MORC3 Restricts Human Cytomegalovirus Infection by Suppressing the Major Immediate‐early Promoter Activity

alexandrossfakianakis shared this article with you from Inoreader MORC3 Restricts Human Cytomegalovirus Infection by Suppressing the Major Immediate‐early Promoter Activity via Journal of Medical Virology Abstract During the long coevolution of human cytomegalovirus (HCMV) and humans, the host has formed a defense system of multiple layers to eradicate the invader, and the virus has developed various strategies to evade host surveillance programs. The intrinsic immunity primarily orchestrated by promyelocytic leukemia (PML) nuclear bodies (PML-NBs) represents the first line of defense against HCMV infection. Here, we demonstrate that microrchidia family CW-type zinc finger 3 (MORC3), a PML-NBs component, is a restriction factor targeting HCMV infection. We show that depletion of MORC3 through knockdown by RNA interference or knockout by CRISPR-Cas9 augmented IE1 gene expression and subsequent viral replication, and overexpressing MORC3 inhibited HCMV replication by suppressing IE1 gene expression. To relief the restriction, HCMV induces transient reduction of MORC3 protein level via the ubiquitin-proteasome pathway during the immediate-early to early stage. However, M ORC3 transcription is upregulated, and the protein level recovers in the late stages. Further analyses with temporal-controlled MORC3 expression and the major immediate-early promoter (MIEP)-based reporters show that MORC3 suppresses MIEP activity and consequent IE1 expression with the assistance of PML. Taken together, our data reveal that HCMV enforces temporary loss of MORC3 to evade its repression against the initiation of immediate-early gene expression. This article is protected by copyright. All rights reserved. View on Web

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Risk Factors for Poor Survival Outcomes in Parotid Metastatic Cutaneous Squamous Cell Carcinoma

alexandrossfakianakis shared this article with you from Inoreader Risk Factors for Poor Survival Outcomes in Parotid Metastatic Cutaneous Squamous Cell Carcinoma via The Laryngoscope Objective We aimed to analyze risk factors associated with poor survival outcomes for metastatic cutaneous head-and-neck SCC to the parotid. Methods All patients undergoing surgery for metastatic cutaneous SCC to the parotid with curative intent between 2011 and 2018, were reviewed. Demographic and clinical characteristics were evaluated. Histopathological data including tumor size and histology, tumor grade, TNM stage, resection margins, lymphovascular invasion, and perineural invasion, were analyzed. Overall survival (OS), disease-specific survival (DSS), and freedom from locoregional recurrence (LRR) were assessed. Results Ninety patients were included (mean age, 77 years; 75 men [83.3%]). A total parotidectomy was performed in 48 patients (53.3%), and 42 (46.7%) underwent a superficial parotidectomy. Seventy patients (77.8%) underwent adjuvant RT. The median follow-up was 31 months (20–39 months). Tumor volume ≥ 50 cm3 and a shorter RT duration (<20 days) were associated with reduced OS (p = 0.002 and p = 0.01, p = 0.02 and p = 0.009, respectively), and DSS (p = 0.004 and p = 0.02, p = 0.04 and p = 0.02, respectively) on univariable and multivariable analysis, respectively. Only a shorter RT duration was associated with worse freedom from LRR on univariable and multivariable analysis, (p = 0.04 and p < 0.001, respectively). However, with death as a competing risk, a shorter duration of RT was not signif icantly associated with freedom from LRR. Conclusion A shorter duration of adjuvant RT, and excised tumor volume ≥50 cm3 were predictive factors of reduced OS and DSS, and a shorter duration of RT was also associated with reduced freedom from LRR in patients with metastatic SCC to the parotid gland. Level of Evidence Level 4 Laryngoscope, 2022 View on Web

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Potential Clinical Utility of a Targeted Circulating Tumor DNA Assay in Esophageal Adenocarcinoma

alexandrossfakianakis shared this article with you from Inoreader Potential Clinical Utility of a Targeted Circulating Tumor DNA Assay in Esophageal Adenocarcinoma via Annals of Surgery - Most Popular Articles Objective: To explore the clinical utility of circulating tumor DNA (ctDNA) in esophageal adenocarcinoma (EAC) by developing a cost-effective and rapid technique utilising targeted amplicon sequencing. Summary of background data: Emerging evidence suggests that levels of ctDNA in the blood can be used to monitor treatment response and in the detection of disease recurrence in various cancer types. Current staging modalities for EAC such as computerised tomography of the chest/abdomen/pelvis (CT) and positron emission tomography (PET) do not reliably detect occult micro-metastatic disease, the presence of which signifies a poor prognosis. After curative-intent treatment, some patients are still at high risk of recurrent disease, and there is no widely accepted optimal surveillance tool for patients with EAC. Methods: Sixty-two patients with EAC were investigated for the presence of ctDNA using a tumor-informed approach. We designed a custom targeted amplicon sequencing panel of target specific primers covering mutational foci in 9 of the most commonly mutated genes in EAC. Serial blood samples were taken before and after neoadjuvant treatment (NAT), and during surveillance. Results: Somatic mutations were detected in pre-treatment biopsy samples of 55 out of 62 (89%) EAC patients. Mutations in TP53 (80%) were the most common. Out of these 55 patients, 20 (36%) had detectable ctDNA at baseline. The majority (90%) of patients with detectable ctDNA had either locally advanced tumors, nodal involvement or metastatic disease. In patients with locally advanced tumors, disease free survival (DFS) was more accurately stratified using pre-treatment ctDNA status [HR 4.34 (95% CI 0.93–20.21); P = 0.05] compared to nodal status on PET-CT. In an exploratory subgroup analysis, patients who are node negative but ctDNA positive have inferior DFS [HR 11.71 (95% CI 1.16-118.80) P = 0.04]. In blood samples taken before and following NAT, clearance of ctDNA after NAT was associated with a favourable response to treatment. Furthermore, patients who are ctDNA positive during post-treatment surveillance are at high risk of relapse. Conclusions: Our study shows that ctDNA has potential to provide additional prognostication over conventional staging investigation such as CT and PET. It may also have clinical utility in the assessment of response to NAT and as a biomarker for the surveillance of recurrent disease. View on Web

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Depletion of d‐ and l‐asparagine in cerebrospinal fluid in acute lymphoblastic leukemia during PEGasparaginase therapy

alexandrossfakianakis shared this article with you from Inoreader Depletion of d‐ and l‐asparagine in cerebrospinal fluid in acute lymphoblastic leukemia during PEGasparaginase therapy via Pediatric Blood & Cancer Abstract Background l-Asparaginase hydrolyzes l-asparagine and not its enantiomer d-asparagine. Unlike l-asparagine, d-asparagine is nonessential for the survival of acute lymphoblastic leukemia (ALL) cells. Studies showed that serum asparagine is depleted below 0.5 μM in ≥96% of the patients during pegylated Escherichia coli l-asparaginase (PEGasparaginase) treatment; however, cerebrospinal fluid (CSF) asparagine levels are depleted in only 20%–30% of the patients. Thus far, studies only reported the total CSF asparagine (sum of d- and l-asparagine) concentrations. Data on the pharmacological goal, which is l-asparagine depletion, are lacking. Method Therefore, we studied this in 30 patients (95 samples) with newly diagnosed ALL. They received two doses of PEGasparaginase on day 4 and 18 in induction. Results Median age at diagnosis was 5.7 years (range 1.5–17.1 years). d-Asparagine and l-asparagine concentrations (median (range)) before PEGasparaginase treatment were 0.038 (0.0–0.103) μM and 6.1 (1.82–11.5) μM, respectively. CSF l-asparagine concentrations were reduced by 85% (76%–100%) and approximately one-third of the patients (32%) had CSF l-asparagine depletion below 0.5 μM 11 days after the second PEGasparaginase dose administration. CSF d-asparagine and l-glutamine levels remained stable before and after administration of PEGasparaginase. The percentage of d-asparagine as a fraction of total asparagine (sum of d- and l-asparagine) was 0.62% before and 4.5% after PEGasparaginase treatment. No correlation was found between higher serum PEGasparaginase activity and CSF l-asparagine concentration. Conclusion l-Asparagine is not a better parameter than total asparagine in CSF due to the negligible amount of d-asparagine in the CSF before and after PEGasparaginase treatment. View on Web

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Ultrasound‐guided totally implantable venous access ports placement via right brachiocephalic vein in pediatric population: A clinical debut

alexandrossfakianakis shared this article with you from Inoreader Ultrasound‐guided totally implantable venous access ports placement via right brachiocephalic vein in pediatric population: A clinical debut via Pediatric Blood & Cancer Abstract Background and objectives To investigate the feasibility and safety of ultrasound-guided totally implantable venous access ports (TIVAPs) via the right brachiocephalic vein (BCV) in pediatric patients. Methods A single-institute retrospective review was performed on 35 pediatric patients with predominantly hematological malignancies (88.6%) who underwent TIVAP implantation via ultrasound-guided right BCV approach from July 2018 to June 2021. The catheter tip was adjusted to be positioned at the cavoatrial junction under pulsed fluoroscopic guidance. Technical success rate, procedural information, and TIVAP-related complications were evaluated. Results All the pediatric TIVAP devices were successfully implanted via right BCV access. Venous access was successful by first attempt in 32 children (91%), two cases (5.7%) required a second attempt, and one patient (2.9%) required a third attempt. The mean procedural time was 44.6 ± 6.4 minutes (range: 34–62 minutes). No intraoperative complications occurred. The average TIVAP indwelling time was 564 ± 208 days (range: 193–1014 days), with a cumulative 19,723 catheter-days. Overall, three patients (8.6%) experienced four postoperative complications (two cases of local hematoma and two catheter dysfunctions) at a rate of 0.2 per 1000 catheter-days. No other complications such as wound dehiscence, delayed incision healing, catheter-related thrombosis (CRT), catheter malposition/fracture, surgical site infection, catheter-related bloodstream infection (CRBSI), pinch-off syndrome, and drug extravasation were observed during follow-up. Conclusions Ultrasound-guided right BCV access for TIVAP placement in pediatric patients appears to be technically feasible, safe, and effective. Further large-sample, prospective studies are warranted. View on Web

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Lifetime exposure to welding fume and risk of some rare cancers

alexandrossfakianakis shared this article with you from Inoreader Lifetime exposure to welding fume and risk of some rare cancers via American Journal of Epidemiology - Advance Access Abstract We investigated the association between exposure to welding fumes and the risk of biliary tract, male breast, bone, thymus cancer, cancer of the small intestine, eye melanoma, and mycosis fungoides among males in a European, multi-center case–control study. From 1995 to 1997, 644 cases and 1,959 control subjects from seven countries were studied with respect to information on welding and potential confounders. We linked the welding histories of the participants with a m easurement-based exposure matrix to calculate lifetime exposure to welding fumes. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models, conditional on country and 5-year age groups, and adjusted for education and relevant confounders. Regular welding was associated with an increased risk of cancer of the small intestine (OR 2.30, CI 1.17, 4.50). Lifetime exposure to welding fumes above the median of exposed controls was associated with an increased risk of cancer of the small intestine (OR 2.00, CI 1.07, 3.72) and male breast (OR 2.07, CI 1.14, 3.77), and some elevation in risk was apparent for bone cancer (OR 1.92, CI 0.85, 4.34) with increasing lifetime exposure to welding fumes. Welding fumes could contribute to an increased risk of some rare cancers. View on Web

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Analyzing Longitudinally Collected Viral Load Measurements in Youth With Perinatally-Acquired HIV Infection: Problems and Possible Remedies

alexandrossfakianakis shared this article with you from Inoreader Analyzing Longitudinally Collected Viral Load Measurements in Youth With Perinatally-Acquired HIV Infection: Problems and Possible Remedies via American Journal of Epidemiology - Advance Access Abstract HIV viral load (VL) is an important quantitative marker of disease progression and treatment response in people living with HIV infection (PLHIV), including children with perinatally-acquired HIV. Measures of VL are often used to predict different outcomes of interest in this population such as HIV-associated neurocognitive disorder. One popular approach to summarizing historical viral burden is the area under a time-VL curve (AUC). However, alternative historical VL summ aries (HVSs) may better answer the research question of interest. In this manuscript, we discuss and contrast AUC with alternative HVSs including the time-averaged AUC, duration of viremia, percent time with suppressed VL, peak VL, and age at peak VL. Using data on youth with perinatally-acquired HIV infection from the Pediatric HIV/AIDS Cohort Study (PHACS) Adolescent Master Protocol (AMP), we show that HVSs and their associations with full scale IQ depend on when the viral loads were measured. When viral load measurements are incomplete, as can be the case in observational studies, analysis results may be subject selection bias. To alleviate bias we detail an imputation strategy and we present a simulation study demonstrating that unbiased estimation of a historical VL summary is possible with a correctly specified imputation model. View on Web

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Clinical Characteristics and Illness Course Based on Pathogen Among Children with Respiratory Illness Presenting to an Emergency Department

alexandrossfakianakis shared this article with you from Inoreader Clinical Characteristics and Illness Course Based on Pathogen Among Children with Respiratory Illness Presenting to an Emergency Department via Journal of Medical Virology ABSTRACT Background Upper respiratory illnesses due to viruses are the most common reason for pediatric emergency department (ED) visits in the United States. We explored the clinical characteristics, hospitalization risk, and symptom duration of children in an ED setting by respiratory pathogen including coinfections. Methods A retrospective analysis was conducted from a randomized controlled trial evaluating a rapid molecular pathogen panel among 931 children 1 month -18 years of age with acute respiratory illness. We assessed hospitalization risk by pathogen using multivariable Poisson regression with robust variance. Symptom duration was assessed using multivariable Cox proportional hazards models. Results Among 931 children, 702 (75%) were aged 0-5 years and 797 (85%) tested positive for a respiratory pathogen. Children with RSV, hMPV and hRV/EV had higher hospitalization risk compared with influenza (adjusted Risk Ratio [aRR]:2.95, 95% CI:1.17-7.45 ; 3.56, 95% CI:1.05-12.02; aRR: 2.58, 95% CI:1.05-6.35 respectively). Children with RSV, parainfluenza and atypical bacterial pathogens had longer illness duration compared with influenza (adjusted Hazards Ratio [aHR]: 2.16 95% CI:1.41-3.29; aHR: 1.67, 95% CI:1.06-2.64; aHR 2.60 95% CI:1.30-5.19 respectively). Conclusions Children with RSV, hMPV and atypical bacterial pathogens had higher illness severity and duration compared with other respiratory pathogens. Coinfection was not associated with increased illness severity. This article is protected by copyright. All rights reserved. View on Web

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The first-in-class ERK inhibitor ulixertinib shows promising activity in MAPK-driven pediatric low-grade glioma models

alexandrossfakianakis shared this article with you from Inoreader The first-in-class ERK inhibitor ulixertinib shows promising activity in MAPK-driven pediatric low-grade glioma models via Neuro-Oncology Advance Access Abstract Background Pediatric low-grade gliomas (pLGG) are the most common pediatric central nervous system tumors, with driving alterations typically occurring in the MAPK pathway. The ERK1/2 inhibitor ulixertinib (BVD-523) has shown promising responses in adult patients with mitogen-activated protein kinase (MAPK)-driven solid tumors. Methods We investigated the anti-tumoral activity of ulixertinib monotherapy as well as in combination with MEK inhibitors (MEKi), BH3-mimetics, or chemotherapy in pLGG. Patient-derived pLGG models reflecting the two most common alterations in the disease, KIAA1549:BRAF-fusion and BRAF V600E mutation (DKFZ-BT66 and BT40, respectively) were used for in vitro and in vivo (zebrafish embryos and mice) efficacy testing. Results Ulix ertinib inhibited MAPK pathway activity in both models, and reduced cell viability in BT40 with clinically achievable concentrations in the low nanomolar range. Combination treatment of ulixertinib with MEKi or BH3-mimetics showed strong evidence of anti-proliferative synergy in vitro. Ulixertinib showed on-target activity in all tested combinations. In vivo, sufficient penetrance of the drug into brain tumor tissue in concentrations above the in vitro IC50 and reduction of MAPK pathway activity was achieved. In a preclinical mouse trial, ulixertinib mono- and combined therapies slowed tumor growth and increased survival. Conclusions These data indicate a high clinical potential of ulixertinib for the treatment of pLGG and strongly support its first clinical evaluation in pLGG as single agent and in combination therapy in a currently planned int ernational phase I/II umbrella trial. View on Web

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