bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Fatostatin Displays High Antitumor Activity in Prostate Cancer by Blocking SREBP-Regulated Metabolic Pathways and Androgen Receptor Signaling
Authors: Li Xiangyan , Chen Yi-Ting , Hu Peizhen , Huang Wen-Chin
Published: April 2023

Abstract
Current research links aberrant lipogenesis and cholesterogenesis with prostate cancer development and progression. Sterol regulatory element-binding proteins (SREBP; SREBP-1 and SREBP-2) are key transcription factors controlling lipogenesis and cholesterogenesis via the regulation of genes related to fatty acid and cholesterol biosynthesis. Overexpression of SREBPs has been reported to be significantly associated with aggressive pathologic features in human prostate cancer. Our previous results showed that SREBP-1 promoted prostate cancer growth and castration resistance through induction of lipogenesis and androgen receptor (AR) activity. In the present study, we evaluated the anti–prostate tumor activity of a novel SREBP inhibitor, fatostatin. We found that fatostatin suppressed cell proliferation and anchorage-independent colony formation in both androgen-responsive LNCaP and androgen-insensitive C4-2B prostate cancer cells. Fatostatin also reduced in vitro invasion and migration in both the cell lines. Further, fatostatin caused G2–M cell-cycle arrest and induced apoptosis by increasing caspase-3/7 activity and the cleavages of caspase-3 and PARP. The in vivo animal results demonstrated that fatostatin significantly inhibited subcutaneous C4-2B tumor growth and markedly decreased serum prostate-specific antigen (PSA) level compared with the control group. The in vitro and in vivo effects of fatostatin treatment were due to blockade of SREBP-regulated metabolic pathways and the AR signaling network. Our findings identify SREBP inhibition as a potential new therapeutic approach for the treatment of prostate cancer. Mol Cancer Ther; 13(4); 855–66. ©2014 AACR.
Data from BRCA2 and RAD51 Promote Double-Strand Break Formation and Cell Death in Response to Gemcitabine
Authors: Jones Rebecca M. , Kotsantis Panagiotis , Stewart Grant S. , Groth Petra , Petermann Eva
Published: April 2023

Abstract
Replication inhibitors cause replication fork stalling and double-strand breaks (DSB) that result from processing of stalled forks. During recovery from replication blocks, the homologous recombination (HR) factor RAD51 mediates fork restart and DSB repair. HR defects therefore sensitize cells to replication inhibitors, with clear implications for cancer therapy. Gemcitabine is a potent replication inhibitor used to treat cancers with mutations in HR genes such as BRCA2. Here, we investigate why, paradoxically, mutations in HR genes protect cells from killing by gemcitabine. Using DNA replication and DNA damage assays in mammalian cells, we show that even short gemcitabine treatments cause persistent replication inhibition. BRCA2 and RAD51 are recruited to chromatin early after removal of the drug, actively inhibit replication fork progression, and promote the formation of MUS81- and XPF-dependent DSBs that remain unrepaired. Our data suggest that HR intermediates formed at gemcitabine-stalled forks are converted into DSBs and thus contribute to gemcitabine-induced cell death, which could have implications for the treatment response of HR-deficient tumors. Mol Cancer Ther; 13(10); 2412–21. ©2014 AACR.
Data from Oncolytic Adenovirus Loaded with L-carnosine as Novel Strategy to Enhance the Antitumor Activity
Authors: Garofalo Mariangela , Iovine Barbara , Kuryk Lukasz , Capasso Cristian , Hirvinen Mari , Vitale Andrea , Yliperttula Marjo , Bevilacqua Maria Assunta , Cerullo Vincenzo
Published: April 2023

Abstract
Oncolytic viruses are able to specifically replicate, infect, and kill only cancer cells. Their combination with chemotherapeutic drugs has shown promising results due to the synergistic action of virus and drugs; the combinatorial therapy is considered a potential clinically relevant approach for cancer. In this study, we optimized a strategy to absorb peptides on the viral capsid, based on electrostatic interaction, and used this strategy to deliver an active antitumor drug. We used L-carnosine, a naturally occurring histidine dipeptide with a significant antiproliferative activity. An ad hoc modified, positively charged L-carnosine was combined with the capsid of an oncolytic adenovirus to generate an electrostatic virus–carnosine complex. This complex showed enhanced antitumor efficacy in vitro and in vivo in different tumor models. In HCT-116 colorectal and A549 lung cancer cell lines, the complex showed higher transduction ratio and infectious titer compared with an uncoated oncolytic adenovirus. The in vivo efficacy of the complex was tested in lung and colon cancer xenograft models, showing a significant reduction in tumor growth. Importantly, we investigated the molecular mechanisms underlying the effects of complex on tumor growth reduction. We found that complex induces apoptosis in both cell lines, by using two different mechanisms, enhancing viral replication and affecting the expression of Hsp27. Our system could be used in future studies also for delivery of other bioactive drugs. Mol Cancer Ther; 15(4); 651–60. ©2016 AACR.
Data from DHA-SBT-1214 Taxoid Nanoemulsion and Anti–PD-L1 Antibody Combination Therapy Enhances Antitumor Efficacy in a Syngeneic Pancreatic Adenocarcinoma Model
Authors: Ahmad Gulzar , Mackenzie Gerardo G. , Egan James , Amiji Mansoor M.
Published: April 2023

Abstract
The goal of this study was to evaluate combination of a novel taxoid, DHA-SBT-1214 chemotherapy, in modulating immune checkpoint marker expression and ultimately in improving antibody-based checkpoint blockade therapy in pancreatic adenocarcinoma (PDAC). DHA-SBT-1214 was encapsulated in an oil-in-water nanoemulsion and administered systemically in Panc02 syngeneic PDAC-bearing C57BL/6 mice. Following treatment with DHA-SBT-1214, expression levels of PD-L1 were measured and anti–PD-L1 antibody was administered in combination. The effects of combination therapy on efficacy and the molecular basis of synergistic effects were evaluated. PD-L1 expression was lower on Panc02 pancreatic tumor cells in vitro, which significantly increased after exposure to different chemotherapy drugs. Administration of DHA-SBT-1214, gemcitabine, and PD-L1 antibody alone failed to increase CD8+ T-cell infiltration inside tumors. However, combination of anti–PD-L1 therapy with a novel chemotherapy drug DHA-SBT-1214 in nanoemulsion (NE-DHA-SBT-1214) significantly enhanced CD8+ T-cell infiltration and the therapeutic effects of the anti–PD-L1 antibody. Furthermore, in the Panc02 syngeneic model, the NE-DHA-SBT-1214 combination therapy group reduced tumor growth to a higher extend than paclitaxel, nab-paclitaxel (Abraxane), gemcitabine, or single anti–PD-L1 antibody therapy groups. Our results indicate that NE-DHA-SBT-1214 stimulated immunogenic potential of PDAC and provided an enhanced therapeutic effect with immune checkpoint blockade therapy, which warrants further evaluation.
Data from HSP90 Inhibitor–SN-38 Conjugate Strategy for Targeted Delivery of Topoisomerase I Inhibitor to Tumors
Authors: Proia David A. , Smith Donald L. , Zhang Junyi , Jimenez John-Paul , Sang Jim , Ogawa Luisa Shin , Sequeira Manuel , Acquaviva Jaime , He Suqin , Zhang Chaohua , Khazak Vladimir , Astsaturov Igor , Inoue Takayo , Tatsuta Noriaki , Osman Sami , Bates Richard C. , Chimmanamada Dinesh , Ying Weiwen
Published: April 2023

Abstract
The clinical benefits of chemotherapy are commonly offset by insufficient drug exposures, narrow safety margins, and/or systemic toxicities. Over recent decades, a number of conjugate-based targeting approaches designed to overcome these limitations have been explored. Here, we report on an innovative strategy that utilizes HSP90 inhibitor–drug conjugates (HDC) for directed tumor targeting of chemotherapeutic agents. STA-12-8666 is an HDC that comprises an HSP90 inhibitor fused to SN-38, the active metabolite of irinotecan. Mechanistic analyses in vitro established that high-affinity HSP90 binding conferred by the inhibitor backbone could be exploited for conjugate accumulation within tumor cells. In vivo modeling showed that the HSP90 inhibitor moiety was required for selective retention of STA-12-8666, and this enrichment promoted extended release of active SN-38 within the tumor compartment. Indeed, controlled intratumoral payload release by STA-12-8666 contributed to a broad therapeutic window, sustained biomarker activity, and remarkable degree of efficacy and durability of response in multiple cell line and patient-derived xenograft models. Overall, STA-12-8666 has been developed as a unique HDC agent that employs a distinct mechanism of targeted drug delivery to achieve potent and sustained antitumor effects. These findings identify STA-12-8666 as a promising new candidate for evaluation as novel anticancer therapeutic. Mol Cancer Ther; 14(11); 2422–32. ©2015 AACR.
Data from Tumors with AKT1E17K Mutations Are Rational Targets for Single Agent or Combination Therapy with AKT Inhibitors
Authors: Davies Barry R. , Guan Nin , Logie Armelle , Crafter Claire , Hanson Lyndsey , Jacobs Vivien , James Neil , Dudley Philippa , Jacques Kelly , Ladd Brendon , D'Cruz Celina M. , Zinda Michael , Lindemann Justin , Kodaira Makoto , Tamura Kenji , Jenkins Emma L.
Published: April 2023

Abstract
AKT1E17K mutations occur at low frequency in a variety of solid tumors, including those of the breast and urinary bladder. Although this mutation has been shown to transform rodent cells in culture, it was found to be less oncogenic than PIK3CA mutations in breast epithelial cells. Moreover, the therapeutic potential of AKT inhibitors in human tumors with an endogenous AKT1E17K mutation is not known. Expression of exogenous copies of AKT1E17K in MCF10A breast epithelial cells increased phosphorylation of AKT and its substrates, induced colony formation in soft agar, and formation of lesions in the mammary fat pad of immunodeficient mice. These effects were inhibited by the allosteric and catalytic AKT inhibitors MK-2206 and AZD5363, respectively. Both AKT inhibitors caused highly significant growth inhibition of breast cancer explant models with AKT1E17K mutation. Furthermore, in a phase I clinical study, the catalytic Akt inhibitor AZD5363 induced partial responses in patients with breast and ovarian cancer with tumors containing AKT1E17K mutations. In MGH-U3 bladder cancer xenografts, which contain both AKT1E17K and FGFR3Y373C mutations, AZD5363 monotherapy did not significantly reduce tumor growth, but tumor regression was observed in combination with the FGFR inhibitor AZD4547. The data show that tumors with AKT1E17K mutations are rational therapeutic targets for AKT inhibitors, although combinations with other targeted agents may be required where activating oncogenic mutations of other proteins are present in the same tumor. Mol Cancer Ther; 14(11); 2441–51. ©2015 AACR.
Data from Nanofluidic Digital PCR and Extended Genotyping of RAS and BRAF for Improved Selection of Metastatic Colorectal Cancer Patients for Anti-EGFR Therapies
Authors: Azuara Daniel , Santos Cristina , Lopez-Doriga Adriana , Grasselli Julieta , Nadal Marga , Sanjuan Xavier , Marin Fátima , Vidal Joana , Montal Robert , Moreno Victor , Bellosillo Beatriz , Argiles Guillem , Elez Elena , Dienstmann Rodrigo , Montagut Clara , Tabernero Josep , Capellá Gabriel , Salazar Ramon
Published: April 2023

Abstract
The clinical significance of low-frequent RAS pathway–mutated alleles and the optimal sensitivity cutoff value in the prediction of response to anti-EGFR therapy in metastatic colorectal cancer (mCRC) patients remains controversial. We aimed to evaluate the added value of genotyping an extended RAS panel using a robust nanofluidic digital PCR (dPCR) approach. A panel of 34 hotspots, including RAS (KRAS and NRAS exons 2/3/4) and BRAF (V600E), was analyzed in tumor FFPE samples from 102 mCRC patients treated with anti-EGFR therapy. dPCR was compared with conventional quantitative PCR (qPCR). Response rates, progression-free survival (PFS), and overall survival (OS) were correlated to the mutational status and the mutated allele fraction. Tumor response evaluations were not available in 9 patients and were excluded for response rate analysis. Twenty-two percent of patients were positive for one mutation with qPCR (mutated alleles ranged from 2.1% to 66.6%). Analysis by dPCR increased the number of positive patients to 47%. Mutated alleles for patients only detected by dPCR ranged from 0.04% to 10.8%. An inverse correlation between the fraction of mutated alleles and radiologic response was observed. ROC analysis showed that a fraction of 1% or higher of any mutated alleles offered the best predictive value for all combinations of RAS and BRAF analysis. In addition, this threshold also optimized prediction both PFS and OS. We conclude that mutation testing using an extended gene panel, including RAS and BRAF with a threshold of 1% improved prediction of response to anti-EGFR therapy. Mol Cancer Ther; 15(5); 1106–12. ©2016 AACR.
Data from Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma
Authors: Giulino-Roth Lisa , van Besien Herman J. , Dalton Tanner , Totonchy Jennifer E. , Rodina Anna , Taldone Tony , Bolaender Alexander , Erdjument-Bromage Hediye , Sadek Jouliana , Chadburn Amy , Barth Matthew J. , Dela Cruz Filemon S. , Rainey Allison , Kung Andrew L. , Chiosis Gabriela , Cesarman Ethel
Published: April 2023

Abstract
Hsp90 is a molecular chaperone that protects proteins, including oncogenic signaling complexes, from proteolytic degradation. PU-H71 is a next-generation Hsp90 inhibitor that preferentially targets the functionally distinct pool of Hsp90 present in tumor cells. Tumors that are driven by the MYC oncoprotein may be particularly sensitive to PU-H71 due to the essential role of Hsp90 in the epichaperome, which maintains the malignant phenotype in the setting of MYC. Burkitt lymphoma (BL) is an aggressive B-cell lymphoma characterized by MYC dysregulation. In this study, we evaluated Hsp90 as a potential therapeutic target in BL. We found that primary BL tumors overexpress Hsp90 and that Hsp90 inhibition has antitumor activity in vitro and in vivo, including potent activity in a patient-derived xenograft model of BL. To evaluate the targets of PU-H71 in BL, we performed high-affinity capture followed by proteomic analysis using mass spectrometry. We found that Hsp90 inhibition targets multiple components of PI3K/AKT/mTOR signaling, highlighting the importance of this pathway in BL. Finally, we found that the anti-lymphoma activity of PU-H71 is synergistic with dual PI3K/mTOR inhibition in vitro and in vivo. Overall, this work provides support for Hsp90 as a therapeutic target in BL and suggests the potential for combination therapy with PU-H71 and inhibitors of PI3K/mTOR. Mol Cancer Ther; 16(9); 1779–90. ©2017 AACR.
Data from Fisetin Enhances Chemotherapeutic Effect of Cabazitaxel against Human Prostate Cancer Cells
Authors: Mukhtar Eiman , Adhami Vaqar Mustafa , Siddiqui Imtiaz Ahmad , Verma Ajit Kumar , Mukhtar Hasan
Published: April 2023

Abstract
Although treatment of prostate cancer has improved over the past several years, taxanes, such as cabazitaxel, remain the only form of effective chemotherapy that improves survival in patients with metastatic castration–resistant prostate cancer. However, the effectiveness of this class of drugs has been associated with various side effects and drug resistance. We previously reported that fisetin, a hydroxyflavone, is a microtubule-stabilizing agent and inhibits prostate cancer cell proliferation, migration, and invasion and suggested its use as an adjuvant for treatment of prostate and other cancer types. In this study, we investigated the effect of fisetin in combination with cabazitaxel with the objective to achieve maximum therapeutic benefit, reduce dose and toxicity, and minimize or delay the induction of drug resistance and metastasis. Our data show for the first time that a combination of fisetin (20 μmol/L) enhances cabazitaxel (5 nmol/L) and synergistically reduces 22Rν1, PC-3M-luc-6, and C4-2 cell viability and metastatic properties with minimal adverse effects on normal prostate epithelial cells. In addition, the combination of fisetin with cabazitaxel was associated with inhibition of proliferation and enhancement of apoptosis. Furthermore, combination treatment resulted in the inhibition of tumor growth, invasion, and metastasis when assessed in two in vivo xenograft mouse models. These results provide evidence that fisetin may have therapeutic benefit for patients with advanced prostate cancer through enhancing the efficacy of cabazitaxel under both androgen-dependent and androgen-independent conditions. This study underscores the benefit of the combination of fisetin with cabazitaxel for the treatment of advanced and resistant prostate cancer and possibly other cancer types. Mol Cancer Ther; 15(12); 2863–74. ©2016 AACR.
Data from Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers
Authors: Goodman Aaron M. , Kato Shumei , Bazhenova Lyudmila , Patel Sandip P. , Frampton Garrett M. , Miller Vincent , Stephens Philip J. , Daniels Gregory A. , Kurzrock Razelle
Published: April 2023

Abstract
Immunotherapy induces durable responses in a subset of patients with cancer. High tumor mutational burden (TMB) may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non–small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free survival (PFS), and overall survival (OS). Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (≥20 mutations/mb) versus low to intermediate TMB was 22/38 (58%) versus 23/113 (20%; P = 0.0001); median PFS, 12.8 months vs. 3.3 months (P ≤ 0.0001); median OS, not reached versus 16.3 months (P = 0.0036). Results were similar when anti-PD-1/PD-L1 monotherapy was analyzed (N = 102 patients), with a linear correlation between higher TMB and favorable outcome parameters; the median TMB for responders versus nonresponders treated with anti-PD-1/PD-L1 monotherapy was 18.0 versus 5.0 mutations/mb (P < 0.0001). Interestingly, anti-CTLA4/anti-PD-1/PD-L1 combinations versus anti-PD-1/PD-L1 monotherapy was selected as a factor independent of TMB for predicting better RR (77% vs. 21%; P = 0.004) and PFS (P = 0.024). Higher TMB predicts favorable outcome to PD-1/PD-L1 blockade across diverse tumors. Benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB. Mol Cancer Ther; 16(11); 2598–608. ©2017 AACR.
Data from Secretory TRAIL-Armed Natural Killer Cell–Based Therapy: In Vitro and In Vivo Colorectal Peritoneal Carcinomatosis Xenograft
Authors: Song Xinxin , Hong Se-Hoon , Kwon William T. , Bailey Lisa M. , Basse Per , Bartlett David L. , Kwon Yong Tae , Lee Yong J.
Published: April 2023

Abstract
Since its discovery in 1995, TNF-related apoptosis-inducing ligand (TRAIL) has sparked growing interest among oncologists due to its remarkable ability to induce apoptosis in malignant human cells, but not in most normal cells. However, one major drawback is its fast clearance rate in vivo. Thus, the development of an alternative means of delivery may increase the effectiveness of TRAIL-based therapy. In this study, we developed a secretory TRAIL-armed natural killer (NK) cell–based therapy and assessed its cytotoxic effects on colorectal cancer cells and its tumoricidal efficacy on colorectal peritoneal carcinomatosis xenograft. We generated genetically modified NK cells by transduction with a lentiviral vector consisting of a secretion signal domain, a trimerization domain, and an extracellular domain of the TRAIL gene. These NK cells secreted a glycosylated form of TRAIL fusion protein that induced apoptotic death. Intraperitoneally, but not intravenously, injected NK cells effectively accumulated at tumor sites, infiltrated tumor tissue, induced apoptosis, and delayed tumor growth. These results shed light on the therapeutic potential of genetically engineered NK cells to treat peritoneal carcinomatosis. Mol Cancer Ther; 15(7); 1591–601. ©2016 AACR.
Data from Targeting BET Proteins BRD2 and BRD3 in Combination with PI3K-AKT Inhibition as a Therapeutic Strategy for Ovarian Clear Cell Carcinoma
Authors: Shigeta Shogo , Lui Goldie Y.L. , Shaw Reid , Moser Russell , Gurley Kay E. , Durenberger Grace , Rosati Rachele , Diaz Robert L. , Ince Tan A. , Swisher Elizabeth M. , Grandori Carla , Kemp Christopher J.
Published: April 2023

Abstract
Ovarian clear cell carcinoma (OCCC) is a rare, chemo-resistant subtype of ovarian cancer. To identify novel therapeutic targets and combination therapies for OCCC, we subjected a set of patient-derived ovarian cancer cell lines to arrayed high-throughput siRNA and drug screening. The results indicated OCCC cells are vulnerable to knockdown of epigenetic gene targets such as bromodomain and extra-terminal domain (BET) proteins BRD2 and BRD3. Subsequent RNA interference assays, as well as BET inhibitor treatments, validated these BET proteins as potential therapeutic targets. Because development of resistance to single targeted agents is common, we next performed sensitizer drug screens to identify potential combination therapies with the BET inhibitor CPI0610. Several PI3K or AKT inhibitors were among the top drug combinations identified and subsequent work showed CPI0610 synergized with alpelisib or MK2206 by inducing p53-independent apoptosis. We further verified synergy between CPI0610 and PI3K–AKT pathway inhibitors alpelisib, MK2206, or ipatasertib in tumor organoids obtained directly from patients with OCCC. These findings indicate further preclinical evaluation of BET inhibitors, alone or in combination with PI3K-AKT inhibitors for OCCC, is warranted.
Data from CD74-NRG1 Fusions Are Oncogenic In Vivo and Induce Therapeutically Tractable ERBB2:ERBB3 Heterodimerization
Authors: Werr Lisa , Plenker Dennis , Dammert Marcel A. , Lorenz Carina , Brägelmann Johannes , Tumbrink Hannah L. , Klein Sebastian , Schmitt Anna , Büttner Reinhard , Persigehl Thorsten , Shokat Kevan M. , Wunderlich F. Thomas , Schram Alison M. , Peifer Martin , Sos Martin L. , Reinhardt H. Christian , Thomas Roman K.
Published: April 2023

Abstract
NRG1 fusions are recurrent somatic genome alterations occurring across several tumor types, including invasive mucinous lung adenocarcinomas and pancreatic ductal adenocarcinomas and are potentially actionable genetic alterations in these cancers. We initially discovered CD74-NRG1 as the first NRG1 fusion in lung adenocarcinomas, and many additional fusion partners have since been identified. Here, we present the first CD74-NRG1 transgenic mouse model and provide evidence that ubiquitous expression of the CD74-NRG1 fusion protein in vivo leads to tumor development at high frequency. Furthermore, we show that ERBB2:ERBB3 heterodimerization is a mechanistic event in transformation by CD74-NRG1 binding physically to ERBB3 and that CD74-NRG1–expressing cells proliferate independent of supplemented NRG1 ligand. Thus, NRG1 gene fusions are recurrent driver oncogenes that cause oncogene dependency. Consistent with these findings, patients with NRG1 fusion-positive cancers respond to therapy targeting the ERBB2:ERBB3 receptors.
Data from Intratumoral Heterogeneity and Clonal Evolution Induced by HPV Integration
Authors: Akagi Keiko , Symer David E. , Mahmoud Medhat , Jiang Bo , Goodwin Sara , Wangsa Darawalee , Li Zhengke , Xiao Weihong , Dunn Joe Dan , Ried Thomas , Coombes Kevin R. , Sedlazeck Fritz J. , Gillison Maura L.
Published: April 2023

Abstract
The human papillomavirus (HPV) genome is integrated into host DNA in most HPV-positive cancers, but the consequences for chromosomal integrity are unknown. Continuous long-read sequencing of oropharyngeal cancers and cancer cell lines identified a previously undescribed form of structural variation, “heterocateny,” characterized by diverse, interrelated, and repetitive patterns of concatemerized virus and host DNA segments within a cancer. Unique breakpoints shared across structural variants facilitated stepwise reconstruction of their evolution from a common molecular ancestor. This analysis revealed that virus and virus–host concatemers are unstable and, upon insertion into and excision from chromosomes, facilitate capture, amplification, and recombination of host DNA and chromosomal rearrangements. Evidence of heterocateny was detected in extrachromosomal and intrachromosomal DNA. These findings indicate that heterocateny is driven by the dynamic, aberrant replication and recombination of an oncogenic DNA virus, thereby extending known consequences of HPV integration to include promotion of intratumoral heterogeneity and clonal evolution.
Significance:
Long-read sequencing of HPV-positive cancers revealed “heterocateny,” a previously unreported form of genomic structural variation characterized by heterogeneous, interrelated, and repetitive genomic rearrangements within a tumor. Heterocateny is driven by unstable concatemerized HPV genomes, which facilitate capture, rearrangement, and amplification of host DNA, and promotes intratumoral heterogeneity and clonal evolution.

See related video: https://vimeo.com/845407469

See related commentary by McBride and White, p. 814.

This article is highlighted in the In This Issue feature, p. 799
Data from Perceived Appropriateness of Assessing for Health-related Socioeconomic Risks Among Adult Patients with Cancer
Authors: Vu Milkie , Boyd Kelly , De Marchis Emilia H. , Garnache Bridgette G. , Gottlieb Laura M. , Gross Cary P. , Lee Nita K. , Lindau Stacy Tessler , Mun Sophia , Winslow Victoria A. , Makelarski Jennifer A.
Published: April 2023

Abstract
Cancer treatment can trigger or exacerbate health-related socioeconomic risks (HRSR; food/housing insecurity, transportation/utilities difficulties, and interpersonal violence). The American Cancer Society and National Cancer Institute recommend HRSR screening and referral, but little research has examined the perceptions of patients with cancer on the appropriateness of HRSR screening in healthcare settings. We examined whether HRSR status, desire for assistance with HRSRs, and sociodemographic and health care–related factors were associated with perceived appropriateness of HRSR screening in health care settings and comfort with HRSR documentation in electronic health records (EHR). A convenience sample of adult patients with cancer at two outpatient clinics completed self-administered surveys. We used χ2 and Fisher exact tests to test for significant associations. The sample included 154 patients (72% female, 90% ages 45 years or older). Thirty-six percent reported ≥1 HRSRs and 27% desired assistance with HRSRs. Overall, 80% thought it was appropriate to assess for HRSRs in health care settings. The distributions of HRSR status and sociodemographic characteristics were similar among people who perceived screening to be appropriate and those who did not. Participants who perceived screening as appropriate were three times as likely to report prior experience with HRSR screening (31% vs. 10%, P = 0.01). Moreover, 60% felt comfortable having HRSRs documented in the EHR. Comfort with EHR documentation of HRSRs was significantly higher among patients desiring assistance with HRSRs (78%) compared with those who did not (53%, P < 0.01). While initiatives for HRSR screening are likely to be seen by patients with cancer as appropriate, concerns may remain over electronic documentation of HRSRs.
Significance:
National organizations recommend addressing HRSRs such as food/housing insecurity, transportation/utilities difficulties, and interpersonal violence among patients with cancer. In our study, most patients with cancer perceived screening for HRSRs in clinical settings as appropriate. Meanwhile, concerns may remain over the documentation of HRSRs in EHRs.
Chronic Pleural Effusion in Ventriculoperitoneal Shunt due to Diaphragmatic CSF Fistula: Report of a Case Treated by Endoscopic Choroid Plexus Coagulation and Literature Review
Authors: Schmid Simon , Bevot Andrea , Neunhoeffer Felix , Michel Jörg , Kumpf Matthias U , Reimold Matthias , Hofbeck Michael , Schuhmann Martin U
Published: April 2023

Introduction: Chronic pleural cerebrospinal fluid (CSF) effusion is a rare complication after ventriculoperitoneal (VP) shunt insertion and only 18 cases in children and adults have been described so far without catheter dislocation to the intrathoracic cavity. Case Presentation: We report on a 4-year-old girl with a complex history of underlying neurogenetic disorder, a hypoxic-ischemic encephalopathy after influenza A infection with septic shock and severe acute respiratory distress syndrome, followed by meningitis at the age of 10 months. In consequence, she developed a severe cerebral atrophy and post-meningitic hydrocephalus requiring placement of a VP shunt. At age 4, she was admitted with community-acquired mycoplasma pneumonia and developed increasing pleural effusions leading to severe respiratory distress and requiring continuous chest tube drainage (up to 1,000–1,400 mL/day) that could not be weaned. β trace protein, in CSF present at concentrations >6 mg/L, was found in the pleural fluid at low concentrations of 2.7 mg/L. An abdomino-thoracic CSF fistula was finally proven by single photon emission computerized tomography combined with low-dose computer tomography. After shunt externalization, the pleural effusion stopped and the chest tube was removed. CSF production rate remains high above 500 mL/24 h. An atrial CSF shunt could not be placed, since a hemodynamically relevant atrial septum defect with frail circulatory balance would not have tolerated the large CSF volumes. Therefore, she underwent a total bilateral endoscopic choroid plexus laser coagulation (CPC) within the lateral ventricles via bi-occipital burr holes. Postoperatively CSF production rate went close to 0 mL and after external ventricular drain removal no signs and symptoms of hydrocephalus developed during a follow-up of now 2.5 years. Conclusion: In summary, pleural effusions in patients with VP shunt can rarely be caused by an abdomino-thoracic fistula, with non-elevated β-trace protein in the pleural fluid. The majority of reported cases in literature were treated by ventriculoatrial shunt. This is the 2nd reported case, which has been successfully treated by radical CPC alone including the temporal horn choroid plexus, making the child shunt independent.
Energy generation by crystalline silicon photovoltaic network per meter square in Iraq
Authors: Ali Tariq Emad , Abdala Mohammed A. , Al-Khaykan Ameer , A. Alwahab Dhulfiqar , M. Counsell Counsell
Published: April 2023

Iraqi people have been without energy for nearly two decades, even though their geographic position provides a high intensity of radiation appropriate for the construction of solar plants capable of producing significant quantities of electricity. Also, the annual sunny hours in Iraq are between 3,600 to 4,300 hours which makes it perfect to use the photovoltaics arrays to generate electricity with very high efficiency compared to many countries, especially in Europe. This paper shows the amount of electric energy generated by the meter square of crystalline silicon in the photovoltaic (PV) array that already installed in 18 states in Iraq for each month of the year. The results of the meter-square of PV array in three tracking positions are presented in this paper. This paper shows that the average electricity generated in North cities (Dohuk, Al-Sulaymaniyah, and Erbil) are less than the southern cities in the winter season (three positions) by about 40-50%. Iraq has a stable PV electrical generation during all the year in all regions except the North cities while the highest cities in electricity generation are (Najaf and Al-Anbar).
Analytical assessment of torque and stator currents of an induction motor due to voltage sags
Authors: Huchche Vijaya , Patne Nita
Published: April 2023

Voltage sag is a frequently encountered phenomenon in a power system to which many three phase induction motors are directly connected. This paper presents a simple analytical method for calculation of net electro-magnetic torque and stator currents of an induction motor subjected to symmetrical as well as unsymmetrical sags in supply voltage. This work presents an innovative path to compute net electro-magnetic torque and increase in stator currents for all seven types of sags using the well-known symmetrical component theory. Such a simple method and expressions used in this paper are not reported in the literature reviewed so far. The computation is further extended for different load conditions while varying the symmetrical sag magnitude. The simplicity of analytical assessment of loading effect on electro-magnetic torque from no-load to full-load condition for all sag types is presented. The outcome of the study was verified by imitating the environments for various types of sag in MATLAB/Simulink. The observations are that the average output torque of a motor decreases and ripple in power increases during unsymmetrical sags.
Geographical information systems based site selection methodology for renewable energy systems in Palestinian territories
Authors: Qutaina Buthayna , Shehada Ahmad , Yasin Aysar , Alsayed Mohammed
Published: April 2023

Renewable energy is the key term for the energy industry sector in the world recently. Palestinian territories (PT) have good potential for multiple renewable energy applications. The purpose of this study was to evaluate the potential sites for solar photovoltaic systems, concentrated solar power systems, and wind farms in the West Bank (WB). The study was derived from geographical information systems (GIS) and multi-criteria decision making (MCDM). The criteria for each application were identified and weighted according to the analytical hierarchy process (AHP). All the resulting layers were multiplied to produce the final suitability map for each application. The results of the study depend on two scenarios, In the first scenario, where area C is included, the areas classified as highly suitable for photovoltaic (PV), concentrated solar power (CSP), and wind turbines are between 14.27 and 7.56 km2. The second scenario is excluding area C, the highly suitable areas were between 4.1 to 2.47km2.
Direct torque control and dynamic performance of induction motor using fractional order fuzzy logic controller
Authors: Kamalapur Geeta , Aspalli Mruttanjaya S.
Published: April 2023

Conventional direct torque control (DTC) is one of the best control systems for regulating the torque of an induction motor (IM). However, the DTC’s enormous waves in flux and torque cause acoustic noise that degrades control performance, especially at low speeds due to the DTC’s low switching frequency. Direct torque control systems, which focus just on torque and flux, have been proposed as a solution to these problems. In order to improve DTC control performance, this work introduces a fractional-order fuzzy logic controller method. The objective is to analyze this technique critically with regard to its efficacy in reducing ripple, its tracking speed, its switching loss, its algorithm complexity, and its sensitivity to its parameters. Simulation in MATLAB/Simulink verifies the anticipated control approach’s performance.
Conducted electromagnetic interference mitigation in super-lift Luo-converter for electric vehicle applications
Authors: Kalaiarasu Srinivasan , Natarajan Sudhakar
Published: April 2023

In this article, a digital chaotic pulse width modulation (DCPWM)-dependent electromagnetic interference (EMI) noise attenuating procedure has been implemented. With the aid of a field programmable gate array (FPGA), a randomized carrier frequency modulation with a fixed duty cycle has been generated through chaotic carrier frequency, and this process is called DCPWM. Conducted EMI suppression is achieved in a 200 kHz, 40 W elementary positive output super lift Luo (EPOSLL) converter using the DCPWM technique. The results are compared and validated with periodic PWM over DCPWM in simulation and hardware with electromagnetic compatibility (EMC) standards. Besides, 9 dBV (2.81 V) of conducted EMI noise has been minimized in the DCPWM approach against periodic pulse width modulation method for the EPOSLL converter in electric vehicles applications.
Comparative performance of modular with cascaded H-bridge three level inverters
Authors: El-Naggar Nada Mohamed , Esmaeel Mohamed Adel , Abu-Zaid Salama
Published: April 2023

The conventional two-level inverter becomes no longer has the ability to cope with the high-power requirement, so this paper discusses two very common topologies of multilevel inverter like modular multi-level converter (MMC) and cascaded H-bridge (CHB) multi-level inverter for induction motor drive applications. This work attempts to investigate the comparison between MMC and CHB. The comparison is done in aspects of the configuration, concept of operation, advantages and disadvantages, the comparison is also consider output voltage (line to line) waveform, total harmonic distortion (THD) of the output line voltage waveform and the current drawn by both inverters. The performance of the inverters under carrier-based pulse width modulation (PWM) technique and mainly in-phase disposition (IPD), level shifted pulse width modulation is viewed. The paper discusses the comparison between the two multilevel inverters (MLIs) with motor drive applications especially induction motor. The operation of the motor is studied under certain value of load torque. The simulation results for the induction motor with the two inverters (modular multi-level and Cascaded H-bride) for three numbers of levels using MATLAB/Simulink are provided). The obtained results are encouraging and promising especially in the improvement of the THD% results.
A proposed optimized equivalent circuit and performance analysis of dielectric barrier discharge ozone generator
Authors: El_Hanash Mohamed , Youssef Mohamed I. , M. Zaky Magdy
Published: April 2023

Traditionally, low-frequency power supplies are used in dielectric barrier discharge (DBD) ozone generators. These generators require a very high output voltage. This may limit ozone production due to limitations imposed by the dielectric strength of the insulating material. Low-frequency generators also present low efficiency, large volumes, and difficulty in controlling ozone production. On the other hand, the advantages of high frequency DBD ozone generators are the increased power density applied to the chamber electrodes, and the voltage applied to the ozone chamber decreases, allowing for higher ozone production efficiency. From this point of view, in order to enhance and control the DBD ozone generator operating at high frequency, it is necessary to determine all parameter values and optimize the equivalent model for this type of generator. This work presents and proposes the practical methodologies used to extract all parameters of the high voltage high frequency (HVHF) transformer which can be used in these systems. Resonant frequency control techniques are presented in this paper. Elimination of the stray capacitance effect will also be implemented in this paper.
Performance of low-cost solar radiation logger
Authors: Risdiyanto Agus , Kristi Ant. Ardath , Junaedi Agus , Susanto Bambang , Rachman Noviadi A. , Muqorobin Anwar , Santosa Harjono P. , Fudholi Ahmad
Published: April 2023

In solar power systems, irradiance value data are among the most important parameters. Such data can be used in installing photovoltaic (PV) modules, such as determining the exact location, tilt angle, and required area, for optimal power efficiency. In this study, the comprehensive simulation and implementation of a solar radiation meter with a PV cell and temperature sensor are presented. The irradiance measurement value is based on the power reading generated by the small capacity of the PV cell at a specific load converted into a digital value in the microcontroller using the implicit Newton polynomial interpolation (NPI) equation as a low-cost alternative method. The effect of temperature is included in the conversion to obtain precise measurement results. Firstly, the structure and characteristics of the PV cell are discussed. Secondly, the parameters, measuring method, and conversion of the measurement reading data using the NPI equation are presented to assess the results. Finally, the simulation of the solar radiation meter using the PSIM and implementation of the hardware are conducted to validate the concepts and compare their results. The proposed hardware has an average error of 2.72% in the implementation of the measurement test.
Enhanced image reconstruction of electrical impedance tomography using simultaneous algebraic reconstruction technique and K-means clustering
Authors: Fahrudin Arfan Eko , Endarko Endarko , Ain Khusnul , Rubiyanto Agus
Published: April 2023

Electrical impedance tomography (EIT), as a non-ionizing tomography method, has been widely used in various fields of application, such as engineering and medical fields. This study applies an iterative process to reconstruct EIT images using the simultaneous algebraic reconstruction technique (SART) algorithm combined with K-means clustering. The reconstruction started with defining the finite element method (FEM) model and filtering the measurement data with a Butterworth low-pass filter. The next step is solving the inverse problem in the EIT case with the SART algorithm. The results of the SART algorithm approach were classified using the K-means clustering and thresholding. The reconstruction results were evaluated with the peak signal noise ratio (PSNR), structural similarity indices (SSIM), and normalized root mean square error (NRMSE). They were compared with the one-step gauss-newton (GN) and total variation regularization based on iteratively reweighted least-squares (TV-IRLS) methods. The evaluation shows that the average PSNR and SSIM of the proposed reconstruction method are the highest of the other methods, each being 24.24 and 0.94; meanwhile, the average NRMSE value is the lowest, which is 0.04. The performance evaluation also shows that the proposed method is faster than the other methods.
Proposed energy efficient clustering and routing for wireless sensor network
Authors: Srinivasalu Gundeboyina , Umadevi Hanumanthappa
Published: April 2023

Wireless sensor network (WSN) is considered a growing research field that includes numerous sensor nodes used to gather, process, and broadcast information. Energy efficiency is considered one of the challenging tasks in the WSN. The clustering and routing are considered capable approaches to solve the issues of energy efficiency and enhance the network’s lifetime. In this research, the multi-objective-energy based black widow optimization algorithm (M-EBWOA) is proposed to perform the cluster-based routing over the WSN. The M-EBWOA-based optimal cluster head discovery is used to assure an energy-aware routing over the WSN. The main goal of this M-EBWOA is to minimize the energy consumed by the nodes while improving the data delivery of the WSN. The performance of the M-EBWOA is analyzed as alive and dead nodes, dissipated energy, packets sent to base station, and life expectancy. The existing research such as low-energy adaptive clustering hierarchy (LEACH), hybrid grey wolf optimizer-based sunflower optimization (HGWSFO), genetic algorithm-particle swarm optimization (GA-PSO), and energy-centric multi-objective Salp Swarm algorithm (ECMOSSA) are used to evaluate the efficiency of M-EBWOA. The alive nodes of the M-EBWOA are 100 for 2,500 rounds, which is higher than the LEACH, HGWSFO, GA-PSO, and ECMOSSA.
Assimilating sense into disaster recovery databases and judgement framing proceedings for the fastest recovery
Authors: Shaik Vaheedbasha , Kalyanasundaram Natarajan
Published: April 2023

The replication between the primary and secondary (standby) databases can be configured in either synchronous or asynchronous mode. It is referred to as out-of-sync in either mode if there is any lag between the primary and standby databases. In the previous research, the advantages of the asynchronous method were demonstrated over the synchronous method on highly transactional databases. The asynchronous method requires human intervention and a great deal of manual effort to configure disaster recovery database setups. Moreover, in existing setups there was no accurate calculation process for estimating the lag between the primary and standby databases in terms of sequences and time factors with intelligence. To address these research gaps, the current work has implemented a self-image looping database link process and provided decision-making capabilities at standby databases. Those decisions from standby are always in favor of selecting the most efficient data retrieval method and being in sync with the primary database. The purpose of this paper is to add intelligence and automation to the standby database to begin taking decisions based on the rate of concurrency in transactions at primary and out-of-sync status at standby.
A new algorithm to enhance security against cyber threats for internet of things application
Authors: Abujassar Radwan S. , Sayed Mohamed , Yaseen Husam
Published: April 2023

One major problem is detecting the unsuitability of traffic caused by a distributed  denial of services (DDoS) attack produced by third party nodes, such as smart phones and other handheld Wi-Fi devices. During the transmission between the devices, there are rising in the number of cyber attacks on systems by using negligible packets, which lead to suspension of the services between source and destination, and can find the vulnerabilities on the network. These vulnerable issues have led to a reduction in the reliability of networks and a reduction in consumer confidence. In this paper, we will introduce a new algorithm called rout attack with detection algorithm (RAWD) to reduce the affect of any attack by checking the packet injection, and to avoid number of cyber attacks being received by the destination and transferred through a determined path or alternative path based on the problem. The proposed algorithm will forward the real time traffic to the required destination from a new alternative backup path which is computed by it before the attacked occurred. The results have showed an improvement when the attack occurred and the alternative path has used to make sure the continuity of receiving the data to the main destination without any affection.
An ontology-based spatial group decision support system for site selection application
Authors: Djelloul Aicha Benelhadj , Hamdadou Djamila
Published: April 2023

This paper presents a new ontology-based multicriteria spatial group decision support system (GDSS) dedicated to site selection problems. Site selection is one of the most complex problems in the construction of a new building. It presents a crucial problem in terms of selecting the appropriate site among a group of decision makers with multiple alternatives (sites); in addition, the site must satisfy several criteria. To deal with this, the present paper introduces an ontology based multicriteria analysis method to solve semantic heterogeneity in vocabulary used by participants in spatial group decision support systems. The advantages of using ontology in GDSS are many: i) it enables the integration of heterogeneous sources of data available on the web and ii) it enables to facilitate meaning and sharing of data used in GDSS by participants. In order to facilitate cooperation and collaboration between participants in GDSS, our work aims to apply ontology at the model's structuration phase. The proposed system has been successfully implemented and exploited for a personalized environment.