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The Kelch-like ECH-associated protein 1 (KEAP1) – Nuclear factor erythroid 2 -related factor 2 (NRF2) pathway is the major transcriptional stress response system in cells against oxidative and electrophilic stress. NRF2 is frequently constitutively active in many cancers, rendering the cells resistant to chemo- and radiotherapy. Loss-of-function (LOF) mutations in the repressor protein KEAP1 are common in non-small cell lung cancer, particularly adenocarcinoma. While the mutations can occur throughout the gene, they are enriched in certain areas, indicating that these may have unique functional importance. In this study, we show that in the GSEA analysis of TCGA lung adenocarcinoma RNA-seq data, the KEAP1 mutations in R320 and R470 were associated with enhanced Tumor Necrosis Factor alpha (TNFα) – Nuclear Factor kappa subunit B (NFκB) signaling as well as MYC and MTORC1 pathways. To address the functional role of these hotspot mutations, affinity purification and mass spectrometry (AP-MS) analysis of wild type (wt) KEAP1 and its mutation forms, R320Q and R470C were employed to interrogate differences in the protein interactome. We identified TNF receptor associated factor 2 (TRAF2) as a putative protein interaction partner. Both mutant KEAP1 forms showed increased interaction with TRAF2 and other anti-apoptotic proteins, suggesting that apoptosis signalling could be affected by the protein interactions. A549 lung adenocarcinoma cells overexpressing mutant KEAP1 showed high TRAF2-mediated NFκB activity and increased protection against apoptosis, XIAP being one of the key proteins involved in anti-apoptotic signalling. To conclude, KEAP1 R320Q and R470C and its interaction with TRAF2 leads to activation of NFκB pathway, thereby protecting against apoptosis.

Dengue fever is an arboviral infection whose presentation ranges from a mild febrile illness to a multisystem complicated syndrome. We report a case of 58-year-old female presenting with fever, myalgia, arthralgia, and vomiting who was found to be infected with dengue and had electrocardiography changes revealing ST-segment elevation myocardial infarction, a rare manifestation in dengue. Dengue fever can affect the cardiovascular system leading to conduction abnormalities, hypotension, arrhythmias, myocarditis, cardiomyopathy, and occasionally myocardial infarction, which has been reported in only a few case reports prior to this. The differentiation between myocarditis and myocardial infarction is essential for which echocardiography and coronary angiography can be helpful. It is essential to keep an eye on the cardiovascular complications in a dengue patient as the presentation can be quite subtle with devastating consequences.

Aim and Objective: This study was intended to compare and determine the potency of strontium-doped nano-hydroxyapatite paste against a topical cream containing casein phosphopeptide-amorphous calcium phosphate and a regular dentifrice for remineralization of white spot lesions of enamel following orthodontic debonding. Methods: Ninety individuals with white spot lesions on their enamel who visited the orthodontic department for de-bonding were selected for the research. Patients were randomly assigned to three distinct groups with each group consisting of 30 patients. Group 1 served as the control and received regular dentifrice, Group 2 received strontium-doped nano-hydroxyapatite paste, and Group 3 received casein phosphopeptide-amorphous calcium phosphate topical cream. Patients were instructed to locally apply a specified amount of the prescribed preparation twice daily for six weeks. The data were analysed using the statistical programme SPSS 22.0 (SPSS Inc., Chicago, IL, USA), and the level of significance had been set at p

The KEAP1-NRF2 pathway is the key regulator of cellular defense against both extrinsic and intrinsic oxidative and electrophilic stimuli. Since its discovery in the 1990s, its seminal role in various disease pathologies has become well appreciated, motivating research to elucidate the intricacies of NRF2 signaling and its downstream effects to identify novel targets for therapy. In this graphical review, we present an updated overview of the KEAP1-NRF2 signaling, focusing on the progress made within the past ten years. Specifically, we highlight the advances made in understanding the mechanism of activation of NRF2, resulting in novel discoveries in its therapeutic targeting. Furthermore, we will summarize new findings in the rapidly expanding field of NRF2 in cancer, with important implications for its diagnostics and treatment.

The NRF2 pathway is frequently activated in various cancer types, yet a comprehensive analysis of its effects across different malignancies is currently lacking. We developed a NRF2 activity metric and utilized it to conduct a pan-cancer analysis of oncogenic NRF2 signaling. We identified an immunoevasive phenotype where high NRF2 activity is associated with low interferon-gamma (IFNγ), HLA-I expression and T cell and macrophage infiltration in squamous malignancies of the lung, head and neck area, cervix and esophagus. Squamous NRF2 overactive tumors comprise a molecular phenotype with SOX2/TP63 amplification, TP53 mutation and CDKN2A loss. These immune cold NRF2 hyperactive diseases are associated with upregulation of immunomodulatory NAMPT, WNT5A, SPP1, SLC7A11, SLC2A1 and PD-L1. Based on our functional genomics analyses, these genes represent candidate NRF2 targets, suggesting direct modulation of the tumor immune milieu. Single-cell mRNA data shows that cancer cells of this subtype exhibit decreased expression of IFNγ responsive ligands, and increased expression of immunosuppressive ligands NAMPT, SPP1 and WNT5A that mediate signaling in intercellular crosstalk. In addition, we discovered that the negative relationship of NRF2 and immune cells are explained by stromal populations of lung squamous cell carcinoma, and this effect spans multiple squamous malignancies based on our molecular subtyping and deconvolution data.

Purpose:To investigate age- and sex-related differences in tear film parameters of normal Indian population and study interparametric relationships.MethodsHealthy subjects with no ocular disease (median ocular surface disease index = 0) were subjected to an automated evaluation of tear meniscus height (TMH), non-invasive tear breakup time (NIBUT) using Keratograph 5M (OCULUS GmbH, Wetzlar, Germany), and tear osmolarity using the TearLab Osmolarity System (TearLab Corporation, California, USA). A mixed-effects model with random intercepts at the patient level was used to evaluate the relationships between explanatory (age, gender, and tear osmolarity) and outcome variables (TMH and NIBUT).ResultsA total of 237 subjects (474 eyes; 150 males) were enrolled with a mean age of 40 ± 17 years (range, 10-78 years). The mean values (± standard deviation) of TMH, NIBUT, and tear osmolarity were 0.34 ± 0.07 mm, 10.95 ± 2.02 s and 289.0 ± 5.8 mOsm/L, respectively. Age had a significant positive relationship with TMH (p < 0.0001; 0.002 mm/year; r = 0.12), but there was no effect on NIBUT (p = 0.26) and tear osmolarity (p = 0.27). There were no sex-based differences in tear film parameters. Interparametric relationship revealed no significant association between TMH and NIBUT (p = 0.12) or tear osmolarity and TMH (p = 0.83) or tear osmolarity and NIBUT values (p = 0.48).ConclusionsIn a normal Indian population, TMH is weakly affected by age and is independent of sex, NIBUT, and tear osmolarity. Tear breakup time and osmolarity show no significant age- and sex-related variation.

Primitive neuroectodermal tumour is a poorly differentiated small round cell neoplasm that primarily affects children and is very rarely seen in adults. Peripheral primitive neuroectodermal tumours are rare compared to the central type and resemble soft tissue sarcoma. Primitive neuroectodermal tumours involving the subcutaneous tissue are rare and only a few cases involving the subcutaneous tissue of the anterior abdominal wall have been reported. However, no cases involving the subcutaneous tissue of the shoulder region have been reported. We report the case of a peripheral primitive neuroectodermal tumour arising from subcutaneous tissue of the right shoulder in a young adult.

Primitive neuroectodermal tumour is a poorly differentiated small round cell neoplasm that primarily affects children and is very rarely seen in adults. Peripheral primitive neuroectodermal tumours are rare compared to the central type and resemble soft tissue sarcoma. Primitive neuroectodermal tumours involving the subcutaneous tissue are rare and only a few cases involving the subcutaneous tissue of the anterior abdominal wall have been reported. However, no cases involving the subcutaneous tissue of the shoulder region have been reported. We report the case of a peripheral primitive neuroectodermal tumour arising from subcutaneous tissue of the right shoulder in a young adult.

Laryngeal schwannomas are rare tumors of neural sheath origin. They normally present as a slow-growing, encapsulated, submucosal mass commonly in the supraglottic region. We describe a 13-year-old boy presenting with a 4-month history of progressive worsening dysphagia. Fiber optic laryngoscopy and computed tomography revealed a polypoidal mass in the laryngeal surface of epiglottis abutting left the aryepiglottic fold, base of the tongue and hypopharyngeal wall. Direct laryngoscopic evaluation and microdebrider assisted debulking was performed with tracheostomy. Schwannoma was confirmed by histopathological study. In a regular follow-up after two months, 70 degree endoscopic evaluation revealed similar mass in the left aryepiglottic fold obscuring the vocal cord. Definite complete excision of the tumor was planned and endoscopic excision of the mass was performed with removal of ipsilateral aryepiglottic fold, arytenoid and false vocal cord with retracheotomy. Rapid occurrence of mass after debulking and biopsy was demonstrated in this case. Though rare, neurogenic tumors of the larynx are life-threatening and need complete removal.

Introduction: Eagle’s syndrome is a poorly understood clinical entity that has variable presentations like recurrent throat pain or foreign body sensation, dysphagia, or facial pain. With a confirmed diagnosis, a surgical approach is considered appropriate for its treatment. This study aims to find out the prevalence of trans-oral extra tonsillar approach of styloidectomy among the operated cases of Department of Otolaryngology-Head and Neck Surgery at a tertiary care hospital. Methods: A descriptive cross-sectional study was conducted among 1,475 who underwent surgery at the Department of Otolaryngology-Head and Neck Surgery in a tertiary care center of Nepal between July 2018 to September 2020 after receiving the ethical clearance from the Institutional Review Committee (Reference number: 0106201802). Convenience sampling was done and data was entered in Statistical Package for the Social Sciences version 20. Point estimate at 95% confidence interval was calculated along with frequency and proportion for binary data. Results: Among 1,475 patients enrolled in the study, 24 (1.62%) patients (95% Confidence Interval= 0.97-2.26) underwent trans-oral extra tonsillar approach of surgery for Eagle’s syndrome during the study duration. Conclusions: The prevalence of styloidectomy among the operated cases of our study is low in comparison to other studies done in similar settings. Transoral extra tonsillar approach can be considered as a novel approach for surgical removal of the styloid process in Eagle’s Syndrome.

Background: Nasal carriage of Staphylococcus aureus has been linked to several community-acquired and nosocomial infections. The present study was undertaken to determine the prevalence and antibiotic susceptibility patterns of S.aureus colonizing the anterior nares of school children in Bharatpur, Nepal. Materials and Methods: In a cross-sectional study, 206 school children aged 3-15 years from fourteen different government schools in Bharatpur, Nepal were enrolled from January to May 2017. Prior to collecting sample, permission was sought from the administration of each school. All the participants were informed about the purposes of the study and the method of sample collection. Isolation of S.aureus and their antimicrobial susceptibility testing were performed by standard microbiological procedures. Results: S. aureus was isolated in 35(16.9%) cases of which 6 (17.1%) were methicillin-resistant S.aureus (MRSA) and 7 (20.0%) were multi-drug resistant (MDR). Prevalence of S. aureus and MRSA was higher in the age group 10-15 years (24.1% and 3.6%) compared to the age group 3-9 years (8.5% and 2.1%) (p=0.003).All the isolates were sensitive towards vancomycin and amikacin. Conclusions: Promotion of good hygienic practices among school going children can be suggested to abate the risk of spread and infections by S.aureus. Keywords: antibiotic resistance; MRSA; nasal carriage; S. aureus; school children.

Introduction: Superior mesenteric artery first pancreaticoduodenectomy is being increasingly used for pancreatic head and peri-ampullary tumors. The aim of our study was to determine the frequency of various approaches of superior mesenteric artery pancreaticoduodenectomy along with its postoperative complications in a tertiary care center. Methods: This is a descriptive cross-sectional study of patients undergoing superior mesenteric artery first pancreaticoduodenectomy with different approaches conducted at Kathmandu Medical College Teaching Hospital, Sinamangal, Kathmandu, Nepal, from May 2018 to April 2020. Ethical approval was taken from the Institutional Review Committee (reference no: 310520193). The whole sampling method was adopted. Thirty-four patients undergoing a superior mesenteric artery first pancreaticoduodenectomy at our center with different approaches were included in the study. The data analysis was done in the Statistical Package for the Social Sciences version 20. Results: For 34 patients chosen for the study, the male: female ratio was 1.6:1, with a mean age of 53.7 years. The medial uncinate approach was done in the majority of the cases, 26 (76.4%), whereas the inferior infracolic (mesenteric) approach was done in 1 (2.9%) case. Regarding postoperative complications, Clavien Dindo grade 3 and grade 4 were present in 11 (32.3%) patients, pancreatic fistula (Grade B and C) was observed in 6 (17.6%) patients, and mortality occurred in 2 (5.8%). The mean hospital stay was 16±9 days. Conclusions: Superior mesenteric artery first pancreaticoduodenectomy with a different approach can be performed with acceptable morbidity and mortality. Early determination of resectibility is achieved in selected cases.

Introduction: Zuckerkandl tubercle is a prominent anatomical structure of the thyroid lobe. Identification and preservation of recurrent laryngeal nerve and parathyroid glands during thyroid surgery can be made easier through assessment of their relationship with the Zuckerkandl tubercle. This study aims to determine the anatomical relationship between Zuckerkandl tubercle and superior parathyroid in patients who underwent thyroidectomy in a tertiary care center. Methods: This descriptive cross-sectional study was conducted at a tertiary care hospital of Nepal following ethical clearance from the Institutional Review Committee (Reference no: 0106201804) among patients who underwent thyroid surgery between July 2018 to February 2020. Convenience sampling was used for collecting data and was entered in Statistical Package for the Social Sciences version 20. Point estimate at 95% confidence interval was calculated along with frequency andproportion for binary data. Results: Out of 59 cases, 27 (96.4%) of superior parathyroid on the left were at the 1-2 o’clock position, and 28 (90.3%) of superior parathyroid on the right were at 10-11 o’clock position. On the left side, the superior parathyroid was adhered to Zuckerkandl tubercle in 10 (35.7%), was within 5 mm in 16 (57.1%), and was >5 mm away from Zuckerkandl tubercle in 2 (7.14%). On the right side, the superior parathyroid was adhered to Zuckerkandl tubercle in 12 (38.7%), was within 5 mm in 13 (41.93%), and was >5 mm away from Zuckerkandl tubercle in 6 (19.3%). Conclusions: Zuckerkandl tubercle has a consistent relationship with the superior parathyroid and can be used as an important landmark for identifying superior parathyroid during thyroid surgery.

Enzymatic and non-enzymatic oxidation of unsaturated fatty acids gives rise to reactive species that covalently modify nucleophilic residues within redox sensitive protein sensors in a process called lipoxidation. This triggers adaptive signaling pathways that ultimately lead to increased resistance to stress. In this graphical review, we will provide an overview of pathways affected by protein lipoxidation and the key signaling proteins being altered, focusing on the KEAP1-NRF2 and heat shock response pathways. We review the mechanisms by which lipid peroxidation products can serve as second messengers and evoke cellular responses via covalent modification of key sensors of altered cellular environment, ultimately leading to adaptation to stress. Keywords: Redox regulation, Protein lipoxidation, Stress response, NRF2, KEAP1, HSF1, Heat shock proteins, Cysteine modification

Oligodontia is a developmental dental anomaly. It is either an isolated trait or part of a syndrome. Oligodontia is characterized by the congenital absence of more than six permanent teeth except the third molars. In this presented case, the treatment plan aimed at psychological, esthetic and functional rehabilitation of the patient who was suffering from oligodontia. After taking a thorough medical and dental history, clinical and radiological examination, the patient was treated with a removable partial denture in the maxillary arch, while a complete denture was made in the mandibular arch. The patients esthetics was greatly improved and early functional rehabilitation of the patient was done. DOI: http://dx.doi.org/10.3329/updcj.v4i1.21167 Update Dent. Coll. j: 2014; 4 (1): 38-43