bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from A Phase II Study of Optimized Individualized Adaptive Radiotherapy for Hepatocellular Carcinoma
Authors: Herr Daniel J. , Wang Chang , Mendiratta-Lala Mishal , Matuszak Martha , Mayo Charles S. , Cao Yue , Parikh Neehar D. , Ten Haken Randy , Owen Dawn , Evans Joseph R. , Stanescu Teodor , Yan Michael , Dawson Laura A. , Schipper Matthew , Lawrence Theodore S. , Cuneo Kyle C.
Published: October 2023

AbstractPurpose:
We hypothesized that optimizing the utility of stereotactic body radiotherapy (SBRT) based on the individual patient's probability for tumor control and risk of liver injury would decrease toxicity without sacrificing local control in patients with impaired liver function or tumors not amenable to thermal ablation.
Patients and Methods:
Patients with Child-Pugh (CP) A to B7 liver function with aggregate tumor size >3.5 cm, or CP ≥ B8 with any size tumor were prospectively enrolled on an Institutional Review Board–approved phase II clinical trial to undergo SBRT with baseline and midtreatment dose optimization using a quantitative, individualized utility-based analysis. Primary endpoints were change in CP score of ≥2 points within 6 months and local control. Protocol-treated patients were compared with patients receiving conventional SBRT at another cancer center using overlap weighting.
Results:
A total of 56 patients with 80 treated tumors were analyzed with a median follow-up of 11.2 months. Two-year cumulative incidence of local progression was 6.4% [95% confidence interval (CI, 2.4–13.4)]. Twenty-one percent of patients experienced treatment-related toxicity within 6 months, which is similar to the rate for SBRT in patients with CP A liver function. An analysis using overlap weighting revealed similar local control [HR, 0.69; 95% CI (0.25–1.91); P = 0.48] and decreased toxicity [OR, 0.26; 95% CI (0.07–0.99); P = 0.048] compared with conventional SBRT.
Conclusions:
Treatment of individuals with impaired liver function or tumors not amenable to thermal ablation with a treatment paradigm designed to optimize utility may decrease treatment-related toxicity while maintaining tumor control.
Data from Neoadjuvant Cabazitaxel plus Abiraterone/Leuprolide Acetate in Patients with High-Risk Prostate Cancer: ACDC-RP Phase II Trial
Authors: Fleshner Neil E. , Sayyid Rashid K. , Hansen Aaron R. , Chin Joseph L.K. , Fernandes Ricardo , Winquist Eric , van der Kwast Theodorus , Sweet Joan , Lajkosz Katherine , Kenk Miran , Hersey Karen , Veloso Rosette , Berlin Doron , Herrera-Caceres Jaime O. , Sridhar Srikala , Moussa Madeleine , Finelli Antonio , Hamilton Robert J. , Kulkarni Girish S. , Zlotta Alexandre R. , Joshua Anthony M.
Published: October 2023

AbstractPurpose:
Early treatment intensification with neoadjuvant therapy may improve outcomes in patients with high-risk, localized prostate cancer treated with radical prostatectomy. Our objective was to compare pathologic, oncologic, and safety outcomes of neoadjuvant abiraterone acetate plus leuprolide acetate with or without cabazitaxel prior to radical prostatectomy in patients with localized, high-risk prostate cancer.
Patients and Methods:
This open-label, multicenter, phase II trial randomized men with clinically localized, D'Amico high-risk prostate cancer to neoadjuvant abiraterone acetate (1,000 mg/day) and leuprolide acetate (22.5 mg every 3 months) with or without cabazitaxel (25 mg/m2) prior to radical prostatectomy. The primary outcome was pathologic complete response (pCR) or minimal residual disease (MRD). Secondary outcomes included surgical margins, lymph node involvement, pathologic stage, 12-month biochemical relapse-free survival (BRFS) rates, and safety profile.
Results:
The per-protocol population consisted of 70 patients [cabazitaxel arm (Arm A): 37, no cabazitaxel arm (Arm B): 33]. Median patient age and prostate-specific antigen levels were 63.5 years [interquartile range (IQR), 58.0–68.0] and 21.9 ng/mL (IQR, 14.6–42.8), respectively. pCR/MRD occurred in 16 (43.2%) versus 15 patients (45.5%) in arms A and B, respectively (P = 0.85). pCR occurred in two (5.4%) versus three patients (9.1%) in arms A and B, respectively (P = 0.66). Patients with ≤ 25% total biopsy cores positive had increased odds of pCR/MRD (P = 0.04). Patients with pCR/MRD had superior 12-month BRFS rates (96.0% vs. 62.0%, P = 0.03). Grade 3+ adverse events occurred in 42.5% and 23.7% of patients in arms A and B, respectively (P = 0.078).
Conclusions:
Neoadjuvant cabazitaxel addition to abiraterone acetate/leuprolide acetate prior to radical prostatectomy did not improve pCR/MRD in clinically localized, high-risk prostate cancer.
Data from Prognostic markers of DNA methylation and NGS sequencing in progressive glioblastoma from the EORTC-26101 trial
Authors: Kessler Tobias , Schrimpf Daniel , Doerner Laura , Hai Ling , Kaulen Leon D. , Ito Jakob , van den Bent Martin , Taphoorn Martin , Brandes Alba A. , Idbaih Ahmed , Dômont Julien , Clement Paul M. , Campone Mario , Bendszus Martin , von Deimling Andreas , Sahm Felix , Platten Michael , Wick Wolfgang , Wick Antje
Published: October 2023

Abstract
Purpose: The EORTC-26101 study was a randomized phase 2 and 3 clinical trial of bevacizumab in combination with lomustine versus lomustine alone in progressive glioblastoma. Other than for progression-free survival (PFS), there was no benefit from addition of bevacizumab for overall survival (OS). However, molecular data allows for the rare opportunity to assess prognostic biomarkers from primary surgery for their impact in progressive glioblastoma. Experimental Design: We analyzed DNA methylation array data and panel sequencing from 170 genes of 380 tumor samples of the EORTC-26101 study. These patients were comparable to the overall study cohort in regards of baseline characteristics, study treatment and survival. Results: 295/380 (78%) of patients’ samples were classified into one of the main glioblastoma groups receptor tyrosine kinase (RTK)1, RTK2 and mesenchymal. There were 10 patients (2.6%) with isocitrate dehydrogenase (IDH) mutant tumors in the biomarker cohort. Patients with RTK1 and RTK2 classified tumors had lower median OS compared to mesenchymal (7.6 vs. 9.2 vs. 10.5 months). O6-methylguanine DNA-methyltransferase (MGMT) promotor methylation was prognostic for PFS and OS. Neurofibromin (NF)1 mutations were predictive of response to bevacizumab treatment. Conclusions: Thorough molecular classification is important for brain tumor clinical trial inclusion and evaluation. MGMT promoter methylation and RTK1 classifier assignment were prognostic in progressive glioblastoma. NF1 mutation may be a predictive biomarker for bevacizumab treatment.
Data from Unique spectrum of activating BRAF alterations in prostate cancer
Authors: Chehrazi-Raffle Alex , Tukachinsky Hanna , Toye Eamon , Sivakumar Smruthy , Schrock Alexa B. , Bergom Hannah E. , Ebrahimi Hedyeh , Pal Sumanta , Dorff Tanya , Agarwal Neeraj , Mahal Brandon A. , Oxnard Geoffrey R. , Hwang Justin , Antonarakis Emmanuel S.
Published: October 2023

Abstract
Purpose:Alterations in BRAF have been reported in 3-5% of prostate cancer, although further characterization is lacking. Here, we describe the nature of BRAF alterations in prostate cancer using a large cohort from commercially available tissue and liquid biopsies subjected to comprehensive genomic profiling (CGP). Experimental Design:Tissue and liquid biopsies from patients with prostate cancer were profiled using FoundationOne®CDx and FoundationOne®Liquid CDx CGP assays, respectively. Tissue biopsies from non-prostate cancer types were used for comparison (n=275,151). Genetic ancestry was predicted using a single nucleotide polymorphism-based approach. Results:Among 15,864 tissue biopsies, BRAF-activating alterations were detected in 520 cases (3.3%). The majority (463 samples, 2.9%) harbored Class II alterations, including BRAF rearrangements (243 samples, 1.5%), K601E (101 samples, 0.6%), and G469A (58 samples, 0.4%). BRAF-altered prostate cancers were enriched for CDK12 mutations (OR 1.87, 9.2% vs 5.2%, p=0.018), but depleted in TMPRSS2 fusions (OR 0.25, 11% vs 32%, p<0.0001), PTEN alterations (OR 0.47, 17% vs 31%, p<0.0001), and APC alterations (OR 0.48, 4.4% vs 8.9%, p=0.018) relative to BRAF wild-type disease. Compared to patients of European ancestry, BRAF alterations were more common in tumors from patients of African ancestry (5.1% vs. 2.9%, p<0.0001) and Asian ancestry (6.0% vs. 2.9%, p<0.001). Conclusions: Activating BRAF alterations were detected in ~3% of prostate cancers, and most were Class II mutations and rearrangements; BRAF V600 mutations were exceedingly rare. These findings suggest that BRAF activation in prostate cancer is unique from other cancers and supports further clinical investigation of therapeutics targeting the MAPK pathway.
Data from SETD2 loss and ATR inhibition synergize to promote cGAS signaling and immunotherapy response in renal cell carcinoma
Authors: Liu Xian-De , Zhang Yan-Ting , McGrail Daniel J. , Zhang Xuesong , Lam Truong , Hoang Anh , Hasanov Elshad , Manyam Ganiraju , Peterson Christine B. , Zhu Haifeng , Kumar Shwetha V. , Akbani Rehan , Pilie Patrick G. , Tannir Nizar M. , Peng Guang , Jonasch Eric
Published: October 2023

Abstract
Purpose: Immune checkpoint blockade (ICB) demonstrates durable clinical benefits in a minority of patients with renal cell carcinoma (RCC). We aimed to identify the molecular features that determine the response and develop approaches to enhance the response. Experimental Design: We investigated the effects of SET domain-containing protein 2 (SEDT2) loss on the DNA damage response pathway, the cytosolic DNA sensing pathway, the tumor immune microenvironment, and the response to Ataxia telangiectasia and rad3 related (ATR) and checkpoint inhibition in RCC. Results: ATR inhibition activated the cyclic GMP–AMP synthase (cGAS)-Interferon regulatory factor 3 (IRF3)-dependent cytosolic DNA-sensing pathway, resulting in the concurrent expression of inflammatory cytokines and immune checkpoints. Among the common RCC genotypes, SETD2 loss is associated with preferential ATR activation and sensitizes cells to ATR inhibition. SETD2 knockdown promoted the cytosolic DNA sensing pathway in response to ATR inhibition. Treatment with the ATR inhibitor VE822 concurrently upregulated immune cell infiltration and immune checkpoint expression in Setd2 knockdown Renca tumors, providing a rationale for ATR inhibition plus ICB combination therapy. Setd2 deficient Renca tumors demonstrated greater vulnerability to ICB monotherapy or combination therapy with VE822 than Setd2 proficient tumors. Moreover, SETD2 mutations were associated with a higher response rate and prolonged overall survival in ICB-treated RCC patients but not in non-ICB-treated RCC patients. Conclusions: SETD2 loss and ATR inhibition synergize to promote cGAS signaling and enhance immune cell infiltration, providing a mechanistic rationale for the combination of ATR and checkpoint inhibition in RCC patients with SETD2 mutations.
Data from SETD2 Loss and ATR Inhibition Synergize to Promote cGAS Signaling and Immunotherapy Response in Renal Cell Carcinoma
Authors: Liu Xian-De , Zhang Yan-Ting , McGrail Daniel J. , Zhang Xuesong , Lam Truong , Hoang Anh , Hasanov Elshad , Manyam Ganiraju , Peterson Christine B. , Zhu Haifeng , Kumar Shwetha V. , Akbani Rehan , Pilie Patrick G. , Tannir Nizar M. , Peng Guang , Jonasch Eric
Published: October 2023

AbstractPurpose:
Immune checkpoint blockade (ICB) demonstrates durable clinical benefits in a minority of patients with renal cell carcinoma (RCC). We aimed to identify the molecular features that determine the response and develop approaches to enhance it.
Experimental Design:
We investigated the effects of SET domain-containing protein 2 (SETD2) loss on the DNA damage response pathway, the cytosolic DNA-sensing pathway, the tumor immune microenvironment, and the response to ataxia telangiectasia and rad3-related (ATR) and checkpoint inhibition in RCC.
Results:
ATR inhibition activated the cyclic GMP–AMP synthase (cGAS)-interferon regulatory factor 3 (IRF3)–dependent cytosolic DNA-sensing pathway, resulting in the concurrent expression of inflammatory cytokines and immune checkpoints. Among the common RCC genotypes, SETD2 loss is associated with preferential ATR activation and sensitizes cells to ATR inhibition. SETD2 knockdown promoted the cytosolic DNA-sensing pathway in response to ATR inhibition. Treatment with the ATR inhibitor VE822 concurrently upregulated immune cell infiltration and immune checkpoint expression in Setd2 knockdown Renca tumors, providing a rationale for ATR inhibition plus ICB combination therapy. Setd2-deficient Renca tumors demonstrated greater vulnerability to ICB monotherapy or combination therapy with VE822 than Setd2-proficient tumors. Moreover, SETD2 mutations were associated with a higher response rate and prolonged overall survival in patients with ICB-treated RCC but not in patients with non–ICB-treated RCC.
Conclusions:
SETD2 loss and ATR inhibition synergize to promote cGAS signaling and enhance immune cell infiltration, providing a mechanistic rationale for the combination of ATR and checkpoint inhibition in patients with RCC with SETD2 mutations.
Data from Intratumoral IL15 Improves Efficacy of Near-Infrared Photoimmunotherapy
Authors: Fukushima Hiroshi , Furusawa Aki , Kato Takuya , Wakiyama Hiroaki , Takao Seiichiro , Okuyama Shuhei , Choyke Peter L. , Kobayashi Hisataka
Published: October 2023

Abstract
IL15 is a potent inducer of differentiation and proliferation of CD8+ T and natural killer (NK) cells, making it a promising candidate for cancer immunotherapy. However, limited efficacy of systemic monotherapy utilizing intravenous IL15 suggests the needs for alternative routes of administration or combination treatment with other therapies. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective anticancer treatment that elicits a massive release of tumor antigens and immunogenic signals. Here, we investigated whether intratumoral IL15 can enhance the effectiveness of cancer cell-targeted NIR-PIT using syngeneic murine tumor models. Intratumoral injection of IL15 was more effective than intraperitoneal IL15 in vivo in suppressing tumor growth and inducing intratumoral immune responses. When the efficacy of CD44-targeted NIR-PIT was compared in vivo between IL15-secreting MC38 (hIL15-MC38) and parental MC38 tumors, the hIL15-MC38/NIR-PIT group showed the best tumor growth inhibition and survival. In addition, the hIL15-MC38/NIR-PIT group showed significant dendritic cell maturation and significant increases in the number and Granzyme B expression of tumor-infiltrating CD8+ T, NK, and natural killer T cells compared with the treated parental line. Furthermore, intratumoral IL15 injection combined with CD44-targeted NIR-PIT showed significant tumor control in MC38 and Pan02-luc tumor models. In bilateral tumor models, CD44-targeted NIR-PIT in hIL15-MC38 tumors significantly suppressed the growth of untreated MC38 tumors, suggesting abscopal effects. Mice that achieved complete response after the combination therapy completely rejected later tumor rechallenge. In conclusion, local IL15 administration synergistically improves the efficacy of cancer cell–targeted NIR-PIT probably by inducing stronger anticancer immunity, indicating its potential as an anticancer treatment strategy.
Data from A Carbonic Anhydrase IX/SLC1A5 axis regulates glutamine metabolism dependent ferroptosis in hypoxic tumor cells
Authors: Venkateswaran Geetha , McDonald Paul C. , Chafe Shawn C. , Brown Wells S. , Gerbec Zachary J. , Awrey Shannon J. , Parker Seth J. , Dedhar Shoukat
Published: October 2023

Abstract
The ability of tumor cells to alter their metabolism to support survival and growth presents a challenge to effectively treat cancers. Carbonic anhydrase IX (CAIX) is a hypoxia-induced, metabolic enzyme that plays a crucial role in pH regulation in tumor cells. Recently, through a synthetic lethal screen, we identified CAIX to play an important role in redox homeostasis. In this study, we show that CAIX interacts with the glutamine transporter, solute carrier family 1 member 5 (SLC1A5), and coordinately functions to maintain redox homeostasis through the glutathione/glutathione peroxidase 4 (GSH/GPX4) axis. Inhibition of CAIX increases glutamine uptake by SLC1A5 and concomitantly increases GSH levels. The combined inhibition of CAIX activity and glutamine metabolism or the GSH/GPX4 axis results in an increase in lipid peroxidation and induces ferroptosis, both in vitro and in vivo. Thus, this study demonstrates co-targeting of CAIX and glutamine metabolism as a potential strategy to induce ferroptosis in tumor cells.
Data from First-in-Human Study of AZD5153, A Small Molecule Inhibitor of Bromodomain Protein 4, in Patients with Relapsed/Refractory Malignant Solid Tumors and Lymphoma
Authors: Hamilton Erika P. , Wang Judy S. , Oza Amit M. , Patel Manish R. , Ulahannan Susanna V. , Bauer Todd , Karlix Janet L. , Zeron-Medina Jorge , Fabbri Giulia , Marco-Casanova Paola , Moorthy Ganesh , Hattersley Maureen M. , Littlewood Gillian M. , Mitchell Patrick D. , Saeh Jamal . , Pouliot Gayle P. , Moore Kathleen N.
Published: October 2023

Abstract
AZD5153, a reversible, bivalent inhibitor of the bromodomain and extraterminal family protein BRD4, has preclinical activity in multiple tumors. This first-in-human, phase 1 study investigated AZD5153 alone or with olaparib in patients with relapsed/refractory solid tumors or lymphoma. Adults with relapsed tumors intolerant of, or refractory to, prior therapies received escalating doses of oral AZD5153 once-daily (QD) or twice-daily (BID) continuously (21-day cycles), or AZD5153 QD/BID continuously or intermittently plus olaparib 300 mg BID, until disease progression or unacceptable toxicity. Between June 30, 2017 and April 19, 2021, 34 patients received monotherapy and 15 received combination therapy. Dose-limiting toxicities were thrombocytopenia/platelet count decreased (n = 4/n = 2) and diarrhea (n = 1). The recommended phase 2 doses (RP2Ds) were AZD5153 30 mg QD or 15 mg BID (monotherapy) and 10 mg QD (intermittent schedule) with olaparib. With AZD5153 monotherapy, common treatment-emergent adverse events (TEAEs) included fatigue (38.2%), thrombocytopenia, and diarrhea (each 32.4%); common grade ≥ 3 TEAEs were thrombocytopenia (14.7%) and anemia (8.8%). With the combination, common TEAEs included nausea (66.7%) and fatigue (53.3%); the most common grade ≥ 3 TEAE was thrombocytopenia (26.7%). AZD5153 had dose-dependent pharmacokinetics, with minimal accumulation, and demonstrated dose-dependent modulation of peripheral biomarkers, including upregulation of HEXIM1. One patient with metastatic pancreatic cancer receiving combination treatment had a partial response lasting 4.2 months. These results show AZD5153 was tolerable as monotherapy and in combination at the RP2Ds; common toxicities were fatigue, hematologic AEs, and gastrointestinal AEs. Strong evidence of peripheral target engagement was observed.
Data from Conditional dependency of LP-184 on prostaglandin reductase 1 is synthetic lethal in pancreatic cancers with DNA damage repair deficiencies
Authors: Restifo Diana , McDermott Joseph R. , Cvetkovic Dusica , Dos Santos Troy , Ogier Charline , Surumbayeva Aizhan , Handorf Elizabeth A. , Schimke Caleb , Ma Charlie , Cai Kathy Q. , Olszanski Anthony J. , Kathad Umesh , Bhatia Kishor , Sharma Panna , Kulkarni Aditya , Astsaturov Igor
Published: October 2023

Abstract
The greater efficacy of DNA-damaging drugs for pancreatic adenocarcinoma (PDAC) relies on targeting cancer-specific vulnerabilities while sparing normal organs and tissues due to their inherent toxicities. We tested LP-184, a novel acylfulvene analog, for its activity in preclinical models of PDAC carrying mutations in the DNA damage repair (DDR) pathways.
Cytotoxicity of LP-184 is solely dependent on prostaglandin reductase 1 (PTGR1), so that PTGR1 expression robustly correlates with LP-184 cytotoxicity in vitro and in vivo. Low-passage patient-derived PDAC xenografts with DDR deficiencies treated ex vivo are more sensitive to LP-184 compared to DDR-proficient tumors. Additional in vivo testing of PDAC xenografts for their sensitivity to LP-184 demonstrates marked tumor growth inhibition in models harboring pathogenic mutations in ATR, BRCA1 and BRCA2. Depletion of PTGR1, however, completely abrogates the anti-tumor effect of LP-184. Testing combinatorial strategies for LP-184 aimed at deregulation of nucleotide excision repair proteins ERCC3 and ERCC4 established synergy.
Our results provide valuable biomarkers for clinical testing of LP-184 in a large subset of genetically defined characterized refractory carcinomas. High PTGR1 expression and deleterious DDR mutations are present in approximately one third of PDAC making these patients ideal candidates for clinical trials of LP-184.
Data from Conditional Dependency of LP-184 on Prostaglandin Reductase 1 is Synthetic Lethal in Pancreatic Cancers with DNA Damage Repair Deficiencies
Authors: Restifo Diana , McDermott Joseph R. , Cvetkovic Dusica , Dos Santos Troy , Ogier Charline , Surumbayeva Aizhan , Handorf Elizabeth A. , Schimke Caleb , Ma Charlie , Cai Kathy Q. , Olszanski Anthony J. , Kathad Umesh , Bhatia Kishor , Sharma Panna , Kulkarni Aditya , Astsaturov Igor
Published: October 2023

Abstract
The greater efficacy of DNA-damaging drugs for pancreatic adenocarcinoma (PDAC) relies on targeting cancer-specific vulnerabilities while sparing normal organs and tissues due to their inherent toxicities. We tested LP-184, a novel acylfulvene analog, for its activity in preclinical models of PDAC carrying mutations in the DNA damage repair (DDR) pathways.

Cytotoxicity of LP-184 is solely dependent on prostaglandin reductase 1 (PTGR1), so that PTGR1 expression robustly correlates with LP-184 cytotoxicity in vitro and in vivo. Low-passage patient-derived PDAC xenografts with DDR deficiencies treated ex vivo are more sensitive to LP-184 compared with DDR-proficient tumors. Additional in vivo testing of PDAC xenografts for their sensitivity to LP-184 demonstrates marked tumor growth inhibition in models harboring pathogenic mutations in ATR, BRCA1, and BRCA2. Depletion of PTGR1, however, completely abrogates the antitumor effect of LP-184. Testing combinatorial strategies for LP-184 aimed at deregulation of nucleotide excision repair proteins ERCC3 and ERCC4 established synergy.

Our results provide valuable biomarkers for clinical testing of LP-184 in a large subset of genetically defined characterized refractory carcinomas. High PTGR1 expression and deleterious DDR mutations are present in approximately one third of PDAC making these patients ideal candidates for clinical trials of LP-184.
Data from TRIM50 Inhibits Gastric Cancer Progression by Regulating the Ubiquitination and Nuclear Translocation of JUP
Authors: Hu Jiajia , Huang Runjie , Liang Chengcai , Wang Yingnan , Wang Min , Chen Yanxing , Wu Chenyi , Zhang Jinling , Liu Zekun , Zhao Qi , Liu Zexian , Wang Feng , Yuan Shuqiang
Published: October 2023

Abstract
Gastric cancer is one of the most frequent cancers in the world. Emerging clinical data show that ubiquitination system disruptions are likely involved in carcinoma genesis and progression. However, the precise role of ubiquitin (Ub)-mediated control of oncogene products or tumor suppressors in gastric cancer is unknown. Tripartite motif-containing 50 (TRIM50), an E3 ligase, was discovered by high-output screening of ubiquitination-related genes in tissues from patients with gastric cancer to be among the ubiquitination-related enzymes whose expression was most downregulated in gastric cancer. With two different databases, we verified that TRIM50 expression was lower in tumor tissues relative to normal tissues. TRIM50 also suppressed gastric cancer cell growth and migration in vitro and in vivo. JUP, a transcription factor, was identified as a new TRIM50 ubiquitination target by MS and coimmunoprecipitation experiments. TRIM50 increases JUP K63-linked polyubiquitination mostly at the K57 site. We discovered that the K57 site is critical for JUP nuclear translocation by prediction with the iNuLoC website and further studies. Furthermore, ubiquitination of the K57 site limits JUP nuclear translocation, consequently inhibiting the MYC signaling pathway. These findings identify TRIM50 as a novel coordinator in gastric cancer cells, providing a potential target for the development of new gastric cancer treatment strategies.
Implications:
TRIM50 regulates gastric cancer tumor progression, and these study suggest TRIM50 as a new cancer target.
Data from Hierarchical Phosphorylation of HOXB13 by mTOR Dictates Its Activity and Oncogenic Function in Prostate Cancer
Authors: Chen Yonghong , Dufour Catherine R. , Han Lingwei , Li Ting , Xia Hui , Giguère Vincent
Published: October 2023

Abstract
Dysregulation of mTOR signaling plays a critical role in promoting prostate cancer growth. HOXB13, a homeodomain transcription factor, is known to influence the androgen response and prostate cancer development. Recently, HOXB13 was found to complex with mTOR on chromatin. However, the functional crosstalk between HOXB13 and mTOR remains elusive. We now report that mTOR directly interacts with and hierarchically phosphorylates HOXB13 at threonine 8 and 41 then serine 31 to promote its interaction with the E3 ligase SKP2 while enhancing its oncogenic properties. Expression of HOXB13 harboring phosphomimetic mutations at the mTOR-targeted sites stimulates prostate cancer cellular growth both in vitro and in murine xenografts. Transcriptional profiling studies revealed a phospho-HOXB13–dependent gene signature capable of robustly discriminating between normal prostate tissues, primary and metastatic prostate cancer samples. This work uncovers a previously unanticipated molecular cascade by which mTOR directly phosphorylates HOXB13 to dictate a specific gene program with oncogenic implications in prostate cancer.
Implications:
Control of HOXB13 transcriptional activity via its direct phosphorylation by the mTOR kinase is a potential therapeutic avenue for the management of advanced prostate cancer.
Data from Analysis of several common APOBEC-type mutations in bladder tumors suggests links to viral infection
Authors: Rao Nina , Starrett Gabriel J. , Piaskowski Mary L. , Butler Kelly E. , Golubeva Yelena , Yan Wusheng , Lawrence Scott M. , Dean Michael , Garcia-Closas Montserrat , Baris Dalsu , Johnson Alison , Schwenn Molly , Malats Nuria , Real Francisco X. , Kogevinas Manolis , Rothman Nathaniel , Silverman Debra T. , Dyrskjøt Lars , Buck Christopher B. , Koutros Stella , Prokunina-Olsson Ludmila
Published: October 2023

Abstract
FGFR3 and PIK3CA are among the most frequently mutated genes in bladder tumors. We hypothesized that recurrent mutations in these genes might be caused by common carcinogenic exposures such as smoking and other factors. We analyzed 2,816 bladder tumors with available data on FGFR3 and/or PIK3CA mutations, focusing on the most recurrent mutations detected in ≥10% of tumors. Compared to tumors with other FGFR3/PIK3CA mutations, FGFR3-Y375C was more common in tumors from smokers than never-smokers (p=0.009), while several APOBEC-type driver mutations were enriched in never-smokers: FGFR3-S249C (p=0.013) and PIK3CA-E542K/PIK3CA-E545K (p=0.009). To explore possible causes of these APOBEC-type mutations, we analyzed RNA-seq data from 798 bladder tumors and detected several viruses, with BK polyomavirus (BKPyV) being the most common. We then performed immunohistochemical (IHC) staining for polyomavirus (PyV) Large T-antigen (LTAg) in an independent set of 211 bladder tumors. Overall, by RNA-seq or IHC-LTAg, we detected PyV in 26 out of 1,010 bladder tumors with significantly higher detection (p=4.4 × 10−5), 25/554 (4.5%) in non-muscle-invasive bladder cancers (NMIBC) versus 1/456 (0.2%) of muscle-invasive bladder cancers (MIBC). In the NMIBC subset, the FGFR3/PIK3CA APOBEC-type driver mutations were detected in 94.7% (18/19) of PyV-positive vs. 68.3% (259/379) of PyV-negative tumors (p=0.011). BKPyV tumor positivity in the NMIBC subset with FGFR3- or PIK3CA-mutated tumors was also associated with a higher risk of progression to MIBC (p=0.019). In conclusion, our results support smoking and BKPyV infection as risk factors contributing to bladder tumorigenesis in the general patient population through distinct molecular mechanisms.
Identification of High-Risk Single Nucleotide Polymorphisms in the Human CYB5R3 Gene Responsible for Recessive Congenital Methemoglobinemia: A Computational Approach
Authors: Bouatrous Emna , Nouira Sonia , Menif Samia , Ouragini Houyem
Published: October 2023

Introduction: NADH-cytochrome b5 reductase deficiency due to pathogenic variants in the CYB5R3 gene causes recessive congenital methemoglobinemia (RCM) type I or type II. In type I, cyanosis from birth is the only major symptom, and the enzyme deficiency is restricted only to erythrocytes. Whereas in type II, cyanosis is associated with severe neurological manifestations, and the enzyme deficiency is generalized to all tissues. Methods: In this study, several computational methods (SIFT, Polyphen-2, PROVEAN, Mutation Assessor, Panther, Phd-SNP, SNPs&GO, SNAP2, Align, GVGD, MutPred2, I-Mutant 2.0, MUpro, Duet, ConSurf and Netsurf-2.0 tools) were used to find the most deleterious nsSNPs in the CYB5R3 gene. Furthermore, structural analysis by Swiss-PDB viewer, protein-ligand docking using FTSite, and protein-protein interaction using STRING were carried out to evaluate the impact of these nsSNPs on the protein structure and function. Results: Our in silico analysis suggested that out of 339 nsSNPs of the CYB5R3 gene, 17 (L47H, L47P, R61P, L73R G76D, G76C, P96H, G104C, S128P, G144D, P145S, L149P, Y151H, M177T, I178T, I216N, and G251V), are the most deleterious. Among them, two (P96H and S128P) were reported to be associated with the severe form RCM type II, six are related to RCM type I (G104C, G144D, P145S, L149P, M177T, and I178T), and the remaining nine high-risk nsSNPs have not yet been reported in RCM patients. Discussion: This study highlighted the potential pathogenic nsSNPs of the CYB5R3 gene. To comprehend how these most harmful nsSNPs contribute to disease, it is crucial to experimentally validate their functional effects.
Clinical Heterogeneity in Patients with Long QT Syndrome and Segregation of Single Nucleotide Variants and Clinical Symptoms in 17 Affected Families
Authors: Bora Elcin , Yıldız Bulut Ayca , Cankaya Tufan , Cinleti Tayfun , Genç Halise Zeynep , Ozcan Emin Evren , Ozpelit Ebru , Ulgenalp Ayfer , Caglayan Ahmet Okay
Published: October 2023

Introduction: Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram. It increases the risk of ventricular arrhythmias, which can cause syncope or sudden cardiac death. In this study, we study the genotype-phenotype relationships of patients referred to us with suspected arrhythmia syndrome. Methods: Seventeen cases and their twenty relatives were evaluated. Next-generation sequencing analysis was performed for 17 LQTS-related genes. Results: We detected seventeen single nucleotide variants (SNVs) with potential pathogenic significance in 26 of the 36 subjects analyzed. KCNH2 c.172G>A, KCNQ1 c.1768G>A, ANK2 c.4666A>T, c.1484_1485delCT, KCNH2 c.1888G>A were reported as pathogenic or likely pathogenic in HGMD variant classification database. Conclusion: Current study pointed out that early diagnosis can be life-saving for patients and their families by taking family history and detailed examination. Also, we highlight the clinical heterogeneity of arrhythmia syndrome through a patient with a dual phenotype.
The Science Teachers’ Communication Behavior in Relation to Students’ Attitude and Performance
Authors: Sierto Maricel E.
Published: October 2023

The purpose of this study was to find out the relationship between the communicative behavior of teachers and the attitudes and performance of students in Science in Sta. Peregrina High School in Balatong B, Pulilan, Bulacan. In particular, the aim of this study was to find answers to the following questions: (1) What is the level Science teachers show in challenging, encouraging and praise, non-verbal support, understanding, and controlling behavior? (2) At what level is the attitude of the students towards science? (3) What is the performance level of students in science subject? (4) Are teachers’ communication and students’ attitudes toward science related to each other? and (5) Are teachers’ communication and students’ performance toward science related to each other? Descriptive quantifiable method of research was utilized in this study. The following conclusions were drawn: (1) Science teachers received very acceptable ratings for challenging, encouraging and praise, non-verbal support, understanding, and controlling behaviour as observed by their students. (2) Students have very acceptable attitudes to Science. (3) Students acquired an acceptable assessment in their Science grade. (4) There was no substantial relationship between challenging, encouraging and praise, controlling behaviour of teachers and the attitude of the students; challenging, encouraging and praise, understanding, and controlling behaviour of teachers and the students’ academic performance. Yet, there was substantial relationship in non-verbal support and understanding behaviour of teachers and attitudes of students.
Evaluation of The Implementation of The Angkutan Cerdas Sekolah Program (ACS) in Ponorogo Regency
Authors: Pangestu Rizky Purna Aji Galih , Sudibyo Desiderius Priyo , Nugroho Rino Ardhian
Published: October 2023

Smart School Transportation (ACS) is a program from the Ponorogo Regency Government as an effort to make it easier for students to get free school transportation. The purpose of this research is to describe the evaluation of the implementation of the ACS Program and to describe the inhibiting and supporting factors for the implementation of the ACS program in Ponorogo Regency. This type of research is descriptive qualitative. Data analysis techniques Qualitative analysis is carried out through data collection, data reduction, data presentation, and withdrawal conclusion. The results of the study show that the ACS program in the District Ponorogo is still not running effectively. In terms of effectiveness, it has not been effective because there are still many underage children who use motorbikes. The efficiency aspect has been fulfilled because it has implemented cost and time efficiency in program operations. In the aspect of adequacy still not fulfilled because of the limited number and capacity of the fleet in transporting students. In the aspect of alignment it is still not evenly distributed because there are still many schools that have not received program services. The responsiveness aspect has received response and support from ACS users and parents. Aspects of provisions, programs This ACS is right on target, namely to transport students. In the implementation of the ACS program, of course, there are inhibiting and supporting factors. The inhibiting factor for the first ACS program was resources, because human resources in the form of Department of Transportation staff were inadequate to carry out socialization and financial resources were also inadequate, which affected the provision of fleets and the provision of program support facilities. The second inhibiting factor is the bureaucratic structure due to the absence of Standard Operating Procedures (SOP) that are clear and regional regulations that cover program implementation. While the supporting factors for the implementation of the first ACS program, namely, communication through transmission and clarity of information have been running optimally. The second supporting factor is the attitude of the implementer that liveliness officer executor socialization from Service Communications Ponorogo Regency for schools and students is carried out continuously every new school year.
Using of Hugot Lines in Teaching Figures of Speech in Filipino Subject
Authors: Aragon Jhoana Marie Lopez
Published: October 2023

Hugot lines are in casual used in different places, even in the classroom. It is a figure of speech. It is also an expression of deep emotion that was tried dig out and indirectly states but has relation to the past and feelings of the speaker. The aim of this study is determine the effects of Hugot line in teaching Figure of Speech or Tayutay in Filipino. The study had utilized Quasi-Experimental research design where assessment tests and narrative inquiry questionnaire was used to gather the required data. Convinience sampling was employed. Two classes have participated consisting of 100 participants or 50 students in each classes. The assessment instrument is composed of 20 questions pertaining to Figures of Speech. The narrative inquiry questionnaire consist of 1 question “What are the effects of Hugot Line in Teaching Figures of Speech?” Based from the results, it concludes that : there is no gap in pre-assessment of the two groups but larger gap in the post-assessment scores where experimental group is much higher; there is no significant differences in the scores in pre-assessment and post-assessments of the groups to each other. Also, 8 themes have emerged from their narratives, including; (a) Interesting, (b) Active Sharing, (c) Easier to Comprehend, (d) Fun, (e) Active in Classes, (f) Meaningful Discussions, (g) Easier to Remember, and (h) can relate to self. Based from the narratives of the students, it shows that there is a positive effect in the teaching process based from the narratives of the students.
Fostering Pre-service Physical Educators’ Retention of Concepts in a Professional Education Course Using Moneypoly Game
Authors: Almario John Ivan F. , Castro Rafael Luis G. , Castro Rafael Luis G. , Pabustan Carl Jemuel S. , David Christian Jay P. , Macabali Allen J. , Tolentino Julius Ceazar G. , Valenzuela Luwy R.
Published: October 2023

Diversified development of educational strategies has been increasingly growing in the field of teacher education to address the challenges in residential-based learning brought by the virtual classroom setting. Necessarily, the application of game-based learning (GBL) is viewed to significantly contribute to complementing the students' learning deficiencies. Hence, this study was conducted to increase concept retention among pre-service physical educators (PSPEs) through a game-based assessment strategy called moneypoly game. This descriptive-qualitative collaborative action research study comprised 48 student-participants enrolled in the professional education course, “Curriculum and Assessment in Physical Education and Health Education for K to 12”, at a teacher education institution in Central Luzon, Philippines during the first semester of the academic year 2022-2023. Educational activities related to the moneypoly game were implemented multiple times during the face-to-face class sessions. Subsequently, open-ended reflective questionnaires were administered to obtain authentic and valid data to capture the increment of concept retention among the PSPEs. Adhering to Braun and Clarke’s Thematic Analysis technique, students’ responses were themed via qualitative analysis software powered by MAXQDA Analytics Pro 2022. Findings revealed three (3) emerging themes that helped learners retain long-term memory of the lessons' concepts. This includes (1) learners’ experiences in the moneypoly game that strengthen their concept retention, (2) contributing factors to students’ constant participation, and (3) significant recommendations to improve the game-based assessment strategy in the next cycle. These characteristics of the moneypoly game influenced the way that students learned and remembered information. This led to the perception that the intervention generated multiform driving forces for the learners' all-encompassing learning. The exploration and utilization of GBL could be applied to other areas of discipline to corroborate the findings made in this study.
The Effect of Organizational Trust and Job Satisfaction on Job Performance with Employee Engagement as a Mediating Variable
Authors: Nabilla Maulidya , Budiono Budiono , Witjaksono Andre Dwijanto , Wardoyo Dewie Tri Wijayati
Published: October 2023

The purpose of this study was to examine and analyze the effect of organizational trust and job satisfaction on job performance through employee engagement at PT. Adikara Jaya Sentosa. This research is a causality study with a quantitative approach. The sampling technique uses a saturated sample with a total of 75 respondents. The statistical analysis used in this study is the partial least squares (PLS) with the help of smartPLS 3.0 software. The results of this study prove that organizational trust has a positive and significant effect on job performance. Organizational trust has a positive and significant effect on employee engagement. Job satisfaction has a positive and significant effect on job performance. Job satisfaction has a positive and significant effect on employee engagement. In the indirect effect analysis, employee engagement is able to mediate the influence between organizational trust and job satisfaction on job performance.
Abstract 280: Association Between Sars-cov-2 Infection And Abdominal Aortic Aneurysms (AAAs)
Authors: Xu Baohui , Ikezoe Toru , Guo Jia , Li Gang , Samura Makoto , zhao sihai , Dalman Ronald L
Published: October 2023

Objectives:
SARS-CoV-2 infection worsens cardiovascular outcomes. We studied the association of SARS-CoV-2 infection with clinical, and the influence of SARS-CoV-2 spike proteins on experimental, AAA progression.

Methods:
AAA patients aged ≥50 years with two diameter measurements and SARS-CoV-2 infection status were screened in an institutional research database during the period of January 1, 2020 to December 31, 2021. The association of risk factors including SARS-CoV-2 infection with AAA progression was analyzed. The influence of SARS-CoV-2 spike proteins on experimental AAAs was assessed in wild type and human ACE2 transgenic mice by injecting SARS-CoV-2 spike proteins.

Results:
We identified 175 AAA patients (26 patients with SARS-CoV-2 infection) with at least two aortic diameter measurements. Mean initial diameter and median annual AAA enlargement rate were 39.1 mmm and 0.9 mm annually, respectively. Univariate analysis found SARS-CoV-2 infection as the only factor associated with rapid AAA enlargement (>2.7 mm/year). In multivariate logistic regression, SARS-CoV-2 infection (odds ratio: 9.7), chronic kidney disease (3.8) and ever smokers (2.0) were associated with rapid AAA enlargement. A reverse association was noted for patients with cancers (0.2), cerebrovascular disease (0.3), diameter measurement interval (0.8) and body mass index (0.9). No association was noted with any other factors. Additionally, recombinant SARS-CoV-2 spike protein 1 or its receptor binding domain, not spike protein 2, treatment accelerated AAA progression in wild type mice. SARS-CoV-2 spike protein 1 treatment also diminished AAA attenuation in human ACE2 transgenic mice.

Conclusions:
Clinical and experimental data suggest that SARS-CoV-2 infection may promote AAA progression. Large cohort validation studies are required to determine whether AAA screening, surveillance and interventional criteria should be modified during or after SARS-CoV-2 infection.
Investigate energy efficiency, cutting force and surface roughness in hard turning of AISI S1 Steel for sustainable manufacturing
Authors: Şahinoğlu Abidin
Published: October 2023

Energy consumption has been a significant issue. CO2 emissions have increased due to increased energy consumption. On the other hand, hard steels have been an essential subject of investigation due to their low energy consumption and good surface quality. Therefore, this experimental study investigates the effects of cutting parameters on cutting forces, power consumption (PC), energy consumption (EC), sound intensity (SI), and surface roughness (Ra) in machining AISI S1 (60 HRC) cold work tool steel. Feed rate (f) on cutting force with 53.23%, power consumption with 94.11% depth of cut (ap), energy efficiency with 74.92% feed rate, over surface roughness value with 86.66%, depth of cut with 94.42% on sound intensity are effective parameters. Mathematical equations related to the cutting parameters were obtained. In addition, mathematical equations were created between cutting force and power consumption, cutting force and sound intensity, and power consumption and sound intensity. Finally, optimum cutting conditions were determined with multiple optimisation methods, which turned out to be 210 m/min cutting speed (v), 0.08 mm cutting depth, and 0.0505 mm/rev feed rate. Accordingly, it was calculated that sound intensity would be reduced by 4.25%, surface roughness value would be decreased by 36.36%, power consumption by 21.74%, Fz by 26.77%, by Fy 52.46% and Fx by 24.44%.
An effective correlation-based data modeling framework for automatic diabetes prediction using machine and deep learning techniques
Authors: Patro Kiran Kumar , Allam Jaya Prakash , Sanapala Umamaheswararao , Marpu Chaitanya Kumar , Samee Nagwan Abdel , Alabdulhafith Maali , Plawiak Pawel
Published: October 2023

The rising risk of diabetes, particularly in emerging countries, highlights the importance of early detection. Manual prediction can be a challenging task, leading to the need for automatic approaches. The major challenge with biomedical datasets is data scarcity. Biomedical data is often difficult to obtain in large quantities, which can limit the ability to train deep learning models effectively. Biomedical data can be noisy and inconsistent, which can make it difficult to train accurate models. To overcome the above-mentioned challenges, this work presents a new framework for data modeling that is based on correlation measures between features and can be used to process data effectively for predicting diabetes. The standard, publicly available Pima Indians Medical Diabetes (PIMA) dataset is utilized to verify the effectiveness of the proposed techniques. Experiments using the PIMA dataset showed that the proposed data modeling method improved the accuracy of machine learning models by an average of 9%, with deep convolutional neural network models achieving an accuracy of 96.13%. Overall, this study demonstrates the effectiveness of the proposed strategy in the early and reliable prediction of diabetes.