A computational model of current control mechanism for long-term potentiation (LTP) in human episodic memory based on gene-gene interaction.

The establishment of long-term potentiation (LTP) is a prime process for the formation of episodic memory. During the establishment of LTP, activations of various components are required in the signaling cascade of the LTP pathway. Past efforts to determine the activation of components relied extensively on the cellular or molecular level. In this paper, we have proposed a computational model based on gene-level cascading and interaction in LTP signaling for the establishment and control of current signals for achieving the desired level of activation in the formation of episodic memory. This paper also introduces a model for a generalized signaling pathway in episodic memory. A back-propagation feedback mechanism is used for updating the interaction levels in the signaling cascade starting from the last stage and ending at the start stage of the signaling cascade. Simulation of the proposed model has been performed for the LTP signaling pathway in the context of human episodic memory. We found through simulation that the qualifying genes correction factors of all stages are updated to their maximum limit. The article explains the signaling pathway for episodic memory and proves its effectiveness through simulation results.

Tacrolimus induces remission in refractory and relapsing lupus nephritis by decreasing P-glycoprotein expression and function on peripheral blood lymphocytes.

P-glycoprotein (P-gp)-mediated efflux of corticosteroids (CS) may contribute to treatment unresponsiveness in Lupus Nephritis (LN) patients. Tacrolimus is a P-gp inhibitor and hence, may overcome this resistance. We aimed to study the response to tacrolimus, along with the expression and function of P-gp on peripheral blood lymphocytes (PBL) in patients with refractory and relapsing proliferative Lupus Nephritis. We enrolled 12 refractory/relapsing LN patients and treated them with corticosteroids and tacrolimus for 6 months. Expression and function of P-gp on PBL was measured by flow cytometry (as relative fluorescence index, RFI and Rhodamine dye efflux assay) before and 3 months after tacrolimus therapy. Renal response was assessed according to ACR response criteria after 3 and 6 months of tacrolimus therapy. 8 out of 12 refractory/relapsing LN patients achieved renal response (5 partial response, PR and 3 complete responses, CR) as early as 3 months, and 11 patients achieved renal response (7 PR and 4 CR) at 6 months from start of tacrolimus therapy. Proteinuria decreased from median urine protein creatinine ratio (UPCR) of 2.80 (2.00-3.40) at baseline to 1.20 (0.66-1.73) at 3 months (p < 0.001) and to 0.80 (0.19-1.30) at 6 months (p < 0.01). There was significant decrease in P-gp expression [RFI, 3.33 (2.87-4.97) vs 2.03 (1.25-3.86), p < 0.05) and P-gp function (RFI, 55.7 (29.7-84.1) vs 26.8 (16.1-37.0), p < 0.01) after 3 months of tacrolimus therapy. Tacrolimus achieves renal response in refractory/relapsing proliferative LN patients which may be partly related to overcoming P-glycoprotein mediated treatment unresponsiveness.

Vaccine composition formulated with a novel TLR7-dependent adjuvant induces high and broad protection against Staphylococcus aureus.

Both active and passive immunization strategies against Staphylococcus aureus have thus far failed to show efficacy in humans. With the attempt to develop an effective S. aureus vaccine, we selected five conserved antigens known to have different roles in S. aureus pathogenesis. They include the secreted factors α-hemolysin (Hla), ess extracellular A (EsxA), and ess extracellular B (EsxB) and the two surface proteins ferric hydroxamate uptake D2 and conserved staphylococcal antigen 1A. The combined vaccine antigens formulated with aluminum hydroxide induced antibodies with opsonophagocytic and functional activities and provided consistent protection in four mouse models when challenged with a panel of epidemiologically relevant S. aureus strains. The importance of antibodies in protection was demonstrated by passive transfer experiments. Furthermore, when formulated with a toll-like receptor 7-dependent (TLR7) agonist recently designed and developed in our laboratories (SMIP.7-10) adsorbed to alum, the five antigens provided close to 100% protection against four different staphylococcal strains. The new formulation induced not only high antibody titers but also a Th1 skewed immune response as judged by antibody isotype and cytokine profiles. In addition, low frequencies of IL-17-secreting T cells were also observed. Altogether, our data demonstrate that the rational selection of mixtures of conserved antigens combined with Th1/Th17 adjuvants can lead to promising vaccine formulations against S. aureus.

Correlation of Neutrophil CD64 with Clinical Profile and Outcome of Sepsis Patients during Intensive Care Unit Stay.

INTRODUCTION: Neutrophil CD64 (nCD64) has been found to identify sepsis from nonseptic patients. It is also reported to be a predictor of survival and severity of sepsis. The goal of this study was to correlate serial nCD64 with Intensive Care Unit (ICU) outcome and severity of sepsis. MATERIALS AND METHODS: A prospective observational study was conducted in 12-bedded critical care unit of a tertiary care center. Adult patients with sepsis were included in this study. Demographics, illness severity scores, clinical parameters, laboratory data, and 28-day outcome were recorded. Serial nCD64 analysis was done (on days 0, 4, and 8) in consecutive patients. RESULTS: Fifty-one consecutive patients were included in the study. Median Acute Physiology and Chronic Health Evaluation II was 16 (12-20) and mean Sequential Organ Failure Assessment was 9 (8-10). Compared to survivors, nonsurvivors had higher nCD64 on day 8 (P = 0.001). nCD64 was higher in the septic shock group compared to sepsis group on days 0 and 8 (P < 0.05). Survivors showed improving trend of nCD64 over time while nonsurvivors did not. This trend was similar in the presence or absence of septic shock. nCD64 count was a good predictor of the septic shock on day 0 (area under the curve [AUC] = 0.747, P = 0.010) and moderate predictor at day 8 (AUC = 0.679, P = 0.028). CONCLUSION: Monitoring serial nCD64 during ICU stay may be helpful in determining the clinical course of septic patients.

Protectome analysis: a new selective bioinformatics tool for bacterial vaccine candidate discovery.

New generation vaccines are in demand to include only the key antigens sufficient to confer protective immunity among the plethora of pathogen molecules. In the last decade, large-scale genomics-based technologies have emerged. Among them, the Reverse Vaccinology approach was successfully applied to the development of an innovative vaccine against Neisseria meningitidis serogroup B, now available on the market with the commercial name BEXSERO® (Novartis Vaccines). The limiting step of such approaches is the number of antigens to be tested in in vivo models. Several laboratories have been trying to refine the original approach in order to get to the identification of the relevant antigens straight from the genome. Here we report a new bioinformatics tool that moves a first step in this direction. The tool has been developed by identifying structural/functional features recurring in known bacterial protective antigens, the so called "Protectome space," and using such "protective signatures" for protective antigen discovery. In particular, we applied this new approach to Staphylococcus aureus and Group B Streptococcus and we show that not only already known protective antigens were re-discovered, but also two new protective antigens were identified.

Structural and functional characterization of the Staphylococcus aureus virulence factor and vaccine candidate FhuD2.

Staphylococcus aureus is a human pathogen causing globally significant morbidity and mortality. The development of antibiotic resistance in S. aureus highlights the need for a preventive vaccine. In the present paper we explore the structure and function of FhuD2 (ferric-hydroxamate uptake D2), a staphylococcal surface lipoprotein mediating iron uptake during invasive infection, recently described as a promising vaccine candidate. Differential scanning fluorimetry and calorimetry studies revealed that FhuD2 is stabilized by hydroxamate siderophores. The FhuD2-ferrichrome interaction was of nanomolar affinity in surface plasmon resonance experiments and fully iron(III)-dependent. We determined the X-ray crystallographic structure of ligand-bound FhuD2 at 1.9 Å (1 Å=0.1 nm) resolution, revealing the bilobate fold of class III SBPs (solute-binding proteins). The ligand, ferrichrome, occupies a cleft between the FhuD2 N- and C-terminal lobes. Many FhuD2-siderophore interactions enable the specific recognition of ferrichrome. Biochemical data suggest that FhuD2 does not undergo significant conformational changes upon siderophore binding, supporting the hypothesis that the ligand-bound complex is essential for receptor engagement and uptake. Finally, immunizations with FhuD2 alone or FhuD2 formulated with hydroxamate siderophores were equally protective in a murine staphylococcal infection model, confirming the suitability and efficacy of apo-FhuD2 as a protective antigen, and suggesting that other class III SBPs might also be exploited as vaccine candidates.

Mammalian cell expressed recombinant trimeric spike protein is a potent vaccine antigen and confers near-complete protection against SARS-CoV-2 infection in Hamster.

Numerous vaccine candidates have emerged in the fight against SARS-CoV-2, yet the challenges posed by viral evolution and the evasion of vaccine-induced immunity persist. The development of broadly protective vaccines is essential in countering the threat posed by variants of concern (VoC) capable of eluding existing vaccine defenses. Among the diverse SARS-CoV-2 vaccine candidates, detailed characterization of those based on the expression of the entire spike protein in mammalian cells have been limited. In our study, we engineered a recombinant prefusion-stabilized trimeric spike protein antigen, IMT-CVAX, encoded by the IMT-C20 gene. This antigen was expressed utilizing a suspension mammalian cell line (CHO-S). The establishment of a stable cell line expressing IMT-CVAX involved the integration of the gene into the CHO genome, followed by the expression, purification, and characterization of the protein. To gauge the vaccine potential of adjuvanted IMT-CVAX, we conducted assessments in small animals. Analyses of blood collected from immunized animals included measurements of anti-spike IgG, SARS-CoV-2 neutralization, and responses from GC-B and Tfh cells. Furthermore, the protective efficacy of IMT-CVAX was evaluated using a Hamster challenge model. Our findings indicate that adjuvanted IMT-CVAX elicits an excellent immune response in both mice and hamsters. Notably, sera from animals immunized with IMT-CVAX effectively neutralize a diverse range of SARS-CoV-2 variants. Moreover, IMT-CVAX immunization conferred complete protection to hamsters against SARS-CoV-2 infection. In hACE2 transgenic mice, IMT-CVAX vaccination induced a robust response from GC-B and Tfh cells. Based on our preclinical model assessments, adjuvanted IMT-CVAX emerges as a highly efficacious vaccine candidate. This protein-subunit-based vaccine exhibits promise for clinical development, offering an affordable solution for both primary and heterologous immunization against SARS-CoV-2 variants.

Causes, outcome and prevention of abandonment in retinoblastoma in India.

BACKGROUND: The high-cure rates of 90% in retinoblastoma are not replicated in developing countries due to late presentation and poor compliance to treatment. The present study takes a closer look at causes of abandonment of therapy and effectiveness of counselling in reducing abandonment. PROCEDURE: A retrospective study of children with retinoblastoma registered at our centre from March 2008 through August 2011. RESULTS: Fifty (49.50%) of 101 children registered for treatment abandoned therapy. Abandonment rates were significantly higher in rural as compared to urban children (P = 0.02). There was no significant difference in rate of abandonment between stages or laterality of disease and other socio-demographic factors. Telephone calls were more effective than letters in tracing patients (31.2% vs. 2.4%). Major reasons cited behind abandonment were financial problems (30%) and unwillingness to enucleate (20%). Of the 12 children who returned and were retreated 6 (50%) died of progressive disease. Nineteen (73%) of those who did not return died at home. Abandonment rates steadily declined from 71.42% in 2008 to 16.66% in 2011 (P = 0.01) due to effective pre-abandonment counselling by a support team under the National Retinoblastoma Registry of India from 2009. CONCLUSIONS: Abandonment rates for children with retinoblastoma continue to be unacceptably high. Rural background, financial constraints and hesitancy to enucleate were important causes behind abandonment. Outcome of patients who abandoned treatment was uniformly dismal. Inclusion of support team and intensified initial counselling helped in improving compliance.

Staphylococcus aureus FhuD2 is involved in the early phase of staphylococcal dissemination and generates protective immunity in mice.

Iron availability plays an essential role in staphylococcal pathogenesis. We selected FhuD2, a lipoprotein involved in iron-hydroxamate uptake, as a novel vaccine candidate against Staphylococcus aureus. Unprecedented for staphylococcal lipoproteins, the protein was demonstrated to have a discrete, punctate localization on the bacterial surface. FhuD2 vaccination generated protective immunity against diverse clinical S. aureus isolates in murine infection models. Protection appeared to be associated with functional antibodies that were shown to mediate opsonophagocytosis, to be effective in passive transfer experiments, and to potentially block FhuD2-mediated siderophore uptake. Furthermore, the protein was found to be up-regulated in infected tissues and was required for staphylococcal dissemination and abscess formation. Herein we show that the staphylococcal iron-hydroxamate uptake system is important in invasive infection and functions as an efficacious vaccine target.

A critical analysis of health system in Nepal; Perspective's based on COVID-19 response.

Background: Nepal moved from a unitary government to a federal system of government in 2015 under its constitution. Nepal is a federal democratic republic governed by three levels of government: a federal, provincial, and local level. The response to COVID-19 in Nepal has been majorly led and controlled by the federal government. All three levels of government are performing their responsibilities; however, they face various challenges in responding to COVID-19. This study aimed to critically analyze Nepal's health system in the context of the COVID-19 response. Methods: We conducted semi-structured in-depth interviews by telephone among the policymakers, health workers, and stakeholders at the federal, provincial, and local levels (n = 41) between January to July 2021. The interviews were audio recorded, transcribed into English, and coded using inductive-deductive approaches. Results: COVID-19 considerably impacted routine health care, mainly maternity services and immunization. Inadequate financial resources, inadequate human resources, and the lack of ventilators, ICUs, and X-ray services were the significant challenges in tackling and managing COVID-19 effectively. Conclusion: The study found that all three levels of government perform their roles and responsibilities and effectively manage the pandemic. The federal and provincial governments focused more on the plans and policy development, while the local government demonstrated greater accountability in implementing those plans and policies. Therefore, all three tiers of government need to coordinate together for preparing and communicating information in times of emergency. Besides, it is imperative to empower local governments to maintain Nepal's federal health system.

Modern-like deep water circulation in Indian Ocean caused by Central American Seaway closure.

Global overturning circulation underwent significant changes in the late Miocene, driven by tectonic forcing, and impacted the global climate. Prevailing hypotheses related to the late Miocene deep water circulation (DWC) changes driven by the closure of the Central American Seaways (CAS) and its widespread impact remains untested due to the paucity of suitable records away from the CAS region. Here, we test the hypothesis of the large-scale circulation changes by providing a high-resolution record of DWC since the late Miocene (11.3 to ~2 Ma) from the north-western Indian Ocean. Our investigation reveals a progressive shift from Pacific-dominated DWC before ~9.0 Ma to the onset of a modern-like DWC system in the Indian Ocean comprising of Antarctic bottom water and northern component water during the Miocene-Pliocene transition (~6 Ma) caused by progressive shoaling of the CAS and suggests its widespread impact.

Prevalence of precursor lesions (P53 signature, SCOUT, STIL, STIC) in fallopian tubes resected for non-neoplastic causes.

Background: High-grade pelvic serous carcinoma is a common cause of death in women worldwide and India. Recent evidence has clearly implicated the changes in the mucosa of the fimbrial end of the fallopian tube in its pathogenesis. Objective: 1) To study histopathology features of surgically resected specimens of fallopian tubes received with non-neoplastic lesions of the uterus and ovary for the presence of any precursor lesions [secretory cell outgrowth (SCOUT), serous tubal intraepithelial lesion (STIL), p53 signatures, and serous tubal intraepithelial carcinoma (STIC)]. 2) To confirm the findings with immunohistochemistry. 3) To correlate the prevalence of precursor lesions with clinical parameters and benign lesions of the uterus and ovaries. Materials and Methods: Assessment of histopathological changes in 100 specimens of distal fallopian tubes was done using the sectioning and extensive examination of the fimbrial end (SEE-FIM) protocol. H and E stain followed by immunohistochemistry for Bcl-2, p53, and Ki-67. The statistical significance of the difference in the mean values of precursor areas was evaluated by an unpaired t-test. Results: Among 100 specimens taken on H and E, precursor lesions were suspected in 49% of the cases. SCOUT, suspicious for STIC, suspicious for STIC with areas of SCOUT, and unequivocal for STIC with areas of SCOUT were seen in 8%, 4%, 33%, and 4% of the cases, respectively. However, on IHC, SCOUTS were confirmed in 45% of the cases, p53 signature in 2%, STIL in 9%, and STIC in 4% of the cases. Conclusion: Sectioning and extensive examination of the fimbrial end (SEE-FIM) should be routinely done as it provides the opportunity to detect the early malignant changes. It may help in evolving the strategies for early detection, management, and reducing mortality.

Abrupt upwelling and CO2 outgassing episodes in the north-eastern Arabian Sea since mid-Holocene.

Identifying the causes and consequences of natural variations in ocean acidification and atmospheric CO2 due to complex earth processes has been a major challenge for climate scientists in the past few decades. Recent developments in the boron isotope (δ11B) based seawater pH and pCO2 (or pCO2sw) proxy have been pivotal in understanding the various oceanic processes involved in air-sea CO2 exchange. Here we present the first foraminifera-based δ11B record from the north-eastern Arabian Sea (NEAS) covering the mid-late Holocene (~ 8-1 ka). Our record suggests that the region was overall a moderate to strong CO2 sink during the last 7.7 kyr. The region behaved as a significant CO2 source during two short intervals around 5.5-4 ka and 2.8-2.5 ka. The decreased pH and increased CO2 outgassing during those abrupt episodes are associated with the increased upwelling in the area. The upwelled waters may have increased the nutrient content of the surface water through either increased supply or weaker export production. This new dataset from the coastal NEAS suggests that, as a potential result of changes in the strength of the El-Nino Southern Oscillation, the region experienced short episodes of high CO2 outgassing and pre-industrial ocean acidification comparable to or even greater than that experienced during the last ~ 200 years.

Prevalence of sleep apnea and lung function abnormalities in patients with acromegaly.

BACKGROUND: Sleep apnea (SA) is highly prevalent in acromegaly. Ethnicity influences the prevalence of SA in the general population. We studied the prevalence of SA and other respiratory comorbidities in North Indian patients with active acromegaly. DESIGN: Prospective, observational. MATERIALS AND METHODS: Consecutive adult patients with active acromegaly (n = 35, age 39.7 ± 13.2 years) and hypersomatotropism (nonsuppression of serum growth hormone after oral glucose and elevated serum insulin-like growth factor-1 [IGF-1]) were evaluated for respiratory symptoms, scoring for SA (Epworth Sleepiness Score [ESS] and STOP-BANG), pulmonary function tests (PFT), high-resolution computerized tomography (HRCT) of the thorax, polysomnography (PSG), and transthoracic echocardiography. Age- and sex-matched healthy individuals (n = 34) served as controls. RESULTS: Acromegaly subjects had dyspnea (34%), cough (37%), excessive daytime somnolence (43%), and fatigue (49%). Clinically significant ESS (>10) and STOP-BANG score (≥3) were present in 41% and 68.6% of subjects, respectively. PFT showed restrictive and obstructive patterns in 45.7% and 11.4% of acromegalics respectively; with higher total lung capacity (TLC), thoracic gas volume (TGV), and residual volume (RV). PSG revealed significantly higher SA events in acromegalics (central [acromegaly 24.63 ± 37.82 vs. control 3.21 ± 5.5], mixed [11 ± 19.46 vs. 3.50 ± 5.96], obstructive [34.86 ± 44.37 vs. 9.71 ± 10.48], and mean apnea-hypopnea index [AHI] [16.91 ± 18.0 vs. 7.86 ± 7.84]). Acromegalics had significantly higher prevalence of obstructive SA (71.4% [mild 31.4%, moderate 20%, severe 20%]) as compared to controls (38.2%). There was no correlation of AHI with serum IGF-1 and disease duration. CONCLUSION: Acromegaly subjects have a significantly higher prevalence of respiratory symptoms, SA, and abnormalities in PFT. Screening for respiratory comorbidities should be routinely recommended in all patients with acromegaly.

Evaluation of physicochemical and functional similarity of a new CHO derived anti-EGFR antibody P-mAb to its reference medicinal product.

Epidermal growth factor receptor (EGFR) is the primary target for the treatment of colorectal cancer, the third most diagnosed cancer worldwide. In recent years, regulatory changes have facilitated the approval of biosimilars aimed to bring more access to biologics to patients. However, it has also expended the requirements of non-clinical characterisation data using state-of-the-art and orthogonal methodologies to demonstrate similarity between proposed biologic and its reference medicinal product (RMP). The current study was aimed to develop a stable CHO-S cell line producing panitumumab biosimilar candidate, P-mAb, a fully human IgG2 anti-EGFR monoclonal antibody and assess its physicochemical and functional similarity with RMP, Vectibix. The single-cell clone from stably transfected CHO-S cell pools was used for the production of P-mAb. This was followed by purification and comparative physicochemical and biological characterisation of P-mAb and RMP using SDS-PAGE, LC/MS, MALDI, MS/MS, CD spectrometry, DSF, SAXS, ITF, MTT assay and binding affinity. SAXS and MST assays are being used for first time in biosimilarity analysis of therapeutic monoclonal antibody. The results of structural and functional analysis of anti-EGFR P-mAb, produced by stable CHO-S cell line revealed high similarity between P-mAb and RMP, vectibix, thus providing the scientific basis of its potential for therapeutic applications.

Bedside lung mechanics predict survival in hypoplastic lung disease.

Newer bedside pulmonary mechanics using conventional ventilators allow for CONTINUOUS serial determinations of tidal volume (V(T)). We sought to determine whether the degree of pulmonary hypoplasia could be measured using bedside pulmonary graphics and whether survival could be predicted in potential extracorporeal membrane oxygenation (ECMO) candidates. Data on all neonates considered for or treated with ECMO at our center between April 2000 and March 2005 were collected. The "maximal bedside V(T)" was measured daily at the peak pressure where "beaking" began with a peak end expiratory pressure of 4 cm H(2)O. Twenty-two patients were reviewed: eight ECMO plus fourteen similar patients in whom the threshold for ECMO intervention was not achieved. Independent of need for ECMO, any patient with V(T) of < 3 mL/kg or < 0.2 mL/cm length died ( N = 4). All other measures of lung capacity or blood gas assessments were less valuable than V(T) in predicting survival. We conclude that bedside V(T) can be easily measured and that values < 3 mL/kg or < 0.2 mL/cm length demarcate severe lung hypoplasia, which in our patient population was incompatible with survival. We speculate that bedside V(T) may assist in evaluating the utility of ECMO.

Translating Treg Therapy for Inflammatory Bowel Disease in Humanized Mice.

Crohn's disease and ulcerative colitis, two major forms of inflammatory bowel disease (IBD) in humans, afflicted in genetically predisposed individuals due to dysregulated immune response directed against constituents of gut flora. The defective immune responses mounted against the regulatory mechanisms amplify and maintain the IBD-induced mucosal inflammation. Therefore, restoring the balance between inflammatory and anti-inflammatory immunepathways in the gut may contribute to halting the IBD-associated tissue-damaging immune response. Phenotypic and functional characterization of various immune-suppressive T cells (regulatory T cells; Tregs) over the last decade has been used to optimize the procedures for in vitro expansion of these cells for developing therapeutic interventional strategies. In this paper, we review the mechanisms of action and functional importance of Tregs during the pathogenesis of IBD and modulating the disease induced inflammation as well as role of mouse models including humanized mice repopulated with the human immune system (HIS) to study the IBD. "Humanized" mouse models provide new tools to analyze human Treg ontogeny, immunobiology, and therapy and the role of Tregs in developing interventional strategies against IBD. Overall, humanized mouse models replicate the human conditions and prove a viable tool to study molecular functions of human Tregs to harness their therapeutic potential.

Serum CA 19-9 and CA 125 as a diagnostic marker in carcinoma of gallbladder.

BACKGROUND: Gall bladder carcinoma is endemic in North India along the Ganges belt. Most of the cases usually present in late stage when prognosis is poor. That mandates a necessity for proper screening in these areas for gall bladder lesions. Tumor markers CA 19-9 and CA 125 have been studied in various GI cancers and may also help in the screening, diagnosis and evaluation of gall bladder carcinoma. Aims: To assess serum CA19-9 and serum CA125 in patients with gall bladder lesions and find out a cut off value for diagnosis of carcinoma gallbladder. METHODS AND MATERIAL: Study included 118 cases, with female: male ratio of 4:1.Out of it, 91 (77 %) cases were benign and 27 (23 %) were malignant. Patients' sera was collected and analyzed for CA19-9 and CA 125 by CMIA method. RESULTS: The Mean (SD) value of CA19-9 for benign and malignant cases was found to be 12.86 (17.54) and 625.35(186.52) U/ml. For CA 125 it was found to be 17.98(13.69) and 239.63(73.72) U/ml respectively. The difference was statistically significant (P< 0.001). When Mean - 2SD value of malignant lesions were taken as cut off a value of CA 19-9 and CA 125 were found be 252.31 U/ml & 92.19U/ml respectively, found to be significant to suggest /diagnose a case of carcinoma gall bladder along with clinicoradiological findings. Taking these value as cut off Sensitivity & Specificity for CA 19-9 and CA 125 in detecting malignant cases were found to be 100% & 98.90% and 100% & 94.50% respectively. CONCLUSIONS: It is concluded that both serum CA 19-9 and serum CA 125 may act as a good adjunct for diagnosis of cases of carcinoma gallbladder along with imaging studies. However, changes in CA19-9 are more significant than CA 125.

Transdermal Immunization of Elastic Liposome-Laden Recombinant Chimeric Fusion Protein of P. falciparum (PfMSP-Fu24) Mounts Protective Immune Response.

Transdermal immunization exhibits poor immunogenic responses due to poor permeability of antigens through the skin. Elastic liposomes, the ultradeformable nanoscale lipid vesicles, overcome the permeability issues and prove a versatile nanocarrier for transcutaneous delivery of protein, peptide, and nucleic acid antigens. Elastic liposome-mediated subcutaneous delivery of chimeric fusion protein (PfMSP-Fu24) of Plasmodium falciparum exhibited improved immunogenic responses. Elastic liposomes-mediated immunization of PfMSP-Fu24 conferred immunity to the asexual blood-stage infection. Present study is an attempt to compare the protective immune response mounted by the PfMSP-Fu24 upon administered through transdermal and intramuscular routes. Humoral and cell-mediated immune (CMI) response elicited by topical and intramuscularly administered PfMSP-Fu24-laden elastic liposomes (EL-PfMSP-Fu24) were compared and normalized with the vehicle control. Sizeable immune responses were seen with the transcutaneously immunized EL-PfMSP-Fu24 and compared with those elicited with intramuscularly administered antigen. Our results show significant IgG isotype subclass (IgG1and IgG3) response of specific antibody levels as well as cell-mediated immunity (CMI) activating factor (IFN-γ), a crucial player in conferring resistance to blood-stage malaria in mice receiving EL-PfMSP-Fu24 through transdermal route as compared to the intramuscularly administered formulation. Heightened immune response obtained by the vaccination of EL-PfMSP-Fu24 was complemented by the quantification of the transcript (mRNA) levels cell-mediated (IFN-γ, IL-4), and regulatory immune response (IL-10) in the lymph nodes and spleen. Collectively, elastic liposomes prove their immune-adjuvant property as they evoke sizeable and perdurable immune response against PfMSP-Fu24 and justify its potential for the improved vaccine delivery to inducing both humoral and CM immune response.

Role of P-gp and HDAC2 and their Reciprocal Relationship in Uncontrolled Asthma.

INTRODUCTION: Resistance to corticosteroid is an essential mechanism in uncontrolled asthma as the corticosteroid is the mainstay of therapy. There are recent reports that epigenetic factors play a crucial role in the regulation of steroid action. Overexpression of P glycoprotein (P-gp) and reduced expression of Histone Deacetylase 2 (HDAC2) have been linked to regulating the steroid action in other diseases like Nephrotic Syndrome (NS). However, their role in uncontrolled asthma is still not clear and warrants further investigation. We evaluated the expression and activity of P-gp and HDAC2 in patients with Controlled Asthma (CA) and Uncontrolled Asthma (UA). METHODS: A total of 60 CA (mean age 51.72±17.02 years, male=38), and 38 of UA (mean age=53.55±11.90 years, male=17) were recruited. The level of control was defined according to (Global Initiative for Asthma) GINA 2016 criteria. The mRNA expression of HDAC2 and P-gp was studied by quantitative real-time Polymerase Chain Reaction (PCR), the functional activity of P-gp was evaluated by a commercially available kit via flow cytometry, and HDAC2 enzymatic activity was measured by commercially available kit by Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: P-gp expression and the functionality were significantly higher in the UA group of patients as compared to the CA group of patients (p<0.005), moreover HDAC2 expression was significantly reduced in UA patients as compared to CA patients, (p<0.005). The enzymatic activity of HDAC2 was also significantly reduced in UA patients as compared to CA patients (p<0.005). CONCLUSION: P-gp overexpression and HDAC2 under expression play an essential role in uncontrolled asthma by impairing the response to corticosteroid.