Management Strategy of a Grade-3 Cerebrospinal Fluid Leak Repair Following Endoscopic Endonasal Transsphenoidal Excision of Pituitary Macroadenoma.

A skull- base defect with grade-3 cerebrospinal fluid (CSF) leak following a pituitary macroadenoma removal is rare and challenging. We provide a simple sample model of multilayer closure with naturally available hard and soft tissue components. Tamponade was provided to the reconstructed site with a simple inflated Foley's catheter bulb. There was no repair failure and cavities were well mucosalised on follow-up. Mucosal and turbinate preservation was fully achieved in this method as no turbinate flaps were raised or large raw surface exposure was there.

Xenoestrogen and Its Interaction with Human Genes and Cellular Proteins: An In-Silico Study.

BACKGROUND: Breast cancer represents one of the leading causes of death worldwide. Apart from genetic factors, the sex hormone estrogen plays a pivotal role in breast cancer development. We are exposed to a plethora of estrogen mimics on a daily basis via various routes. Nevertheless, how xenoestrogens, the exogenous estrogen mimics, modulate cancer-associated signaling pathways and interact with specific genes is still underexplored. Hence, this study aims to explore the direct or indirect binding partners of xenoestrogens and their expression upon exposure to these estrogenic compounds. METHODS: The collection of genes linked to the xenoestrogens Octylphenol, Nonylphenol, Bisphenol-A, and 2,2-bis(4-hydroxyphenyl)-1,1,1-trichloroethane were gathered from the Comparative Toxicogenomics Database. Venny 2.1 was utilized to pinpoint the genes shared by these xenoestrogens. Subsequently, the shared genes underwent Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis using the Database for Annotation, Visualization, and Integrated Discovery bioinformatics resource. A xenoestrogen-protein interaction network was constructed using Search Tool for Interactions of Chemicals. The expressions of common genes were studied with the microarray dataset GSE5200 from the Gene Expression Omnibus database. Also, the expression of a common gene set within different breast cancer subtypes was identified using the University of California, Santa Cruz Xena. RESULTS: The genes linked to xenoestrogens were identified, and 13 genes were found to interact with all four xenoestrogens. Through DAVID analysis, the genes chosen are found to be enriched for various functions and pathways, including pathways in cancer, chemical carcinogenesis-receptor activation, and estrogen signaling pathways. The results of the Comparative Toxicogenomics Database and the chemical-protein interaction network derived from STITCH were similar. Microarray data analysis showed significantly high expression of all 13 genes in another study, with Bisphenol-A and Nonylphenol treated MCF-7 cells, most of the genes are expressed in luminal A or basal breast cancer subtype. CONCLUSION: In summary, the genes associated with the four xenoestrogens were mostly linked to pathways related to tumorigenesis, and the expression of these genes was found to be higher in breast cancer.

Interlay Cartilage Rim Augmented Fascia Tympanoplasty: An Effective Graft Model in Mucosal Chronic Otitis Media.

To study the efficacy of interlay cartilage rim augmented fascia tympanoplasty in mucosal chronic otitis media. A retrospective, observational study was conducted in a tertiary care hospital including charts of patients spanning a duration of one year, where 15 patients diagnosed with chronic otitis media-mucosal disease with large and subtotal perforations (with or without ossicular erosion), and had undergone interlay cartilage rim augmented fascia tympanoplasty, were analysed for morphological and functional improvement following surgery. Pre- and post-operative otomicroscopic examination and pure tone audiometry findings were the parameters considered. 86.6% had a well-healed, non-retracted, undisplaced mobile neotympanum, 6.7% who underwent a type III (minor columella) tympanoplasty had a medialised neotympanum and 1 subject (6.7%) who underwent a type I tympanoplasty had a residual pinpoint perforation which healed with conservative management. The overall morphological success rate was 93.3%. The mean hearing gain following surgery was 20.84 dB with a minimum gain of 10 dB and a maximum gain of 30 dB. The mean air-bone gap closure gain achieved was 19.2 dB with a minimum gain of 6.4 dB and a maximum gain of 30 dB. The interlay cartilage-fascia rim augmentation tympanoplasty is a novel, effective graft model suggested for large and sub-total central perforations. Future randomized studies with a larger sample size could be performed with longer follow-up to assess the outcome of this technique.

Videostroboscopy and Voice Profile in Long-Term Combination Inhaler Users With Obstructive Lower Airway Disease.

OBJECTIVE: Dysphonia is one of the most common side effects of long-term inhaler therapy containing corticosteroids in asthma or asthma-chronic obstructive pulmonary disease overlap (ACO) patients. This common, often reversible side effect is due to the structural changes in the vocal folds resulting from steroid deposition. This study determines the structural changes and voice profile of patients on long-term inhaler therapy by videostroboscopy and perceptual voice profile analysis. It also determines the duration, formulation, and drug delivery system producing the least side effects during therapy. STUDY DESIGN: Prospective case-control study. SETTING: Tertiary care hospital. METHODS: In total, 196 patients diagnosed with moderate to severe asthma or ACO were divided into cases (patients on at least 6-month combination inhaler therapy) and controls (newly diagnosed patients not on inhaler therapy) and recruited in the study. They were assessed by videostroboscopy for structural changes and GRBAS (grade of hoarseness, roughness, breathiness, asthenia, and strain) perceptual scale for voice profile changes. RESULTS: The prevalence of dysphonia was significantly higher in cases (62.2%) than controls (27.6%). Prevalence of laryngeal structural changes and voice profile changes were higher in cases. The prevalence of dysphonia and structural changes among cases was much lower when a spacer was used (P < .001). CONCLUSION: This study adds evidence to the long-term side effects of combination inhaler therapy containing corticosteroids on the larynx as demonstrated by videostroboscopy and perceptual voice profile analysis. It also propagates the use of spacers in drug delivery to reduce the prevalence of side effects during long-term inhaler therapy.

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

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 (Double 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.

Deregulated estrogen receptor signaling and DNA damage response in breast tumorigenesis.

Carriers of BRCA1 mutations have a higher chance of developing cancers in hormone-responsive tissues like the breast, ovary and prostate, compared to other tissues. These tumors generally exhibit basal-like characters and do not express estrogen receptor (ER) or progesterone receptor (PR). Intriguingly, BRCA1 mutated breast cancers have a less favorable clinical outcome, as they will not respond to hormone therapy. BRCA1 has been reported to exhibit ligand dependent and independent transcriptional inhibition of ER-α; however, there exists a controversy on whether BRCA1 induces or inhibits ER-α expression. The mechanisms associated with resistance of BRCA1 mutated cancers to hormone therapy, as well as the tissue restriction exhibited by BRCA1 mutated tumors are still largely unknown. BRCA1 mutated tumors possess increased DNA damages and decreased genomic integrity, as BRCA1 plays a cardinal role in high fidelity DNA damage repair pathways, like homologous recombination (HR). The existence of cross regulatory signaling networks between ER-α and BRCA1 speculates a role of ER on BRCA1 dependent DDR pathways. Thus, the loss or haploinsufficiency of BRCA1 and the consequential deregulation of ER-α signaling may result in persistence of unrepaired DNA damages, eventually leading to tumorigenesis. Therefore, understanding of this cross-talk between ER-α and BRCA1, with regard to DDR, will provide critical insights to steer drug development and therapy for breast/ovarian cancers. This review discusses the mechanisms by which estrogen and ER signaling influence BRCA1 mediated DNA damage response and repair pathways in the mammalian system.

Perspectives on mechanistic implications of ROS inducers for targeting viral infections.

In this perspective, we propose to leverage reactive oxygen species (ROS) induction as a potential therapeutic measure against viral infections. Our rationale for targeting RNA viral infections by pro-oxidants is routed on the mechanistic hypothesis that ROS based treatment paradigm could impair RNA integrity faster than the other macromolecules. Though antiviral drugs with antioxidant properties confer potential abilities for preventing viral entry, those with pro-oxidant properties could induce the degradation of nascent viral RNA within the host cells, as RNAs are highly prone to ROS mediated degradation than DNA/proteins. We have previously established that Plumbagin is a highly potent ROS inducer, which acts through shifting of the host redox potential. Besides, it has been reported that Plumbagin treatment has the potential for interrupting viral RNA replication within the host cells. Since the on-going Corona Virus Disease - 2019 (COVID-19) global pandemic mediated by Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2) exhibits high infectivity, the development of appropriate antiviral therapeutic strategies remains to be an urgent unmet race against time. Therefore, additional experimental validation is warranted to determine the appropriateness of repurposable drug candidates, possibly ROS inducers, for fighting the pandemic which could lead to saving many lives from being lost to COVID-19.

Gene expression signatures: A tool for analysis of breast cancer prognosis and therapy.

Breast Cancer is the most predominant female cancer in developed as well as developing countries. The treatment strategies of breast cancers depends on an array of factors like age at diagnosis, menstrual status, dietary pattern, immunological response, genetic variations of the cancer cells etc. Recent technological advancements in cancer diagnosis lead to the emergence of gene expression pattern for better understanding of the tumor behavior. It has not only bolstered the prognosis, but also the early diagnosis and therapy. The accuracy in disease prognosis can be boosted when gene expression signatures are combined with traditional clinicopathological features. This review explains how the evolution of gene expression signatures for breast cancers, its advantages and future prospects. In addition, an overview of currently available gene expression signature analysis tools and consolidated information on their current status and specific benefits, that can be availed for breast cancer diagnosis are also discussed.