Interaction of S100A13 with C2 domain of receptor for advanced glycation end products (RAGE).

S100A13 is involved in several key biological functions like angiogenesis, tumor formation and cell apoptosis. It is a homodimeric protein that belongs to the S100 protein family. S100A13 is co-expressed with acidic fibroblast growth factor (FGF1) and interleukin-1α which are key angiogenesis inducers. The S100 proteins have been shown to be involved in several cellular functions such as calcium homeostasis, cell growth and differentiation dynamic of cytoskeleton. Its biological functions are mainly mediated through the receptor for advanced glycation end products (RAGE) signaling. RAGE is involved in inflammatory processes and is associated with diabetic complications, tumor outgrowth, and neurodegenerative disorders. RAGE induces cellular signaling upon binding of different ligands, such as S100 proteins, glycated proteins, and HMGB1. RAGE signaling is complex, and it depends on the cell type and concentration of the ligand. Molecular level interactions of RAGE and S100 proteins are useful to understand the RAGE signaling diversity. In this report we focus on the molecular level interactions of S100A13 and RAGE C2 domain. The binding between RAGE C2 and S100A13 is moderately strong (Kd~1.3µM). We have solved the solution structure of the S100A13-RAGE C2 complex and pronounce the interface regions in S100A13-RAGE C2 complex which are helpful for drug development of RAGE induced diseases.

Characterization of an extremely halotolerant Staphylococcus arlettae HPSSN35C isolated from Dwarka Beach, India.

An extremely halotolerant bacterium designated as HPSSN35C was isolated from saline soil of Dwarka beach, India. It exhibited growth over a wide range of NaCl in medium varying from 0 to 6 M. The isolate produced peach-pink pigment above ∼1.3 M NaCl. The culture was characterized using biochemical tests, bioMerieux Staph identification kit, API ID32 Staph system, and Biolog. Due to slow growth and extreme salt tolerance no ID was obtained in Biolog. Antibiotic sensitivity to various antibiotics was tested. Phenotypic characterization showed that it belonged to the novobiocin resistant staphylococci group. Analysis of 16S rRNA gene sequence comparison of 1452 base pairs showed that isolate is closely related to Staphylococcus saprophyticus group with close relationship to Staphylococcus arlettae (99% similarity). The halotolerant S. arlettae described in literature till date have been reported to tolerate 4.5 M NaCl and produce white to yellow pigment. The present study reports for the first time extremely halotolerant S. arlettae exhibiting growth up to ∼6 M NaCl and producing peach-pink pigment above ∼1.3 M NaCl.

Transcranial direct current stimulation-efficacy in mild cognitive impairment: A meta-analysis.

Objectives: Mild cognitive impairment (MCI) is a transition state in which individuals have cognitive abilities that are in between those of normal aging and dementia. Although not everyone with MCI develops dementia, the risk of progression to dementia is higher in people with MCI. Interventions at this stage can prevent or delay the onset of dementia. In recent years, studies on non-invasive brain stimulation techniques, namely transcranial direct current stimulation (tDCS), have gained momentum for cognitive enhancement in MCI. Since there are very few studies that also report varied results, it becomes important to analyze the effect of tDCS in MCI. The aim of this study was to systematically review the available evidence about using tDCS for MCI and to assess its efficacy using meta-analysis. Materials and Methods: Eight single- or double-blinded randomized controlled trials were included in the study. Montreal cognitive assessment (MoCA) and mini-mental state examination (MMSE) for global cognition; and digit span test forward and backward, trail-making test (TMT) A and B; and logical memory test (LMT) assessing specific cognitive domains were considered. A random-effects model was used wherein the standardized mean difference (SMD) and its 95% confidence intervals were reported. Results: The effect of the active tDCS (MoCA [SMD 0.37, 95% CI -0.22-0.95], MMSE [SMD 0.26, 95% CI 0.25-0.77], TMT-A [SMD -0.01, 95% CI -0.42-0.40], and LMT [SMD 0.80, 95% CI -0.24-1.83]) when compared with the sham tDCS was statistically insignificant. Conclusion: The current meta-analysis identified insignificant improvement in cognitive performance with active tDCS treatment as compared to sham tDCS among people with MCI.

Immunogenicity and safety of Mebella™ vaccine developed by Human Biologicals Institute in a Phase II/III, randomized, multicentric, non-inferiority study.

BACKGROUND: The goal of 'Measles and Rubella Strategic Framework 2021-2030' is to make "A world free from measles and rubella". To be a part of this journey, Human Biologicals Institute has developed Mebella™ vaccine, which is a lyophilized Measles and Rubella (Live) vaccine. A randomized, single blind, comparative, multicenter Phase II/III trial was conducted to compare the immunogenicity and safety of Mebella™ vaccine with MR-VAC® vaccine in healthy subjects. METHODS: A total of 888 subjects were enrolled in four age groups (222 subjects in each group) of 18 years to 49 years; 2 years to below 18 years; 12 months to below 24 months; and 9 months to below 12 months of age. The subjects were randomized in 2:1 ratio to receive single dose of either Mebella™ vaccine of Human Biologicals Institute or MR-VAC® vaccine. Immunogenicity was assessed at 42 days after the vaccination and was compared between the vaccine arms in each group. Safety was also assessed and compared between the vaccine arms during the study period. RESULTS: A total of 875 subjects completed the study out of 888 enrolled subjects. The seroprotection rates, seroconversion rates, and geometric mean titres for both Measles and Rubella components of Mebella™ vaccine were found to be comparable and non-inferior to the MR-VAC® vaccine after 42 days of vaccination. Injection site pain was the most common local adverse event reported whereas fever was the only systemic adverse event reported in both the vaccine arms. No serious adverse event was reported. CONCLUSION: It was concluded from the study results that the test vaccine, Mebella™, was immunogenic and well tolerated and was non-inferior to the comparator vaccine, MR-VAC®, when administered to healthy subjects of 9 months to 49 years of age. Clinical Trial Registry of India Identifier: CTRI/2020/07/026930.

Immunogenicity and safety of HavisureTM vaccine developed by Human Biologicals Institute in healthy subjects of 12 months to 49 years of age: A phase II/III, randomized, single blind, non-inferiority study.

BACKGROUND: Hepatitis A is an inflammation of the liver caused by the hepatitis A virus (HAV). It is transmitted mainly because of poor personal hygiene via the faecal/oral route through ingestion of contaminated food or water or through the direct contact with an infectious person. Though most of the infected individuals recover from the infection, a few may develop fatal fulminant hepatitis. In this randomized, multicenter study, immunogenicity and safety of Havisure™ vaccine of Human Biologicals Institute was compared with Havrix® vaccine. METHODS: The study was carried out in 528 eligible healthy subjects, in two age groups across eight centres in India. Group A included subjects of 19-49 years and Group B subjects of 12 months to below 19 years of age. All subjects received two doses of either Havisure™ vaccine or Havrix® vaccine as per randomization at six months interval. Blood samples for antibody titre estimation were collected before vaccination and 4-6 weeks after 2nd dose of vaccination. Immunogenicity was assessed by estimating seroconversion rate, seroprotection rate, and geometric mean titres of antibodies. Safety was evaluated by collection and analysis of data on solicited and unsolicited adverse events. RESULTS: Of 528 enrolled subjects, 493 subjects completed the study. There was 100% seroconversion and seroprotection in both the vaccine arms. There was no statistical difference in the geometric mean titres between the two vaccine arms. Pain and swelling at the site of injection were the most common local adverse events whereas fever and headache were the most common systemic adverse events observed in both vaccine arms. No serious adverse event was reported in the study. CONCLUSION: The study results indicate that the Havisure™ vaccine is immunogenic and safe when administered to healthy subjects of 12 months to 49 years of age, and is non-inferior to Havrix® Vaccine.

WITHDRAWN: Interaction of FGF1 with a novel anti-angiogenic drug SSR128129E.

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The heterohexameric complex structure, a component in the non-classical pathway for fibroblast growth factor 1 (FGF1) secretion.

Fibroblast growth factors (FGFs) are key regulators of cell proliferation, tumor-induced angiogenesis, and migration. FGFs are essential for early embryonic development, organ formation, and angiogenesis. FGF1 also plays an important role in inflammation, wound healing, and restenosis. The biological effects of FGF1 are mediated through the activation of the four transmembrane phosphotyrosine kinase fibroblast growth factor receptors in the presence of heparin sulfate proteoglycans and, therefore, require the release of the protein into the extracellular space. FGF1 is exported through a non-classical release pathway involving the formation of a specific multiprotein complex. The protein constituents of this complex include FGF1, S100A13, and the p40 form of synaptotagmin 1 (Syt1). Because FGF1 plays an important role in tumor formation, it is clear that preventing the formation of the multiprotein complex would be an effective strategy to inhibit a wide range of cancers. To understand the molecular events in the FGF1 release pathway, we studied the FGF1-S100A13 tetrameric and FGF1-S100A13-C2A hexameric complex structures, which are both complexes possibly formed during the non-classical pathway of FGF1 release.

Safety and immunogenicity of inactivated hepatitis-A vaccine developed by Human Biologicals Institute in two age groups of healthy subjects: A phase I open label study.

BACKGROUND: Hepatitis-A is an acute viral infection of the liver. Hepatitis-A virus has worldwide spread and is endemic in India. Though the disease is self-limiting in most cases, outbreaks are reported frequently from both developing and developed countries of the world. Severity and fatality occur more among infected symptomatic adults. The infection can be prevented with proper and timely immunization. This phase I, single arm, open label, multicenter trial was designed to assess the safety and immunogenicity of the inactivated hepatitis-A vaccine developed by Human Biologicals Institute when administered in a single dose in two age groups of healthy subjects. METHODS: This study was carried out in 55 subjects in two healthy age groups at two centers in India. Group A included subjects of 19-49 years and group B subjects of 12-18 years of age. Enrolled subjects received a single dose of inactivated hepatitis A vaccine. Blood samples were collected at baseline and 4-6 weeks after vaccination. Safety was assessed by collection and analysis of data on solicited and unsolicited adverse events and immunogenicity was assessed by estimating the seroconversion rate, seroprotection rate and the geometric mean titres of antibodies. RESULTS: Among the 55 subjects enrolled, 15 reported adverse events. No serious adverse event was reported. Pain at the injection site was the lone local adverse event. Systemic adverse events reported in Group A were: fatigue, headache, diarrhoea, fever, anorexia, nausea and upper respiratory tract infection, whereas there was no systemic event reported in Group B. There was 100% seroconversion and seroprotection and significant rise in antibody titre levels were observed in both the groups post vaccination. CONCLUSIONS: This study found HBI inactivated hepatitis-A vaccine to be safe and highly immunogenic when administered as a single dose in adolescent and adult subjects.

Molecular level interactions of S100A13 with amlexanox: inhibitor for formation of the multiprotein complex in the nonclassical pathway of acidic fibroblast growth factor.

S100A13 and acidic fibroblast growth factor (FGF1) are involved in a wide array of important biological processes, such as angiogenesis, cell differentiation, neurogenesis, and tumor growth. Generally, the biological function of FGF1 is to recognize a specific tyrosine kinase on the cell surface and initiate the cell signal transduction cascade. Amlexanox (2-amino-7-isopropyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acid) is an antiallergic drug that binds S100A13 and FGF1 and inhibits the heat shock induced release of S100A13 and FGF1. In the present study, we investigated the interaction of amlexanox with S100A13 using various biophysical techniques, including isothermal titration calorimetry, fluorescence spectrophotometry, and multidimensional NMR spectroscopy. We report the three-dimensional solution structure of the S100A13-amlexanox complex. These data show that amlexanox binds specifically to the FGF1-S100A13 interface and prevents the formation of the FGF1-releasing complex. In addition, we demonstrate that amlexanox acts as an antagonist of S100A13 by binding to its FGF1 binding site and subsequently inhibiting the nonclassical pathway of these proteins. This inhibition likely results in the ability of amlexanox to antagonize the angiogenic and mitogenic activity of FGF1.

S100A13-C2A binary complex structure-a key component in the acidic fibroblast growth factor for the non-classical pathway.

Fibroblast growth factors (FGFs) are key regulators of cell proliferation, differentiation, tumor-induced angiogenesis and migration. FGFs are essential for early embryonic development, organ formation and angiogenesis. They play important roles in tumor formation, inflammation, wound healing and restenosis. The biological effects of FGFs are mediated through the activation of the four transmembrane phosphotyrosine kinase receptors (FGFRs) in the presence of heparin sulfate proteoglycans (HSPGs) and therefore require the release of FGFs into the extracellular space. However, FGF-1 lacks the signal peptide required for the releasing of these proteins through the classical endoplasmic reticulum (ER)-Golgi secretary pathway. Maciag et al. demonstrated that FGF-1 is exported through a non-classical release pathway involving the formation of a specific multiprotein complex [M. Landriscina, R. Soldi, C. Bagala, I. Micucci, S. Bellum, F. Tarantini, I. Prudovsky, T. Maciag, S100A13 participates in the release of fibroblast growth factor 1 in response to heat shock in vitro, J. Biol. Chem. 276 (2001) 22544-22552; C.M. Carreira, T.M. LaVallee, F. Tarantini, A. Jackson, J.T. Lathrop, B. Hampton, W.H. Burgess, T. Maciag, S100A13 is involved in the regulation of fibroblast growth factor-1 and p40 synaptotagmin-1 release in vitro, J. Biol. Chem. 273 (1998) 22224-22231; T.M. LaValle, F. Tarantini, S. Gamble, C.M. Carreira, A. Jackson, T. Maciag, Synaptotagmin-1 is required for fibroblast growth factor-1 release, J. Biol. Chem. 273 (1998) 22217-22223; C. Bagalá, V. Kolev, A. Mandinova, R. Soldi, C. Mouta, I. Graziani, I, Prudovsky, T. Maciag, The alternative translation of synaptotagmin 1 mediates the non-classical release of FGF1, Biochem. Biophys. Res. Commun. 310 (2003) 1041-1047]. The protein constituents of this complex include FGF-1, S100A13 (a Ca(2+)-binding protein), and the p40 form of synaptotagmin 1 (Syt1). To understand the molecular events in the FGF-1 releasing pathway, we have studied the interactions of S100A13 with C2A by (1)H-(15)N HSQC titration and 3D-filtered NOESY experiments. We characterized the binary complex structure of S100A13-C2A by using a variety of multi-dimensional NMR experiments. This complex acts as a template for FGF-1 dimerization and multiprotein complex formation.

Immunogenicity and safety of a liquid Pentavalent (DTwP-Hb-Hib) combination vaccine manufactured by Human Biologicals Institute in 6-8 weeks old healthy infants: A phase III, randomized, single blind, non-inferiority study.

BACKGROUND: A liquid Pentavalent (DTwP-Hb-Hib) combination vaccine, developed by Human Biologicals Institute, underwent a Phase III clinical study in India. In this randomized, single blind, non-inferiority study, the immunogenicity and safety of this Investigational vaccine was compared with Pentavac SD® vaccine in 6-8 weeks old healthy infants. METHODS: A total of 405 healthy infants aged 6-8 weeks old were randomized in 2:1 ratio to receive three doses of either the Investigational liquid Pentavalent (DTwP-Hb-Hib) combination vaccine or Pentavac SD® vaccine at four to six weeks interval. Immunogenicity was compared by estimation of antibody titers before the first dose and 4-6 weeks after the third dose of vaccination. Safety of each vaccine was assessed and compared by collection of data on solicited and unsolicited adverse events throughout the study period. RESULTS: Out of a total of 405 enrolled subjects, 387 subjects completed the study. The seroconversion rates, seroprotection rates and geometric mean titres of the Investigational liquid Pentavalent (DTwP-Hb-Hib) combination vaccine group were found to be comparable and non-inferior to the Pentavac SD® vaccine group at 4-6 weeks after the third dose of vaccination. Pain, erythema and swelling at the site of injection were found to be the most common local adverse events whereas fever, irritability and unusual crying were found to be the most common systemic adverse events in both the vaccine groups. No vaccine related serious adverse event was reported. In this study, both the Investigational vaccine as well as the Comparator vaccine were found to be immunogenic and well tolerated. CONCLUSION: After assessment of the results of the study it was concluded that the Investigational liquid Pentavalent (DTwP-Hb-Hib) combination vaccine developed by Human Biologicals Institute was immunogenic and safe when administered to infants aged 6-8 weeks and was non-inferior in immunogenicity and safety to Pentavac SD® vaccine. Clinical Trial Registry of India Identifier: CTRI/2016/01/006541.

Multilevel Thresholding Method Based on Electromagnetism for Accurate Brain MRI Segmentation to Detect White Matter, Gray Matter, and CSF.

This work explains an advanced and accurate brain MRI segmentation method. MR brain image segmentation is to know the anatomical structure, to identify the abnormalities, and to detect various tissues which help in treatment planning prior to radiation therapy. This proposed technique is a Multilevel Thresholding (MT) method based on the phenomenon of Electromagnetism and it segments the image into three tissues such as White Matter (WM), Gray Matter (GM), and CSF. The approach incorporates skull stripping and filtering using anisotropic diffusion filter in the preprocessing stage. This thresholding method uses the force of attraction-repulsion between the charged particles to increase the population. It is the combination of Electromagnetism-Like optimization algorithm with the Otsu and Kapur objective functions. The results obtained by using the proposed method are compared with the ground-truth images and have given best values for the measures sensitivity, specificity, and segmentation accuracy. The results using 10 MR brain images proved that the proposed method has accurately segmented the three brain tissues compared to the existing segmentation methods such as K-means, fuzzy C-means, OTSU MT, Particle Swarm Optimization (PSO), Bacterial Foraging Algorithm (BFA), Genetic Algorithm (GA), and Fuzzy Local Gaussian Mixture Model (FLGMM).

Multiplex Approach in Classification, Diagnosis, and Prognostication in Acute Myeloid Leukemia: An Experience from Tertiary Cancer Center in South India.

INTRODUCTION: Acute myeloid leukemia (AML) is a heterogeneous group of disorders classified as per FAB subtypes and more recently by WHO by underlying genetic abnormalities. AIMS AND OBJECTIVES: This study aims to analyze the morphology, immunophenotype, cytogenetic and molecular abnormalities in around 200 patients of AML diagnosed over a period of 7 years at our institute and to determine relative frequency of various subtypes (based on FAB and WHO classification). An attempt to characterize the associations between hematological parameters, immunophenotype and these subtypes was also made. MATERIALS AND METHODS: All cases diagnosed as AML on morphology, cytochemistry and/or immunophenotyping and tested for recurrent genetic abnormalities during period of Jan 2008-July 2014 were included in the study. RESULTS: Age of presentation was younger in our AML patients as compared to western literature. Amongst FAB and WHO subtypes, M2 and t (15;17) PML-RARA were the most common groups respectively. As expected, CD33, CD13, were the most commonly expressed markers followed by HLA-DR, CD117, CD34 and CD14. Aberrant expression was seen in 62(41.6%) cases, most common was CD7 (15.4%), followed by CD56 (14.8%), CD19 (6.7%) and CD2 (4.7%). Significant associations between immunophenotypic markers and FAB subtypes as well as WHO subtypes were established. CONCLUSION: This is a hospital based study, giving a detailed account of frequencies of AML subtypes, hematological parameters and immunophenotypic markers in AML patients at our institute. Being a large and one of its kind study to establish significant associations between various haematological and immunophenotypic parameters with respective AML subtypes and genetic abnormalities, it might prove to be very useful in Indian setup where facilities for cytogenetic analysis are not available in many laboratories.

Surgical Management of Oro-Antral Communications Using Resorbable GTR Membrane and FDMB Sandwich Technique: A Clinical Study.

The paper describes a new technique for closure of the oro-antral communication, in which both hard (bone) and soft tissue closure was achieved. The technique uses a Guided Tissue Regeeration (GTR) membrane and Freez Dried Mineralized Bone (FDMB) allograft for closure of the defect. Aim of the study was to assess the advantages of the surgical management of oro-antral communications using resorbable GTR membrane and FDMB sandwich technique. A total 10 patients were selected in whom dental extractions were complicated by formation of oro-antral communication (OAC). The resorbable guided tissue regeneration membrane (PERIOCOL-GTR) and freeze dried mineralized bone allograft material was used. Some cancellous granules of freeze dried bone allograft was sandwiched between sheaths of appropriately trimmed collagen membrane which was previously sutured together on three sides using 3/0 resorbable polyglycolic acid suture (vicryl). The fourth side was then adequately closed using the same suture after the bone graft had been inserted, thus creating a closed sandwich. The prepared sandwich was then tucked into the OAC in such a way that it formed a convexity towards the sinus and a concavity towards the alveolar bone. The rough surface of the sandwich is faced to the alveolar bone and additional bone graft is filled into this concavity. Suturing done without tension. Post-operative orthopantomogram was taken to radiologically quantify the amount of bone grafting/augmentation and closure of oro-antral fistula. There was an average of 11.84 mm bone formation after 6 months, the average width preserved and obtained was 6.9 mm. By the end of 4 months there was evidence of bone formation in 7 subjects and in three subjects bony trabeculae formed was almost similar to the adjacent bone. By the end of 6 months follow-up of 7 subjects showed trabeculae indistinguishable from the adjacent bone. The study was done in 10 patients with a follow-up period of 6 months and found to be excellent in the formation of new bone. The technique is simple and excellent for closure of the oro-antral communications especially when subsequent placement of end osseous implant is considered without the need of donor site surgery for bone grafting.

CALLA negative precursor B lymphoblastic leukemia with MLL gene translocation and an unusual FISH signal pattern.

Rearrangements of the mixed lineage leukemia (MLL) gene at 11q23 commonly occur in infants with CALLA negative B lymphoblastic leukemia (B-ALL). Most often, these are detected by conventional karyotyping; however, fluorescent in-situ hybridization (FISH) with the help of a dual-color break-apart probe is used to identify cryptic translocations. When there is an MLL gene translocation, the usual FISH signal pattern is 1 red-1 green-1 yellow fusion signal pattern. We present a case of an infant with CALLA negative precursor B-ALL with a characteristic translocation t(4;11) (q21;q23), however, with an unusual MLL FISH signal pattern.

Periostitis ossificans (Garrè's osteomyelitis) radiographic study of two cases.

BACKGROUND: Periostitis Ossificans (PO) is a non-suppurative type of Osteomyelitis, commonly occurring in children and young adults, in mandible. The most common cause for PO is periapical infection of mandibular first molar. Radiographically PO is characterized by the presence of lamellae of newly formed periosteal bone outside the cortex, giving the characteristic appearance of "onion skin". CASE REPORTS: Two male children 11 years of age reported to the Department of Oral Medicine with a painless and persistent bony hard swelling in the mandible, with a short duration (Figs 1, 5). Both the patients had grossly decayed mandibular permanent first molar tooth with periapical infection and buccal cortical plate expansion (Figs 2, 6). The radiographic study revealed different appearances, the Orthopantomograph of case I showed a single radiopaque lamella outside the lower cortical border, without altering original mandibular contour (Fig. 3) and in case II showed a newly formed bony enlargement on the outer aspect of the lower cortical border without altering the original mandibular contour (Fig. 7). Occlusal radiograph of both the patients showed two distinct radiopaque lamellae of periosteal bone outside the buccal cortex (Figs 4, 8). Kawai et al. classified PO of mandible into type I and type II, based on whether the original contour of mandible is preserved or not. Each type is further classified into two sub types (Table 1). In case I, the orthopantomographic appearance is characteristic of type I-1 (Fig. 3), but the appearance in occlusal radiograph is characteristic of type I-2 (Fig. 4). In case II, the appearances in both the radiographs are characteristic of type I-2 (Figs 7, 8). CONCLUSIONS: Apart from the typical onion skin appearance, PO shows various other radiographic appearances. The radiographic appearance of Periostitis Ossificans may reflect the duration, progression and the mode of healing of the disease process. The radiographic classification of PO depends on the type of radiographs taken for evaluation.