Genetic dependencies associated with transcription factor activities in human cancer cell lines.

Transcription factors (TFs) are important mediators of aberrant transcriptional programs in cancer cells. In this study, we focus on TF activity (TFa) as a biomarker for cell-line-selective anti-proliferative effects, in that high TFa predicts sensitivity to loss of function of a given gene (i.e., genetic dependencies [GDs]). Our linear-regression-based framework identifies 3,047 pan-cancer and 3,952 cancer-type-specific candidate TFa-GD associations from cell line data, which are then cross-examined for impact on survival in patient cohorts. One of the most prominent biomarkers is TEAD1 activity, whose associations with its predicted GDs are validated through experimental evidence as proof of concept. Overall, these TFa-GD associations represent an attractive resource for identifying innovative, biomarker-driven hypotheses for drug discovery programs in oncology.

Postoperative Cosmetic Scores and Revision Rates After Nasal Mohs Reconstructive Surgery.

OBJECTIVE: Few studies have examined the impact of preoperative and surgical factors on the change in cosmetic survey scores after nasal Mohs reconstruction using a subset of the 10-item Standardized Cosmesis and Health Nasal Outcomes Survey-Cosmesis (SCHNOS-C). We aim to determine preoperative and surgical factors that impact cosmetic outcomes following Mohs nasal reconstruction. STUDY DESIGN: Retrospective analysis. SETTING: Nasal Mohs reconstruction patients at a tertiary medical center. METHODS: All patients receiving Mohs reconstruction of any nasal subunit at a tertiary medical center were analyzed. Variables collected included demographic and Mohs defect/reconstruction characteristics. Primary outcomes were changes in cosmetic (SCHNOS-C) scores and revision rates. Multivariable analysis was used to identify independent predictors of cosmetic scores/revision. RESULTS: We included 296 patients for analysis. On multivariable logistic regression, factors contributing to better final cosmetic scores were receiving a skin/composite graft (odds ratio [OR]: 0.22, 95% confidence interval: 0.06-0.68, P = .014) compared to a local flaps. Women were more likely to have worsening cosmetic scores (OR: 2.27, 1.06-4.99, P = .037). Only initial cosmetic scores independently predicted receiving any revision (OR: 1.11, 1.03-1.20, P = .006). CONCLUSION: Average SCHNOS-C scores after nasal reconstruction of Mohs defects are low. Only worse patient reported SCHNOS-C scores predicted revision. It is important to understand preoperative and surgical factors that affect cosmetic outcomes to optimize patient counseling and reconstructive planning. Patient perception is a key factor in predicting revisions.

Endoscopic Repair of Internal Carotid Artery Injury with a Lateral Tongue Muscle Patch Graft: Novel Technique and Literature Review.

Objectives Iatrogenic injury to the internal carotid artery (ICA) is one of the most catastrophic complications of endoscopic sinus and skull base surgery. Previous research has shown that packing with a crushed muscle graft at the injury site can be an effective management technique to control bleeding and prevent the need for ICA sacrifice. Here, we describe a novel and readily available repair donor site-an autologous lateral tongue muscle patch. Design Three representative cases of a successful repair of ICA injuries using a lateral tongue muscle patch are included in this study. The graft measured approximately 2 × 3 cm and was taken from the lateral intrinsic tongue musculature. We describe the harvest of the graft, its advantages, and the details of operative repair. Results The lateral tongue provides a large and readily accessible source of muscle within the surgical field that can be quickly harvested during an endoscopic procedure. For the first case, an expanding parasellar ICA pseudoaneurysm was managed with a tongue muscle patch and nasal packing. In the second case, a cavernous ICA injury was sustained during craniopharyngioma resection. Case three involved an ICA injury during endonasal debridement of invasive fungal rhinosinusitis. None of the patients required embolization or neurovascular stenting. Postoperative angiograms and serial computed tomography angiograms showed complete resolution of the pseudoaneurysm, and the patients continued to do well at least 1 year after repair. Conclusion Lateral tongue muscle graft is an effective and efficient method to manage ICA injuries during endoscopic endonasal surgery. Advantages include the speed of harvest, donor site being readily accessible in the surgical field, and low donor site morbidity. It should be added to the repertoire of possible donor sites for addressing catastrophic sinonasal bleeding.

Synergistic Manifestations in Cardiac Cysticercosis Complicated by Snake Bite: A Case Report and Literature Review.

Cysticercosis presents a prevalent issue on a global scale. Nevertheless, disseminated cysticercosis (DCC) is infrequent; even rarer is asymptomatic DCC. Here, we present a unique case of asymptomatic DCC involving the heart in a young male who came to medical attention following a fatal snake bite, ultimately leading to his demise. Despite the widespread dissemination of cysticercosis affecting multiple organs, the individual remained asymptomatic for the condition. We present a case of a 23-year-old male who was brought to the emergency department with a history of alleged snake bites. The patient was declared dead upon arrival at the All India Institute of Medical Sciences (AIIMS), Rishikesh, India. Autopsy findings revealed multiple significant cardiac abnormalities, including atheromatous changes with calcification in the root of the aorta and aortic valve, along with numerous collateral vessels originating from the left main coronary artery. Additionally, cystic nodules containing cysticercus larvae were identified within the myocardium, suggesting cardiac cysticercosis. The cause of death was determined to be complications related to the snakebite. This case emphasizes the importance of considering multiple potential etiologies in complex clinical presentations, especially in the tropics.

Explorative Discovery of Gene Signatures and Clinotypes in Glioblastoma Cancer Through GeneTerrain Knowledge Map Representation.

This study introduces the GeneTerrain Knowledge Map Representation (GTKM), a novel method for visualizing gene expression data in cancer research. GTKM leverages protein-protein interactions to graphically display differentially expressed genes (DEGs) on a 2-dimensional contour plot, offering a more nuanced understanding of gene interactions and expression patterns compared to traditional heatmap methods. The research demonstrates GTKM's utility through four case studies on glioblastoma (GBM) datasets, focusing on survival analysis, subtype identification, IDH1 mutation analysis, and drug sensitivities of different tumor cell lines. Additionally, a prototype website has been developed to showcase these findings, indicating the method's adaptability for various cancer types. The study reveals that GTKM effectively identifies gene patterns associated with different clinical outcomes in GBM, and its profiles enable the identification of sub-gene signature patterns crucial for predicting survival. The methodology promises significant advancements in precision medicine, providing a powerful tool for understanding complex gene interactions and identifying potential therapeutic targets in cancer treatment.

Comparative Outcomes for Microvascular Free Flap Monitoring Outside the Intensive Care Unit.

OBJECTIVE: There is a trend towards nonintensive care unit (ICU) or specialty ward management of select patients. Here, we examine postoperative outcomes for patients transferred to a general ward following microvascular free flap (FF) reconstruction of the head and neck. STUDY DESIGN: Retrospective quality control study. SETTING: Single tertiary care center. METHODS: Consecutive patients who underwent FF of the head and neck before and after a change in protocol from immediate postoperative monitoring in the ICU ("Pre-protocol") to the general ward setting ("Post-protocol"). Outcomes included overall length of stay (LOS), ICU LOS, FF compromise, and postoperative complications. RESULTS: A total of 150 patients were included, 70 in the pre-protocol group and 80 in the post-protocol group. There were no significant differences in age, sex, comorbidities, tumor stage, or type of FF. Mean LOS decreased from 8.18 to 7.68 days (P = .4), and mean ICU LOS decreased significantly from 5.2 to 1.7 days (P < .01). There were no significant differences in postoperative or airway-related complications (P = .6) or FF failure rate (2.9% vs 2.6%, P > .9). There was a non-significant increase in ancillary consults in the post-protocol group (45% vs 33%, P = .13) and a significant increase in rapid response team calls, a nurse-driven safety net for abnormal vitals or mental status (19% vs 3%, P = .003). CONCLUSION: We show the successful implementation of a protocol shifting care of FF patients from the ICU to a general ward postoperatively, suggesting management on the floor with less frequent flap monitoring is safe and conserves ICU beds. Additional teaching and familiarity with these patients may over time reduce the rapid response calls.

Redesigning the kinetics of lysozyme amyloid aggregation by cephalosporin molecules.

In lysozyme amyloidosis, fibrillar aggregates of lysozyme are associated with severe renal, hepatic, and gastrointestinal manifestations, with no definite therapy. Current drugs are now being tested in amyloidosis clinical trials as aggregation inhibitors to mitigate disease progression. The tetracycline group among antimicrobials in use is in phase II of clinical trials, whereas some macrolides and cephalosporins have shown neuroprotection. In the present study, two cephalosporins, ceftazidime (CZD) and cefotaxime (CXM), and a glycopeptide, vancomycin (VNC), are evaluated for inhibition of amyloid aggregation of hen egg white lysozyme (HEWL) under two conditions (i) 4 M guanidine hydrochloride (GuHCl) at pH 6.5 and 37° C, (ii) At pH 1.5 and 65 °C. Fluorescence quench titration and molecular docking methods report that CZD, CXM, and VNC interact more strongly with the partially folded intermediates (PFI) in comparison to the protein's natural state (N). However, only CZD and CXM proficiently inhibit the aggregation. Transmission electron microscopy, tinctorial assessments, and aggregation kinetics all support oligomer-level inhibition. Transition structures in CZD-HEWL and CXM-HEWL aggregation are shown by circular dichroism (CD). On the other hand, kinetic variables and soluble fraction assays point to a localized association of monomers. Intrinsic fluorescence (IF),1-Anilino 8-naphthalene sulphonic acid, and CD demonstrate structural and conformational modifications redesigning the PFI. GuHCl-induced unfolding and differential scanning fluorimetry suggested that the PFI monomers bound to CZD and CXM exhibited partial stability. Our results present two mechanisms that function in both solution conditions, creating a novel avenue for the screening of putative inhibitors for drug repurposing. We extend our proposed mechanisms in the designing of physical inhibitors of amyloid aggregation considering shorter time frames and foolproof methods.Communicated by Ramaswamy H. Sarma.

Drug repurposing has overcome failures in drug discovery and has reduced the overall time and cost of drug discovery and development.We examined the effect of screened antibiotics, ceftazidime (CZD), cefotaxime (CXM), and vancomycin (VNC) on lysozyme aggregation under two solution conditions.These antibiotics inhibit/modulate the aggregation reactions by strongly interacting with aggregation-prone intermediate and modulation of conformation and stability.Our study puts forward with caution two cephalosporins for aggregation inhibition studies.

Adaptor molecules mediate negative regulation of macrophage inflammatory pathways: a closer look.

Macrophages play a central role in initiating, maintaining, and terminating inflammation. For that, macrophages respond to various external stimuli in changing environments through signaling pathways that are tightly regulated and interconnected. This process involves, among others, autoregulatory loops that activate and deactivate macrophages through various cytokines, stimulants, and other chemical mediators. Adaptor proteins play an indispensable role in facilitating various inflammatory signals. These proteins are dynamic and flexible modulators of immune cell signaling and act as molecular bridges between cell surface receptors and intracellular effector molecules. They are involved in regulating physiological inflammation and also contribute significantly to the development of chronic inflammatory processes. This is at least partly due to their involvement in the activation and deactivation of macrophages, leading to changes in the macrophages' activation/phenotype. This review provides a comprehensive overview of the 20 adaptor molecules and proteins that act as negative regulators of inflammation in macrophages and effectively suppress inflammatory signaling pathways. We emphasize the functional role of adaptors in signal transduction in macrophages and their influence on the phenotypic transition of macrophages from pro-inflammatory M1-like states to anti-inflammatory M2-like phenotypes. This endeavor mainly aims at highlighting and orchestrating the intricate dynamics of adaptor molecules by elucidating the associated key roles along with respective domains and opening avenues for therapeutic and investigative purposes in clinical practice.

Morphometric Evaluation of Sutural Patterns at the Pterion and Asterion in Dry Indian Skulls: Surgical Relevance.

INTRODUCTION: The pterion and asterion serve as crucial landmarks on the skull, representing the antero-lateral and postero-lateral fontanelles in neonates, respectively. In clinical practice, these points play a pivotal role in guiding the understanding of deeper structures and their relationships to the head's surface. The thin calvarium at these junctures is susceptible to fractures, and the underlying vessels are prone to tear, often leading to extradural hematoma formation, necessitating burr hole surgery for evacuation. MATERIAL AND METHODS: The study involved 40 human dry skulls in Indians (n= 27 male (10.8%), n= 13 female (5.2%)) of unknown age, evaluating morphometric characteristics of 80 pterions and asterions. Measurements were conducted using a digital caliper (SKADIOO±0.2mm/0.01") in millimeters on both sides of each skull. The investigation also included an examination of sutural patterns in Pterion and asterion. RESULTS: Three types of sutural patterns were identified in the pterion, the most common being the sphenoparietal variety (75% on the right, 70% on the left), followed by the epipteric variety, which was the second most common (11.3% on the right, 12.5% on the left), and then the frontotemporal type (1.3% on the right, 2.5% on the left). Two sutural patterns were observed in the asterion: type 1 (presence of sutural bone) in 17.9% of skulls and type 2 (absence of sutural bone) in 82.1%. CONCLUSION: The differences in pterion and asterion positions across various populations explored in previous studies motivated us to conduct this research in the Indian population. Our findings revealed that among Indians, the predominant pterion type is predominantly sphenoparietal, whereas type 2 is the most prevalent in asterion. Understanding the clinical significance of the pterion and asterion is crucial for healthcare professionals to ensure precise and safe surgical procedures, particularly for the effective treatment of head trauma patients.

Calcifying Aponeurotic Fibroma of Leg Masquerading as Hemangioma in an Adolescent Male along with Review of Literature.

Calcifying aponeurotic fibroma (CAF) is a rare soft tissue tumor which falls under the WHO category of benign fibroblastic and myofibroblastic tumors. It typically occurs on the distal extremities (hands and foot) of children and adolescents. Other less common sites include wrists, ankles, trunk and rarely legs and arms. These tumors present as a painless soft tissue mass, arising in the subcutis, and are usually connected to tendons or aponeuroses. Computed tomography (CT) and magnetic resonance imaging (MRI) are the radiological investigations of choice; however, histopathology remains the diagnostic modality of choice for the diagnosis of CAF. We present a rare case of a 17-year-old boy who presented with a gradually progressive mass lesion on the leg which was later diagnosed as calcifying aponeurotic fibroma on histopathology.

Prevalence and predictors of risk factors for cardiovascular diseases among women aged 15-49 years across urban and rural India: findings from a nationwide survey.

BACKGROUND: Women's health is usually looked upon in terms of their reproductive health. However, cardio-vascular diseases are one of the leading causes of death and disability among women, globally as well as in India. Risk factors of today can be disease of tomorrow. Gradience in level of epidemiological transition is observed across different states. The study aims to estimate the national and regional prevalence, and sociodemographic determinants of biological and behavioural risk factors for cardiovascular diseases. MATERIALS AND METHODS: The present study was conducted among women in the age group of 15 to 49 years using nationally representative sample from fifth round National Family Health Survey in India. The data analysis in the current study included 7,24,115 women in the age group of 15 to 49 years. SPSS version 20 was used for the purpose of analysis. Weighted prevalence was computed for the studied behavioral and biological (dependent variable) risk factors using women specific weights as provided in the dataset. Binary logistic regression model was employed to calculate the adjusted odds ratio (OR) with the corresponding 95% confidence interval (CI) to study the sociodemographic determinants (independent variables) of these risk factors. RESULTS: Highest prevalent risk factor for cardiovascular diseases was reported to be central obesity (78.2%), followed by overweight/obesity (23.9%), oral contraceptive use (13.4%), raised blood pressure (11.8%), raised blood sugar (8.6%), tobacco use (4.0%), and alcohol use (0.7%). Higher odds of all the studied risk factors were reported with increasing age. All of the studied risk factors, except for alcohol consumption [OR (95%CI): 0.9 (0.8-0.96)], had higher odds in rural areas compared to urban areas. Compared to other castes, the odds of tobacco [OR (95% CI): 2.01 (1.91-2.08)] and alcohol consumption [OR (95% CI): 5.76 (5.12-6.28)], and raised blood pressure [OR (95% CI): 1.07(1.04-1.11)] was significantly higher among the people belonging to schedule tribe. CONCLUSION AND RECOMMENDATION: The present study highlights the state-wise disparities in the burden and predictors of risk factors for cardio-vascular diseases among women of reproductive age. The study provides insights to these disparities, and focuses on the need of tailoring the disease prevention and control measures suiting to the local needs.

Pannexin-3 stabilizes the transcription factor Bcl6 in a channel-independent manner to protect against vascular oxidative stress.

Targeted degradation regulates the activity of the transcriptional repressor Bcl6 and its ability to suppress oxidative stress and inflammation. Here, we report that abundance of endothelial Bcl6 is determined by its interaction with Golgi-localized pannexin 3 (Panx3) and that Bcl6 transcriptional activity protects against vascular oxidative stress. Consistent with data from obese, hypertensive humans, mice with an endothelial cell-specific deficiency in Panx3 had spontaneous systemic hypertension without obvious changes in channel function, as assessed by Ca2+ handling, ATP amounts, or Golgi luminal pH. Panx3 bound to Bcl6, and its absence reduced Bcl6 protein abundance, suggesting that the interaction with Panx3 stabilized Bcl6 by preventing its degradation. Panx3 deficiency was associated with increased expression of the gene encoding the H2O2-producing enzyme Nox4, which is normally repressed by Bcl6, resulting in H2O2-induced oxidative damage in the vasculature. Catalase rescued impaired vasodilation in mice lacking endothelial Panx3. Administration of a newly developed peptide to inhibit the Panx3-Bcl6 interaction recapitulated the increase in Nox4 expression and in blood pressure seen in mice with endothelial Panx3 deficiency. Panx3-Bcl6-Nox4 dysregulation occurred in obesity-related hypertension, but not when hypertension was induced in the absence of obesity. Our findings provide insight into a channel-independent role of Panx3 wherein its interaction with Bcl6 determines vascular oxidative state, particularly under the adverse conditions of obesity.

Evaluating Pediatric Ophthalmic Care Using Sentiment Analysis of Physician Review Sites.

PURPOSE: To assess patient satisfaction within pediatric ophthalmology and identify trends in patient sentiment. METHODS: Pediatric ophthalmologists in the United States were identified using the American Association for Pediatric Ophthalmology and Strabismus member directory. Demographic data were recorded using publicly available websites. Online written reviews and Stars ratings were obtained from Healthgrades.com. A sentiment analysis package, Valence Aware Dictionary for Sentimental Reasoning (VADER), was used to generate a compound score of reviews, and word frequency analyses were applied. RESULTS: A total of 377 pediatric ophthalmologists (2,640 online reviews) were evaluated. Physicians received an average of 4.22/5 Stars and a compound sentiment score of 0.56, indicating positive sentiment. No differences in scores were observed by gender or location, although physicians with fewer years in practice had higher Stars ratings compared to peers (P < .001). The three most common words in the word frequency analysis of all reviews were "surgery," "staff," and "time," with heavy emphasis on bedside manner and addressing patient concerns. CONCLUSIONS: This study demonstrates overall high patient satisfaction in pediatric ophthalmology care, with differences in sentiment based on physician demographic features. The study highlights that patient perspective is influenced by non-clinical features of care. These data may be used by pediatric ophthalmologists seeking to improve health care delivery. [J Pediatr Ophthalmol Strabismus. 2024;61(3):211-218.].

Early Postoperative Complications in Microtia Reconstruction: An Analysis of the NSQIP-P Database.

OBJECTIVES: Microtia and anotia repair require techniques that consider both aesthetics and function. The outcomes of different reconstructive frameworks such as costal cartilage or a porous polyethylene implant have not been evaluated on a national scale. We aim to understand differences in outcomes/complication rates and operative times between different reconstructive frameworks used in microtia/anotia reconstruction. METHODS: This was a retrospective review of the National Surgical Quality Improvement Program Pediatric database between 2012-2019. Patients with ICD-9/10 codes for microtia/anotia were isolated. Reconstruction methods were identified using CPT codes for rib graft, ear cartilage graft, and alloplastic implants (biocompatible implants, porous polyethylene, etc). Outcomes included operative-time, wound complications, and unplanned re-operations within 30 days of surgery. Multivariable logistic regression was performed to control for confounders. RESULTS: We included 593 patients for analysis. Reconstruction with rib grafts (N = 506, 85%) was the most common. In 58 patients (9.8%), an implant was used for the auricular framework, whereas in 47 (7.9%) ear cartilage grafts were used. The overall wound complication rate was 3.4%. On univariate analysis, alloplastic implants exhibited a higher rate of wound complications (8.6% vs. 2.8%, p = 0.037) and longer operative times (350 min vs. 235 min, p < 0.001). After controlling for demographics and comorbidities, implants conferred an independently increased risk of wound complications (OR 3.52, 1.10-9.54, p = 0.020). CONCLUSION: Although the use of alloplastic implants (e.g., porous polyethylene) may confer an increased risk of early complications, the long-term clinical implications of these findings are unclear relative to aesthetic benefits. Multi-institutional studies are needed to validate these findings using patient-specific and surgeon-specific data. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:1214-1219, 2024.

How Often is Cancer Present in Oral Cavity Re-resections After Initial Positive Margins?

OBJECTIVE: To evaluate the rate at which carcinoma is present in the re-resection specimen following initial positive margins during head and neck cancer surgery and its impact on oncologic outcomes. STUDY DESIGN: Retrospective chart review. METHODS: A single institution retrospective chart review of patients that underwent curative-intent surgery for oral cavity cancer was performed. Final pathology reports were reviewed to identify patients with initial positive margins who underwent re-resection during the same operation. Initial positive margin was defined as severe dysplasia, carcinoma in situ (CIS), or carcinoma. Cox proportional hazards and Kaplan-Meier analyses were used to assess for associations with survival outcomes. RESULTS: Among 1873 total patients, 190 patients (10.1%) had initial positive margins and underwent re-resection during the same surgery. Additional carcinoma, CIS, or severe dysplasia was found in 29% of re-resections, and 31% of patients with initial positive margins had final positive margins. Half of the patients with a final positive margin had a positive margin at an anatomic site different than the initial positive margin that was re-resected. The median follow-up was 636 days (range 230-1537). Re-resection with cancer and final positive margin status was associated with worse overall survival (OS; p = 0.044 and p = 0.05, respectively). However, only age, T4 disease, and surgery for recurrent oral cavity cancer were independently associated with OS (p < 0.001, p = 0.005, and p = 0.001, respectively). CONCLUSIONS: Fewer than a third of oral cavity re-resections contain further malignancy, which may suggest that surgeons have difficulty relocating the site of initial positive margin. Final positive margins are often at anatomic sites different than the initial positive margin. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:717-724, 2024.

Sirolimus-induced Hypertriglyceridemia Leads to Acute Pancreatitis and Diabetic Ketoacidosis Post Stem Cell Transplant for Sickle Cell Disease.

Sirolimus (mammalian target of rapamycin inhibitor) is a potent immunosuppressive agent, used in patients receiving hematopoietic stem cell transplant (HSCT) for Graft vs Host disease prophylaxis. Compared to calcineurin inhibitors, sirolimus has no neurotoxicity or nephrotoxicity, but sirolimus causes dose-dependent thrombocytopenia, leukopenia, delayed wound healing, hyperlipidemia, and hypertriglyceridemia. Here we report a case of acute pancreatitis and diabetic ketoacidosis in a patient with sickle cell disease post haploidentical family donor HSCT which was managed conservatively without plasmapheresis. Based on our review of the literature, this is the first reported case of developing acute pancreatitis as an adverse effect of sirolimus-induced hypertriglyceridemia leading to diabetic ketoacidosis in a recipient of HSCT.