Correlation of Iron Status and Micronutrients With Anaemia of Childhood Haematopoietic Malignancies: A Study From Northern India.

BACKGROUND: Most cancer patients undergoing chemotherapy develop anemia during their course of treatment. There is a need for early treatment for chemotherapy-induced anemia to prevent morbidity and mortality. MATERIAL AND METHOD: This is a hospital-based study, conducted over one year and included 59 children who are known cases of hematological malignancy aged up to 18 years. Standard methods were used to measure micronutrients and complete blood count. Statistical analysis was done using SPSS for Windows, Version 15.0 (Released 2006; SPSS Inc., Chicago, United States). RESULTS: The majority of subjects (n=21; 35.6%) were aged six to nine years with male dominance. Micronutrient deficiency and significant anemia were noted in 40-50% and 64.4% of cases, respectively. Both malignancy and blood indices showed no association with micronutrients. CONCLUSION: Anemia with micronutrient deficiency is common in children with hematopoietic malignancies receiving chemotherapy. However, no significant association was noted between red cell indices and levels of micronutrients.

Engineered vitamin E-tethered non-immunogenic facial lipopeptide for developing improved siRNA based combination therapy against metastatic breast cancer.

RNA interference based therapeutic gene silencing is an emerging platform for managing highly metastatic breast cancer. Cytosolic delivery of functional siRNA remains the key obstacle for efficient RNAi therapy. To overcome the challenges of siRNA delivery, we have engineered a vitamin E-tethered, short, optimum protease stabilized facial lipopeptide based non-immunogenic, biocompatible siRNA transporter to facilitate the clinical translation in future. Our designed lipopeptide has an Arginine-Sarcosine-Arginine segment for providing optimum protease-stability, minimizing adjacent arginine-arginine repulsion and reducing intermolecular aggregation and α-tocopherol as the lipidic moiety for facilitating cellular permeabilization. Interestingly, our designed non-immunogenic siRNA transporter has exhibited significantly better long term transfection efficiency than HiPerFect and can transfect hard to transfect primary cell line, HUVEC. Our engineered siRNA therapeutics demonstrated high efficacy in managing metastasis against triple negative breast cancer by disrupting the crosstalk of endothelial cells and MDA-MB-231 and reduced stemness and metastatic markers, as evidenced by downregulating critical oncogenic pathways. Our study aimed at silencing Notch1 signalling to achieve "multi-targeted" therapy with a single putative molecular medicine. We have further developed mechanistically rational combination therapy combining Notch1 silencing with a repurposed drug m-TOR inhibitor, metformin, which demonstrated synergistic interaction and enhanced antitumor efficacy against cancer metastasis.

Harnessing Peptide-Functionalized Multivalent Gold Nanorods for Promoting Enhanced Gene Silencing and Managing Breast Cancer Metastasis.

Small interfering RNA (siRNA) has become the cornerstone against undruggable targets and for managing metastatic breast cancer. However, an effective gene silencing approach is faced with a major challenge due to the delivery problem. In our present study, we have demonstrated efficient siRNA delivery, superior gene silencing, and inhibition of metastasis in triple-negative breast cancer cells (MDA-MB-231) using rod-shaped (aspect ratio: 4) multivalent peptide-functionalized gold nanoparticles and compared them to monovalent free peptide doses. Multivalency is a new concept in biology, and tuning the physical parameters of multivalent nanoparticles can enhance gene silencing and antitumor efficacy. We explored the effect of the multivalency of shape- and size-dependent peptide-functionalized gold nanoparticles in siRNA delivery. Our study demonstrates that peptide functionalization leads to reduced toxicity of the nanoparticles. Such designed peptide-functionalized nanorods also demonstrate antimetastatic efficacy in Notch1-silenced cells by preventing EMT progression in vitro. We have shown siRNA delivery in the hard-to-transfect primary cell line HUVEC and also demonstrated that the Notch1-silenced MDA-MB-231 cell line has failed to form nanobridge-mediated foci with the HUVEC in the co-culture of HUVEC and MDA-MB-231, which promote metastasis. This antimetastatic effect is further checked in a xenotransplant in vivo zebrafish model. In vivo studies also suggest that our designed nanoparticles mediated inhibition of micrometastasis due to silencing of the Notch1 gene. The outcome of our study highlights that the structure-activity relationship of multifunctional nanoparticles can be harnessed to modulate their biological activity.

Emerging Approaches for Enabling RNAi Therapeutics.

RNA interference (RNAi) is a primitive evolutionary mechanism developed to escape incorporation of foreign genetic material. siRNA has been instrumental in achieving the therapeutic potential of RNAi by theoretically silencing any gene of interest in a reversible and sequence-specific manner. Extrinsically administered siRNA generally needs a delivery vehicle to span across different physiological barriers and load into the RISC complex in the cytoplasm in its functional form to show its efficacy. This review discusses the designing principles and examples of different classes of delivery vehicles that have proved to be efficient in RNAi therapeutics. We also briefly discuss the role of RNAi therapeutics in genetic and rare diseases, epigenetic modifications, immunomodulation and combination modality to inch closer in creating a personalized therapy for metastatic cancer. At the end, we present, strategies and look into the opportunities to develop efficient delivery vehicles for RNAi which can be translated into clinics.

Emerging concepts in designing next-generation multifunctional nanomedicine for cancer treatment.

Nanotherapy has emerged as an improved anticancer therapeutic strategy to circumvent the harmful side effects of chemotherapy. It has been proven to be beneficial to offer multiple advantages, including their capacity to carry different therapeutic agents, longer circulation time and increased therapeutic index with reduced toxicity. Over time, nanotherapy evolved in terms of their designing strategies like geometry, size, composition or chemistry to circumvent the biological barriers. Multifunctional nanoscale materials are widely used as molecular transporter for delivering therapeutics and imaging agents. Nanomedicine involving multi-component chemotherapeutic drug-based combination therapy has been found to be an improved promising approach to increase the efficacy of cancer treatment. Next-generation nanomedicine has also utilized and combined immunotherapy to increase its therapeutic efficacy. It helps in targeting tumor immune response sparing the healthy systemic immune function. In this review, we have summarized the progress of nanotechnology in terms of nanoparticle designing and targeting cancer. We have also discussed its further applications in combination therapy and cancer immunotherapy. Integrating patient-specific proteomics and biomarker based information and harnessing clinically safe nanotechnology, the development of precision nanomedicine could revolutionize the effective cancer therapy.

Clinical Correlation and Role of Cyclin D1 Expression in Glioblastoma Patients: A Study From North India.

Background/Aims Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor. Cyclin D1 is a protein that in humans is encoded by the CCND1 gene. Cyclin D1 protein is frequently overexpressed in malignant gliomas. Methods It is an observational study comprising 40 biopsy-proven cases of GBM in a span of one and half years. Immunohistochemistry (IHC) was used with Cyclin D1 monoclonal antibody. Cyclin D1 on the outcome was assessed using the Kaplan-Meier survival estimate and compared by log-rank test. Results Cyclin D1 was expressed in 60% of patients. The majority (72.5%) of patients expired during the study period, out of which 69% showed immune-expression in contrast to living subjects, out of which only 45.5% of patients exhibited expression. The maximum number of glioblastoma patients were aged between 41 and 50 years (40%), followed by those aged between 31 and 40 years (20%). The male to female ratio of study subjects was 3.44:1. Conclusion The study concluded that there is no significant association between Cyclin D1 expression status and different demographic, clinical, and outcome variables.

Peptide-based topical agents and intravenous hemostat for rapid hemostasis.

Traumatic coagulopathy due to severe external injury and internal hemorrhage is life-threatening to accident victims and soldiers on the battlefield, causing considerable number of deaths worldwide. Patients with inherited bleeding disorders (such as haemophilia, von Willebrand disease, inherited qualitative platelet defects, and afibrinogenemia) also contribute to the vast number of deaths due to abnormal bleeding, and these patients are difficult to handle during surgery. Platelets and different plasma proteins play an essential role in blood coagulation and in the maintenance of the body's hemostatic balance. The improper function or deficiency of these factors cause abnormal bleeding. To address such bleeding disorders, external clotting agents (such as extracellular protein-inspired natural and synthetic peptide-based sealants and peptide-functionalized polymer/liposome-based sealants) have been developed by different groups of researchers. The primary focus of this review is to provide molecular insights into the existing biologically inspired peptide-based sealants, highlighting the advantages and limitations of such reported designed sealants to handle blood clotting, and also provide insights into the design of improved next-generation surgical sealants.

Cardiovascular disease risk in the siblings of women with polycystic ovary syndrome.

STUDY QUESTION: Do the siblings of Asian Indian women with polycystic ovary syndrome (PCOS) manifest increased cardiovascular disease (CVD) risk by carotid intima-media thickness (CIMT) and brachial artery flow-mediated dilatation (FMD)? SUMMARY ANSWER: Siblings had functional endothelial dysfunction (FMD was reduced) when compared to age and BMI-matched controls while sisters but not brothers had structural endothelial dysfunction (CIMT was increased). WHAT IS KNOWN ALREADY: Siblings of women with PCOS have increased metabolic risk but it varies with ethnicity. Among Asian Indians the only previous study has shown reduced FMD in brothers. STUDY DESIGN, SIZE, DURATION: This study was a tertiary care hospital-based cross-sectional case control study in the outpatient department of the endocrine clinic over 18 months. In total, 41 brothers and 35 sisters of women with PCOS (diagnosed by 2003 Rotterdam criteria) were recruited. PARTICIPANTS/MATERIALS, SETTING, METHODS: Age (±2 years), sex and BMI- (±1 kg/m2) matched controls were selected. Cases and controls underwent clinical and biochemical investigations. Cardiologists performed doppler ultrasonogram to determine CIMT and FMD in a blinded fashion. MAIN RESULTS AND THE ROLE OF CHANCE: FMD was decreased in brothers [median 12.3% interquartile range (5.1, 19) versus 18.4% (12.6, 21.5), P = 0.002] and in sisters [10.8% (5.8, 17.2) versus 14.7% (11.4, 18.2), P = 0.027] when compared to controls. CIMT was higher in sisters [median 0.4 mm (0.35, 0.5) versus 0.3 mm (0.3, 0.4), P= 0.002] when compared to controls but not in brothers. Metabolic syndrome was more common in brothers (27% versus 5% in controls, P = 0.007) even after matching for age and BMI. Insulin resistance (homeostatic model assessment for insulin resistance and acanthosis) was higher in brothers as compared to controls. Dehydroepiandrosterone sulphate was significantly elevated in brothers. LIMITATIONS, REASONS FOR CAUTION: There may have been referral bias of patients with PCOS in a tertiary care institute, and the radiological assessment was performed by two cardiologists serially on different time frames over the study duration. Power was only 50% in CIMT for brothers. WIDER IMPLICATIONS OF THE FINDINGS: Siblings of women with PCOS had higher CVD risk over and above the already pre-existing higher metabolic risk associated with Asian Indian ethnicity and therefore the siblings require vigilant management. Endothelial dysfunction and insulin resistance seems to be a heritable trait of PCOS independent of obesity, which if confirmed in other ethnicities would have important implications. STUDY FUNDING/COMPETING INTEREST(S): Funded by Intramural Research Grant (PGI/DIR/RC/943/2013) from the Sanjay Gandhi Postgraduate Institute of Medical Sciences. No competing interests.

Familial clustering of metabolic phenotype in brothers of women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a complex polygenic endocrine disorder. Familial clustering of phenotype has been known and it endorses the heritability of the disease. Among brothers of women with PCOS, we found significantly higher waist circumference, elevated blood pressure and insulin resistance when compared with age and BMI matched controls. Serum DHEAS level (6.2 vs. 4.5 µmol/L) was also significantly elevated among brothers. These findings in Indian ethnicity are concordant with previous studies and emphasize the need for counseling the first-degree family members of women with PCOS for lifestyle modification to reduce future risk of metabolic syndrome. We reiterate that insulin resistance (independent of obesity) and DHEAS may represent a PCOS phenotype. Funding agency - intramural grant Sanjay Gandhi Post Graduate Institute of Medical Sciences. CTRI registration number CTRI/2017/02/007891.