Anticancer potential of the S-heterocyclic ring containing drugs and its bioactivation to reactive metabolites.

Sulfur-containing heterocyclic derivatives have been disclosed for binding with a wide range of cancer-specific protein targets. Various interesting derivatives of sulfur-containing heterocyclics such as benzothiazole, thiazole, thiophene, thiazolidinedione, benzothiophene, and phenothiazine, etc have been shown to inhibit diverse signaling pathways implicated in cancer. Significant progress has also been made in molecular targeted therapy against specific enzymes such as kinase receptors due to potential binding interactions inside the ATP pocket. Sulfur-containing heterocyclic ring metal complexes i.e., benzothiazole, thiazole, thiophene, benzothiophene and phenothiazines are among the most promising active anticancer compounds. However, sulfur heteroaromatic rings, particularly thiophene, are of high structural alert due to their metabolism to reactive metabolites. The mere presence of a structural alert itself does not determine compound toxicity therefore, this review focuses on some specific findings that shed light on factors influencing the toxicity. In the current review, synthetic strategies of introducing the sulfur core ring in the synthesized derivatives are discussed with their structure-activity relationships to enhance our understanding of toxicity mechanisms and develop safer therapeutic options. The sulfur-containing marketed anticancer drugs included in this review direct the synthesis of novel compounds and will help in the development of potent, safer sulfur-based anticancer drugs in near future.

ECEL1 related distal arthrogryposis 5D in an Indian cohort-Report of recognizable musculoskeletal phenotype and a possible founder variant.

Distal arthrogryposis type 5D (DA5D) is clinically characterized by knee extension contractures, distal joint contractures, clubfoot, micrognathia, ptosis, and scoliosis. We report nine affected individuals from eight unrelated Indian families with DA5D. Although the overall musculoskeletal phenotype is not very distinct from other distal arthrogryposis, the presence of fixed knee extension contractures with or without scoliosis could be an important early pointer to DA5D. We also report a possible founder variant in ECEL1 along with four novel variants and further expand the genotypic spectrum of DA5D.

Causes and consequences of tipping points in river delta social-ecological systems.

The sustainability of social-ecological systems within river deltas globally is in question as rapid development and environmental change trigger "negative" or "positive" tipping points depending on actors' perspectives, e.g. regime shift from abundant sediment deposition to sediment shortage, agricultural sustainability to agricultural collapse or shift from rural to urban land use. Using a systematic review of the literature, we show how cascading effects across anthropogenic, ecological, and geophysical processes have triggered numerous tipping points in the governance, hydrological, and land-use management of the world's river deltas. Crossing tipping points had both positive and negative effects that generally enhanced economic development to the detriment of the environment. Assessment of deltas that featured prominently in the review revealed how outcomes of tipping points can inform the long-term trajectory of deltas towards sustainability or collapse. Management of key drivers at the delta scale can trigger positive tipping points to place social-ecological systems on a pathway towards sustainable development.

Sex Bias in Treatment Abandonment of Childhood Cancer in India.

OBJECTIVES: To explore the magnitude of sex bias and determinants of treatment abandonment (TA) in childhood cancer in India. METHODS: Individual data of children (0-19 y) registered between January 1, 2017 and July 31, 2022, was compiled. TA was defined as defaulting curative intent treatment ≥4 wk. Defaulting treatment irrespective of intent ≥4 wk was defined as Treatment Default (TD). The primary outcome was the proportion of male-to-female children with TA. Secondary outcomes included the proportion of male-to-female children with upfront TA, TA at relapse, TD, TD-p (TD only in the palliative setting). The impact of clinico-demographic factors on TA was analysed using multivariable regression and propensity score matching (PSM). RESULTS: Three thousand two hundred eighty four patients were analysed. The overall male-to-female ratio (MFR) was 2.08 (95% CI 1.94-2.24). Of 2906 patients treated with curative intent, 415 (14·3%) abandoned treatment. TA was higher in females than males (16·4% vs. 13·3%; p = 0·022) with adjusted MFR of 0·81 (0·66-0·98). The adjusted MFR of TA for treatment-naïve and relapsed patients and TD were 0·73 (0·59-0·91), 1·13 (0·65-1·96) and 0·84 (0·71-1·00) respectively. Sex independently predicted TA on multivariable analysis. However, on PSM analysis including socio-economic variables, lower maternal education predicted higher TA in children with cancer (10·1% vs. 6%, p = 0·015). CONCLUSIONS: Child sex predicted TA in childhood cancer in India with more females abandoning treatment. Maternal education is a more crucial factor predicting TA over child sex, when socio-economic factors were considered. Hence, policies promoting female education and gender equality may mitigate sex-based gaps in childhood cancer care.

Treatment outcomes in patients with Ewing sarcoma of the spine in a resource-challenged setting: 17-year experience from a single center in India.

Ewing sarcoma (ES) of the spine is a rare childhood cancer with sparse literature on treatment outcomes. We aimed to describe survival outcomes and prognostic factors in patients with spinal ES treated at a single institute in a resource-challenged setting. We conducted a retrospective analysis of patients with spinal ES registered at a tertiary care oncology center between 2003-2019. Clinical patient data was retrieved from hospital records. Cox regression analysis was used to identify the association of baseline clinical parameters with event free survival (EFS) and overall survival (OS). A cohort of 85 patients was analyzed including 38 (45%) patients with metastatic disease. The median age was 15 years with 73% being male. Local therapy was administered in 62 (72.9%) patients with surgery alone in 8 (9.4%), radiotherapy alone in 36 (42.4%) and both in 18 (21.2%) patients. A higher proportion of males received local therapy than females (80.3% versus 59.1%; p = 0.049). The median EFS and OS were 20.1 and 28.6 months, respectively. On univariable analysis, age ≤ 15 years, female sex, serum albumin ≤3.5 g/dL and hemoglobin ≤11 g/dL were associated with inferior EFS while younger age, female sex, hypoalbuminemia and metastatic disease were associated with inferior OS. On multivariable analysis, only hypoalbuminemia was predictive for inferior EFS (HR:2.41; p = 0.005) while hypoalbuminemia (HR:2.06;p = 0.033) and female sex (HR:1.83; p = 0.046) were associated with inferior OS. We concluded that hypoalbuminemia confers poor prognosis in ES spine. Survival outcomes are poorer in females treated in our setting, possibly due to prevailing sex-based biases.

Expanding the therapeutic arsenal against cancer: a computational investigation of hybrid xanthone derivatives as selective Topoisomerase 2α ATPase inhibitors.

The DNA topoisomerase II (topo II) enzyme plays an important role in the replication, recombination, and repair of DNA. Despite their widespread applications in cancer therapy, new, selective, and potent topo II inhibitors with better pharmaceutical profiles are needed to handle drug resistance and severe adverse effects. In this respect, an array of 36 new anticancer compounds was designed based on a Xanthone core tethered to multifunctional Pyridine-amines and Imidazole scaffold via alkyl chain linkers. An integrated in silico approach was used to understand the structural basis and mechanism of inhibition of the hybrid xanthone derivatives. In this study, we established an initial virtual screening workflow based on pharmacophore mapping, docking, and cancer target association to validate the target selection process. Next, a simulation-based docking was conducted along with pharmacokinetic analysis to filter out the five best compounds (7, 10, 25, 27, and 30) having binding energies within the range of -60.45 to -40.97 kcal/mol. The screened compounds were further subjected to molecular dynamics simulation for 200 ns followed by MM-GBSA and ligand properties analysis to assess the stability and binding affinity to hTOP2α. The top-ranking hits 3,7-bis(3-(2-aminopyridin-3-ylhydroxy)propoxy)-1-hydroxy-9H-xanthen-9-one (ligand 7) and 3,8-bis(3-(2-aminopyridin-3-ylhydroxy)propoxy)-1-hydroxy-9H-xanthen-9-one (ligand 25) were found to have no toxicity, optimum pharmacokinetic and, DFT properties and stable intermolecular interactions with the active site of hTopo IIα protein. In conclusion, further in vitro and in vivo experimental validation of the identified lead molecules is warranted for the discovery of new human Topoisomerase 2 alpha inhibitors.Communicated by Ramaswamy H. Sarma.

Faces of Fibrodysplasia Ossificans Progressiva: Lessons from a Clinical Masquerader.

OBJECTIVES: To evaluate the natural history and to highlight the possible masqueraders causing diagnostic delay and iatrogenic interventions in Fibrodysplasia Ossificans Progressiva (FOP). METHODS: Patient details with suspected FOP were retrieved from the patient registry from 2012 through 2021. Clinical records, X-rays, clinical photographs, and molecular testing results were captured. Follow-up was recorded where available. RESULTS: A total of 16 patients with a clinical diagnosis of FOP were found. Twelve patients with both clinical and molecular records were included in this study. The median age of onset and diagnosis was 1.5 y and 6.5 y respectively with a median diagnostic delay of 3.5 y. The disease course was progressive in ten patients. Seven out of twelve patients were subjected to invasive procedures due to misdiagnosis, which exacerbated their disease progression. CONCLUSIONS: Clinical suspicion followed by molecular testing is straightforward for a confirmed diagnosis of FOP. It is not only diagnostic, cost-effective, and saves time but also avoids unnecessary interventions in these patients.

Development of a Novel Red Clay-Based Drug Delivery Carrier to Improve the Therapeutic Efficacy of Acyclovir in the Treatment of Skin Cancer.

Acyclovir (ACV) is a promising candidate for drug repurposing because of its potential to provide an effective treatment for viral infections and non-viral diseases, such as cancer, for which limited treatment options exist. However, its poor physicochemical properties limit its application. This study aimed to formulate and evaluate an ACV-loaded red clay nanodrug delivery system exhibiting an effective cytotoxicity. The study focused on the preparation of a complex between ACV and red clay (RC) using sucrose stearate (SS) (nanocomplex F1) as an immediate-release drug-delivery system for melanoma treatment. The synthesized nanocomplex, which had nanosized dimensions, a negative zeta potential and the drug release of approximately 85% after 3 h, was found to be promising. Characterization techniques, including FT-IR, XRD and DSC-TGA, confirmed the effective encapsulation of ACV within the nanocomplex and its stability due to intercalation. Cytotoxicity experiments conducted on melanoma cancer cell lines SK-MEL-3 revealed that the ACV release from the nanocomplex formulation F1 effectively inhibited the growth of melanoma cancer cells, with an IC50 of 25 ± 0.09 µg/mL. Additionally, ACV demonstrated a significant cytotoxicity at approximately 20 µg/mL in the melanoma cancer cell line, indicating its potential repurposing for skin cancer treatment. Based on these findings, it can be suggested that the RC-SS complex could be an effective drug delivery carrier for localized cancer therapy. Furthermore, the results of an in silico study suggested the addition of chitosan to the formulation for a more effective drug delivery. Energy and interaction analyses using various modules in a material studio demonstrated the high stability of the composite comprising red clay, sucrose stearate, chitosan and ACV. Thus, it could be concluded that the utilization of the red clay-based drug delivery system is a promising strategy to improve the effectiveness of targeted cancer therapy.

An Overview of 1,2,3-triazole-Containing Hybrids and Their Potential Anticholinesterase Activities.

Acetylcholine (ACh) neurotransmitter of the cholinergic system in the brain is involved in learning, memory, stress responses, and cognitive functioning. It is hydrolyzed into choline and acetic acid by two key cholinesterase enzymes, viz., acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). A loss or degeneration of cholinergic neurons that leads to a reduction in ACh levels is considered a significant contributing factor in the development of neurodegenerative diseases (NDs) such as Alzheimer's disease (AD). Numerous studies have shown that cholinesterase inhibitors can raise the level of ACh and, therefore, enhance people's quality of life, and, at the very least, it can temporarily lessen the symptoms of NDs. 1,2,3-triazole, a five-membered heterocyclic ring, is a privileged moiety, that is, a central scaffold, and is capable of interacting with a variety of receptors and enzymes to exhibit a broad range of important biological activities. Recently, it has been clubbed with other pharmacophoric fragments/molecules in hope of obtaining potent and selective AChE and/or BuChE inhibitors. The present updated review succinctly summarizes the different synthetic strategies used to synthesize the 1,2,3-triazole moiety. It also highlights the anticholinesterase potential of various 1,2,3-triazole di/trihybrids reported in the past seven years (2015-2022), including a rationale for hybridization and with an emphasis on their structural features for the development and optimization of cholinesterase inhibitors to treat NDs.

Formulation and validation of a baseline prognostic score for osteosarcoma treated uniformly with a non-high dose methotrexate-based protocol from a low middle income healthcare setting: a single centre analysis of 594 patients.

Introduction: The outcomes of osteosarcoma in low middle income countries (LMICs) are different due to patients presenting in advanced stages, resource constraints and the use of non-high-dose-methotrexate (HDMTX)-based regimens. This study derived and validated a prognostic score for osteosarcoma that integrates biologic and social factors and is tailored for patients from an LMIC setting using a non-HDMTX-based protocol. Materials and methods: A retrospective study including osteosarcoma patients enrolled for treatment at a single tertiary care centre in India between 2003-19 was conducted. Baseline biologic and social characteristics were extracted from medical records and survival outcomes were noted. The cohort was randomised into a derivation and validation cohort. Multivariable Cox regression was used to identify baseline characteristics that were independently prognostic for survival outcomes in the derivation cohort. A score was derived from the prognostic factors identified in the derivation cohort and further validated in the validation cohort with estimation of its predictive ability. Results: 594 patients with osteosarcoma were eligible for inclusion in the study. Around one-third of the cohort had metastatic disease with 59% of the patients residing in rural areas. The presence of metastases at baseline (HR 3.39; p<0.001; score=3), elevated serum alkaline phosphatase (SAP) >450 IU/L (HR 1.57; p=0.001; score=1) and baseline tumour size > 10 cm (HR 1.68; p<0.001; score=1) were identified to be independent factors predicting inferior event free survival (EFS) and were included in development of the prognostic score. Patients were categorized as low risk (score 0), intermediate risk (score 1-3) and high risk (4-5). Harrell's c-indices for the score were 0.682, 0.608 and 0.657 respectively for EFS in the derivation, validation and whole cohort respectively. The timed AUC of ROC was 0.67 for predicting 18-month EFS in the derivation, validation and whole cohorts while that for 36-month EFS were 0.68, 0.66 and 0.68 respectively. Conclusions: The study describes the outcomes among osteosarcoma patients from an LMIC treated uniformly with a non-HDMTX-based protocol. Tumor size, baseline metastases and SAP were prognostic factors used to derive a score with good predictive value for survival outcomes. Social factors did not emerge as determinants of survival.

Ubiquitin specific peptidase 37 and PCNA interaction promotes osteosarcoma pathogenesis by modulating replication fork progression.

BACKGROUND: Osteosarcoma is a type of bone cancer that predominantly affects young individuals, including children and adolescents. The disease progresses through heterogeneous genetic alterations, and patients often develop pulmonary metastases even after the primary tumors have been surgically removed. Ubiquitin-specific peptidases (USPs) regulate several critical cellular processes, such as cell cycle progression, transcriptional activation, and signal transduction. Various studies have revealed the significance of USP37 in the regulation of replication stress and oncogenesis. METHODS: In this study, the Cancer Genome Atlas (TCGA) database was analyzed to investigate USP37 expression. RNA sequencing was utilized to assess the impact of USP37 overexpression and depletion on gene expression in osteosarcoma cells. Various molecular assays, including colony formation, immunofluorescence, immunoprecipitation, and DNA replication restart, were employed to examine the physical interaction between USP37 and PCNA, as well as its physiological effects in osteosarcoma cells. Additionally, molecular docking studies were conducted to gain insight into the nature of the interaction between USP37 and PCNA. Furthermore, immunohistochemistry was performed on archived tissue blocks from osteosarcoma patients to establish a correlation between USP37 and PCNA expression. RESULTS: Analysis of the TCGA database revealed that increased expression of USP37 was linked to decreased progression-free survival (PFS) in osteosarcoma patients. Next-generation sequencing analysis of osteosarcoma cells demonstrated that overexpression or knockdown of USP37 led to the expression of different sets of genes. USP37 overexpression provided a survival advantage, while its depletion heightened sensitivity to replication stress in osteosarcoma cells. USP37 was found to physically interact with PCNA, and molecular docking studies indicated that the interaction occurs through unique residues. In response to genotoxic stress, cells that overexpressed USP37 resolved DNA damage foci more quickly than control cells or cells in which USP37 was depleted. The expression of USP37 varied in archived osteosarcoma tissues, with intermediate expression seen in 52% of cases in the cohort examined. CONCLUSION: The results of this investigation propose that USP37 plays a vital role in promoting replication stress tolerance in osteosarcoma cells. The interaction between USP37 and PCNA is involved in the regulation of replication stress, and disrupting it could potentially trigger synthetic lethality in osteosarcoma. This study has expanded our knowledge of the mechanism through which USP37 regulates replication stress, and its potential as a therapeutic target in osteosarcoma merits additional exploration.

A Study on Pharmacokinetic Functionalities and Safety Margins of an Optimized Simvastatin Nanoformulation.

A pharmaceutical formulation with favorable pharmacokinetic parameters is more likely to be efficacious and safe to overcome the failures of the drug resulting from lack of efficacy, poor bioavailability, and toxicity. In this view, we aimed to evaluate the pharmacokinetic functionalities and safety margin of an optimized CS-SS nanoformulation (F40) by in vitro/in vivo methods. The everted sac technique was used to evaluate the improved absorption of a simvastatin formulation. In vitro protein binding in bovine serum and mice plasma was performed. The formulation's liver and intestinal CYP3A4 activity and metabolic pathways were investigated by the qRT-PCR technique. The excretion of cholesterol and bile acids was measured to demonstrate the formulation's cholesterol depletion effect. Safety margins were determined by histopathology as well as fiber typing studies. In vitro protein binding results revealed the existence of a high percentage of free drugs (22.31 ± 3.1%, 18.20 ± 1.9%, and 16.9 ± 2.2%, respectively) compared to the standard formulation. The controlled metabolism in the liver was demonstrated from CYP3A4 activity. The formulation showed enhanced PK parameters in rabbits such as a lower Cmax, clearance, and a higher Tmax, AUC, Vd, and t1/2. qRT-PCR screening further proved the different metabolic pathways followed by simvastatin (SREBP-2) and chitosan (PPAR-γ pathway) in the formulation. The results from qRT-PCR and histopathology confirmed the toxicity level. Hence, this pharmacokinetic profile of the nanoformulation proved it has a unique synergistic hypolipidemic modality.

Prepubic inflammatory liposarcoma presenting as urosepsis.

Inflammatory well-differentiated liposarcoma is a rare soft-tissue tumor which is predominantly retroperitoneal in origin. We report a 72-year-old male without co-morbidities with suspected urosepsis and an obstructing ureteric calculus. Despite adequate diversion and broad-spectrum antimicrobials, the leukocytosis persisted. Further imaging revealed a locally infiltrating prepubic mass which was suspicious of a lymphoid malignancy and was found to be a high-grade liposarcoma on biopsy. He underwent open wide local resection of the tumor and the histopathology revealed an inflammatory well-differentiated liposarcoma with areas of neutrophilic abscess and necrosis. A dramatic response to the surgical resection was seen and the leukocytosis resolved within a few days.

Factors affecting the incorporation of extracorporeally irradiated autograft for the treatment of bone tumours-a retrospective analysis from a tertiary referral centre.

PURPOSE: Re-implantation of the tumor bearing autograft following extracorporeal radiation therapy (ECRT) has been established as an oncologically safe biological reconstruction technique following resection of bone sarcomas. However, factors affecting the ECRT graft-host bone incorporation have not been fully investigated. An insight into the factors that influence graft incorporation can circumvent the complications and increase graft survival. METHODS: A total of 96 osteotomies in 48 patients with intercalary resections of primary extremity bone sarcomas (mean age 15.8 years, mean follow-up 42.1 months) were analyzed retrospectively for factors ECRT autograft-host bone union. RESULTS: On univariate analysis, age < 20 years, metaphyseal osteotomy site, V-shaped diaphyseal osteotomy, and use of additional plate at diaphyseal osteotomy had a significantly faster time to union, while gender, tumour type, bone involved, resection length, chemotherapy, type of fixation, and use of intra-medullary fibula did not influence union time. In multivariate analysis, V-shaped diaphyseal osteotomy and use of additional plate at diaphyseal ostetomy were the independent factors with favourable time to union. None of the analyzed factors was found to have a significant effect on the union rate. The major complications were non-union in 11.4% patients, graft failure in 2.1%, infection in 12.5%, and soft tissue local recurrences in 14.5% patients. CONCLUSION: Modified diaphyseal osteotomy and augmentation of the stability of the reconstruction using additional small plates enhance the incorporation of ECRT autograft.

Determinants and impact of diagnostic interval in bone sarcomas: A retrospective cohort study.

BACKGROUND: Diagnostic delays in cancers are frequent in developing countries due to poor health infrastructure. Existing literature from developed countries suggests that diagnostic interval in bone sarcomas is primarily dictated by tumour biology with no impact on survival. This study evaluates the social and biological determinants of the diagnostic interval in bone sarcomas in a resource-challenged setting and assesses its impact on treatment outcomes. METHODS: A retrospective single-institutional study was conducted on patients with high-grade bone sarcomas recorded in the sarcoma clinic database between 2003 and 2018. Baseline clinical characteristics and treatment outcomes were recorded. Logistic regression was performed to assess the impact of baseline clinical and social characteristics (distance from treating centre and rural vs. urban residence) on the diagnostic interval. Further, the impact of diagnostic interval on histologic response to neoadjuvant chemotherapy, amputation requirement in extremity sarcomas and survival was evaluated. RESULTS: A total of 1227 patients were included for analysis. The median diagnostic interval was 4 months (3-7 months). Age above 18 years, Ewing sarcoma (ES) diagnosis, absence of fever at presentation and tumour size above 7.5 cm were predictors of a longer diagnostic interval (>4 months). The length of the diagnostic interval did not impact amputation requirement or survival outcomes. However, the proportion of patients with good necrosis post-neoadjuvant chemotherapy was lower among patients with longer diagnostic intervals (25% vs. 34·16%; p-value = .04). CONCLUSION: Tumour characteristics rather than social factors determined the diagnostic interval. Diagnostic interval did not impact survival outcomes even in a resource-constrained setting.

Recent Advances on Natural and Non-Natural Xanthones as Potential Anticancer Agents: A Review.

BACKGROUND: Xanthones, natural or synthetic, due to their wide range of biological activities, have become an interesting subject of investigation for many researchers. Xanthonic scaffold has proven to have a vital role in anticancer drug development since many of its derivatives have shown anticancer activities on various cell lines. In addition, targeting epigenetic markers in cancer has yielded promising results. There have also been reports on the impact of xanthone and related polyphenolic compounds on epigenetics markers in cancer prevention and therapy. OBJECTIVE: The objective of this review is to comprehensively highlight the main natural and nonnatural sources of xanthones having potential anti-cancer effects along with their key structural elements, structure-activity relationships (SARs), mechanisms of action, and epigenetic profile of xanthone- based anti-cancer compounds. The challenges and future directions of xanthone-based therapies are also discussed briefly. METHOD: The methods involved in the preparation of the present review included the collection of all recent information up to November 2021 from various scientific databases, indexed periodicals, and search engines such as Medline Scopus, Google Scholar, PubMed, PubMed Central, Web of Science, and Science Direct. RESULTS: Exploration of the diversity of the xanthone scaffold led to the identification of several derivatives having prominent anti-cancer activity. Their unique structural diversity and synthetic modifications showed the ongoing endeavour of enriching the chemical diversity of the xanthone molecular framework to discover pharmacologically interesting compounds. However, studies regarding their modes of action, pharmacokinetic properties, clinical data, epigenetics, and safety are limited. CONCLUSION: Elucidation of the exact biological mechanisms and the associated targets of xanthones will yield better opportunities for these compounds to be developed as potential anticancer drugs. Further clinical studies with conclusive results are required to implement xanthones as treatment modalities in cancer.

Role of sodium dependent SLC13 transporter inhibitors in various metabolic disorders.

The sodium dependent SLC13 family transporters comprise of five genes SLC13A1, SLC13A2 (NaDC1), SLC13A3 (NaDC3), SLC13A4 and SLC13A5 (NaCT). Among them, NaDC1, NaDC3 and NaCT are sodium dependent transporters belonging to family of dicarboxylates (succinate, malate, α-ketoglutarate) and tricarboxylates (citrate). The mouse and the human NaCT structures have still not been crystallized, therefore structural information is taken from the related bacterial transporter of VcINDY. Citrate in the cytosol works as a precursor for the fatty acid synthesis, cholesterol, and low-density lipoproteins. The excess citrate from the matrix is translocated to the cytosol for fatty acid synthesis through these transporters and thus controls the energy balance by downregulating the glycolysis, tricarboxylic acid (TCA), and fatty acid breakdown. These transporters play an important role in regulating various metabolic diseases including cancer, diabetes, obesity, fatty liver diseases and CNS disorders. These di and tricarboxylate transporters are emerging as new targets for metabolic disorders such as obesity and diabetes. The mutation in the function of the NaCT causes several neurological diseases including neonatal epilepsy and impaired brain development whereas mutation of genes coding for citrate transport present in the liver may provide positive effect. Therefore, continued efforts from the earlier work on citrate transporters are required for the development of citrate inhibitors. This review discusses the structure, function, and regulation of the NaCT transporter. The review also highlights citrate role in diagnosing diseases such as cancer, diabetes, fatty liver, and diabetes. The therapeutic perspective of synthetic inhibitors against NaCT transporters is succinctly summarized.

An insight into the neuroprotective effects and molecular targets of pomegranate (Punica granatum) against Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that still has no permanent cure. The drugs prescribed in the present days are only for symptomatic relief for the patients. Many studies correlating the reduction in the incidence of AD with the diet consumed have been published. These studies showed that a diet rich in polyphenols is associated with a decrease in the incidence of AD. The present review is focused on the ability of pomegranate and its bioactive components to ameliorate the progression of AD and their ability to exert a neuroprotective effect. Various studies showing the ability of pomegranate in inhibiting enzymes, reducing reactive oxygen species, inhibition of microglial activation, inhibition of tau protein hyperphosphorylation, maintenance of synaptic plasticity, anti-inflammatory activity and its ability to inhibit Beta secretase-1 (BACE-1) has been reviewed in this article. In spite of the lack of studies on humans, there are compelling evidence indicating that pomegranate can reduce various risk factors involved in the causation of AD and thus can be used as a persistent nutraceutical to slow ageing and for providing neuroprotection for the treatment of AD.Highlights An overview of traditional and pharmacological uses of pomegranate (POM).Potential of POM in the treatment of neurodegenerative diseases especially in AD.Insight into the molecular mechanisms of neuroprotective effects of POM in AD.Clinical evaluation studies involving POM and its bioactive components.

Non-invasive intravoxel incoherent motion MRI in prediction of histopathological response to neoadjuvant chemotherapy and survival outcome in osteosarcoma at the time of diagnosis.

BACKGROUND: Early prediction of response to neoadjuvant chemotherapy (NACT) is important to aid personalized treatment in osteosarcoma. Diffusion-weighted Intravoxel Incoherent Motion (IVIM) MRI was used to evaluate the predictive value for response to NACT and survival outcome in osteosarcoma. METHODS: Total fifty-five patients with biopsy-proven osteosarcoma were recruited prospectively, among them 35 patients were further analysed. Patients underwent 3 cycles of NACT (Cisplatin + Doxorubicin) followed by surgery and response adapted adjuvant chemotherapy. Treatment outcomes were histopathological response to NACT (good-response ≥ 50% necrosis and poor-response < 50% necrosis) and survival outcome (event-free survival (EFS) and overall survival (OS)). IVIM MRI was acquired at 1.5T at baseline (t0), after 1-cycle (t1) and after 3-cycles (t2) of NACT. Quantitative IVIM parameters (D, D*, f & D*.f) were estimated using advanced state-of-the-art spatial penalty based IVIM analysis method bi-exponential model with total-variation penalty function (BETV) at 3 time-points and histogram analysis was performed. RESULTS: Good-responders: Poor-responders ratio was 13 (37%):22 (63%). EFS and OS were 31% and 69% with 16.27 and 25.9 months of median duration respectively. For predicting poor-response to NACT, IVIM parameters showed AUC = 0.87, Sensitivity = 86%, Specificity = 77% at t0, and AUC = 0.96, Sensitivity = 86%, Specificity = 100% at t1. Multivariate Cox regression analysis showed smaller tumour volume (HR = 1.002, p = 0.001) higher ADC-25th-percentile (HR = 0.047, p = 0.005) & D-Mean (HR = 0.1, p = 0.023) and lower D*-Mean (HR = 1.052, p = 0.039) were independent predictors of longer EFS (log-rank p-values: 0.054, 0.0034, 0.0017, 0.0019 respectively) and non-metastatic disease (HR = 4.33, p < 10-3), smaller tumour-volume (HR = 1.001, p = 0.042), lower D*-Mean (HR = 1.045, p = 0.056) and higher D*.f-skewness (HR = 0.544, p = 0.048) were independent predictors of longer OS (log-rank p-values: < 10-3, 0.07, < 10-3, 0.019 respectively). CONCLUSION: IVIM parameters obtained with a 1.5T scanner along with novel BETV method and their histogram analysis indicating tumour heterogeneity were informative in characterizing NACT response and survival outcome in osteosarcoma.