The Lineage-Defining Transcription Factors SOX2 and NKX2-1 Determine Lung Cancer Cell Fate and Shape the Tumor Immune Microenvironment.

The major types of non-small-cell lung cancer (NSCLC)-squamous cell carcinoma and adenocarcinoma-have distinct immune microenvironments. We developed a genetic model of squamous NSCLC on the basis of overexpression of the transcription factor Sox2, which specifies lung basal cell fate, and loss of the tumor suppressor Lkb1 (SL mice). SL tumors recapitulated gene-expression and immune-infiltrate features of human squamous NSCLC; such features included enrichment of tumor-associated neutrophils (TANs) and decreased expression of NKX2-1, a transcriptional regulator that specifies alveolar cell fate. In Kras-driven adenocarcinomas, mis-expression of Sox2 or loss of Nkx2-1 led to TAN recruitment. TAN recruitment involved SOX2-mediated production of the chemokine CXCL5. Deletion of Nkx2-1 in SL mice (SNL) revealed that NKX2-1 suppresses SOX2-driven squamous tumorigenesis by repressing adeno-to-squamous transdifferentiation. Depletion of TANs in SNL mice reduced squamous tumors, suggesting that TANs foster squamous cell fate. Thus, lineage-defining transcription factors determine the tumor immune microenvironment, which in turn might impact the nature of the tumor.

CXCL8/CXCR2 signaling mediates bone marrow fibrosis and is a therapeutic target in myelofibrosis.

Proinflammatory signaling is a hallmark feature of human cancer, including in myeloproliferative neoplasms (MPNs), most notably myelofibrosis (MF). Dysregulated inflammatory signaling contributes to fibrotic progression in MF; however, the individual cytokine mediators elicited by malignant MPN cells to promote collagen-producing fibrosis and disease evolution are yet to be fully elucidated. Previously, we identified a critical role for combined constitutive JAK/STAT and aberrant NF-κB proinflammatory signaling in MF development. Using single-cell transcriptional and cytokine-secretion studies of primary cells from patients with MF and the human MPLW515L (hMPLW515L) murine model of MF, we extend our previous work and delineate the role of CXCL8/CXCR2 signaling in MF pathogenesis and bone marrow fibrosis progression. Hematopoietic stem/progenitor cells from patients with MF are enriched for a CXCL8/CXCR2 gene signature and display enhanced proliferation and fitness in response to an exogenous CXCL8 ligand in vitro. Genetic deletion of Cxcr2 in the hMPLW515L-adoptive transfer model abrogates fibrosis and extends overall survival, and pharmacologic inhibition of the CXCR1/2 pathway improves hematologic parameters, attenuates bone marrow fibrosis, and synergizes with JAK inhibitor therapy. Our mechanistic insights provide a rationale for therapeutic targeting of the CXCL8/CXCR2 pathway among patients with MF.

Cell cycle machinery in oncology: A comprehensive review of therapeutic targets.

The cell cycle is tightly regulated to ensure controlled cell proliferation. Dysregulation of the cell cycle machinery is a hallmark of cancer that leads to unchecked growth. This review comprehensively analyzes key molecular regulators of the cell cycle and how they contribute to carcinogenesis when mutated or overexpressed. It focuses on cyclins, cyclin-dependent kinases (CDKs), CDK inhibitors, checkpoint kinases, and mitotic regulators as therapeutic targets. Promising strategies include CDK4/6 inhibitors like palbociclib, ribociclib, and abemaciclib for breast cancer treatment. Other possible targets include the anaphase-promoting complex/cyclosome (APC/C), Skp2, p21, and aurora kinase inhibitors. However, challenges with resistance have limited clinical successes so far. Future efforts should focus on combinatorial therapies, next-generation inhibitors, and biomarkers for patient selection. Targeting the cell cycle holds promise but further optimization is necessary to fully exploit it as an anti-cancer strategy across diverse malignancies.

Basic Science in Movement Disorders: Fueling the Engine of Translation into Clinical Practice.

Basic Science is crucial for the advancement of clinical care for Movement Disorders. Here, we provide brief updates on how basic science is important for understanding disease mechanisms, disease prevention, disease diagnosis, development of novel therapies and to establish the basis for personalized medicine. We conclude the viewpoint by a call to action to further improve interactions between clinician and basic scientists. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Potential anticancer effect of free and nanoformulated Deferasirox for breast cancer treatment: in-vitro and in-vivo evaluation.

BACKGROUND: Breast cancer (BC) stands as the second-leading cause of mortality among women worldwide. Many chemotherapeutic treatments for BC come with significant adverse effects. Additionally, BC is recognized as one of the most resistant forms of malignancy to treatment. Consequently, there exists a critical need for innovative therapeutic agents that are both highly effective and exhibit reduced toxicity and side effects for patients. Deferasirox (DFX), an iron-chelating drug approved by the FDA for oral use, emerges as a promising contender in the fight against BC proliferation. DFX, primarily administered orally, is utilized to address chronic iron excess resulting from blood transfusions, and it is the inaugural treatment for chronic iron overload syndrome. However, DFX encounters limitations due to its poor water solubility. AIM: This study aimed at incorporating DFX into lipid nanocapsules (DFX-LNCs) followed by investigating the anticancer effect of the DFX nanoform as compared to free DFX in-vitro and on an orthotopic BC mouse model in-vivo. METHODS: The DFX-LNCs was prepared and imaged using TEM and also characterized in terms of particle size (PS), zeta potential (ZP), and polydispersity index (PDI) using DLS. Moreover, drug release, cytotoxicity, and anticancer effect were assessed in-vitro, and in-vivo. RESULTS: The results revealed that DFX-LNCs are more cytotoxic than free DFX with IC50 of 4.417 µg/ml and 16.114 µg/ml, respectively, while the plain LNCs didn't show any cytotoxic effect on the 4T1 cell line (IC50 = 122.797 µg/ml). Besides, the apoptotic effect of DFX-LNCs was more pronounced than that of free DFX, as evidenced by Annexin V/PI staining, increased BAX expression, and decreased expression of BcL-2. Moreover, DFX-LNCs showed a superior antitumor effect in-vivo with potent antioxidant and anti-proliferative effects. CONCLUSION: The newly developed DFX nanoform demonstrated a high potential as a promising therapeutic agent for BC treatment.

Health inequity in genomic personalized medicine in underrepresented populations: a look at the current evidence.

Improvements in sequencing technology coupled with dramatic declines in the cost of genome sequencing have led to a proportional growth in the size and number of genetic datasets since the release of the human genetic sequence by The Human Genome Project (HGP) international consortium. The HGP was undeniably a significant scientific success, a turning point in human genetics and the beginning of human genomics. This burst of genetic information has led to a greater understanding of disease pathology and the potential of employing this data to deliver more precise patient care. Hence, the recognition of high-penetrance disease-causing mutations which encode drivers of disease has made the management of most diseases more specific. Nonetheless, while genetic scores are becoming more extensively used, their application in the real world is expected to be limited due to the lack of diversity in the data used to construct them. Underrepresented populations, such as racial and ethnic minorities, low-income individuals, and those living in rural areas, often experience greater health disparities and worse health outcomes compared to the general population. These disparities are often the result of systemic barriers, such as poverty, discrimination, and limited access to healthcare. Addressing health inequity in underrepresented populations requires addressing the underlying social determinants of health and implementing policies and programs which promoted health equity and reduce disparities. This can include expanding access to affordable healthcare, addressing poverty and unemployment, and promoting policies that combat discrimination and racism.

Deep learning applications in visual data for benign and malignant hematologic conditions: a systematic review and visual glossary.

Deep learning (DL) is a subdomain of artificial intelligence algorithms capable of automatically evaluating subtle graphical features to make highly accurate predictions, which was recently popularized in multiple imaging-related tasks. Because of its capabilities to analyze medical imaging such as radiology scans and digitized pathology specimens, DL has significant clinical potential as a diagnostic or prognostic tool. Coupled with rapidly increasing quantities of digital medical data, numerous novel research questions and clinical applications of DL within medicine have already been explored. Similarly, DL research and applications within hematology are rapidly emerging, although these are still largely in their infancy. Given the exponential rise of DL research for hematologic conditions, it is essential for the practising hematologist to be familiar with the broad concepts and pitfalls related to these new computational techniques. This narrative review provides a visual glossary for key deep learning principles, as well as a systematic review of published investigations within malignant and non-malignant hematologic conditions, organized by the different phases of clinical care. In order to assist the unfamiliar reader, this review highlights key portions of current literature and summarizes important considerations for the critical understanding of deep learning development and implementations in clinical practice.

Cross-cultural adaptation and validation of a self-reporting tool to assess health-related quality of life for Egyptians with extremity bone sarcomas in childhood or adolescence.

BACKGROUND: Validated self-reporting tools are required to evaluate the functional outcome and health-related quality of life (HRQOL) for those who had extremity bone sarcomas in their childhood or adolescence. Our study pursued cross-cultural adaptation and validation of the pediatric Toronto Extremity Salvage Score (pTESS) and Toronto Extremity Salvage Score (TESS) to assess the functional outcome for Egyptian children and adult survivors following surgeries of extremity bone sarcomas. In the modified versions of pTESS and TESS, mental domains were added to allow the evaluation of HRQOL using a specific instrument for childhood bone cancer. METHODS: The internal consistency and test-retest reliability of the studied forms were assessed with Cronbach's alpha and Intra-class coefficients (ICC), respectively. For convergent validity, correlations between scores of the generic Pediatric Quality of Life Inventory (PedsQL 4.0) and pTESS /TESS scores were reported. Factor Analysis was feasible for pTESS-leg; due to the insufficient samples, only the average inter-item correlation coefficients were reported for the remaining versions. RESULTS: Out of 233 participants, 134 responded to pTESS-leg, 53 to TESS-leg, 36 to pTESS-arm, and only 10 to TESS-arm. All versions showed excellent internal consistency (Cronbach's alpha >0.9), good test-retest reliability (ICC >0.8), moderate to strong correlations with PedsQL, and acceptable average inter-item correlation coefficients (≥0.3). Three factors were extracted for the pTESS-leg, in which all mental items were loaded on one separate factor with factor loadings exceeding 0.4. Active chemotherapy, less than one year from primary surgery, or tibial tumors were associated with significantly inferior pTESS/TESS scores in the lower extremity group. CONCLUSION: The Egyptian pTESS and TESS are valid and reliable self-reporting tools for assessing the functional outcome following surgeries for extremity bone sarcomas. The modified pTESS and TESS versions, which include additional mental domains, enabled the assessment of the overall health status of our population. Future studies should include a larger sample size and evaluate the ability of pTESS/TESS to track progress over time.

Dissolution mechanism of cellulose in a benzyltriethylammonium/urea deep eutectic solvent (DES): DFT-quantum modeling, molecular dynamics and experimental investigation.

In this paper, a benzyltriethylammonium/urea DES was investigated as a new green and eco-friendly medium for the progress of organic chemical reactions, particularly the dissolution and the functionalization of cellulose. In this regard, the viscosity-average molecular weight of cellulose (M̄w) during the dissolution/regeneration process was investigated, showing no significant degradation of the polymer chains. Moreover, X-ray diffraction patterns indicated that the cellulose dissolution process in the BTEAB/urea DES decreased the crystallinity index from 87% to 75%, and there was no effect on type I cellulose polymorphism. However, a drastic impact of the cosolvents (water and DMSO) on the melting point of the DES was observed. Besides, to understand the evolution of cellulose-DES interactions, the formation mechanism of the system was studied in terms of H-bond density and radial distribution function (RDF) using molecular dynamics modeling. Furthermore, density functional theory (DFT) was used to evaluate the topological characteristics of the polymeric system such as potential energy density (PED), laplacian electron density (LED), energy density, and kinetic energy density (KED) at bond critical points (BCPs) between the cellulose and the DES. The quantum theory of atoms in molecules (AIM), Bader's quantum theory (BQT), and reduced density gradient (RDG) scatter plots have been exploited to estimate and locate non-covalent interactions (NCIs). The results revealed that the dissolution process is attributed to the physical interactions, mainly the strong H-bond interactions.

Endoscopic third ventriculostomy for management of hydrocephalus associated with Chiari malformation type II in children.

BACKGROUND: Hydrocephalus is commonly associated with Chiari malformation (CM) particularly CM type II. The traditional treatment of hydrocephalus in these patients has been cerebrospinal fluid diversion by shunts. Endoscopic third ventriculostomy (ETV) has emerged as an alternative procedure in these patients. PURPOSE: Assessment of the clinical and radiological outcomes of ETV in the management of hydrocephalus in children with CM II. METHODS: This is a prospective study conducted on 18 patients with CM II associated with hydrocephalus admitted to Cairo University hospitals between January 2020 and June 2021. These patients had been managed surgically by ETV. Clinical outcome was assessed based on improvement of manifestations of increased intracranial pressure while radiological outcome was based on the findings of postoperative computed tomography. In cases with early failure, serial lumbar puncture (LP) was performed for 2 days. RESULTS: ETV was performed as a secondary procedure in 4 cases. The overall success rate of the procedure was 72%, and its success rate as a secondary procedure was 100%. Serial LP was effective in decreasing early failure in 44.4% of cases. Radiological regression of hydrocephalic changes was detected in 50% of the cases. CONCLUSION: ETV is an efficient and safe procedure in the treatment of hydrocephalus in children with Chiari malformation II, particularly when performed as a secondary procedure. Serial LP following the procedure increases the success rate in patients with early failure.

Online Health Communities: an alternative feasible data registry tool for developing countries.

Given the many challenges facing healthcare access in many developing countries and the added limitations observed in emergencies like COVID-19 pandemic, the authors here discuss an alternative and feasible approach to overcome all these limitations.

Topical Lidocaine And Or/ Intravenous Midazolam Before Radial Coronary Angiography To Prevent Radial Artery Spasm.

Objectives: To investigate the possible advantage of topical lidocaine and intravenous midazolam in preventing spasm and pain related to the radial artery. Method: The prospective, comparative study was conducted at the catheterization laboratory of the cardiology department Kafrelsheikh University Hospital, Egypt, from January 2021 to January 2022, and comprised adult patients of either gender who were due to undergo coronary angiography and/or percutaneous coronary intervention for different indications. The patients were randomised control group I which was administered a cocktail of nitroglycerine, verapamil and heparin, intervention group II which was administered the control cocktail plustopical lidocaine, group III which was administered the control cocktail plus midazolam intravenously, and group IV which was administered the control cocktail plus topical lidocaine and intravenous midazolam. The groups were compared for frequency of radial artery spasm, accesssite cross-over and the difference in occurrence as well as procedure events, including the puncture number, time and complications. Data was analysed using SPSS 25. RESULTS: Of the 120 patients, there were 30(25%) in each of the 4 groups. Overall, there were 72(60%) males and 48(40%) females. Gender and mean age were not significantly different among the groups (p>0.05). Spasm of the radial artery occurred in 22(18.3%) patients, with higher incidence in the group I 12(40%). The median visual analogue scale score was higher in patients with radial artery spasm patients (p<0.001). The groups showed no significant differences in terms of frequency related to ad hoc percutaneous coronary intervention, contrast volume and fluoroscopy time (p>0.05), while they showed a significant difference in puncture time (p<0.05). Significant differences were noted among the groups in the incidence of radial artery spasm, visual analogue scale scores, requirement of multiple punctures, and the number of indicated punctures (p<0.05). Access site cross-over was more in the group I, while age, complication rates, visual analogue scale score, incidence of multiple punctures, and puncture time were significantly higher in patients with radial artery spasm (p<0.05). CONCLUSIONS: Cutaneous analgesia and procedural sedation before transradial access for coronary interventions were found to be associated with a substantial reduction in radial artery spasm and procedure-related discomfort.

Effect Of Corticosteroid And Immune-Suppressive Drugs On Oral Manifestations In Hospitalized COVID-19 Patients.

Objectives: To explore if the oral lesions in coronavirus disease-2019 patients are caused by the drugs used in the treatment or by the virus itself. Method: The cross-sectional study was conducted from September 2020 to September 2021 at the Kafrelsheikh University Hospital, Egypt, and comprised coronavirus disease-2019 patients of either gender aged 20-60 years having severe pneumonia and breathing difficulties who had no comorbidities. Based on the level of interleukin-6 and procalcitonin, the patients were classified into high group I receiving tocilizumab and methylprednisolone, medium group II receiving methylprednisolone alone, and low group III receiving antiviral drugs. The oral manifestations were recorded at the time of admission before treatment and at 2 weeks after the respective treatment. Data was analysed using SPSS 20. RESULTS: Of the 90 patients, 30(33.3%) were in group I; 16(%) males and 14(%) females with mean age 44.82±6.10 years. Group II had 27(%) patients; 14(%) males and 13(%) females with mean age 43.74±4.87 years. Group III had 33(%) patients; 9(%) males and 14(%) females with mean age 42.66±2.51 years (p>0.05). There was no significant difference among the groups at baseline and after 2 weeks of treatment regarding oral manifestations. Intragroup comparison demonstrated a significant difference in the two values in all the three groups (p<0.05). CONCLUSIONS: Oral lesions in coronavirus disease-2019 patients were caused by the virus itself rather than the drugs used in its treatment.

The Effect Of Interleukin-6 And Procalcitonin Level On The Development Of Oral Manifestation In Hospitalized COVID-19 Patients.

Objectives: To evaluate the effect of interleukin-6 and procalcitonin levels in plasma on the development of oral manifestation in patients of coronavirus disease-2019. Method: The case-control study was conducted from January to September 2021 at Kafrelsheikh University Hospital, Egypt, and comprised severe coronavirus disease.One hundred patients of either gender aged 30-60 years were included.. The patients were divided into two equal groups, with group I having patients with oral manifestations, and group II had those without any oral symptoms. Plasma samples from both the groups were used to determine serum interleukin-6 and procalcitonin levels using electrochemiluminescence immunoassay. Data was analysed using SPSS 20. RESULTS: Of the 100 patients, 50(50%) were in each of the two groups. Group I had 29(58%) males and 21(42%) females with overall mean age 44.83±6.12 years. Group II had 26(52%) males and 24(48%) females with overall mean age of 43.68±4.62 years. Interleukin 6 wassignificantly high in group I than in group II (p<0.05), while there was no significant difference between the groups for procalcitonin level (p>0.05). CONCLUSIONS: Interleukin-6 level could play an important role in the development of oral manifestation in coronavirus disease-2019 patients.

Underrepresented Populations in Parkinson's Genetics Research: Current Landscape and Future Directions.

BACKGROUND: Human genetics research lacks diversity; over 80% of genome-wide association studies have been conducted on individuals of European ancestry. In addition to limiting insights regarding disease mechanisms, disproportionate representation can create disparities preventing equitable implementation of personalized medicine. OBJECTIVE: This systematic review provides an overview of research involving Parkinson's disease (PD) genetics in underrepresented populations (URP) and sets a baseline to measure the future impact of current efforts in those populations. METHODS: We searched PubMed and EMBASE until October 2021 using search strings for "PD," "genetics," the main "URP," and and the countries in Latin America, Caribbean, Africa, Asia, and Oceania (excluding Australia and New Zealand). Inclusion criteria were original studies, written in English, reporting genetic results on PD from non-European populations. Two levels of independent reviewers identified and extracted information. RESULTS: We observed imbalances in PD genetic studies among URPs. Asian participants from Greater China were described in the majority of the articles published (57%), but other populations were less well studied; for example, Blacks were represented in just 4.0% of the publications. Also, although idiopathic PD was more studied than monogenic forms of the disease, most studies analyzed a limited number of genetic variants. We identified just nine studies using a genome-wide approach published up to 2021, including URPs. CONCLUSION: This review provides insight into the significant lack of population diversity in PD research highlighting the immediate need for better representation. The Global Parkinson's Genetics Program (GP2) and similar initiatives aim to impact research in URPs, and the early metrics presented here can be used to measure progress in the field of PD genetics in the future. © 2022 International Parkinson and Movement Disorder Society.

Different segmental resection techniques and postoperative complications in patients with colorectal endometriosis: A systematic review.

INTRODUCTION: The aim of this study was to analyze the available literature by conducting a systematic review to assess the possible effects of nerve-sparing segmental resection and conventional bowel resection on postoperative complications for the treatment of colorectal endometriosis. MATERIAL AND METHODS: Pubmed, Clinical Trials.gov, Cochrane Library, and Web of Science were comprehensively searched from 1997 to 2021 in order to perform a systematic review. Studies including patients undergoing segmental resection for colorectal endometriosis including adequate follow-up, data on postoperative complications and postoperative sequelae were enrolled in this review. Selected articles were evaluated and divided in two groups: Nerve-sparing resection (NSR), and conventional segmental resection not otherwise specified (SRNOS). Within the NSRs, studies mentioning preservation of the rectal artery supply (artery and nerve-sparing SR - ANSR) and not reporting preservation of the artery supply (NSR not otherwise specified - NSRNOS) were further analyzed. PROSPERO ID: CRD42021250974. RESULTS: A total of 7549 patients from 63 studies were included in the data analysis. Forty-three of these publications did not mention the preservation or the removal of the hypogastric nerve plexus, or main rectal artery supply and were summarized as SRNOS. The remaining 22 studies were listed under the NSR group. The mean size of the resected deep endometriosis lesions and patients' body mass index were comparable between SRNOS and NSR. A mean of 3.6% (0-16.6) and 2.3% (0-10.5%) of rectovaginal fistula development was reported in patients who underwent SRNOS and NSR, respectively. Anastomotic leakage rates varied from 0% to 8.6% (mean 1.7 ± 2%) in SRNOS compared with 0% to 8% (mean 1.7 ± 2%) in patients undergoing NSR. Urinary retention (4.5% and 4.9%) and long-term bladder catheterization (4.9% and 5.6%) were frequently reported in SRNOS and NSR. There was insufficient information about pain or the recurrence rates for women undergoing SRNOS and NSR. CONCLUSIONS: Current data describe the outcomes of different segmental resection techniques. However, the data are inhomogeneous and not sufficient to reach a conclusion regarding a possible advantage of one technique over the other.

Glimepiride mitigates tauopathy and neuroinflammation in P301S transgenic mice: role of AKT/GSK3ß signaling.

BACKGROUND AND OBJECTIVE: Tauopathy is a group of neurodegenerative diseases in which the pathogenesis processes are related to tau protein. The imbalances between the activities of kinases and phosphatases of tau protein lead to tau hyperphosphorylation and subsequent neurodegeneration. Numerous studies suggest a strong linkage between type 2 diabetes mellitus (T2D) and neurodegenerative diseases. Therefore, finding a drug with a dual therapeutic activity against T2D and neuroprotective will be a promising idea. Hence, the potential neuroprotective effect of Glimepiride (GPD) against tauopathy was evaluated in the current study. METHODS: P301S mice model was employed for tauopathy and C57BL/6 wild type mice (WT) was used as control. Phosphorylated and acetylated tau protein levels was assessed in cortex and hippocampus by western blot. Effect of GPD on tauopathy related enzymes, neuroinflammation, apoptotic markers were evaluated. Furthermore, the neuroprotective effects against anxiety like behavior and motor impairment was analyzed using Parallel rod floor and Open field tests. RESULTS: GPD significantly ameliorates motor impairment, anxiety like behavior and neurodegeneration in P301S mice. Phosphorylated tau and acetylated tau were significantly decreased in both cortex and hippocampus of P301S mice via decreasing GSK3ß, increasing ratio of phosphorylated-AKT to total-AKT, increasing PP2A and normalization of CDK5 levels. Furthermore, GPD treatment also decreased neuroinflammation and apoptosis by reducing NF-kB, TNF-α and caspase 3 levels. CONCLUSION: The current data suggests that GPD exerts a protective effect against tauopathy, behavioural consequences, neurodegeneration, neuroinflammation and apoptosis. GPD is therefore a promising agent for the treatment of neurodegenerative diseases associated with tauopathy.

Thyroid-Stimulating Hormone Favors Runx2-Mediated Matrix Mineralization in HOS and SaOS2 Cells: An In Vitro and In Silico Approach.

Osteoporosis is a skeletal disease that is both systemic and silent characterized by an unbalanced activity of bone remodeling leading to bone loss. Rising evidences demonstrate that thyroid stimulating hormone (TSH) has an important role in the regulation on the metabolism of bone. However, TSH regulation on human osteoblast essential transcriptional factors has not been identified. Current study examined the role of TSH on human osteoblastic Runx2 expression and their functional genes by in vitro and in slico analysis. Human osteoblast like (HOS and SaoS-2) cells were cultured with DMEM and treated with hTSH at the concentration of 0.01 ng/mL and 10 ng/mL. After treatment, osteoblastic Runx2 and IGF-1R beta expression were studied using RT-PCR and western blot analysis. TSH treatment induced osteoblastic essential transcriptional factor, Runx2 in HOS and SaOS2 cells on 48 h duration and elevated the expression of IGF-IR ß gene and Protein in SaoS-2 cells. TSH also promotes Runx2 responsive genes such as ALP, Collagen and osteocalcin in SaOS2 cells on day 2 to day 14 of 10 ng/mL of treatment and favors' matrix mineralization matrix in these cells. In addition, TSH facilitated human osteoblastic cells to mineralize their matrix confirmed by day 21 of alizarin red calcium staining. In silico study was performed to check CREB and ELK1 interaction with Runx2. Results of in silico analysis showed that TSH mediated signalling molecules such as CREB and ELK1 showed interaction with Runx2 which involve in osteobalstic gene expression and differentiation. Present findings confirm that TSH promotes Runx2 expression, osteoblastic responsive genes and bone matrix formation.

Evidence for pathogenicity of variant ATM Val1729Leu in a family with ataxia telangiectasia.

Ataxia telangiectasia is a rare autosomal recessive multisystem disorder caused by mutations in the gene of ATM serine/threonine kinase. It is characterized by neurodegeneration, leading to severe ataxia, immunodeficiency, increased cancer susceptibility, and telangiectasia. Here, we discovered a co-segregation of two ATM gene variants with ataxia telangiectasia in an Egyptian family. While one of these variants (NM_000051.4(ATM_i001):p.(Val128*)) has previously been reported as pathogenic, the other one (NM_000051.4(ATM_i001):p.(Val1729Leu)) is regarded as a variant of uncertain significance. Our findings in this family provide additional evidence for causality of the second variant and argue that its status should be changed to pathogenic.

Pegylated interferon alfa-2a for polycythemia vera or essential thrombocythemia resistant or intolerant to hydroxyurea.

Prior studies have reported high response rates with recombinant interferon-α (rIFN-α) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). To further define the role of rIFN-α, we investigated the outcomes of pegylated-rIFN-α2a (PEG) therapy in ET and PV patients previously treated with hydroxyurea (HU). The Myeloproliferative Disorders Research Consortium (MPD-RC)-111 study was an investigator-initiated, international, multicenter, phase 2 trial evaluating the ability of PEG therapy to induce complete (CR) and partial (PR) hematologic responses in patients with high-risk ET or PV who were either refractory or intolerant to HU. The study included 65 patients with ET and 50 patients with PV. The overall response rates (ORRs; CR/PR) at 12 months were 69.2% (43.1% and 26.2%) in ET patients and 60% (22% and 38%) in PV patients. CR rates were higher in CALR-mutated ET patients (56.5% vs 28.0%; P = .01), compared with those in subjects lacking a CALR mutation. The median absolute reduction in JAK2V617F variant allele fraction was -6% (range, -84% to 47%) in patients achieving a CR vs +4% (range, -18% to 56%) in patients with PR or nonresponse (NR). Therapy was associated with a significant rate of adverse events (AEs); most were manageable, and PEG discontinuation related to AEs occurred in only 13.9% of subjects. We conclude that PEG is an effective therapy for patients with ET or PV who were previously refractory and/or intolerant of HU. This trial was registered at www.clinicaltrials.gov as #NCT01259856.