Enhancing antitumor response by efficiently generating large-scale TCR-T cells targeting a single epitope across multiple cancer antigens.

The need to contrive interventions to curb the rise in cancer incidence and mortality is critical for improving patients' prognoses. Adoptive cell therapy is challenged with quality large-scale production, heightening its production cost. Several cancer types have been associated with the expression of highly-immunogenic CTAG1 and CTAG2 antigens, which share common epitopes. Targeting two antigens on the same cancer could improve the antitumor response of TCR-T cells. In this study, we exploited an efficient way to generate large-fold quality TCR-T cells and also demonstrated that the common epitopes of CTAG1 and CTAG2 antigens provide an avenue for improved cancer-killing via dual-antigen-epitope targeting. Our study revealed that xeno/sera-free medium could expand TCR-T cells to over 500-fold, posing as a better replacement for FBS-supplemented media. Human AB serum was also shown to be a good alternative in the absence of xeno/sera-free media. Furthermore, TCR-T cells stimulated with beads-coated T-activator showed a better effector function than soluble T-activator stimulated TCR-T cells. Additionally, TCR-T cells that target multiple antigens in the same cancer yield better anticancer activity than those targeting a single antigen. This showed that targeting multiple antigens with a common epitope may enhance the antitumor response efficacy of T cell therapies.

NY-ESO-1-specific T cell receptor-engineered T cells and Tranilast, a TRPV2 antagonist bivalent treatment enhances the killing of esophageal cancer: a dual-targeted cancer therapeutic route.

BACKGROUND: Esophageal cancer (EC) is a global canker notorious for causing high mortality due to its relentless incidence rate, convoluted with unyielding recurrence and metastasis. However, these intricacies of EC are associated with an immoderate expression of NY-ESO-1 antigen, presenting a lifeline for adoptive T cell therapy. We hypothesized that naturally isolated higher-affinity T cell receptors (TCRs) that bind to NY-ESO-1 would allow T lymphocytes to target EC with a pronounced antitumor response efficacy. Also, targeting TRPV2, which is associated with tumorigenesis in EC, creates an avenue for dual-targeted therapy. We exploited the dual-targeting antitumor efficacy against EC. METHODS: We isolated antigen-specific TCRs (asTCRs) from a naive library constructed with TCRs obtained from enriched cytotoxic T lymphocytes. The robustness of our asTCRs and their TCR-T cell derivatives, Tranilast (TRPV2 inhibitor), and their bivalent treatment were evaluated with prospective cross-reactive human-peptide variants and tumor cells. RESULTS: Our study demonstrated that our naive unenhanced asTCRs and their TCR-Ts perpetuated their cognate HLA-A*02:01/NY-ESO-1(157-165) specificity, killing varying EC cells with higher cytotoxicity compared to the known affinity-enhanced TCR (TCRe) and its wild-type (TCR0) which targets the same NY-ESO-1 antigen. Furthermore, the TCR-Ts and Tranilast bivalent treatment showed superior EC killing compared to any of their monovalent treatments of either TCR-T or Tranilast. CONCLUSION: Our findings suggest that dual-targeted immunotherapy may have a superior antitumor effect. Our study presents a technique to evolve novel, robust, timely therapeutic strategies and interventions for EC and other malignancies.

Interaction between gut microbiota metabolites and dietary components in lipid metabolism and metabolic diseases.

Gut microbiota composition has caused perplexity in developing precision therapy to cure metabolic disorders. However, recent research has focused on using daily diet and natural bioactive compounds to correct gut microbiota dysbiosis and regulate host metabolism. Complex interactions between the gut microbiota and dietary compounds disrupt or integrate the gut barrier and lipid metabolism. In this review, we investigate the role of diet and bioactive natural compounds in gut microbiota dysbiosis and also the modulation of lipid metabolism by their metabolites. Recent studies have revealed that diet, natural compounds and phytochemicals impact significantly on lipid metabolism in animals and humans. These findings suggest that dietary components or natural bioactive compounds have a significant impact on microbial dysbiosis linked to metabolic diseases. The interaction between dietary components or natural bioactive compounds and gut microbiota metabolites can regulate lipid metabolism. Additionally, natural products can shape the gut microbiota and improve barrier integrity by interacting with gut metabolites and their precursors, even in unfavourable conditions, potentially contributing to the alignment of host physiology.

Maternal High Fat Diet and its expressions in the Heart and Liver in the Mice Embryogenesis.

BACKGROUND: The developmental biology for the nonalcoholic fatty liver disease and coronary heart disease are known but elaborative ideas of triglycerides phenomenon in the embryo-genesis of the liver and the heart are still not clear. OBJECTIVE: The aim of the study was to relate different triglycerides like LXRα, LPL, LDL R, PPARG-, and SREBP-1C expression in the high fat-fed mice with the normal-fed diet mice in the process of developmen-tal and embryo-genesis biology. METHODS: Tissue preparation was done by RIPA lysis. Different protein content was obtained via western blot for the 6 samples namely A.3 months embryo B.4 months embryo C.Birth day embryo D.3 days infant E. 2 weeks infant F. 4 weeks infant. Protein lysates from the heart tissues of the mice were obtained via ho-mogenization and centrifugation. Hematoxylin and Eosin staining (H and E) were done to see the fat droplets in the liver tissues at the different developmental stages. RESULT: LXRα,SREBP-1C expression in 3 months embryo and 4 months embryo is highly expressed in the high-fat diet. LDL-R in the high-fat diet mice is increased in 3 days infant heart but in 3 months and 4 months embryo it has low expression but from the 0th day to the 4 weeks the expression is in a decreasing trend. Similarly, LPL is highly expressed in 3 months embryo and 0th day(Birthday) and thus low expression indecreasing order until 4 weeks infant. Thus, these results collectively show that a maternal HF diet in-creases the expression of proteins such as LPL, and LDLr in the embryo phase and thus getting normal ex-pressions in the adult phase that facilitate Triglycerides (TAG) hydrolysis across the liver and the heart. Also, maternal high-fat diet increases the SREBP1c expression, leading to stimulation of LPL Expression. CONCLUSION: In summary, using a pregnant mice model, we found that a maternal high-fat diet increases fe-tal fat accumulation. Elevated placental LPL activity and expression of genes that facilitate placental lipid transport suggest that enhanced placental lipid transport may play a key role in maternal nutrition and obesi-ty-induced fetal fat accumulation.

Molecular mechanisms of resistance and treatment efficacy of clofazimine and bedaquiline against Mycobacterium tuberculosis.

Clofazimine (CFZ) and bedaquiline (BDQ) are currently used for the treatment of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) strains. In recent years, adding CFZ and BDQ to tuberculosis (TB) drug regimens against MDR Mtb strains has significantly improved treatment results, but these improvements are threatened by the emergence of MDR and extensively drug-resistant (XDR) Mtb strains. Recently, CFZ and BDQ have attracted much attention for their strong clinical efficacy, although very little is known about the mechanisms of action, drug susceptibility test (DST), resistance mechanisms, cross-resistance, and pharmacokinetics of these two drugs. In this current review, we provide recent updates on the mechanisms of action, DST, associated mutations with individual resistance and cross-resistance, clinical efficacy, and pharmacokinetics of CFZ and BDQ against Mtb strains. Presently, known mechanisms of resistance for CFZ and/or BDQ include mutations within the Rv0678, pepQ, Rv1979c, and atpE genes. The cross-resistance between CFZ and BDQ may reduce available MDR-/XDR-TB treatment options. The use of CFZ and BDQ for treatment in the setting of limited DST could allow further spread of drug resistance. The DST and resistance knowledge are urgently needed where CFZ and BDQ resistance do emerge. Therefore, an in-depth understanding of clinical efficacy, DST, cross-resistance, and pharmacokinetics for CFZ and BDQ against Mtb can provide new ideas for improving treatment outcomes, reducing mortality, preventing drug resistance, and TB transmission. Along with this, it will also help to develop rapid molecular diagnostic tools as well as novel therapeutic drugs for TB.

Overview on Thioredoxin-Interacting Protein (TXNIP): A Potential Target for Diabetes Intervention.

BACKGROUND: Diabetes mellitus (DM) is a common metabolic disorder characterized by a persistent increment of blood glucose. Type 2 DM is characterized by insulin resistance and ß-cell dysfunction. Thioredoxin-interacting protein (TXNIP) is among the factors that control the production and loss of pancreatic ß-cells. OBJECTIVE: Recent studies have shown that high glucose can significantly up-regulate the expression of the TXNIP. Overexpression of TXNIP in ß-cells not only induced apoptosis but also decreased the production of insulin. At the same time, TXNIP deficiency protected the apoptosis of ß-cells, leading to increased insulin production. Therefore, finding small molecules that can modulate TXNIP expression and downstream signalling pathways is essential. Thus, the inhibition of TXNIP has beneficial effects on the cardiovascular system and other tissues such as the heart and the kidney in DM. Therefore, DM treatment must target small TXNIP activity, inhibit expression, and promote endogenous cell mass and insulin production. CONCLUSION: This review briefly describes the effect mechanism, regulatory mechanism, and crystal structure of TXNIP. In addition, we highlight how TXNIP signalling networks contribute to diabetes and interact with drugs that inhibit the development often and its complexes. Finally, the current status and prospects of TXNIP targeted therapy are also discussed.

Prospects for controlling future pandemics of SARS in highlights of SARS-CoV-2.

Throughout human history infectious diseases have emerged to become global threats once in a while. Sometimes the previously established infections surfaced due to geographical extension or by increasing their transmissibility or pathogenicity while in other instances new infections have periodically emerged by transmitting from animals to humans. A proper strengthening of the existing health care system, disease surveillance, advancement in medical technology and healthy lifestyle is a must for controlling the future re-emergence of pandemics. Similarly, a deeper understanding of (1) key medical and social elements; (2) treatment and prevention options; (3) epidemic preparedness of the health care system; and (4) investing in ethno medicine research is necessary to prevent the future devastating pandemic emergencies.

Causal effects of dietary calcium, zinc and iron intakes on coronary artery disease in men: G-estimation and inverse probability of treatment weighting (IPTW) analyses.

BACKGROUND & AIMS: Dietary minerals have significant effects on the risk of cardiovascular disease. However, the results of previous studies were not uniform across different countries. The current study aims to determine the causal effects of dietary calcium, zinc, and iron intakes on coronary artery disease (CAD) among Nepalese men. METHODS: A matched case-control study was carried out at Shahid Gangalal National Heart Center. Dietary intakes of 466 male participants over the past 12 months were evaluated using a semi-quantitative customized food frequency questionnaire. G-estimation and inverse probability treatment weighting (IPTW) analyses were performed to determine the causal odds of CAD due to dietary calcium, zinc, and iron intakes. RESULTS: Daily dietary calcium, zinc, and iron intakes were categorized into two groups: less than versus more than the median value and less than versus equal or more than recommended daily allowance (RDA). In G-estimation, dietary calcium intake was inversely associated with CAD in both medians (OR: 91; 91%CI: 0.86, 95) and RDA categories (OR: 0.88: 95%CI: 0.84, 0.97). However, in IPTW analysis, only median calcium intake was significantly associated with CAD (OR: 7; 91%CI: 0.5, 98). We observed a significant inverse association of equal or more than RDA of dietary zinc intake with CAD (OR: 0.91: 95%CI: 0.87, 0.96 in G-estimation, OR: 0.73: 95%CI: 0.66, 0.82 in IPTW); however, more than median dietary zinc intake showed inverse but not significant association with CAD in both analyses. Dietary iron intake was inversely but not significantly associated with CAD in G-estimation in both groups. Nevertheless, in IPTW analysis, equal or more than RDA iron intake was significantly positively (OR: 1.4; 95%CI: 1.14, 1.73) related to CAD. CONCLUSIONS: A significant inverse association of dietary zinc intake above RDA indicates the potential protective effect of higher dietary zinc against CAD. However, causal odds of CAD are inconsistent across the median or RDA of calcium and iron intakes. Therefore, cohort and randomized clinical trial studies with a large sample size are recommended to substantiate these nutrients' causal link with CAD development in the Nepalese population.

Xanthine Oxidase and Transforming Growth Factor Beta-activated Kinase 1: Potential Targets for Gout Intervention.

BACKGROUND: Gout, inflammatory arthritis caused by the deposition of monosodium urate crystals into affected joints and other tissues, has become one of the major health problems of today's world. The main risk factor for gout is hyperuricemia, which may be caused by excessive or insufficient excretion of uric acid. The incidence is usually in the age group of 30- 50 years, commonly in males. In developed countries, the incidence of gout ranges from 1 to 4%. Despite effective treatments, there has been an increase in the number of cases over the past few decades. OBJECTIVE: In recent years, the development of targeted drugs in gout has made significant achievements. The global impact of gout continues to increase, and as a result, the focus of disease-modifying therapies remains elusive. In addition, the characterization of available instrumental compounds is urgently needed to explore the use of novel selective and key protein-ligand interactions for the effective treatment of gout. Xanthine oxidase (XO) is a key target in gout to consider the use of XO inhibitors in patients with mild to moderate condition, however, the costs are high, and no other direct progress has been made. Despite many XO inhibitors, a selective potent inhibitor for XO is limited. Likewise, in recent years, attention has been focused on different strategies for the discovery and development of new selectivity ligands against transforming growth factor beta- activated kinase 1 (TAK1), a potential therapeutic target for gout. Therefore, the insight on human XO structure and TAK1 provides a clue into protein-ligand interactions and provides the basis for molecular modeling and structure-based drug design. CONCLUSION: In this review, we briefly introduce the clinical characteristics, the development of crystal, inhibitors, and crystal structure of XO and TAK1 protein.

Overview of Protein Kinase B Enzyme: A Potential Target for Breast and Prostate Cancer.

Protein kinase B (AKT) PI3K / AKT / mTOR signaling pathways play a crucial role in modulating cell survival, proliferation, metastasis, metabolism, angiogenesis, and apoptosis. The AKT family consists of three isoforms: AKT1, AKT2, and AKT3. Moreover, it has high sequence homology in the kinase domain and has similar substrate specificity to other members of AGC protein kinase. Recent studies have shown that AKT signals disappear in some tumors. Overexpression and activation of AKT are not sufficient to induce the phenotype of malignant tumors. However, many studies have shown the importance of AKT in carcinogenesis including, breast and prostate cancers, second and third global cancer burden, respectively, in terms of incidence and death. Inhibition of AKT signaling may be beneficial in terms of therapeutic use and understanding of the function of AKT. To date, limited numbers of AKT inhibitors have been identified, and none are strongly selective for AKT isoforms. In this regard, we discussed the current insight of AKT inhibitors in drug development, protein structure, and mechanism as well as the role of AKT in the development of drug targets for breast cancer and prostate cancer.

Dietary nutrients of relative importance associated with coronary artery disease: Public health implication from random forest analysis.

Dietary nutrients have significant effects on the risk of cardiovascular diseases. However, the results were not uniform across different countries. The study aims to determine the relative importance of dietary nutrients associated with coronary artery disease (CAD) among the Nepalese population. A hospital-based matched case-control study was carried out at Shahid Gangalal National Heart Center in Nepal. In the present study, patients with more than seventy percent stenosis in any main coronary artery branch in angiography were defined as cases, while those presenting normal coronary angiography or negative for stressed exercise test were considered controls. Dietary intakes of 612 respondents over the past 12 months were evaluated using a semi-quantitative customized food frequency questionnaire. In conditional regression model, the daily average dietary intake of ß-carotene (OR: 0.54; 95%CI: 0.34, 0.87), and vitamin C (OR: 0.96; 95%CI: 0.93, 0.99) were inversely, whereas dietary carbohydrate (OR: 1.16; 95%CI: 1.1, 1.24), total fat/oil (OR: 1.47; 95%CI: 1.27, 1.69), saturated fatty acid (SFA) (OR: 1.2; 95%CI: 1.11, 1.3), cholesterol (OR: 1.01; 95%CI: 1.001, 1.014), and iron intakes (OR: 1.11; 95%CI: 1.03, 1.19) were positively linked with CAD. Moreover, in random forest analysis, the daily average dietary intakes of SFA, vitamin A, total fat/oil, ß-carotene, and cholesterol were among the top five nutrients (out of 12 nutrients variables) of relative importance associated with CAD. The nutrients of relative importance imply a reasonable preventive measure in public health nutrients specific intervention to prevent CAD in a resource-poor country like Nepal. The findings are at best suggestive of a possible relationship between these nutrients and the development of CAD, but prospective cohort studies and randomized control trials will need to be performed in the Nepalese population.

Serum and glucocorticoid inducible protein kinases (SGKs): a potential target for cancer intervention.

The serum and glucocorticoid inducible protein kinase (SGK) family members share similar structure, substrate specificity and function with AKT and signal downstream of the phosphatidylinositol 3-kinase (PI3K) signalling pathway. They regulate a range of fundamental cellular processes such as cell proliferation and survival, thereby playing an important role in cancer development. This perspective intends to give an overview on the involvement of SGKs (particularly SGK3) in cancer progression, and compares the actions of SGK3 and AKT in cell cycle regulation, oncogenic signalling, and the potential as a therapeutic target for cancer.

Identification, structure modification, and characterization of potential small-molecule SGK3 inhibitors with novel scaffolds.

The serum and glucocorticoid-regulated kinase (SGK) family has been implicated in the regulation of many cellular processes downstream of the PI3K pathway. It plays a crucial role in PI3K-mediated tumorigenesis, making it a potential therapeutic target for cancer. SGK family consists of three isoforms (SGK1, SGK2, and SGK3), which have high sequence homology in the kinase domain and similar substrate specificity with the AKT family. In order to identify novel compounds capable of inhibiting SGK3 activity, a high-throughput screening campaign against 50,400 small molecules was conducted using a fluorescence-based kinase assay that has a Z' factor above 0.5. It identified 15 hits (including nitrogen-containing aromatic, flavone, hydrazone, and naphthalene derivatives) with IC50 values in the low micromolar to sub-micromolar range. Four compounds with a similar scaffold (i.e., a hydrazone core) were selected for structural modification and 18 derivatives were synthesized. Molecular modeling was then used to investigate the structure-activity relationship (SAR) and potential protein-ligand interactions. As a result, a series of SGK inhibitors that are active against both SGK1 and SGK3 were developed and important functional groups that control their inhibitory activity identified.

Telementoring in endocrine surgery: preliminary Indian experience.

Telemedicine is starting to play an important role in the health field in India. In this case report we describe the successful use of telementoring to remove a parathyroid tumor in a patient with residual hyperparathyroidism after two previous unsuccessful attempts in tumor excision. A 21-yr-old patient crippled with advanced hyperparathyroidism was taken up for third-time exploration at Amrita Institute of Medical Sciences (AIMS), Kochi, with guidance from the Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, using telemedicine technology. These two centers are located 2,500 km apart, and telementoring from the more experienced endocrine surgeons at SGPGIMS resulted in successful tumor localization and removal. For this session both the institutions were provided with a dedicated 512 Kbps very small aperture terminal (VSAT) link and two-way video-audio connectivity. Even though two previous explorations were unsuccessful, with the help of telemedicine technology the same surgeon was successful in locating and removing the tumor. The video and audio quality was of good enough quality for the expert at SGPGIMS to guide the team at AIMS satisfactorily. The patient benefited since he did not have to travel to a far-off specialized center for surgery. This case report testifies to the usefulness of telemedicine in the field of surgery, especially in developing countries, which have few medical experts in certain specialized areas.