishiro Naozumi , Kato Eiko , Yamamoto Hikaru , Takemoto Koji , Ito Miharu , Hayashi Seiji , Sugiyama Yuichiro , Maeda Takashi , Takahashi Yoshiyuki , Sato Yoshiaki
Published: December 2023

Introduction: The effects of hydrocortisone (HDC) administration to extremely low birth weight (ELBW) infants on later development remain unclear. This study examined the association between HDC dosage during neonatal period and neurodevelopmental outcomes in ELBW infants. Methods: This study was a retrospective cohort study conducted in eight centers in Japan. The subjects of this study were ELBW infants born between April 2015 and March 2017. The association between postnatal total HDC dosage up to 36 weeks postmenstrual age and the developmental quotient (DQ) at 3 years of age was examined. Multiple linear regression evaluated the association, adjusting for weeks of gestation, birth weight, and the presence of bronchopulmonary dysplasia, late-onset circulatory collapse, intracranial hemorrhage, necrotizing enterocolitis, and sepsis. Results: This study included 218 ELBW infants, of whom 144 underwent a developmental test at 3 years of age. Simple linear regression analysis revealed a significant association between total HDC dosage and DQ at 3 years of age (coefficients: −2.65, 95% CI: −3.73, −1.57). Multiple linear regression analysis adjusted for the presence of bronchopulmonary dysplasia and late-onset circulatory collapse also revealed a significant association between total HDC dosage and DQ at 3 years of age (coefficients: −2.66, 95% CI: −3.89, −1.42). Conclusion: Higher total HDC dosage up to 36 weeks postmenstrual age in ELBW infants was associated with impaired neurodevelopmental outcomes. Although HDC is often needed in the treatment of ELBW infants, clinicians should be aware that an increased dose of HDC may be associated with impaired neurodevelopmental outcomes.
The Effects of Mindfulness for Youth (MYmind) versus Group Cognitive Behavioral Therapy in Improving Attention and Reducing Behavioral Problems among Children with Attention-Deficit Hyperactivity Disorder and Their Parents: A Randomized Controlled Trial
Authors: Wong Samuel Yeung Shan , Chan Stanley Kam Chung , Yip Benjamin Hon Kei , Wang Wenyue , Lo Herman Hay Ming , Zhang Dexing , Bögels Susan M.
Published: December 2023

Introduction: There is a lack of studies evaluating mindfulness-based interventions for children with attention-deficit hyperactivity disorder (ADHD) compared with an evidence-based control. This randomized controlled trial (RCT) evaluated the effects of mindfulness for youth (MYmind) in improving children’s attention, behavior, and parent-related outcomes versus cognitive behavioral therapy (CBT). Methods: A total of 138 families of children with ADHD aged 8–12 years were recruited from the community with 69 randomized to MYmind and 69 to CBT. Participants were assessed at baseline, immediately after intervention, at 3 months and 6 months. The primary outcome was the attention score of the Sky Search subtest of the Test of Everyday Attention for Children (TEA-Ch). Secondary outcomes were child behavior and parent-related assessments. Linear mixed models were used to assess the efficacy of MYmind compared with CBT. Results: Both MYmind and CBT significantly improved children’s attention score at 6 months (MYmind: β = 1.48, p = 0.013, Cohen’s d = 0.32; CBT: β = 1.46, p = 0.008, d = 0.27). There were significant within-group improvements in most secondary outcomes. No significant difference was shown for both primary or secondary outcomes between the two arms at any time point. Conclusions: Both MYmind and CBT appeared to improve children’s attention and behavior outcomes, although no difference was found between these two interventions. This is the largest RCT so far comparing MYmind and CBT although there was loss of follow-up assessments during the pandemic. Further RCTs adopting a non-inferiority design are needed to validate the results.
Adherence to the Mediterranean Diet Is Associated with Decreased Fecal Calprotectin Levels in Children with Crohn’s Disease in Clinical Remission under Biological Therapy
Authors: Sigall Boneh Rotem , Assa Amit , Lev-Tzion Raffi , Matar Manar , Shouval Dror , Shubeli Chen , Tsadok Perets Tsachi , Chodick Gabriel , Shamir Raanan
Published: December 2023

Introduction: Adherence to the Mediterranean diet (MD) was shown to be associated with decreased disease activity in adult patients with Crohn’s disease (CD). Nevertheless, data on its association with fecal calprotectin (FC), particularly in children, remain limited. This study aimed to assess the association between adherence to the MD and FC as an indicator of mucosal healing in patients who are predominantly in remission while undergoing biological therapy. Methods: This was a cross-sectional study among children with CD. Adherence to MD was evaluated using both the KIDMED questionnaire and a food frequency questionnaire (FFQ). Israeli Mediterranean Diet Adherence Screener (I-MEDAS) score was calculated, and FC samples were obtained. Results: Of 103 eligible patients, 99 were included (mean age 14.3 ± 2.6 years; 38.4% females); 88% were in clinical remission, and 30% presented with elevated FC. The mean KIDMED score was higher among patients who had FC <200 μg/g compared to patients with FC >200 μg/g (5.48 ± 2.58 vs. 4.37 ± 2.47, respectively; p = 0.04). A moderate correlation between the KIDMED score and the I-MEDAS score was observed (r = 0.46; p = 0.001). In a multivariate regression analysis, adherence to MD was associated with decreased calprotectin levels, OR 0.75 [95% CI: 0.6–0.95], p = 0.019. Vegetable consumption was found to be inversely associated with elevated FC (0.9 portion/day [0.3–2.9] in FC >200 μg/g vs. 2.2 portions/day [0.87–3.82] in FC <200 μg/g; p = 0.049). Conclusions: In children with CD who are mostly in clinical remission under biological therapy, high adherence to MD is associated with decreased FC levels. Encouraging vegetable consumption, especially during remission, may benefit these patients.
Classification of six banana ripeness levels based on statistical features on machine learning approach
Authors: Kosasih Rifki , Sudaryanto Sudaryanto , Fahrurozi Achmad
Published: December 2023

Banana plants are often cultivated because they have many benefits. In producing, we need to maintain the quality of bananas by looking at banana ripeness levels before being distributed to markets. The level of banana ripeness is related to marketing reach. If the marketing reach is far, bananas should be harvested when the ripeness level of bananas is still relatively low. A system that can classify the degree of ripeness of bananas can help overcome this problem. In this study, our dataset includes 6 ripeness levels of bananas, more than in previous related studies. Furthermore, we use the statistical features extraction method to find the parameters that affect the level of banana ripeness, considering the texture and color of the banana peel which determines the level of ripeness visually. The extraction used is features extraction based on a histogram, then we employ four features, i.e., mean, skewness, energy descriptor, and smoothness, generated from the image dataset. In the next stage, we perform classification based on the features that have been obtained. In this study, we use Naive Bayes classifier and support vector machine (SVM) algorithms. Based on the result of this research, the best performance is the Naive Bayes classifier, with an accuracy is 86.67%, a weighted average precision of 83.55%, and a weighted average recall of 86.67%.
Double step method in lipid extraction from biomass Aurantiochytrium sp powder
Authors: Sulistiawati Endah , Suhendra Suhendra , Setyawan Martomo , Mahsunah Anis Herliyati
Published: December 2023

Aurantiochytrium sp is a marine microalgae that is rich in lipids. Extraction of lipids from microalgae requires effort to select a suitable solvent and extraction method. This research used a double-step extraction method to study a mixture of n-hexane and methanol as a solvent. The variables studied were stirring time, the n-hexane to methanol (H/M) mixture ratio, and the solvent-to-biomass ratio (S/B). This research concluded that an optimum stirring time was 30 min, and a mixture of n-hexane and methanol solvents with a volume ratio of 1:1 is optimum. The optimum solvent-to-biomass ratio was S/B=20 mL/g dry microalgae. Under these conditions, the yield of oil was 83.88%. Double-step extraction can increase the yield by 10-40%.
Clinical, epidemiological, and laboratory profiles of bacterial infection or colonization among patients hospitalized in COVID-19 and non-COVID-19 intensive care units (ICUs) in Southeast Pará
Authors: Ribeiro Edlainny Araujo , Mundoca Mateus Pereira , Cachoeira Mateus Taborda , Nobre Luana Lopes , Rocha Marcia Juciele da
Published: December 2023

Objectives: To compare the clinical, epidemiological, and laboratory profiles of bacterial infection or colonization among patients hospitalized in COVID-19 and non-COVID-19 intensive care units (ICUs) in Southeast Pará, Brazil. Methods: This was a retrospective analytical study based on the analyses of electronic medical records and microbiological reports of patients admitted to the ICU of a regional hospital located in Pará in the Brazilian Amazon due to complications associated with COVID-19 and other causes from March 2020 to December 2021. The sample consisted of data from the medical records of 343 patients collected after approval by the ethics and research committee (opinion number 5281433)was granted. The data extracted from the bacteriological and antibiogram culture reports were analyzed to characterize the clinical-epidemiological profile of the patients. The data were transferred and tabulated in Microsoft Excel 2019 to conduct a descriptive analysis, and the associated statistical analyses were performed using Stata 17.0 statistical software. Results: Of the total patients, 59.5% were hospitalized in the COVID-19 ICU and 40.5% were hospitalized in the non-COVID-19 ICU. Most individuals admitted to the COVID-19 ICU and non-COVID-19 ICU were aged between 66 and 78 years and between 54 and 66 years, respectively. The hospitalization duration in the COVID-19 ICU was fewer than 15 days, whereas that in the non COVID-19 ICU was 15 to 30 days. Deaths were more frequent in the Covid-19 ICU compared to the non-Covid-19 ICU (64% versus 41%). In contrast, hospital discharge was more frequent in the non-Covid-19 ICU (58.3% versus 34.8%).The most prevalent comorbidity in both ICUs was circulatory system disease. Gram-negative bacteria were the most frequent etiological agent in both groups and were present in 63.1% of the cultures analyzed. Regarding the phenotypic profile of resistance, carbapenemase production was detected in 43.0% of the cultures analyzed. Multidrug resistance against antimicrobial drugs was more frequent in the non-COVID-19 ICU(55.7%). Most of the antimicrobial drug prescriptions for were empirical. Conclusions: The recurrence of secondary infections and bacterial colonization in both COVID-19 and non-COVID-19 ICU patients should not be underestimated. The clinical, microbiological, and bacterial resistance profiles elucidated in this study highlight the need to develop and implement holistic and assertive strategies to control and mitigate these problems. Which will contribute to an improved prognosis for patients and quality of life patients.
Agreement Between Guideline Thresholds Using an “All‐in‐One” Device to Measure Office, Home, and Ambulatory Blood Pressures
Authors: Kario Kazuomi , Tomitani Naoko , Hoshide Satoshi , Nishizawa Masafumi , Yoshida Tetsuro , Kabutoya Tomoyuki , Fujiwara Takeshi , Mizuno Hiroyuki ,   the HI‐JAMP Study Group
Published: December 2023

Background

Blood pressure (BP) thresholds for diagnosing and managing hypertension vary for office, home, and ambulatory readings, and between guideline documents. This analysis determined corresponding office, home, and ambulatory BP thresholds using baseline data from the HI‐JAMP (Home‐Activity Information and Communication Technology–Based Japan Ambulatory Blood Pressure Monitoring Prospective) study, which used a validated “all‐in‐one” BP monitoring device.

Methods and Results

Data from 2322 treated patients with hypertension who underwent office BP measurement, then 24‐hour ambulatory BP monitoring, then home BP monitoring for 5 days were analyzed. Corresponding BP thresholds for office, home, and ambulatory measurements were determined using Deming regression. Values equivalent to office systolic BP (SBP) of 120 and 140 mm Hg were as follows: 115.9 and 127.7 mm Hg for 24‐hour ambulatory SBP; 120.8 and 134.0 mm Hg for daytime ambulatory SBP; 104.9 and 117.9 mm Hg for nighttime ambulatory SBP; and 122.0 and 134.2 mm Hg for morning‐evening average home SBP. Deming regression showed that morning‐evening average home SBP and daytime ambulatory SBP were almost the same (home SBP=0.99×daytime ambulatory SBP+0.27 mm Hg;
r
=0.627). Morning‐evening average home SBP values of 120 and 135 mm Hg were equivalent to daytime ambulatory SBP values of 119.1 and 133.9 mm Hg, respectively. A home SBP threshold of 130 mm Hg corresponded to 24‐hour and nighttime ambulatory SBP values of 123.5 and 113.6 mm Hg, whereas a home SBP threshold of 135 mm Hg corresponded to 24‐hour and nighttime ambulatory SBP values of 128.0 and 119.2 mm Hg.

Conclusions

Ambulatory and home BP thresholds in this analysis were similar to those proposed by existing guidelines. The similarity between the home BP and daytime ambulatory BP thresholds was a clinically relevant finding.
Outside the Laboratory Assessment of Upper Limb Laterality in Patients With Stroke: A Cross-Sectional Study
Authors: Gulde Philipp , Vojta Heike , Schmidle Stephanie , Rieckmann Peter , Hermsdörfer Joachim
Published: December 2023

BACKGROUND:

The rehabilitation of upper limb sensorimotor performance after stroke requires the assessment of daily use, the identification of key levels of impairment, and monitoring the course of recovery. It needs to be answered, how laboratory-based assessments and everyday behavior are connected, which dimension of metrics, that is, volume, intensity, or quality, is most sensitive to reduced function, and what sensor, that is, gyroscope or accelerometer, is best suited to gather such data.

METHODS:

Performance in laboratory-based sensorimotor tests, as well as smartwatch-derived kinematic data of everyday life relative upper limb activity, during 1 day of inpatient neurorehabilitation (Germany, 2022) of 50 patients with stroke, was cross-sectionally assessed and resulting laterality indices (performance ratios) between the limbs were analyzed using ANCOVAs and principal component analysis.

RESULTS:

Laboratory-based tests revealed the strongest laterality indices, followed by smartwatch-based (intensity>quality>volume) metrics. Angular velocity-based metrics revealed higher laterality indices than acceleration-based ones. Laterality indices were overall well associated; however, a principal component analysis suggested upper limb impairments to be unidimensional.

CONCLUSIONS:

Our findings suggest that the use of sensors can deliver valid information of stroke-related laterality. It appeared that commonly used metrics that estimate the volume of use (ie, energy expenditure) are not the most sensitive. Especially reached intensities could be well used for monitoring, because they are more dependent on the performance of the sensorimotor system and less on confounders like age. The unidimensionality of the upper limb laterality suggests that an impaired limb with reduced movement quality and the inability to reach higher intensities will be used less in everyday life, especially when it is the nondominant side.
Development and Human Factors Evaluation of a Portable Auditory Localization Training System
Authors: Thompson Brandon S. , Lee Kichol , Casali John G. , Cave Kara M.
Published: December 2023

Objective

To design and develop a Portable Auditory Localization Acclimation Training (PALAT) system capable of producing psychoacoustically accurate localization cues; evaluate the training effect against a proven full-scale, laboratory-grade system under three listening conditions; and determine if the PALAT system is sensitive to differences among electronic level-dependent hearing protection devices (HPDs).

Background

In-laboratory auditory localization training has demonstrated the ability to improve localization performance with the open (natural) ear, that is, unoccluded, and while wearing HPDs. The military requires a portable system capable of imparting similar training benefits as those demonstrated in laboratory experiments.

Method

In a full-factorial repeated measures design experiment, 12 audiometrically normal participants completed localization training and testing using an identical, optimized training protocol on two training systems under three listening conditions (open ear, TEP-100, and ComTac™ III). Statistical tests were performed on mean absolute accuracy score and front-back reversal errors.

Results

No statistical difference existed between the PALAT and laboratory-grade DRILCOM systems on two dependent localization accuracy measurements at all stages of training. In addition, the PALAT system detected the same localization performance differences among the three listening conditions.

Conclusion

The PALAT system imparted similar training benefits as the DRILCOM system and was sensitive to HPD localization performance differences.

Application

The user-operable PALAT system and optimized training protocol can be employed by the military, law enforcement, and various industries, to improve auditory localization performance in conditions where auditory situation awareness is critical to safety.
Comparative Effectiveness of 2 Chlorhexidine Gluconate-Containing Dressings in Reducing Central Line-Associated Bloodstream Infections, Hospital Stay, and Costs
Authors: Hou Yuefeng , Griffin Leah , Bernatchez Stéphanie F. , Hommes Joseph , Kärpänen Tarja , Palka-Santini Maria
Published: December 2023

Chlorhexidine gluconate (CHG)-containing dressings are recommended to prevent central line associated bloodstream infections (CLABSIs) and other catheter-related infections. This study compared the effect of 2 CHG dressings on CLABSI, cost of care, and contact dermatitis. A retrospective analysis was conducted using the Premier Healthcare Database of hospitalized patients (n = 53 149) with central venous catheters (CVCs) and receiving either a transparent CHG gel dressing (n = 14 488) or an opaque CHG sponge dressing (n = 38 661) between January 2019 and September 2020. Two cohorts (n = 14 488 each), CHG-Gel and CHG-Sponge, were matched 1:1 using a propensity score method on 33 patient and facility characteristics. CLABSI and contact dermatitis rates, hospital length of stay (LOS), and hospitalization costs were compared using mixed-effect multiple regression. This approach effectively controlled for random clustering effects across hospitals and patients’ Diagnosis-Related Group (DRG) classifications. CHG gel dressings were associated with a 41% decrease in CLABSI rates ( P = .0008) compared to CHG sponge dressings (0.35%vs 0.60%). A 0.4-day shorter LOS (9.53vs 9.90 days, P = .0001) and a cost saving of $3576 per hospital stay ($40 197 vs $43 774, P = .0179) was observed with CHG gel dressing use. There was no statistically significant difference in contact dermatitis rates ( P = .7854) between the CHG-Gel and CHG-Sponge cohorts. The findings of this study suggest that the use of CHG gel dressings may be more effective in reducing the risk of CLABSIs and associated clinical costs compared to CHG sponge dressings in hospitalized patients. Moreover, there appears to be no significant discrepancy in contact dermatitis rates between CHG gel and CHG sponge dressings. Healthcare providers may consider using CHG gel dressings as a standard practice for patients with CVCs to reduce the risk of infections and improve patient outcomes.
National Health Mission and the Status of Public Healthcare in Indian States
Authors: Ghosh Sourindra Mohan
Published: December 2023

This contribution makes the 18th part of the social change indicators series, a collation of available data on developmental issues. This note looks at the status of public healthcare through six select public healthcare infrastructure and workforce indicators in the post-NHM periods in the states of India. Abandoning the primary health care approach—where the state plays the primary role of planner and provider—perpetuated the inadequate public expenditure on health in India. The National Health Mission (NHM)—the largest health programme in India that was launched in 2005 to achieve universal access to equitable, affordable, and quality healthcare services—suffered through this. Public healthcare in India was in poor shape when the NHM was launched. Several key indicators have further deteriorated since then. A few indicators registered modest improvement during the first 10 years of the NHM, but even that has plateaued in the more recent period of 2014–2021. These sobering findings call for a renewed thrust on public investment in health for robust primary health care.
Book review: T. M. Krishna, Sebastian and Sons: A Brief History of Mrdangam Makers
Authors: Banoth Sai Priya , Mishra Sujit Kumar
Published: December 2023

T. M. Krishna, Sebastian and Sons: A Brief History of Mrdangam Makers, Westland Publications, 2020, 366 pp., ₹799, ISBN: 9789389152180 (Hardcover).