Modulation of BRCA1 mediated DNA damage repair by deregulated ER-α signaling in breast cancers

xlomafota13 shared this article with you from Inoreader Modulation of BRCA1 mediated DNA damage repair by deregulated ER-α signaling in breast cancers Via American Journal of Cancer Research Am J Cancer Res. 2022 Jan 15;12(1):17-47. eCollection 2022. ABSTRACT BRCA1 mutation carriers have a greater risk of developing cancers in hormone-responsive tissues like breasts and ovaries. However, this tissue-specific incidence of BRCA1 related cancers remains elusive. The majority of the BRCA1 mutated breast cancers exhibit typical histopathological features of high-grade tumors, with basal epithelial phenotype, classified as triple-negative molecular subtype and have a higher percentage of DNA damage and chromosomal abnormality. Though there are many studies relating BRCA1 with ER-α (Estrogen receptor-α), it has not been reported whether E2 (Estrogen) -ER-α signaling can modulate the DNA repair activities of BRCA1. The present study analyzes whether deregulation of ER-α signaling, arising as a result of E2/ER-α deficiency, could impact the BRCA1 dependent DDR (DNA Damage Response) pathways, predominantly those of DNA-DSB (Dou ble Strand break) repair and oxidative damage response. We demonstrate that E2/E2-stimulated ER-α can augment BRCA1 mediated high fidelity repairs like HRR (Homologous Recombination Repair) and BER (Base Excision Repair) in breast cancer cells. Conversely, a condition of ER-α deficiency itself or any interruption in ligand-dependent ER-α transactivation resulted in delayed DNA damage repair, leading to persistent activation of γH2AX and retention of unrepaired DNA lesions, thereby triggering tumor progression. ER-α deficiency not only limited the HRR in cells but also facilitated the DSB repair through error prone pathways like NHEJ (Non Homologous End Joining). ER-α deficiency associated persistence of DNA lesions and reduced expression of DDR proteins were validated in human mammary tumors. PMID:35141003 | PMC:PMC8822286 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Definitive radiation therapy and liver local therapy in de novo liver metastatic nasopharyngeal carcinoma: Large cohort study

xlomafota13 shared this article with you from Inoreader Definitive radiation therapy and liver local therapy in de novo liver metastatic nasopharyngeal carcinoma: Large cohort study Via Head & Neck Abstract Background We aimed to evaluate patients suitable for definitive radiation therapy (DRT) and liver local therapy (LLT) in addition to palliative chemotherapy (PCT) among those with de novo liver metastatic nasopharyngeal carcinoma (lmNPC). Methods The overall survival (OS) and progression-free survival (PFS) rates were calculated and compared in 610 patients with lmNPC. Results Both the PCT+DRT and PCT+DRT+LLT groups had better survival outcomes than the PCT group. Among patients with complete response/partial response (CR/PR) after PCT, no significant differences in survival rates were observed between those treated with PCT+DRT and PCT+DRT+LLT (2-year PFS: 27.0% vs. 32.9%, p = 0.263). Among patients with progressive disease/stable disease (PD/SD) after PCT, significantly better survival rates were observed in patients treated with PCT+DRT+LLT. Conclusions DRT might benefit patients with lmNPC regardless of the tumor response after PCT. For patients with CR/PR, LLT might not be needed. For patients with PD/SD, LLT might improve survival outcomes. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Trends in Subglottic Stenosis Management: Resource Utilization and Pediatric Otolaryngology Training

xlomafota13 shared this article with you from Inoreader Trends in Subglottic Stenosis Management: Resource Utilization and Pediatric Otolaryngology Training Via The Laryngoscope Objectives/Hypothesis The role for endoscopic management in children with subglottic stenosis (SGS) has grown, but there are no data on resource utilization or the impact on surgical training in pediatric otolaryngology. This study hypothesizes that this shift has increased resource utilization and has impacted surgical training by shifting the focus toward more endoscopic techniques. Study Design Retrospective database review. Methods The Kids' Inpatient Database for 2003, 2006, 2009, and 2012 was queried for admissions with the diagnosis of SGS. Surgical caseload was studied using the Accreditation Council for Graduate Medical Education Accreditation data system for 2010 to 2017. Results Admissions with SGS remained constant between 2003 and 2012. Hospital charges per admission did not change between 2003 and 2009 but increased in 2012. Tracheostomy decreased from 10.5% of admissions in 2003 to 6.8% in 2012. The percentage requiring repair of the larynx did not change; other operations on the larynx increased from 4.5% in 2003 to 11.6% in 2012. The median number of laryngoplasties performed per trainee decreased from 14 to nine between 2010 and 2017, whereas the number of laryngoscopy with intervention procedures increased from 34 to 56. Conclusions The evolution of SGS management appears to have led to a decrease in tracheostomy and an increase in certain procedures that may include endoscopic procedures. Recently, there has been a shift in airway surgical training, with trainees logging less open laryngotracheoplasty and more interventional laryngoscopy. Although these trends cannot be directly linked, the changes in trainee surgical experience may be justified by the decrease in larger open procedures and associated resource utilization. Level of Evidence 2c Laryngoscope, 132:S1–S9, 2022 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Bacterial meningitis due to the Streptococcus mitis group in children with cerebrospinal fluid leak

xlomafota13 shared this article with you from Inoreader Bacterial meningitis due to the Streptococcus mitis group in children with cerebrospinal fluid leak Via leak of cerebrospinal fluid IDCases. 2022 Jan 13;27:e01406. doi: 10.1016/j.idcr.2022.e01406. eCollection 2022. ABSTRACT The Streptococcus mitis group constitutes a part of the oral flora in humans and has been reported to cause infective endocarditis, brain abscesses, sepsis, pneumonia, and peritonitis. However, the S. mitis group rarely causes meningitis in children. We experienced a case of bacterial meningitis due to the S. mitis group in a 14-year-old girl with Gorham-Stout disease undergoing treatment with sirolimus for skull base osteolysis and cerebrospinal fluid (CSF) leak. Antibiotic treatment was initiated with linezolid and levofloxacin due to allergies against β-lactam antibiotics. On the third treatment day, antibiotics were switched to penicillin G according to CSF culture results, which were positive for penicillin-susceptible S. mitis group. Antibiotic therapy was successfully completed after 14 days without any neurological sequelae. There have apparently been no reports of S. mitis meningitis in pediatric patients with skull base osteolysis and CSF leak as in our case. Our findings suggest that clinicians should be aware of the possibility of S. mitis meningitis for patients with skull base osteolysis and/or CSF leakage. PMID:35145856 | PMC:PMC8801995 | DOI:10.1016/j. idcr.2022.e01406 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Comparison of manual and automated digital image analysis systems for quantification of cellular protein expression

xlomafota13 shared this article with you from Inoreader Comparison of manual and automated digital image analysis systems for quantification of cellular protein expression Via Cellular and Molecular Biology Histol Histopathol. 2022 Feb 11:18434. doi: 10.14670/HH-18-434. Online ahead of print. ABSTRACT OBJECTIVE: Quantifying protein expression in immunohistochemically stained histological slides is an important tool for oncologic research. The use of computer-aided evaluation of IHC-stained slides significantly contributes to objectify measurements. Manual digital image analysis (mDIA) requires a user-dependent annotation of the region of interest (ROI). Others have built-in machine learning algorithms with automated digital image analysis (aDIA) and can detect the ROIs automatically. We aimed to investigate the agreement between the results obtained by aDIA and those derived from mDIA systems. METHODS: We quantified chromogenic intensity (CI) and calculated the positive index (PI) in cohorts of tissue microarrays (TMA) using mDIA and aDIA. To consider the different distributions of staining within cellular sub-compartments and diffe rent tumor architecture our study encompassed nuclear and cytoplasmatic stainings in adenocarcinomas and squamous cell carcinomas. RESULTS: Within all cohorts, we were able to show a high correlation between mDIA and aDIA for the CI (p<0.001) along with high agreement for the PI. Moreover, we were able to show that the cell detections of the programs were comparable as well and both proved to be reliable when compared to manual counting. CONCLUSION: mDIA and aDIA show a high correlation in acquired IHC data. Both proved to be suitable to stratify patients for evaluation with clinical data. As both produce the same level of information, aDIA might be preferable as it is time-saving, can easily be reproduced, and enables regular and efficient output in large studies in a reasonable time period. PMID:35146728 | DOI:10.14670/HH-18-434 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Selected by bioinformatics and molecular docking analysis, Dhea and 2–14,15-Eg are effective against cholangiocarcinoma

xlomafota13 shared this article with you from Inoreader Selected by bioinformatics and molecular docking analysis, Dhea and 2–14,15-Eg are effective against cholangiocarcinoma Via Head and neck cancers by Lei Qin, Jun Kuai, Fang Yang, Lu Yang, Peisheng Sun, Lanfang Zhang, Guangpeng Li Object To identify novel targets for the diagnosis, treatment and prognosis of cholangiocarcinoma, we screen ideal lead compounds and preclinical drug candidates with MYC inhibitory effect from the ZINC database, and verify the therapeutic effect of Dhea and 2–14,15-Eg on cholangiocarcinoma. Methods The gene expression profiles of GSE132305, GSE89749, and GSE45001 were obtained respectively from the Gene Expression Omnibus database. The DEGs were identified by comparing the gene expression profiles of cholangiocarcinoma and normal tissues. GO, KEGG analysis and PPI network analyses were performed. LibDock, ADME and toxicity prediction, molecular docking and molecular dynamics simulations were used to identify potential inhibitors of MYC. Moreover, in vitro, MTT assay, colony-forming assay, the scratch assay and Western blotting were performed to verify the therapeutic effect of Dhea and 2–14,15-Eg. Results PPI network analysis showed that ALB, MYC, APOB, IGF1 and KNG1 were hub genes, of which MYC was mainly studied in this study. A battery of computer-aided virtual techniques showed that Dhea and 2–14,15-Eg have lower rodent carcinogenicity, Ames mutagenicity, developmental toxicity potential, and high tolerance to cytochrome P4502D6, as well as could exist stably in natural circumstances. In vitro assays showed that Dhea and 2–14,15-Eg inhibited cholangiocarcinoma cellular viability, proliferation, and migration inhibiting expression of MYC. Conclusion This study suggested that Dhea and 2–14,15-Eg were novel potential inhibitors of MYC targeting, as well as are a promising drug in dealing with cholangiocarcinoma and have a perspective application. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Vertical rectus abdominis myocutaneous flap to reconstruct thigh and groin defects: A retrospective cohort and systematic review

xlomafota13 shared this article with you from Inoreader Vertical rectus abdominis myocutaneous flap to reconstruct thigh and groin defects: A retrospective cohort and systematic review Via Journal of plastic, reconstructive & aesthetic surgery : JPRAS J Plast Reconstr Aesthet Surg. 2022 Jan 19:S1748-6815(22)00028-6. doi: 10.1016/j.bjps.2022.01.015. Online ahead of print. ABSTRACT BACKGROUND: The vertical rectus abdominis myocutaneous (VRAM) flap is one of the options for soft-tissue reconstruction in the groin and thigh. The aim of this study is to evaluate the clinical outcomes, risk factors for complications, and the utility of using mesh to prevent abdominal hernia. METHODS: A retrospective review of patients who underwent VRAM flap reconstruction to reconstruct proximal thigh and groin defects from 1997 to 2018 was performed. Data regarding patient demographics, surgical characteristics, and postoperative outcomes were collected. Proportional hazard regression analysis was performed to assess the association of the risk of recipient site complications. A systematic review was performed to assess the outcomes and summarize the evidence from published studies. RESULTS: Fifty-three patients were identified and included in this study. In most of the cases, the procedures were performed after tumor resection (77%) and in the rest of the cases, they were performed for chronic complicated wounds (23%). Twenty-five (47.2%) patients developed complications. Intraoperative and postoperative radiotherapy, chronic kidney disease, history of prior tumor resection, and reconstructions of chronic complicated wounds were associated with an increased risk of recipient site complications. A systematic review identified 9 articles, for a total of 189 reconstructions. The pooled complications and failure rates were 31.2% and 2.1%, respectively. Stratified analysis showed that the rate of abdominal hernia was similar in patients with mesh (16.7%) and in patients with primary closure only (15.1%; p = 0.761). CONCLUSION: Defects in the groin or proximal thigh can be treated successfully with the VRAM flap. Although wound complications and hernia rates are high, the reconstruction failure rate is low. PMID:35148978 | DOI:10.1016/j.bjps.2022.01.015 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Two‐Incision Approach for Hypoglossal Nerve Stimulator Placement: A Single Institution Assessment

xlomafota13 shared this article with you from Inoreader Two‐Incision Approach for Hypoglossal Nerve Stimulator Placement: A Single Institution Assessment Via The Laryngoscope Objective(s) Upper airway stimulator (UAS) placement is a treatment for obstructive sleep apnea (OSA) with few complications and low morbidity. UAS placement has traditionally been performed using a three-incision approach, however, it has been implanted using a two-incision approach. This approach could significantly decrease operation time without a difference in postoperative complications, demonstrating its safety and feasibility for UAS placement. The objective was to assess operative time and complication rate in the two-incision approach for UAS placement compared to the three-incision approach. Study Design Retrospectively reviewed. Methods Patients who underwent UAS placement using the two- or three-incision approach at a single academic institution from November 2014 to June 2021 were retrospectively reviewed. The two-incision approach did not include the incision at the mid-axillary line. Main outcome measures included operation time and complication rates. Results Three-hundred forty-eight patients underwent UAS placement. The three-incision approach demonstrated an average operation time of 143.3 minutes whereas the two-incision approach averaged 129.4 minutes (P < .001). There was no significant difference in rate of postoperative complications between the two- and three-incision cohorts including pneumothorax (0% vs. 0.4%, P > .99), patient-reported discomfort (5.6% vs. 6.5%, P > .99), activity restriction (0% vs. 1.4%, P > .50), and incisional pain (0.0% vs. 1.0%, P > .99). No patients experienced incision site bleeding or infection. The two-incision approach was associated with decreased rate of revision surgery (0.0% vs. 5.4%, P = .048). Conclusion The UAS two-incision approach proved to have a significantly shorter operative time without an increase in complications as compared to the three-incision approach. This approach is a safe and feasible option. Level of Evidence III Laryngoscope, 2022 View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Management of postradiation late hemorrhage following treatment for HPV‐positive oropharyngeal squamous cell carcinoma

xlomafota13 shared this article with you from Inoreader Management of postradiation late hemorrhage following treatment for HPV‐positive oropharyngeal squamous cell carcinoma Via Head & Neck Abstract Background Acute oropharyngeal hemorrhage is a serious complication for patients with oropharyngeal squamous cell carcinoma (OPSCC), particularly in patients with a history of radiation therapy (RT). Methods Retrospective case series from at a tertiary care center for treated patients with HPV-positive OPSCC presenting with oropharyngeal hemorrhage. Results Median time from completion of chemoradiation to first hemorrhagic event was 186 days (range 66–1466 days). Seven patients (58%) required intervention to secure their airway. All patients were evaluated for endovascular intervention, six (50%) were embolized. Eight patients (67%) had a second hemorrhagic event; median time to second bleed was 22 days (range 3–90 days). Conclusions Acute oropharyngeal hemorrhage is a sequelae following treatment for HPV-positive OPSCC. The majority of bleeds occurred within a year of completion of treatment. While more research is needed to determine optimal treatment paradigms, endovascular intervention should be considered, even if noninvasive imaging does not demonstrate active bleeding. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.