Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A.

BACKGROUND: Valoctocogene roxaparvovec delivers a B-domain-deleted factor VIII coding sequence with an adeno-associated virus vector to prevent bleeding in persons with severe hemophilia A. The findings of a phase 3 study of the efficacy and safety of valoctocogene roxaparvovec therapy evaluated after 52 weeks in men with severe hemophilia A have been published previously. METHODS: We conducted an open-label, single-group, multicenter, phase 3 trial in which 134 men with severe hemophilia A who were receiving factor VIII prophylaxis received a single infusion of 6×1013 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in the annualized rate of treated bleeding events at week 104 after receipt of the infusion. The pharmacokinetics of valoctocogene roxaparvovec were modeled to estimate the bleeding risk relative to the activity of transgene-derived factor VIII. RESULTS: At week 104, a total of 132 participants, including 112 with data that were prospectively collected at baseline, remained in the study. The mean annualized treated bleeding rate decreased by 84.5% from baseline (P<0.001) among the participants. From week 76 onward, the trajectory of the transgene-derived factor VIII activity showed first-order elimination kinetics; the model-estimated typical half-life of the transgene-derived factor VIII production system was 123 weeks (95% confidence interval, 84 to 232). The risk of joint bleeding was estimated among the trial participants; at a transgene-derived factor VIII level of 5 IU per deciliter measured with chromogenic assay, we expected that participants would have 1.0 episode of joint bleeding per year. At 2 years postinfusion, no new safety signals had emerged and no new serious adverse events related to treatment had occurred. CONCLUSIONS: The study data show the durability of factor VIII activity and bleeding reduction and the safety profile of valoctocogene roxaparvovec at least 2 years after the gene transfer. Models of the risk of joint bleeding suggest that the relationship between transgene-derived factor VIII activity and bleeding episodes is similar to that reported with the use of epidemiologic data for persons with mild-to-moderate hemophilia A. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.).

Paraspeckles interact with SWI/SNF subunit ARID1B to regulate transcription and splicing.

Paraspeckles are subnuclear RNA-protein structures that are implicated in important processes including cellular stress response, differentiation, and cancer progression. However, it is unclear how paraspeckles impart their physiological effect at the molecular level. Through biochemical analyses, we show that paraspeckles interact with the SWI/SNF chromatin-remodeling complex. This is specifically mediated by the direct interaction of the long-non-coding RNA NEAT1 of the paraspeckles with ARID1B of the cBAF-type SWI/SNF complex. Strikingly, ARID1B depletion, in addition to resulting in loss of interaction with the SWI/SNF complex, decreases the binding of paraspeckle proteins to chromatin modifiers, transcription factors, and histones. Functionally, the loss of ARID1B and NEAT1 influences the transcription and the alternative splicing of a common set of genes. Our findings reveal that dynamic granules such as the paraspeckles may leverage the specificity of epigenetic modifiers to impart their regulatory effect, thus providing a molecular basis for their function.

(mis)-Targeting of SWI/SNF complex(es) in cancer.

The ATP-dependent chromatin remodeling complex SWI/SNF (also called BAF) is critical for the regulation of gene expression. During the evolution from yeast to mammals, the BAF complex has evolved an enormous complexity that contains a high number of subunits encoded by various genes. Emerging studies highlight the frequent involvement of altered mammalian SWI/SNF chromatin-remodeling complexes in human cancers. Here, we discuss the recent advances in determining the structure of SWI/SNF complexes, highlight the mechanisms by which mutations affecting these complexes promote cancer, and describe the promising emerging opportunities for targeted therapies.

Plakophilin3 increases desmosome assembly, size and stability by increasing expression of desmocollin2.

Previous reports show that the desmosomal plaque protein plakophilin3 (PKP3) is essential for desmosome formation. Here, we report that PKP3 over-expression decreases calcium dependency for de novo desmosome formation and makes existing cell-cell adhesion junctions more resilient in low calcium medium due to an increase in desmocollin2 expression. PKP3 overexpression increases the stability of other desmosomal proteins independently of the increase in DSC2 levels and regulates desmosome formation and stability by a multimodal mechanism affecting transcription, protein stability and cell border localization of desmosomal proteins.

Hepatitis C Virus Clearance and Diffusing Capacity for Carbon Monoxide in Women With and Without Human Immunodeficiency Virus.

Hepatitis C virus (HCV) infection is associated with extrahepatic effects, including reduced diffusing capacity of the lungs. It is unknown whether clearance of HCV infection is associated with improved diffusing capacity. In this sample of women with and without human immunodeficiency virus, there was no association between HCV clearance and diffusing capacity.

Two-Stage Training Framework Using Multicontrast MRI Radiomics for IDH Mutation Status Prediction in Glioma.

Purpose To develop a radiomics framework for preoperative MRI-based prediction of isocitrate dehydrogenase (IDH) mutation status, a crucial glioma prognostic indicator. Materials and Methods Radiomics features (shape, first-order statistics, and texture) were extracted from the whole tumor or the combination of nonenhancing, necrosis, and edema regions. Segmentation masks were obtained via the federated tumor segmentation tool or the original data source. Boruta, a wrapper-based feature selection algorithm, identified relevant features. Addressing the imbalance between mutated and wild-type cases, multiple prediction models were trained on balanced data subsets using random forest or XGBoost and assembled to build the final classifier. The framework was evaluated using retrospective MRI scans from three public datasets (The Cancer Imaging Archive [TCIA, 227 patients], the University of California San Francisco Preoperative Diffuse Glioma MRI dataset [UCSF, 495 patients], and the Erasmus Glioma Database [EGD, 456 patients]) and internal datasets collected from the University of Texas Southwestern Medical Center (UTSW, 356 patients), New York University (NYU, 136 patients), and University of Wisconsin-Madison (UWM, 174 patients). TCIA and UTSW served as separate training sets, while the remaining data constituted the test set (1617 or 1488 testing cases, respectively). Results The best performing models trained on the TCIA dataset achieved area under the receiver operating characteristic curve (AUC) values of 0.89 for UTSW, 0.86 for NYU, 0.93 for UWM, 0.94 for UCSF, and 0.88 for EGD test sets. The best performing models trained on the UTSW dataset achieved slightly higher AUCs: 0.92 for TCIA, 0.88 for NYU, 0.96 for UWM, 0.93 for UCSF, and 0.90 for EGD. Conclusion This MRI radiomics-based framework shows promise for accurate preoperative prediction of IDH mutation status in patients with glioma. Keywords: Glioma, Isocitrate Dehydrogenase Mutation, IDH Mutation, Radiomics, MRI Supplemental material is available for this article. Published under a CC BY 4.0 license. See also commentary by Moassefi and Erickson in this issue.

Synthesizing 3D Multi-Contrast Brain Tumor MRIs Using Tumor Mask Conditioning.

Data scarcity and data imbalance are two major challenges in training deep learning models on medical images, such as brain tumor MRI data. The recent advancements in generative artificial intelligence have opened new possibilities for synthetically generating MRI data, including brain tumor MRI scans. This approach can be a potential solution to mitigate the data scarcity problem and enhance training data availability. This work focused on adapting the 2D latent diffusion models to generate 3D multi-contrast brain tumor MRI data with a tumor mask as the condition. The framework comprises two components: a 3D autoencoder model for perceptual compression and a conditional 3D Diffusion Probabilistic Model (DPM) for generating high-quality and diverse multi-contrast brain tumor MRI samples, guided by a conditional tumor mask. Unlike existing works that focused on generating either 2D multi-contrast or 3D single-contrast MRI samples, our models generate multi-contrast 3D MRI samples. We also integrated a conditional module within the UNet backbone of the DPM to capture the semantic class-dependent data distribution driven by the provided tumor mask to generate MRI brain tumor samples based on a specific brain tumor mask. We trained our models using two brain tumor datasets: The Cancer Genome Atlas (TCGA) public dataset and an internal dataset from the University of Texas Southwestern Medical Center (UTSW). The models were able to generate high-quality 3D multi-contrast brain tumor MRI samples with the tumor location aligned by the input condition mask. The quality of the generated images was evaluated using the Fréchet Inception Distance (FID) score. This work has the potential to mitigate the scarcity of brain tumor data and improve the performance of deep learning models involving brain tumor MRI data.

Glucocorticoid-resistant asthma: more than meets the eye.

INTRODUCTION: For decades glucocorticoids have been considered as the gold standard for the treatment of asthma. We present a case report of typical glucocorticoid-resistant asthma and current consensus in definitions of "severe refractory", "difficult" and "glucocorticoid-resistant" asthma. METHODS: Full-text papers and abstracts were identified on the basis of a comprehensive literature search primarily in MEDLINE (1966 to June 2012) but also in the Cochrane Central Register of Controlled Trials database. RESULTS: Glucocorticoid-resistant asthmatics are a small subset of patients who pose noteworthy diagnostic challenges while contributing disproportionately to health care costs. Recognition of various asthma phenotypes has aided in characterizing groups with severe asthma and given a better understanding of its pathophysiological process. The molecular mechanism of glucocorticoid action is complicated and several pathways have been identified to explain drug resistance, which in turn is crucial for drug development. Tobacco smoking appears to be the single most important contributor of glucocorticoid resistance. We present the emerging and promising concepts in the management of glucocorticoid-resistant asthma, which mainly include drugs targeting specific molecules, receptors, inflammatory cells or immune processes. CONCLUSION: The challenges in making a diagnosis of glucocorticoid-resistant asthma may contribute to underestimating its prevalence and impact on patient care. Considerable progress has been made in identifying distinct phenotypes and mechanisms of glucocorticoid resistance; therefore the future of new drug development in management of asthma is promising.

Medico-legal autopsies after sunset: Ethical issues.

From the British era, regular medico-legal autopsies have never been done in India after sunset, except for those specially permitted by the law enforcement agencies. The Ministry of Health and Family Welfare, Government of India, issued a notification on November 15, 2021, regarding the "Conduct of post-mortem in hospitals after sunset". This has given rise to much debate on whether post-mortems can be conducted after sunset in an ethical manner. Here, we briefly discuss the various issues related to the carrying out of post-mortems after sunset in India.

MRI-Based Deep Learning Method for Classification of IDH Mutation Status.

Isocitrate dehydrogenase (IDH) mutation status has emerged as an important prognostic marker in gliomas. This study sought to develop deep learning networks for non-invasive IDH classification using T2w MR images while comparing their performance to a multi-contrast network. Methods: Multi-contrast brain tumor MRI and genomic data were obtained from The Cancer Imaging Archive (TCIA) and The Erasmus Glioma Database (EGD). Two separate 2D networks were developed using nnU-Net, a T2w-image-only network (T2-net) and a multi-contrast network (MC-net). Each network was separately trained using TCIA (227 subjects) or TCIA + EGD data (683 subjects combined). The networks were trained to classify IDH mutation status and implement single-label tumor segmentation simultaneously. The trained networks were tested on over 1100 held-out datasets including 360 cases from UT Southwestern Medical Center, 136 cases from New York University, 175 cases from the University of Wisconsin-Madison, 456 cases from EGD (for the TCIA-trained network), and 495 cases from the University of California, San Francisco public database. A receiver operating characteristic curve (ROC) was drawn to calculate the AUC value to determine classifier performance. Results: T2-net trained on TCIA and TCIA + EGD datasets achieved an overall accuracy of 85.4% and 87.6% with AUCs of 0.86 and 0.89, respectively. MC-net trained on TCIA and TCIA + EGD datasets achieved an overall accuracy of 91.0% and 92.8% with AUCs of 0.94 and 0.96, respectively. We developed reliable, high-performing deep learning algorithms for IDH classification using both a T2-image-only and a multi-contrast approach. The networks were tested on more than 1100 subjects from diverse databases, making this the largest study on image-based IDH classification to date.

Comparison of Remineralization Potential of Casein Phosphopeptide: Amorphous Calcium Phosphate, Nano-hydroxyapatite and Calcium Sucrose Phosphate on Artificial Enamel Lesions: An In Vitro Study.

Aim and objective: To evaluate and compare the remineralization potential of CPP-ACP, nano-hydroxyapatite, and calcium sucrose phosphate toothpaste on artificial enamel caries lesions by means of microhardness testing. Materials and methods: Twenty sound human primary molars, extracted for therapeutic reasons were selected for this study. From each tooth, two enamel specimens were prepared and embedded in acrylic resin blocks, and each block contains five tooth samples. After polishing, the baseline hardness of the enamel surface (KHN) was determined by Knoop microhardness testing. Then the specimens were randomly assigned into four groups (n = 10), according to the remineralizing agent used: group I: Control, group II: GC Tooth MousseTM (CCP-ACP), group III: AcclaimTM (nano-HAP), and group IV: EnaFix (CaSP). The specimens were then immersed in a demineralizing solution and post-lesion KHN values were obtained as baseline measurements. Later remineralizing agent was applied and after 7 days of remineralization, posttreatment KHN tests were conducted. Results: Data were analyzed using paired t- test, analysis of variance, and Tukey HSD test. Mean enamel surface microhardness (KHN) values after remineralization shows that group IV (EnaFixTM) had maximum hardness number (114.71 ± 12.27) followed by group III (Acclaim) (85.14 ± 22.82) and group II (GC Tooth Mousse) (56.42 ± 19.90). The difference was statistically significant (p < 0.001). Similarly the %SMHR was also highest in group IV (EnaFix), followed by group III (Acclaim) and group II (GC Tooth Mousse). Conclusion: EnaFix (calcium sucrose phosphate) shows a maximum increase in the enamel surface microhardness followed by Acclaim (nano-HAP) and GC Tooth Mousse. Clinical significance: Calcium Sucrose Phosphate in toothpaste strengthened the enamel more than nano hydroxyapatite and CPP-ACP, and can be an alternative to the use of fluoride toothpaste in children. How to cite this article: Sebastian R, Paul ST, Azher U, et al. Comparison of Remineralization Potential of Casein Phosphopeptide: Amorphous Calcium Phosphate Nano-hydroxyapatite and Calcium Sucrose Phosphate on Artificial Enamel Lesions: An In Vitro Study. Int J Clin Pediatr Dent 2022;15(1):69-73.

DNA methylation mediated downregulation of histone H3 variant H3.3 affects cell proliferation contributing to the development of HCC.

Chromatin alterations brought by histone variants and modifications potentially regulate gene transcription from tumor initiation to progression. Histone H3.3 variant is one such epigenetic player important for disease progression and development. Though many studies have implicated H3.3 role in cancer progression and metastasis, its regulation, importance of specific modifications and chaperones have been not understood yet. We report DNA methylation mediated downregulation of histone H3 variant H3.3 in HCC and a concomitant increase in the level of the H3.2 variant. The loss of H3.3 in cancer tissues correlates with a decrease in the histone modifications associated with active transcription like H3K9/K14/K27Ac and H3K4Me3. The ectopic overexpression of H3.3 and H3.2 did not affect global PTMs and cell physiology, probably owing to the deregulation of specific histone chaperones CAF-1 (for H3.2) and HIRA (for H3.3) as observed in HCC tissues. Notably, knockdown of P150, a subunit of CAF-1 leads to a cell cycle arrest in S-phase in a neoplastic rat liver cell line, possibly due to the decrease in the histone levels necessary for DNA packaging. Remarkably, modulation of H3.3 in pre-neoplastic rat liver cells lead to an increase in cell proliferation and a decreased transcription of tumor suppressor genes, recapitulating the tumor cell phenotype. Our data suggests, inhibition of DNA methylation and histone deacetylation leads to the restoration of histone H3 variant expression in tumor cells.

Elevated levels of the methyltransferase SETD2 causes transcription and alternative splicing changes resulting in oncogenic phenotypes.

The methyltransferase SETD2 regulates cryptic transcription, alternative splicing, and the DNA damage response. It is mutated in a variety of cancers and is believed to be a tumor suppressor. Counterintuitively, despite its important role, SETD2 is robustly degraded by the proteasome keeping its levels low. Here we show that SETD2 accumulation results in a non-canonical deposition of the functionally important H3K36me3 histone mark, which includes its reduced enrichment over gene bodies and exons. This perturbed epigenetic landscape is associated with widespread changes in transcription and alternative splicing. Strikingly, contrary to its role as a tumor suppressor, excessive SETD2 results in the upregulation of cell cycle-associated pathways. This is also reflected in phenotypes of increased cell proliferation and migration. Thus, the regulation of SETD2 levels through its proteolysis is important to maintain its appropriate function, which in turn regulates the fidelity of transcription and splicing-related processes.

Pulmonary Function Trajectories in People with HIV: Analysis of the Pittsburgh HIV Lung Cohort.

Rationale: Human immunodeficiency virus (HIV) infection is associated with chronic lung disease and impaired pulmonary function; however, longitudinal pulmonary function phenotypes in HIV are undefined. Objectives: To identify pulmonary function trajectories, their determinants, and outcomes. Methods: We used data from participants with HIV in the Pittsburgh HIV Lung Cohort with three or more pulmonary function tests between 2007 and 2020. We analyzed post-bronchodilator forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC, and diffusing capacity of the lung for carbon monoxide (DlCO) using group-based trajectory modeling to identify subgroups of individuals whose measurements followed a similar pattern over time. We examined the association between participant characteristics and trajectories using multivariable logistic regression. In exploratory adjusted analyses restricted to individuals with available plasma cytokine data, we investigated the association between 18 individual standardized cytokine concentrations and trajectories. We compared mortality, dyspnea prevalence, respiratory health status, and 6-minute-walk distance between phenotypes. Results: A total of 265 participants contributed 1,606 pulmonary function measurements over a median follow-up of 8.1 years. We identified two trajectories each for FEV1 and FVC: "low baseline, slow decline" and "high baseline, rapid decline." There were three trajectory groups for FEV1/FVC: "rapid decline," "moderate decline," and "slow decline." Finally, we identified two trajectories for DlCO: "baseline low" and "baseline high." The low baseline, slow decline FEV1 and FVC, rapid decline, and moderate decline FEV1/FVC, and baseline low DlCO phenotypes were associated with increased dyspnea prevalence, worse respiratory health status, and decreased 6-minute-walk distance. The baseline low DlCO phenotype was also associated with worse mortality. Current smoking and pack-years of smoking were associated with the adverse FEV1, FEV1/FVC, and DlCO phenotypes. Detectable viremia was the only HIV marker associated with the adverse DlCO phenotype. C-reactive protein and endothelin-1 were associated with the adverse FEV1 and FVC phenotypes, and endothelin-1 trended toward an association with the adverse DlCO phenotype. Conclusions: We identified novel, distinct longitudinal pulmonary function phenotypes with significant differences in characteristics and outcomes. These findings highlight the importance of lung dysfunction over time in people with HIV and should be validated in additional cohorts.

Antimicrobial Efficacy of Commercially Available Low-fluoride and Fluoride-free Dentifrices for Children.

AIM AND OBJECTIVE: The objective of this study was to evaluate and compare the antimicrobial efficacy of low-fluoride and fluoride-free dentifrices against Streptococcus mutans. MATERIALS AND METHODS: The antimicrobial efficacy of four commercially available low-fluoride child formula dentifrices and four fluoride-free dentifrices against S. mutans was determined using the agar diffusion test. Fifty microliters of various dilutions (1:1, 1:2, 1:4) of each dentifrice were inoculated on the assigned plates under aseptic conditions. Saline was taken as negative control and 0.2% chlorhexidine was considered as a positive control. The plates were incubated at 37°C for 24 hours and the zone of inhibition around the wells was measured. RESULTS: All the tested low-fluoride dentifrices showed varying degrees of antimicrobial activity against S. mutans with F2 (Pediflor®) and F4 (Cheerio™) showing greater zones of inhibition when compared to F1 (Colgate®kids) and F3 (Kidodent). When the mean zones of inhibition produced by non-fluoridated dentifrices were compared with that of fluoridated dentifrices, no statistically significant difference was noted between NF1, NF3, NF4, and F2, F4. The antibacterial activity of F1 and F3 was significantly lower when compared to others. However, no antibacterial activity was noted with NF2. CONCLUSION: Both low-fluoride and fluoride-free formulations tested in the study exhibited antimicrobial activity against S. mutans. In very young children where the risk of fluorosis is of concern, fluoride-free formulations can be considered as safe alternatives to fluoride formulations. CLINICAL SIGNIFICANCE: Several dentifrices, both fluoride-free and low-fluoride formulations, are being aggressively marketed for young children. Though these toothpastes are being very commonly used by young parents for their infants and toddlers, there is very little published literature available on their antimicrobial activity and this study focuses on addressing this. HOW TO CITE THIS ARTICLE: Reddy D, Selvan A, Paul ST, et al. Antimicrobial Efficacy of Commercially Available Low-fluoride and Fluoride-free Dentifrices for Children. Int J Clin Pediatr Dent 2021;14(2):183-186.

Structural basis of the interaction between SETD2 methyltransferase and hnRNP L paralogs for governing co-transcriptional splicing.

The RNA recognition motif (RRM) binds to nucleic acids as well as proteins. More than one such domain is found in the pre-mRNA processing hnRNP proteins. While the mode of RNA recognition by RRMs is known, the molecular basis of their protein interaction remains obscure. Here we describe the mode of interaction between hnRNP L and LL with the methyltransferase SETD2. We demonstrate that for the interaction to occur, a leucine pair within a highly conserved stretch of SETD2 insert their side chains in hydrophobic pockets formed by hnRNP L RRM2. Notably, the structure also highlights that RRM2 can form a ternary complex with SETD2 and RNA. Remarkably, mutating the leucine pair in SETD2 also results in its reduced interaction with other hnRNPs. Importantly, the similarity that the mode of SETD2-hnRNP L interaction shares with other related protein-protein interactions reveals a conserved design by which splicing regulators interact with one another.

Severe undernutrition in children affects tuberculin skin test performance in Southern India.

BACKGROUND: Undernutrition impairs immunity to Mycobacterium tuberculosis and is a risk factor for tuberculosis disease (TB). We aim to investigate if severe undernutrition affects the tuberculin skin test (TST) response among household contacts (HHCs) of pulmonary TB cases. METHODS: We analyzed data from HHCs (> five years) of pulmonary TB cases in Southern India. Undernutrition was defined as per World Health Organization based on body mass index (BMI) for adults (undernutrition 16-18.4 and severe undernutrition <16 kg/m2) and BMI relative to the mean for children (undernutrition 2SD-3SD and severe undernutrition < 3SDs below mean). Univariate and multivariate models of TST positivity (> five mm) were calculated using logistic regression with generalized estimating equations. RESULTS: Among 1189 HHCs, 342 were children (age 5-17 years) and 847 were adults. Prevalence of TST positivity in well-nourished, undernourished and severely undernourished children was 135/251 (53.8%), 32/68 (47.1%), and 7/23 (30.4%) respectively; among adults, prevalence of TST positivity was 304/708 (42.9%), 43/112 (38.4%) and 12/26 (46.2%), respectively. Severe undernutrition in children was associated with decreased odds of TST positivity (adjusted odds ratio 0.3; 95%CI 0.1-0.9). CONCLUSION: Severe undernutrition in children was associated with decreased odds of TST positivity. False-negative TSTs may result from undernutrition; caution is warranted when interpreting negative results in undernourished populations.

Real-World Rates of Bleeding, Factor VIII Use, and Quality of Life in Individuals with Severe Haemophilia A Receiving Prophylaxis in a Prospective, Noninterventional Study.

Regular prophylaxis with exogenous factor VIII (FVIII) is recommended for individuals with severe haemophilia A (HA), but standardised data are scarce. Here, we report real-world data from a global cohort. Participants were men ≥18 years old with severe HA (FVIII ≤ 1 IU/dL) receiving regular prophylaxis with FVIII. Participants provided 6 months of retrospective data and were prospectively followed for up to 12 months. Annualised bleeding rate (ABR) and FVIII utilisation and infusion rates were calculated. Differences between geographic regions were explored. Of 294 enrolled participants, 225 (76.5%) completed ≥6 months of prospective follow-up. Pre-baseline and on-study, the median (range) ABR values for treated bleeds were 2.00 (0-86.0) and 1.85 (0-37.8), respectively; the median (range) annualised FVIII utilisation rates were 3629.0 (1008.5-13541.7) and 3708.0 (1311.0-14633.4) IU/kg/year, respectively; and the median (range) annualised FVIII infusion rates were 120.0 (52.0-364.0) and 122.4 (38.0-363.8) infusions/year, respectively. The median (range) Haemo-QoL-A Total Score was 76.3 (9.4-100.0) (n = 289), ranging from 85.1 in Australia to 67.7 in South America. Physical Functioning was the most impacted Haemo-QoL-A domain in 4/6 geographic regions. Despite differences among sites, participants reported bleeding requiring treatment and impaired physical functioning. These real-world data illustrate shortcomings associated with FVIII prophylaxis for this global cohort of individuals with severe HA.

HISTome2: a database of histone proteins, modifiers for multiple organisms and epidrugs.

BACKGROUND: Epigenetics research is progressing in basic, pre-clinical and clinical studies using various model systems. Hence, updating the knowledge and integration of biological data emerging from in silico, in vitro and in vivo studies for different epigenetic factors is essential. Moreover, new drugs are being discovered which target various epigenetic proteins, tested in pre-clinical studies, clinical trials and approved by the FDA. It brings distinct challenges as well as opportunities to update the existing HIstome database for implementing and applying enormous data for biomedical research. RESULTS: HISTome2 focuses on the sub-classification of histone proteins as variants and isoforms, post-translational modifications (PTMs) and modifying enzymes for humans (Homo sapiens), rat (Rattus norvegicus) and mouse (Mus musculus) on one interface for integrative analysis. It contains 232, 267 and 350 entries for histone proteins (non-canonical/variants and canonical/isoforms), PTMs and modifying enzymes respectively for human, rat, and mouse. Around 200 EpiDrugs for various classes of epigenetic modifiers, their clinical trial status, and pharmacological relevance have been provided in HISTome2. The additional features like 'Clustal omega' for multiple sequence alignment, link to 'FireBrowse' to visualize TCGA expression data and 'TargetScanHuman' for miRNA targets have been included in the database. CONCLUSION: The information for multiple organisms and EpiDrugs on a common platform will accelerate the understanding and future development of drugs. Overall, HISTome2 has significantly increased the extent and diversity of its content which will serve as a 'knowledge Infobase' for biologists, pharmacologists, and clinicians. HISTome2: The HISTone Infobase is freely available on http://www.actrec.gov.in/histome2/ .

Mechanisms of Antisense Transcription Initiation with Implications in Gene Expression, Genomic Integrity and Disease Pathogenesis.

Non-coding antisense transcripts arise from the strand opposite the sense strand. Over 70% of the human genome generates non-coding antisense transcripts while less than 2% of the genome codes for proteins. Antisense transcripts and/or the act of antisense transcription regulate gene expression and genome integrity by interfering with sense transcription and modulating histone modifications or DNA methylation. Hence, they have significant pathological and physiological relevance. Indeed, antisense transcripts were found to be associated with various diseases including cancer, diabetes, cardiac and neurodegenerative disorders, and, thus, have promising potentials for prognostic and diagnostic markers and therapeutic development. However, it is not clearly understood how antisense transcription is initiated and epigenetically regulated. Such knowledge would provide new insights into the regulation of antisense transcription, and hence disease pathogenesis with therapeutic development. The recent studies on antisense transcription initiation and its epigenetic regulation, which are limited, are discussed here. Furthermore, we concisely describe how antisense transcription/transcripts regulate gene expression and genome integrity with implications in disease pathogenesis and therapeutic development.