MUC4 Based Immunotherapy for Pancreatic Cancer

Pancreatic Cancer (PC) is a lethal disease claiming approximately 45000 lives in the US in 2018, and it establishes an elaborate immunosuppressive tumor microenvironment that aids in disease pathogenesis. Immunotherapy has emerged as a strategy to target tumor cells by reprogramming patient’s immune system. Challenges present in PC immunotherapy are: i) identifying a tumor-associated antigen that could be targeted, ii) identifying adjuvants that could efficiently deliver antigens, iii) eliciting robust anti-tumor responses and iv) overcoming peripheral tolerance and immunosuppression elicited by the tumor. Firstly, we detected circulating autoantibodies to MUC4 present in PC patients and observed that IgM autoantibodies to MUC4 peptides significantly correlate with overall PC patient survival, thus suggesting that MUC4 could potentially be targeted for PC immunotherapy. Our group is the first to successfully purify recombinant MUC4β protein and characterize its immunogenic activity. We addressed the challenge of protein delivery by encapsulating MUC4β in novel polyanhydride nanoparticles (MUC4 nanovaccine). In the second part of the dissertation, we characterized MUC4 nanovaccine in both in vitro and in vivo system. Our studies showed that MUC4 nanovaccine could robustly activate dendritic cells (DCs) and induce secretion of Th1 cytokines in vitro. High levels of Th1 IgG2b anti-MUC4β antibodies were detected in MUC4 nanovaccine-immunized mice. As described in the third part of the dissertation, we observed that ex vivo T-cells activated by MUC4 nanovaccine-pulsed DCs showed enhanced cytotoxic killing of miniMUC4 tumor cells, when compared to soluble MUC4β mixed with empty nanoparticles (MUC4+NP). We validated our data in an in vivo subcutaneous PC tumor mouse model, and observed enhanced immune cells infiltration and corresponding levels of necrosis in miniMUC4 tumors corroborated with low tumor volume of miniMUC4 tumor (in comparison to contralateral vector control tumor) in MUC4-immunized mice. Furthermore, the presence of PD-L1 surface expression on miniMUC4 tumor cells indicated active immunosuppression lodged by tumor cells in response to IFNγ-secreting infiltrating cytotoxic T-cells. Taken together, studies in this dissertation demonstrate that MUC4 nanovaccine could serve as a potential strategy for PC immunotherapy

PSYCHOSOCIAL FACTORS INFLUENCING DEPRESSIVE SYMPTOMS AMONG OLDER ADULTS FROM NORTHERN INDIA

This is a pre-copyedited, author-produced version of an article accepted for publication in Innovation in Aging following peer review. The version of record Banerjee, K., & Baker, T. A. (2019). PSYCHOSOCIAL FACTORS INFLUENCING DEPRESSIVE SYMPTOMS AMONG OLDER ADULTS FROM NORTHERN INDIA. Innovation in Aging, 3(Suppl 1), S313. https://doi.org/10.1093/geroni/igz038.1146 is available online at: https://doi.org/10.1093/geroni/igz038.1146. This work is licensed under a Creative Commons Attribution 4.0 International License.Global data show a significant increase in the number of adults 65+ years of age in India. Despite this increase, there is a dearth of available resources to adequately service their mental health needs. Data indicate that residents in Northern India, in particular, report poorer mental health outcomes than those in the South. The prevalence and impact of neuropsychiatric disorders and depression remain particularly significant, but largely unexplored. The aim of this study was to examine possible psychosocial and health factors affecting depressive symptoms in North India. Data were taken from the Longitudinal Ageing Study in India (LASI). Participants included adults aged 45 years and above (n=792), from the states of Rajasthan and Punjab. A multiple linear regression model was calculated to determine the influence of identified demographic and psychosocial factors (e.g., financial and social support, life satisfaction) on depressive symptoms. Data show that low life satisfaction (β= -0.19,p<0.001), poorer self-reported health (β=0.15,p<0.01), and being a care provider (β= -0.12,p<0.01) were significant predictors of depressive symptoms. These results indicate an increased need for care-giver mental health support along with policy aimed at awareness about caregiver burnout, health care access, and economic instrumental support services. A magnified view of the impact of life satisfaction on depression will be of immense value for understanding the unique needs and challenges of working with this population

Golgi localization and dynamics of hyaluronan binding protein 1 (HABP1/p32/C1QBP) during the cell cycle

Hyaluronan binding protein 1 (HABP1) is a negatively charged multifunctional mammalian protein with a unique structural fold. Despite the fact that HABP1 possesses mitochondrial localization signal, it has also been localized to other cellular compartments. Using indirect immunofluorescence, we examined the sub-cellular localization of HABP1 and its dynamics during mitosis. We wanted to determine whether it distributes in any distinctive manner after mitotic nuclear envelope disassembly or is dispersed randomly throughout the cell. Our results reveal the golgi localization of HABP1 and demonstrate its complete dispersion throughout the cell during mitosis. This distinctive distribution pattern of HABP1 during mitosis resembles its ligand hyaluronan, suggesting that in concert with each other the two molecules play critical roles in this dynamic process

LIPID PEROXIDATION AND ANTIOXIDANT STATUS: A COMPARISON BETWEEN MIDDLE AGED AND ELDERLY POPULATION

Objective : In recent years a large body of experimental research indicates that oxidative stress and antioxidant defenses are related to processes  such as aging and several diseases.Vitamins and antioxidant enzymes have a fundamental role in defending organisms from oxidative stress.The objective of present study was to compare age related oxidative stress in middle aged and older subjects. Design: The present hospital based nonintervention cross sectional study was designed to evaluate age related oxidative stress and its impact in 40 middle aged (35-55y) and 40 older subjects (60y)  by measuring Thiobarbituric Acid Reactive substances (TBARs) for lipid  peroxidation vis-à-vis antioxidant defense with estimatimation of plasma superoxide dismutase (SOD) and serum alpha-tocopherol concentration . Intervention: none Results: On the basis of the data obtained from our study it was evident that concentration of Thiobarbituric Acid reactive substances were significantly higher in older subjects, whereas enzymatic antioxidant serum superoxide dismutase and free radical scavenging alpha-tocopherol (vitamin E) were significantly lower in elderly age group than middle aged subjects. Conclusion :The present study provides some important information regarding age related oxidative stress in elderly population compared to middle aged subjects. Lipid peroxidation which refers to oxidative degradation of lipids and acts as an oxidative  stressor in the organism is significantly higher in elderly subjects but in so far as antioxidants are concerned we observe that they are significantly lower in elderly than middle aged subjects. Keywords: aging, antioxidant ,lipid peroxidation, oxidative stres

EFFECT OF SUB MAXIMAL EXERCISE ON ENDOTHELIUM-DERIVED NITRIC OXIDE CONCENTRATIONS IN HEALTHY YOUNG SUBJECTS.

Objective: To determine any possible contribution of 10 minutes single session sub maximal exercise on Nitric oxide level in healthy young population.Design: A descriptive observational study on forty healthy volunteers (20 male &amp; 20 female) of 20-30 years designed to evaluate the level of nitric oxide after 10 minutes cycling.Intervention:  Young populations are allowed to exercise in a bicycle ergo meter for 10 minutes regular exercise under protocol YMCA Sub maximal Cycle Ergo meter Testing against a constant workload.  Main outcome measures: Serum Creatine Phosphokinase  and  Nitrate-Nitrite ratio (Surrogate marker of nitric oxide)  measured. Continuous heart rate monitoring is done from ECG system. Vo2 max calculated and energy expenditure for physical activity obtained from prediction equation after adjusting age, gender &amp; body mass.Results: Comparison of Activity Energy Expenditure (AEE) before and after exercise done, (p value&lt;0.0001)(n = 40).  Significant amount of  work done in this exercise. Increase in the serum creatine phosphokinase level (p value&lt;0.0001). Serum Nitrate-Nitrite ratio (nitric oxide level) showed increase (p value 0.1113) in post exercise level.Conclusion: As far as energy expenditure concerned, significant muscular activity in both male &amp; female showed insignificant endothelium derived Nitric oxide production. On the basis of the data obtained it is evident that in a single session sub maximal exercise beneficial effect of vasodilator Nitric oxide was not observed in studied  young population.Keywords: sub maximal exercise, activity energy expenditure, nitrate-nitrite ratio

Plasmodium falciparum uses gC1qR/HABP1/p32 as a receptor to bind to vascular endothelium and for platelet-mediated clumping

The ability of Plasmodium falciparum-infected red blood cells (IRBCs) to bind to vascular endothelium, thus enabling sequestration in vital host organs, is an important pathogenic mechanism in malaria. Adhesion of P. falciparum IRBCs to platelets, which results in the formation of IRBC clumps, is another cytoadherence phenomenon that is associated with severe disease. Here, we have used in vitro cytoadherence assays to demonstrate, to our knowledge for the first time, that P. falciparum IRBCs use the 32-&lt;Da human protein gC1qR/HABP1/p32 as a receptor to bind to human brain microvascular endothelial cells. In addition, we show that P. falciparum IRBCs can also bind to gC1qR/HABP1/p32 on platelets to form clumps. Our study has thus identified a novel host receptor that is used for both adhesion to vascular endothelium and platelet-mediated clumping. Given the association of adhesion to vascular endothelium and platelet-mediated clumping with severe disease, adhesion to gC1qR/HABP1/p32 by P. falciparum IRBCs may play an important role in malaria pathogenesis

Chiral synthesis of optically active S(+)-2,6,7,7a-tetrahydro-1β-hydroxy-4-formyl-7aβ-methylindene

The chiral aldol cylization of the prochiral triketone 3 using l-valine afforded the optically active compound 4 in high chemical and optical yield. The configuration and optical purity of (+)4 was determined by ORD, chemical resolution and NMR chiral lsr studies. The title compound (+)7 was prepared from (+)4 following our earlier reported procedure

日本イエズス会版『サルヴァトル・ムンヂ』ポルトガル語全訳注 : 第一誡「御一体のデウスを敬ひ,貴み奉るべし」に関わる10の尋問

A new method for the preparation of the synthon (±)-2,6,7,7a-tetrahydro-1β-hydroxy-4-formyl-7aβ-methylindene (1,a) for the total synthesis of steroids in both (±) and (+) forms, starting from the known β-ketoester, (±)-methyl 1β-t-butoxy-5,6,7,7a-tetrahydro-7aβ-methyl-5-keto-4-indancarboxylate (2,a) has been described. An alternative route to (1,a) has been investigated. Although the compound, (±)-1β-hydroxy-5,6,7,7a-tetrahydro-7aβ-methyl-5-keto-4-methoxymethylindan (2,b) could not be prepared, interesting pathways leading to two unexpected products, (±)-5,6,7,7a-tetrahydro-4,7a-dimethyl-5H-indene-1,5-dione and (±)-2,6-diketo-3-methyltricyclo-(5,2,1,0)decan-8-ol (3 and 4), were encountered during an attempted annelation reaction of the ketone, N-diethylamino-5-methoxypentan-3-one (6), with 2-methylcyclopentan-1,3-dione (5). Trapping of the intermediate, (±)-3a,4,5,6,7,7a-hexahydro-3a-hydroxy-4-methylene-7a-methylindene-1,5-dione (7), through the formation of the adduct, (±)-3a,4,5,6,7,7a-hexahydro-3a-hydroxy-4-(1', 3'-diketo-2'-methylcyclopentano-2'-methylene)-7a-methylindene-1,5-dione (8), established the mechanism of the formation of the products (3 and 4)

Investigations towards the synthesis of a CD-steroid intermediate

The development of a new synthesis of 2,6,7,7a-tetrahydro-lβ-hydroxy-4-formyl-7a-methylindene was undertaken involving the preparation of 2,6,7,7a-tetra-hydro-1β-hydroxy-4-methoxymethyl-7a-methylindene because of the erratic yield in the last oxidation step of the reported synthesis of the former compound. Although various attempts to prepare the latter were not successful, interesting rearrangement products, the dienone, 5,6,7,7a-tetrahydro-4,7a-dimethyl-5H-indene-1,5-dione and the tricyclic keto alcohol, 2,6-diketo-3-methyltricyclo(5,2,1,0)decan-8-ol, were obtained, the structures of which have been proved by spectral data. Mechanisms for the formation of these products have been proposed