The utility of next-generation sequencing in distinguishing between separate primary lung carcinomas and intrapulmonary metastasis: A case report.

The distinction between separate primary lung carcinomas (SPLCs) and intrapulmonary metastases (IPMs) is crucial to accurate cancer staging. Histopathology-based classification cannot always determine the relatedness of multiple tumors taken from the lung. Recently, next-generation sequencing (NGS) has been used for biomarker determination, but it also has the potential to inform clonality determination among multiple tumors. Here we present a patient with three lung tumors, each diagnosed as adenocarcinoma by histopathology with a differential diagnosis of SPLC versus IPM. We pursued molecular profiling by NGS, which revealed three unique mutational patterns ruling out the possibility of clonal relatedness among the cancers. Our case supports the utility of NGS in supplementing histopathological methods to distinguish between SPLCs and IPMs and to guide treatment decisions.

Three biomarkers (HER2, PD-L1, and microsatellite status) in a large cohort of metastatic gastroesophageal adenocarcinomas: The MD Anderson Cancer Center experience.

Human epidermal growth factor receptor-2 (HER2), programmed death-ligand 1 (PD-L1), and microsatellite (MS) status are well-established biomarkers in gastroesophageal adenocarcinomas (GEAs). However, it is unclear how the combination of these biomarkers is associated with clinicopathological factors and prognosis. This retrospective study included baseline metastatic GEA patients who were tested for all three biomarkers (HER2, PD-L1, and MS status) at the MD Anderson Cancer Center between 2012 and 2022. Stratification was performed according to the combination of biomarker profiles: triple negative (TN), single positive (SP), and multiple positive (MP). Comparative analyses of clinicopathological factors and survival using combinations of biomarkers were performed. Among the 698 GEA patients analyzed, 251 (36.0%) were classified as TN, 334 (47.9%) as SP, and 113 (16.1%) as MP. The MP group showed a significant association with tumors located in the esophagus (p < .001), well to moderate differentiation (p < .001), and the absence of signet ring cells (p < .001). In the survival analysis, MP group had a significantly longer overall survival (OS) compared to the other groups (MP vs. TN, p < .001 and MP vs. SP, p < .001). Multivariate Cox regression analysis revealed that MP serves as an independent positive prognostic indicator for OS (hazard ratio = 0.63, p < .01). Our findings indicate that MP biomarkers are associated with a favorable prognosis in metastatic GEA. These results are reflective of clinical practice and offer valuable insights into how therapeutics and future biomarkers could influence therapy/prognosis.

Premature mortality trends in 183 countries by cancer type, sex, WHO region, and World Bank income level in 2000-19: a retrospective, cross-sectional, population-based study.

BACKGROUND: Cancer is a leading cause of mortality worldwide. By 2040, over 30 million new cancers are predicted, with the greatest cancer burden in low-income countries. In 2015, the UN passed the Sustainable Development Goal 3.4 (SDG 3.4) to tackle the rising burden of non-communicable diseases, which calls for a reduction by a third in premature mortality from non-communicable diseases, including cancer, by 2030. However, there is a paucity of data on premature mortality rates by cancer type. In this study, we examine annual rates of change for cancer-specific premature mortality and classify whether countries are on track to reach SDG 3.4 targets. METHODS: This is a retrospective, cross-sectional, population-based study investigating premature mortality trends from 2000-19 using the WHO Global Health Estimates data. All cancers combined and thirteen individual cancers in 183 countries were examined by WHO region, World Bank income level, and sex. The risk of premature mortality was calculated for ages 30-69 years, independent of other competing causes of death, using standard life table methods. The primary objective was to compute average annual rate of change in premature mortality from 2000 to 2019. Secondary objectives assessed whether this annual rate of change would be sufficient to reach SDG 3.4. targets for premature mortality by 2030. FINDINGS: This study was conducted using data retrieved for the years 2000-19. Premature mortality rates decreased in 138 (75%) of 183 countries across all World Bank income levels and WHO regions, however only eight (4%) countries are likely to meet the SDG 3.4 targets for all cancers combined. Cancers where early detection strategies exist, such as breast and colorectal cancer, have higher declining premature mortality rates in high-income countries (breast cancer 48 [89%] of 54 and colorectal cancer 45 [83%]) than in low-income countries (seven [24%] of 29 and four [14%]). Cancers with primary prevention programmes, such as cervical cancer, have more countries with declining premature mortality rates (high-income countries 50 [93%] of 54 and low-income countries 26 [90%] of 29). Sex-related disparities in premature mortality rates vary across WHO regions, World Bank income groups, and by cancer type. INTERPRETATION: There is a greater reduction in premature mortality for all cancers combined and for individual cancer types in high-income countries compared with lower-middle-income and low-income countries. However, most countries will not reach the SDG 3.4 target. Cancers with early detection strategies in place, such as breast and colorectal cancers, are performing poorly in premature mortality compared with cancers with primary prevention measures, such as cervical cancer. Investments toward prevention, early detection, and treatment can potentially accelerate declines in premature mortality. FUNDING: WHO.

Surgical Outcomes and Utilization of Laparoscopic Versus Robotic Techniques for Elective Colectomy in Asian American and Native Hawaiian-Pacific Islanders (AAPI) Diagnosed With Colon Cancer.

INTRODUCTION: Asian American and Native Hawaiian-Pacific Islanders (AAPI) are the fastest growing racial-ethnic group, with 18.9 million people in 2019, and is predicted to rise to 46 million by 2060. Colorectal cancer (CRC) is the most common cancer in AAPI men and the third most common in women. Treatment techniques like laparoscopic colectomy (LC) emerged as the standard of care for CRC resections; however, new robotic technologies can be advantageous. Few studies have compared clinical outcomes across minimally invasive approaches for AAPI patients with CRC. This study compares utilization and clinical outcomes of LC versus robotic colectomies (RCs) in AAPI patients. METHODS: We queried the American College of Surgeons National Surgical Quality Improvement Program database for elective RC and LC in AAPI patients from 2012 to 2020. Outcomes included unplanned conversion to open, operative time, complications, 30-d mortality, and length of stay. Multivariable logistic regression analyses assessed the association between outcomes and the operative approach. RESULTS: Between 2012 and 2020, 83,841 patients underwent elective LC or RC. Four thousand six hundred fifty-eight AAPI patients underwent 3817 (82%) LCs and 841 (18%) RCs. In 2012, all procedures were performed laparoscopically; by 2020, 27% were robotic. Mean operative time was shorter in LC (192 versus 249 min, P < 0.001). On multivariable logistic regression, there was no difference in infection (odds ratio [OR] 0.8, 95% confidence interval [CI] 0.59-1.12), anastomotic leak (OR 0.97, 95% CI 0.59-1.61), or death (OR 0.9, 95% CI 0.31-2.61). Length of stay was shorter for RC (-0.44 d, 95% CI -0.71 to -0.18 d). CONCLUSIONS: Overall, AAPI postoperative outcomes are similar between LC and RC. Future studies that evaluate costs and resource utilization can assist hospitals in determining whether implementing robotic-assisted technologies in their hospitals and communities will be appropriate.

Comparative evaluation of microhardness of three restorative materials after immersion in chlorhexidine mouthwash: An in vitro study.

Aim: To evaluate and compare the microhardness of Filtek Z250XT, Beautifil II, and Neo Spectra ST HV after immersion in chlorhexidine mouthwash. Materials and Methods: Thirty disc specimens (10 for each group) made of three different restorative materials, Group 1 - Filtek (3M ESPE), Group 2 - Beautifil II (Shofu), and Group 3 - Neo Spectra ST HV (Dentsply). To simulate 1 year of daily mouthwash use, 10 specimens from each group were immersed in chlorhexidine, kept in an incubator at 37°C for 12 h, and later subjected to microhardness measurement using Vicker's hardness test. Finally, analysis of variance and post hoc tests were used to analyze the results statistically. Results: A significant reduction in microhardness was observed after immersion in chlorhexidine in Groups 1 and 3 compared to Group 2. Conclusions: Filtek Z250XT exhibits the highest microhardness compared to the other two materials. However, Beautifil II is more resistant to chlorhexidine mouthwash and does not show a significant reduction compared to the other two restorative materials.

Neuroparacoccidioidomycosis.

Paracoccidioidomycosis (PCM) is caused by a dimorphic fungus Paracoccidioides Brasiliensis and is endemic to subtropical areas of Central and South America. CNS involvement of PCM is extremely variable. NeuroPCM is found in 9.65% to 27.18% of PCM cases .Most neuro PCM patients presents with simultaneous involvement of other organ but isolated or initial CNS involvement may be a feature in 21%. Here we report a case of CNS PCM and this appears to be first reported case of PCM and CNS PCM in India.

Efficacy of sucrose application in minimizing pain perception related to dental injection in children aged 3 to 9 years: a randomized control trial.

Background: Dental fear and anxiety are significant challenges in managing behavior in children. Oral administration of sucrose or sweet-tasting solutions has shown effectiveness in reducing procedural pain in infants and neonates. This study aimed to investigate whether pre-application of sucrose solution had an effect on minimizing pain perception during injection and to assess the potential impact of the child's age and sweet preference. Methods: A randomized control clinical trial was conducted on 60 children aged 3-9 years requiring buccal infiltration injections. Following parental consent, demographic data of the children were recorded. Sweet preferences was assessed using a modified forced-choice test. Children were equally and randomly allocated into study (sucrose) and control groups using a lottery method. Sucrose solution or distilled water, respectively, was applied to the lateral surface of the tongue for 2 min. Topical anesthetic was applied at the site of injection, followed by local anesthesia administration. The children rinsed their mouths thrice with water immediately after anesthetic injection. A video was recorded during injection which was then scored by three blinded examiners on the Sound Eye Motor (SEM) scale. The children also self-evaluated using Wong-Baker Faces Pain Rating Scale (WBFPS). Results: The mean SEM scores and WBFPS scores were analyzed using the Kruskall-Wallis test. The mean SEM score in the study group was 1.37 ± 0.61, compared to 3.17 ± 0.87 in the control group, showing a statistically significant difference (P < 0.001). Mean pain scores assessed by WBFPS in the study group were 0.60 ± 1.4, while in the control group, they were 6.27 ± 2.33, also showing a statistically significant difference (P < 0.001). Children with a sweet preference demonstrated a subjective reduction in pain perception. Conclusion: Application of sucrose before dental injections in children helps to minimize pain upon injection across all age groups.

Inhibitory effects of medium-chain fatty acids on the proliferation of human breast cancer cells via suppression of Akt/mTOR pathway and modulating the Bcl-2 family protein.

Medium-chain fatty acids (MCFAs) have 6-12 carbon atoms and are instantly absorbed into the bloodstream before traveling to the portal vein and the liver, where they are immediately used for energy and may have antitumor effects. Its role in breast cancer is poorly understood. To investigate the apoptosis-inducing effect of MCFAs in breast cancer cells, cell viability assay, colony formation assay, cell migration assay, cell invasion assay, nuclear morphology, cell cycle assay, intracellular reactive oxygen species (ROS), matrix metalloproteinase (MMP), apoptosis, RT-qPCR analysis, and Western blot analysis were performed. In the present study, MCFA treatments reduced proliferative capability, increased ROS level, increased the depletion of MMP, induced G0/G1 and S phase cell cycle arrest, and late apoptosis of breast cancer cells in an effective concentration. Besides, MCFA treatment contributed to the upregulation of proapoptotic protein (BAK) and caspase-3, and the downregulation of antiapoptotic protein (Bcl-2). Mechanistically, phosphorylation levels of EGFR, Akt, and mTOR were significantly reduced in breast cancer cells treated with MCFAs. However, no significant changes in apoptosis and signaling-related proteins were observed in lauric acid-treated ER-positive cancer cells. Our findings suggested that MCFAs suppressed breast cancer cell proliferation by modulating the PI3K/Akt/mTOR signaling pathway. MCFAs may be a promising therapeutic drug for treating breast cancer.

High expression of CD9 and Epidermal Growth Factor Receptor promotes the development of tongue cancer.

Tongue cancer is distinguished by aggressive behavior, a high risk of recurrence, lymph, and distant metastases. Hypoxia-Induced Factor 1 α functions as a CD9 transcription factor. CD9 is a transmembrane protein that may be found on the cell membrane. It can modulate the expression of the Epidermal Growth Factor Receptor (EGFR) pathway. ELISA was used to measure serum CD9, p-EGFR, and p-Akt levels in 70 tongue cancer patients and 35 healthy controls. RT-PCR was used to analyze the gene expression of the related genes. The gene as well as protein expression of CD9, EGFR/p-EGFR, and Akt/p-Akt was significantly higher in case subjects when compared with the controls. The expression of CD9 was higher in case subjects who were smokers/alcoholics when to control subjects who were smokers/alcoholics. Overexpression of CD9 due to hypoxic conditions leads to the activation of EGFR-signaling pathway resulting in cancer progression, resistance to chemotherapy. Hence, CD9 could be a potential target to suppress cancer progression.

The in-silico study of the structural changes in the Arthrobacter globiformis choline oxidase induced by high temperature.

BACKGROUND: Choline oxidase, a flavoprotein, is an enzyme that catalyzes the reaction which converts choline into glycine betaine. Choline oxidase started its journey way back in 1933. However, the impact of the high temperature on its structure has not been explored despite the long history and availability of its crystal structure. Both choline oxidase and its product, glycine betaine, have enormous applications spanning across multiple industries. Understanding how the 3D structure of the enzyme will change with the temperature change can open new ways to make it more stable and useful for industry. PROCESS: This research paper presents the in-silico study and analysis of the structural changes of A. globiformis choline oxidase at temperatures from 25 °C to 60 °C. A step-wise process is depicted in Fig. 1. RESULTS: Multiple sequence alignment (MSA) of 11 choline oxidase sequences from different bacteria vs Arthrobacter globiformis choline oxidase showed that active site residues are highly conserved. The available crystal structure of A. globiformis choline oxidase with cofactor Flavin Adenine Dinucleotide (FAD) in the dimeric state (PDB ID: 4MJW)1 was considered for molecular dynamics simulations. A simulated annealing option was used to gradually increase the temperature of the system from 25 °C to 60 °C. Analysis of the conserved residues, as well as residues involved in Flavin Adenine Dinucleotide (FAD) binding, substrate binding, substate gating, and dimer formationwas done. At high temperatures, the formation of the inter-chain salt bridge between Arg50 and Glu63 was a significant observation near the active site of choline oxidase. CONCLUSION: Molecular dynamics studies suggest that an increase in temperature has a significant impact on the extended Flavin Adenine Dinucleotide (FAD) binding region. These changes interfere with the entry of substrate to the active site of the enzyme and make the enzyme inactive.

Enzyme engineering of choline oxidase for improving stability.

Functioning as a flavoprotein, choline oxidase facilitates the transformation of choline into glycine betaine. Notably, choline oxidase and its resultant product, glycine betaine, find extensive applications across various industries and fields of study. However, its high sensitivity and tendency to lose functional activity at high temperatures reduces its industrial usage. MD simulation and mutation studies have revealed the role of certain residues responsible for the enzyme's thermal instability. This study focuses on inducing thermal stability to choline oxidase of A. globiformis through computational approaches at a maximum temperature of 60 °C. MD simulation analysis showed that Trp 331, Val 464 and Ser 101 contribute to structural instability, leading to the instability at 60 °C. Mutation of these residues with phenylalanine residues and simulation of the mutated enzyme at 60 °C exhibited thermostability and insignificant residual fluctuation. The re-docking and MM/GBSA analyses further validated the mutated enzyme's binding affinity and catalytic activity.Communicated by Ramaswamy H. Sarma.

Enhancing special care dentistry with waiting room based multisensory­adapted dental environment: A randomized controlled-trial.

AIM: To assess the effectiveness of waiting room based multisensory adapted dental environment (SADE) as a novel, non-invasive behavior management technique in alleviating anxiety levels in children with Down syndrome. MATERIALS AND METHODS: This study was conducted in the Department of Pediatric and Preventive Dentistry, D.Y. Patil University School of Dentistry, Nerul, Navi Mumbai. A total of 40 children between 8 and 13 years of age diagnosed with Down syndrome were included in our study. Prior to the first dental evaluation, they were divided equally into two groups using simple randomization via lottery system. Group A (Intervention group): Patients were subjected to a sensory adapted environment (SADE) in the waiting room for 10 min prior to dental evaluation. Group B (Control group): Patients were subjected to a regular dental environment (RDE) in the waiting room for 10 min prior to dental evaluation. Outcome parameters evaluated at baseline and post dental evaluation were anxiety and behavior, using a pulse oximeter and the Modified Venham's Scale respectively. Data were subjected to statistical analysis using SPSS version 21.0 (SPSS Inc. Chicago, IL). The 'p' value < .05 was taken as significant at 95% confidence interval. RESULTS: Mann-Whitney U test was used to carry out the inter group analysis which showed a significant increase in the heart rate (26.00, p = .00) in Group B and a significant decrease in the Modified Venham Scale score (90.00, p = .001) in Group A. The Wilcoxon Signed ranks test was used to carry out the intra group analysis for which a significant difference between the two time intervals for heart rate (-3.69, p = .00) and Modified Venham Scale score (-1.46, p = .03) was obtained in Group A whereas a significant difference was obtained only in the heart rate (-3.04, p = .002) in Group B. CONCLUSION: Multisensory-adapted dental environment (SADE) in the waiting room effectively improves behavior, reduces anxiety and sensory discomfort among children with Down syndrome.

Cancer surgery on the global stage: Updates and progress.

Over 5 billion people lack access to basic surgical procedures, and it is estimated, the number of surgical procedures needed for cancer care will increase by 5 million from 2018 to 2040. The greatest increase in demand will occur in low- and middle-income countries. In this article, we highlight progress made in surgical cancer care globally and gaps that still needs to be addressed. We highlight political support, workforce progress and shortages, impact of the COVID-19 pandemic, and the importance of high value cancer care.

Efficacy of sucrose application in minimizing pain perception related to dental injection in children aged 3 to 9 years: a randomized control trial

Background@#Dental fear and anxiety are significant challenges in managing behavior in children. Oral administration of sucrose or sweet-tasting solutions has shown effectiveness in reducing procedural pain in infants and neonates.This study aimed to investigate whether pre-application of sucrose solution had an effect on minimizing pain perception during injection and to assess the potential impact of the child’s age and sweet preference. @*Methods@#A randomized control clinical trial was conducted on 60 children aged 3–9 years requiring buccal infiltration injections. Following parental consent, demographic data of the children were recorded. Sweet preferences was assessed using a modified forced-choice test. Children were equally and randomly allocated into study (sucrose) and control groups using a lottery method. Sucrose solution or distilled water, respectively, was applied to the lateral surface of the tongue for 2 min. Topical anesthetic was applied at the site of injection, followed by local anesthesia administration. The children rinsed their mouths thrice with water immediately after anesthetic injection. A video was recorded during injection which was then scored by three blinded examiners on the Sound Eye Motor (SEM) scale. The children also self-evaluated using Wong-Baker Faces Pain Rating Scale (WBFPS). @*Results@#The mean SEM scores and WBFPS scores were analyzed using the Kruskall–Wallis test. The mean SEM score in the study group was 1.37 ± 0.61, compared to 3.17 ± 0.87 in the control group, showing a statistically significant difference (P < 0.001). Mean pain scores assessed by WBFPS in the study group were 0.60 ± 1.4, while in the control group, they were 6.27 ± 2.33, also showing a statistically significant difference (P < 0.001). Children with a sweet preference demonstrated a subjective reduction in pain perception. @*Conclusion@#Application of sucrose before dental injections in children helps to minimize pain upon injection across all age groups.

Effectiveness of an extraoral cold and vibrating device in reducing pain perception during deposition of local anesthesia in pediatric patients aged 3-12 years: a split-mouth crossover study.

Background: Local anesthetic injections may induce pain in children, leading to fear and anxiety during subsequent visits. Among the various approaches recommended to reduce pain, one is the use of a Buzzy Bee™ device that operates on the concept of gate control theory and distraction. The literature regarding its effectiveness during the deposition of local anesthesia remains limited; hence, the aim of the present study was to determine the efficacy of extraoral cold and vibrating devices in reducing pain perception during the deposition of local anesthesia. Methods: A split-mouth crossover study in which 40 children aged 3-12 years requiring maxillary infiltration or inferior alveolar nerve block for extractions or pulp therapy in the maxillary or mandibular posterior teeth were included. The control intervention involved the application of topical anesthetic gel for one minute (5% lignocaine gel), followed by the administration of local anesthetic (2% lignocaine with 1:80,000 adrenaline) at a rate of 1 ml/minute. Along with the control protocol, the test intervention involved using the Buzzy Bee™ device for 2 minutes before and during the deposition of the local anesthetic injection. The heart rate and face, legs, arms, cry, and consolability revised (FLACC-R) scale scores were recorded by the dentist to assess the child's pain perception. Results: The mean age of the participants in Group A and Group B was 7.050 ± 3.12 years and 7.9 ± 2.65 years respectively. A reduction in the mean heart rate and FLACC-R score was observed during the deposition of local anesthetic solution in the tissues when the Buzzy Bee™ was used in both groups at different visits in the same subjects (P < 0.05) The Buzzy Bee™ device was effective in reducing the heart rate and FLACC-R scores when used during maxillary infiltration and inferior alveolar nerve block local anesthesia techniques (P < 0.05). Conclusion: The use of extraoral cold and vibrating devices significantly reduces pain perception during local anesthetic deposition in pediatric patients. Considering the results of this study, the device may be incorporated as an adjunct in routine dental practice while administering local anesthesia in children.

Global Cancer Surgery: pragmatic solutions to improve cancer surgery outcomes worldwide.

The first Lancet Oncology Commission on Global Cancer Surgery was published in 2015 and serves as a landmark paper in the field of cancer surgery. The Commission highlighted the burden of cancer and the importance of cancer surgery, while documenting the many inadequacies in the ability to deliver safe, timely, and affordable cancer surgical care. This Commission builds on the first Commission by focusing on solutions and actions to improve access to cancer surgery globally, developed by drawing upon the expertise from cancer surgery leaders across the world. We present solution frameworks in nine domains that can improve access to cancer surgery. These nine domains were refined to identify solutions specific to the six WHO regions. On the basis of these solutions, we developed eight actions to propel essential improvements in the global capacity for cancer surgery. Our initiatives are broad in scope, pragmatic, affordable, and contextually applicable, and aimed at cancer surgeons as well as leaders, administrators, elected officials, and health policy advocates. We envision that the solutions and actions contained within the Commission will address inequities and promote safe, timely, and affordable cancer surgery for every patient, regardless of their socioeconomic status or geographic location.

AI-Based Homology Modelling of Fatty Acid Transport Protein 1 Using AlphaFold: Structural Elucidation and Molecular Dynamics Exploration.

Fatty acid transport protein 1 (FATP1) is an integral transmembrane protein that is involved in facilitating the translocation of long-chain fatty acids (LCFA) across the plasma membrane, thereby orchestrating the importation of LCFA into the cell. FATP1 also functions as an acyl-CoA ligase, catalyzing the ATP-dependent formation of fatty acyl-CoA using LCFA and VLCFA (very-long-chain fatty acids) as substrates. It is expressed in various types of tissues and is involved in the regulation of crucial signalling pathways, thus playing a vital role in numerous physiological and pathological conditions. Structural insight about FATP1 is, thus, extremely important for understanding the mechanism of action of this protein and developing efficient treatments against its anomalous expression and dysregulation, which are often associated with pathological conditions such as breast cancer. As of now, there has been no prior prediction or evaluation of the 3D configuration of the human FATP1 protein, hindering a comprehensive understanding of the distinct functional roles of its individual domains. In our pursuit to unravel the structure of the most commonly expressed isoforms of FATP1, we employed the cutting-edge ALPHAFOLD 2 model for an initial prediction of the entire protein's structure. This prediction was complemented by molecular dynamics simulations, focusing on the most promising model. We predicted the structure of FATP1 in silico and thoroughly refined and validated it using coarse and molecular dynamics in the absence of the complete crystal structure. Their relative dynamics revealed the different properties of the characteristic FATP1.

Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of lysine demethylation and oxidative phosphorylation.

The histone H3 lysine 4 (H3K4) methyltransferase KMT2D (also called MLL4) is one of the most frequently mutated epigenetic modifiers in medulloblastoma (MB) and other types of cancer. Notably, heterozygous loss of KMT2D is prevalent in MB and other cancer types. However, what role heterozygous KMT2D loss plays in tumorigenesis has not been well characterized. Here, we show that heterozygous Kmt2d loss highly promotes MB driven by heterozygous loss of the MB suppressor gene Ptch in mice. Heterozygous Kmt2d loss upregulated tumor-promoting programs, including oxidative phosphorylation and G-protein-coupled receptor signaling, in Ptch-mutant-driven MB genesis. Mechanistically, both downregulation of the transcription-repressive tumor suppressor gene NCOR2 by heterozygous Kmt2d loss and upregulation of the oncogene MycN by heterozygous Ptch loss increased the expression of tumor-promoting genes. Moreover, heterozygous Kmt2d loss extensively diminished enhancer signals (e.g., H3K27ac) and H3K4me3 signature, including those for tumor suppressor genes (e.g., Ncor2). Combinatory pharmacological inhibition of oxidative phosphorylation and the H3K4 demethylase LSD1 drastically reduced tumorigenicity of MB cells bearing heterozygous Kmt2d loss. These findings reveal the mechanistic basis underlying the MB-promoting effect of heterozygous KMT2D loss, provide a rationale for a therapeutic strategy for treatment of KMT2D-deficient MB, and have mechanistic implications for the molecular pathogenesis of other types of cancer bearing heterozygous KMT2D loss.

Association between iron profile status and insulin resistance in patients with type 2 diabetes mellitus.

Introduction: Individuals' burden of insulin resistance and metabolic syndrome, such as type 2 diabetes mellitus, is increasing. This indicates to intrigue into various facets of prevention, early screening, prognostication and feasible treatment alternatives in this arena. Aim: This study targets to evaluate iron profile status among people diagnosed with type 2 diabetes mellitus and normoglycemic in order to deduce association between iron parameters and insulin resistance, if any exist. Methodology: A case-control study of total 123 subjects, comprising males and females in the age group of 30 - 70 years were recruited for the study. Case group constituted 81 participants who were diagnosed with type 2 diabetes mellitus and control group constituted 42 healthy individuals who attended routine health check-ups in the hospital. Iron profile parameters including Serum Iron, Serum Ferritin, Total Iron binding Capacity and Glycemic profile parameter like fasting blood glucose, serum insulin were estimated. Transferrin saturation and HOMA-IR were calculated. Result: Ferritin and Transferrin saturation was found to be higher in cases than in controls with significance of p = 0.003 and p = 0.021 respectively and TIBC (total iron-binding capacity) was lesser in cases with p = 0.031. Comparison of Serum Iron values did not yield a significant result. Correlation study between ferritin and insulin resistance parameters yielded a satisfactory result in the cases (p<0.05) and controls (p<0.01) separately. Conclusion: This study implies that there is a clear link between iron profile status, notably ferritin, and the emergence of insulin resistance, and hence insulin production. This study supports the function of the micronutrient iron in the etiology of type 2 diabetes and its consequences.