Estrogen Receptor 1 Gene Polymorphism and its Association with Idiopathic Short Stature in North Indian Population.

Background: In the hypothalamic-pituitary-gonadotrophin (HPG) axis, estrogen plays a key role in the bone maturation regulation and growth plates closure. This study was designed to explore the link between single nucleotide polymorphisms (SNPs) in estrogen receptor 1 (ESR1) gene with idiopathic short stature (ISS) susceptibility in the North Indian population. Methods: Four SNPs of the ESR1 gene (rs543650, rs6557177, rs2234693 and rs9340799) were genotyped by Sanger sequencing in 52 ISS patients and 68 controls. Linkage disequilibrium (LD) and haplotyping were done by SNPstat and SHESISplus softwares. Extent of LD was determined by calculating D' and r2 values in SNPs paired combinations. Results: A significant positive association was found between rs6557177 and rs543650 genotype and ISS susceptibility as compared to controls. The frequencies of the rs6557177 CC genotype (p=0.030; OR=0.13; 95% CI:0.01-1.10) and rs543650 genotype TT (p =0.043; OR=0.29; 95% CI: 0.09-0.92) were observed to be increased in ISS group as compared with the control group. However, no significant correlation was observed between clinical parameters of patients and these SNPs. rs543650 shown strong LD with rs2234693 and rs9340799, similarly rs2234693 and rs9340799. Conclusion: Our study showed that CC genotype at rs6557177 and TT genotype of rs543650 of ESR1 constitutes risk factor for developing ISS in North Indian children. In the future, these findings may lead to a better understanding of the SNPs associated with ISS susceptibility.

SHOX Variations in Idiopathic Short Stature in North India and a Review of Cases from Asian Countries

Objective: Short stature homeobox (SHOX) haploinsufficiency underlies idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis. The worldwide prevalence of SHOX variations in ISS varies from 2.5% to 15.0%. The aim of this study was to assess the implication of SHOX variation in ISS in North Indians and compare this with other cases of SHOX variations from Asian population. Methods: SHOX gene analysis was carried out by multiplex ligation-dependent probe amplification followed by Sanger sequencing in 54 patients with variable phenotypes. Comparison with other reports in a meta-analysis comprising the current study and 11 previous studies (n=979) was performed. Results: SHOX analysis resulted in 12.9% positivity (7.4% deletions and 5.5% duplications). SHOX association was seen significantly related to gender, with predominance in females (p=0.047). Short arms and forearms were the only significantly associated trait seen in 51.9% of children. The overall prevalence of SHOX variation was 15.2% in Asians with ISS. No significant difference was found in geographical region-specific analysis. Conclusion: This study summarises findings from the last decade and provides an updated picture of the prevalence of SHOX variations in Asians, emphasizing their potential as therapeutic targets in ISS patients. Further high quality, large investigations including functional validation is warranted to validate this association.

Understanding the Constraints and Optimization of Serum Immunofixation Electrophoresis and Serum Free Light Chains for Detecting Monoclonal Proteins: A Single-Center Experience.

Introduction Serum immunofixation electrophoresis (SIFE) and serum free light chain (SFLC) assay are imperative investigations in diagnosis and follow-up of multiple myeloma (MM). SFLC assays are reported to have higher sensitivity than SIFE. However, discrepancies have been reported between them. The current study was aimed at assessing concordance and discordance between SIFE and SFLC results in MM. Methods A total of 450 observations of both SIFE and SFLC were obtained from treatment-naive and follow-up MM patients. Results One hundred and twenty-nine (28.7%) values were observed as discordant, that is, positive SIFE with normal SFLC ratio or negative SIFE with abnormal SFLC ratio ( p -value < 0.00001). Proportion of discordance was higher in SIFE positive-SFLC normal cases than SIFE negative-SFLC abnormal cases. Discordance was more frequent in follow-up cases. Conclusion Negative SFLC alone may not be reliable for MM follow-up. Algorithm may be based on SFLC measurements on each follow-up till attainment of normal SFLC ratio. Once SFLC normalizes, follow-up may be done with SIFE. If SIFE is positive, further follow-up with SIFE may be initiated.

Transcriptome analysis identifies TODL as a novel lncRNA associated with proliferation, differentiation, and tumorigenesis in liposarcoma through FOXM1.

Liposarcoma, the most common soft tissue sarcoma, is a group of fat cell mesenchymal tumors with different histological subtypes. The dysregulation of long non-coding RNAs (lncRNAs) has been observed in human cancers including a few studies in sarcoma. However, the global transcriptome analysis and potential role of lncRNAs remain unexplored in liposarcoma. The present investigation uncovers the transcriptomic profile of liposarcoma by RNA sequencing to gain insight into the global transcriptional changes in liposarcoma. Our RNA sequencing analysis has identified that many oncogenic lncRNAs are differentially expressed in different subtypes of liposarcoma including MALAT1, PVT1, SNHG15, LINC00152, and MIR210HG. Importantly, we identified a highly overexpressed, unannotated, and novel lncRNA in dedifferentiated liposarcomas. We have named it TODL, transcript overexpressed in dedifferentiated liposarcoma. TODL lncRNA displayed significantly higher expression in dedifferentiated liposarcoma cell lines and patient samples. Interestingly, functional studies revealed that TODL lncRNA has an oncogenic function in liposarcoma cells by regulating proliferation, cell cycle, apoptosis, differentiation, and tumorigenesis in the murine model. Silencing of TODL lncRNA highlighted the enrichment of several key oncogenic signaling pathways including cell cycle, transcriptional misregulation, FOXM1 network, p53 signaling, PLK1 signaling, FoxO, and signaling Aurora signaling pathways. RNA pull-down assay revealed the binding of TODL lncRNA with FOXM1, an oncogenic transcription factor, and the key regulator of the cell cycle. Silencing of TODL lncRNA also induces adipogenesis in dedifferentiated liposarcomas. Altogether, our finding indicates that TODL could be utilized as a novel, specific diagnostic biomarker, and a pharmacological target for therapeutic development in controlling aggressive and metastatic dedifferentiated liposarcomas.

TP63, SOX2, and KLF5 Establish a Core Regulatory Circuitry That Controls Epigenetic and Transcription Patterns in Esophageal Squamous Cell Carcinoma Cell Lines.

BACKGROUND & AIMS: We investigated the transcriptome of esophageal squamous cell carcinoma (ESCC) cells, activity of gene regulatory (enhancer and promoter regions), and the effects of blocking epigenetic regulatory proteins. METHODS: We performed chromatin immunoprecipitation sequencing with antibodies against H3K4me1, H3K4me3, and H3K27ac and an assay for transposase-accessible chromatin to map the enhancer regions and accessible chromatin in 8 ESCC cell lines. We used the CRC_Mapper algorithm to identify core regulatory circuitry transcription factors in ESCC cell lines, and determined genome occupancy profiles for 3 of these factors. In ESCC cell lines, expression of transcription factors was knocked down with small hairpin RNAs, promoter and enhancer regions were disrupted by CRISPR/Cas9 genome editing, or bromodomains and extraterminal (BET) family proteins and histone deacetylases (HDACs) were inhibited with ARV-771 and romidepsin, respectively. ESCC cell lines were then analyzed by whole-transcriptome sequencing, immunoprecipitation, immunoblots, immunohistochemistry, and viability assays. Interactions between distal enhancers and promoters were identified and verified with circular chromosome conformation capture sequencing. NOD-SCID mice were given injections of modified ESCC cells, some mice where given injections of HDAC or BET inhibitors, and growth of xenograft tumors was measured. RESULTS: We identified super-enhancer-regulated circuits and transcription factors TP63, SOX2, and KLF5 as core regulatory factors in ESCC cells. Super-enhancer regulation of ALDH3A1 mediated by core regulatory factors was required for ESCC viability. We observed direct interactions between the promoter region of TP63 and functional enhancers, mediated by the core regulatory circuitry transcription factors. Deletion of enhancer regions from ESCC cells decreased expression of the core regulatory circuitry transcription factors and reduced cell viability; these same results were observed with knockdown of each core regulatory circuitry transcription factor. Incubation of ESCC cells with BET and HDAC disrupted the core regulatory circuitry program and the epigenetic modifications observed in these cells; mice given injections of HDAC or BET inhibitors developed smaller xenograft tumors from the ESCC cell lines. Xenograft tumors grew more slowly in mice given the combination of ARV-771 and romidepsin than mice given either agent alone. CONCLUSIONS: In epigenetic and transcriptional analyses of ESCC cell lines, we found the transcription factors TP63, SOX2, and KLF5 to be part of a core regulatory network that determines chromatin accessibility, epigenetic modifications, and gene expression patterns in these cells. A combination of epigenetic inhibitors slowed growth of xenograft tumors derived from ESCC cells in mice.

Oral health in relation to nutritional status, age and sex among14-18 years children of Naraingarh, Haryana / Saúde Bucal em relação ao estado nutricional, idade e sexo de crianças de 14-18 anos de Naraingarh, Haryana

Objetivo: Descrever a prevalência de cárie dentária e estudar a associação entre o estado nutricional e de saúde bucal baseada em vários índices, em adolescentes de comunidades sob privilegiados. Material e Métodos: O estudo teve uma amostra transversal de 196 crianças aparentemente saudáveis (104 meninos e 92 meninas), na faixa etária de14 a 18 anos, pertencentes a comunidades menos privilegiadas. Cada indivíduo teve a altura e o peso corporal medidos para determinar o estado nutricional. Vários traços de saúde bucal como cárie dental, placa, cálculo e gengivite foram analisados clinicamente. Resultados: O índice CPOD (dentes cariados, perdidos devido à cárie e dentes obturados)foi baixo entre os adolescentes; sendo 0,48 para os meninos e 0,93 para as meninas. A prevalência de cálculo foi maior entre as meninas de todas as faixas etárias, enquanto a prevalência de placa foi maior entre os meninos. As diferenças entre os gêneros foram significantes apenas para os índices de placa e CPOD. A falta de adequação da alimentação não foi um fator determinante para a magnitude observada de depósitos, placa e índices de cálculo, com exceção para os índice de condições de saúde bucal e CPOD, nos quais foram observados maiores índices em crianças com baixo peso. Conclusão: O estado nutricional inadequado não foi um dos principais determinantes da saúde oral, indicando a consciência geral de higiene oral e sua observância como ator importante. As meninas foram mais propensas a cárie dentária do que os meninos, sendo a severidade da cárie também maior para as meninas.

determinant of oral health indicating the generalawareness of oral hygiene and its observance wasa major factor. Females were more prone to dental caries than the males and the severity was also significantly higher in the former.

Unusually High Levels of CA19-9 Associated with Mature Cystic Teratoma of the Ovary.

Introduction. Mature cystic teratoma is the benign tumor of the ovary. CA19-9 levels, although a marker of pancreatic malignancy, have been found to be raised in large ovarian mature cystic teratomas. Case Report. We report a case of a young female who had unusually high levels of CA19-9 in the blood associated with large ovarian mature cystic teratoma. The levels returned to normal 12 weeks after cystectomy was performed. Conclusion. This case highlights the fact that although raised tumor marker may be associated with a benign pathology thorough evaluation to rule out malignancy still must be done.

To excise or ablate endometriosis? A prospective randomized double-blinded trial after 5-year follow-up.

STUDY OBJECTIVE: To compare reduction of pain after laparoscopy for ablation or excision of endometriosis. DESIGN: Prospective, randomized, double-blind study (Canadian Task Force classification I). SETTING: Endometriosis and pelvic pain clinic at a university teaching hospital. PATIENTS: Women of reproductive age with pelvic pain and visually proved endometriosis. INTERVENTIONS: Subjects completed a questionnaire rating various kinds of pain using visual analog scales (VAS). After visual identification subjects were randomized to treatment via ablation or excision by supervised training gynecologists as primary surgeons. Follow-up questionnaires documented pain levels every 3 months for 1 year and then every 6 months for 5 years. MEASUREMENTS AND MAIN RESULTS: Change in pain VAS scores during 5 years after the operation and rates of pregnancy, repeat surgery, and use of hormone therapy were evaluated. There was a reduction in all pain scores over the 5-year follow-up in both treatment groups. A significantly greater reduction in dyspareunia VAS scores was observed in the excision group at 5 years (p = .03 at univariate analysis, and p = .007 at multivariate analysis). More women in the ablation group continued to receive medical treatment of endometriosis at 5 years (p = .004). CONCLUSIONS: Surgical treatment of endometriosis provides symptom reduction for up to 5 years. In some limited areas such as deep dyspareunia, excision is more effective than ablation.