A multianalytical approach to evaluate the association of 55 SNPs in 28 genes with obesity risk in North Indian adults.

OBJECTIVES: The aim of the study was to investigate the association of 55 SNPs in 28 genes with obesity risk in a North Indian population using a multianalytical approach. METHODS: Overall, 480 subjects from the North Indian population were studied using strict inclusion/exclusion criteria. SNP Genotyping was carried out by Sequenom Mass ARRAY platform (Sequenom, San Diego, CA) and validated Taqman® allelic discrimination (Applied Biosystems® ). Statistical analyses were performed using SPSS software version 19.0, SNPStats, GMDR software (version 6) and GENEMANIA. RESULTS: Logistic regression analysis of 55 SNPs revealed significant associations (P < .05) of 49 SNPs with BMI linked obesity risk whereas the remaining 6 SNPs revealed no association (P > .05). The pathway-wise G-score revealed the significant role (P = .0001) of food intake-energy expenditure pathway genes. In CART analysis, the combined genotypes of FTO rs9939609 and TCF7L2 rs7903146 revealed the highest risk for BMI linked obesity. The analysis of the FTO-IRX3 locus revealed high LD and high order gene-gene interactions for BMI linked obesity. The interaction network of all of the associated genes in the present study generated by GENEMANIA revealed direct and indirect connections. In addition, the analysis with centralized obesity revealed that none of the SNPs except for FTO rs17818902 were significantly associated (P < .05). CONCLUSIONS: In this multi-analytical approach, FTO rs9939609 and IRX3 rs3751723, along with TCF7L2 rs7903146 and TMEM18 rs6548238, emerged as the major SNPs contributing to BMI linked obesity risk in the North Indian population.

Association of FTO and IRX3 genetic variants to obesity risk in north India.

BACKGROUND: Obesity is an increasingly important health problem worldwide as well as in developing countries like India. Recent genetic studies suggest that obesity associated FTO and IRX3 are functionally linked and many effects due to genetic variants in FTO gene act through IRX3. AIM: To evaluate the association of FTO and IRX3 genetic variants towards obesity risk. SUBJECTS AND METHODS: North Indian individuals categorised as non-obese (BMI < 30 kg/m(2)) and obese (BMI ≥ 30 kg/m(2)) were selected. FTO rs8050136, rs1421085, rs9939609, rs17817449 and IRX3 rs3751723 were genotyped by means of validated Taqman® allelic discrimination to evaluate their association with obesity by means of single locus logistic regression by SPSS ver. 19 and multi-locus linkage and haplotype analysis by SNPStats and gene-gene interaction with Generalised Multifactor Dimensionality Reduction (GMDR) ver.6. RESULTS: In single locus analysis, FTO rs8050136 CA (p = 0.0001; OR (95% CI) = 2.4 (1.7-3.4) and AA (p = 0.0001; OR (95% CI) = 3.1 (1.9-5.2); FTO rs1421085 TA (p = 0.0001; OR (95% CI) = 2.1 (1.4-3.0) and AA (p = 0.0001; OR (95% CI) = 3.0 (1.8-5.0); FTO rs9939609 TC (p = 0.0001; OR (95% CI) = 2.1 (1.5-3.1) and CC (p = 0.0001; OR (95% CI) = 4.2 (2.5-7.3) along with TG (p = 0.001; OR (95% CI) = 2.1 (1.3-3.2) and GG (p = 0.021; OR (95% CI) = 3.8 (1.2-11.8) genotypes of FTO rs17817449 with GT (p = 0.0001; OR (95% CI) = 2.1 (1.5-3.1) and TT (p = 0.012; OR (95% CI) = 3.3 (1.8-3.6) genotypes of IRX3 rs3751723 were significantly associated with obesity. In multi-locus analysis, SNPs of FTO and IRX3 were in strong linkage disequilibrium and in haplotype and GMDR analysis the SNPs were significantly associated with obesity risk (p < 0.05). CONCLUSION: This is the first study to reveal that genetic variants of both FTO and IRX3 genes are in high linkage disequilibrium (LD) and are associated with obesity risk in North Indians.

A Comprehensive Review on Current Treatments and Challenges Involved in the Treatment of Ovarian Cancer.

Ovarian cancer (OC) is the second most common gynaecological malignancy. It typically affects females over the age of 50, and since 75% of cases are only discovered at stage III or IV, this is a sign of a poor diagnosis. Despite intraperitoneal chemotherapy's chemosensitivity, most patients relapse and face death. Early detection is difficult, but treatment is also difficult due to the route of administration, resistance to therapy with recurrence, and the need for precise cancer targeting to minimize cytotoxicity and adverse effects. On the other hand, undergoing debulking surgery becomes challenging, and therapy with many chemotherapeutic medications has manifested resistance, a condition known as multidrug resistance (MDR). Although there are other therapeutic options for ovarian cancer, this article solely focuses on co-delivery techniques, which work via diverse pathways to overcome cancer cell resistance. Different pathways contribute to MDR development in ovarian cancer; however, usually, pump and non-pump mechanisms are involved. Striking cancerous cells from several angles is important to defeat MDR. Nanocarriers are known to bypass the drug efflux pump found on cellular membranes to hit the pump mechanism. Nanocarriers aid in the treatment of ovarian cancer by enhancing the delivery of chemotherapeutic drugs to the tumour sites through passive or active targeting, thereby reducing unfavorable side effects on the healthy tissues. Additionally, the enhanced permeability and retention (EPR) mechanism boosts the bioavailability of the tumour site. To address the shortcomings of conventional delivery, the current review attempts to explain the current conventional treatment with special reference to passively and actively targeted drug delivery systems (DDSs) towards specific receptors developed to treat ovarian cancer. In conclusion, tailored nanocarriers would optimize medication delivery into the intracellular compartment before optimizing intra-tumour distribution. Other novel treatment possibilities for ovarian cancer include tumour vaccines, gene therapy, targeting epigenetic alteration, and biologically targeted compounds. These characteristics might enhance the therapeutic efficacy.

Challenges and Therapeutic Approaches for the Protein Delivery System: A Review.

The protein delivery system is one of the innovative or novel drug delivery systems in the present era. Proteins play an indispensable role in our body and are mainly found in every part, like tissue and cells of our body. It also controls various functions, such as maintaining our tissue, transportation, muscle recovery, enzyme production and acting as an energy source for our body. Protein therapeutics have big future perspectives, and their use in the treatment of a wide range of serious diseases has transformed the delivery system in the pharmaceutical and biotechnology industries. The chief advantage of protein delivery is that it can be delivered directly to the systemic circulation. So far, parenteral routes, such as intravenous, intramuscular, and subcutaneous, are the most often used method of administering protein drugs. Alternative routes like buccal, oral, pulmonary, transdermal, nasal, and ocular routes have also shown a remarkable success rate. However, as with all other types of delivery, here, several challenges are posed due to the presence of various barriers, such as the enzymatic barrier, intestinal epithelial barrier, capillary endothelial barrier, and blood-brain barrier. There are several approaches that have been explored to overcome these barriers, such as chemical modification, enzymatic inhibitors, penetration enhancers, and mucoadhesive polymers. This review article discusses the protein, its functions, routes of administration, challenges, and strategies to achieve ultimate formulation goals. Recent advancements like the protein Pegylation method and Depofoam technology are another highlight of the article.

Psoriasis: Striving for Potential Biomarkers.

Psoriasis is a chronic disease that is caused by multiple factors and is identified by itchiness, unpleasant, red, or white scaly patches on the skin, particularly on regularly chafed body regions such as the lateral areas of the limbs. Reports suggest that globally around 2%-3% of the population suffers from psoriasis. In this review, we have discussed the clinical classification of psoriasis and also the ideal characteristics of the biomarkers. An overview regarding the discovery of the biomarker and method for validating the study has been discussed. A growing body of research suggests a link to certain other systemic symptoms such as cardiovascular disorder, metabolic syndrome, and few other comorbidities such as hypertension and nonalcoholic fatty liver disease. Natural killer (NK) cells are lymphocyte cells that concentrate on the destruction of virally infected and malignant cells; these tend to produce a wide range of inflammatory cytokines, some of which are associated with the etiology of psoriasis. Detailed information on the molecular pathogenesis of psoriasis in which interleukin (IL)-17, IL-23, tumor necrosis factor-α (TNF-α), and CCL20 play a very significant role in the development of psoriasis. In this review, we have discussed an overview of the recent state of the biomarkers available for the diagnosis and treatment of psoriasis by emphasizing on the available biomarkers such as epigenomic, transcriptomic, glycomic, and metabolomic. The most recent advancements in molecular-targeted therapy utilizing biologics and oral systemic therapy (methotrexate, apremilast) enable to adequately treat the most serious psoriatic symptoms and also the studies have validated the efficacy of biologic therapy such as TNF-α antagonist (infliximab, adalimumab), IL-23 antagonist (guselkumab, risankizumab), and IL-17 antagonist (secukinumab, ixekizumab). Finally, an overview about the technological opportunities as well as various challenges has been discussed.

Artificial Intelligence: An Emerging Intellectual Sword for Battling Carcinomas.

Artificial Intelligence (AI) is a branch of computer science that deals with mathematical algorithms to mimic the abilities and intellectual work performed by the human brain. Nowadays, AI is being effectively utilized in addressing difficult healthcare challenges, including complex biological abnormalities, diagnosis, treatment, and clinical prognosis of various life-threatening diseases, like cancer. Deep neural networking (DNN), a subset of AI, is prominently being applied in clinical research programs on cancer. AI acts as a promising tool in radiotherapy, mammography, imaging, cancer prognosis, cancer genomics and molecular signaling, pathology, drug discovery, chemotherapy, immunotherapy, and clinical decision support system. This article provides an elaborative view concerning the application of AI in cancer, an explorative review that how AI has been used as a trenchant tool in the past, present and future of cancer. This review article provides a new prospective that how the mimic of human intellectual (AI technology) has put forward an unprecedented accuracy in the field of clinical research of cancer.

Vaccines: An Important Tool for Infectious Disease.

Vaccines are usually regarded as one of the most important tools in the battle against infectious diseases. Even though currently accessible vaccinations are an incredible success story in contemporary medicine and have had a significant impact on global morbidity and death rates, it is evident that current vaccine delivery approaches need to be improved. To allow the successful creation of vaccinations against contagious diseases that have proven challenging to manage with conventional procedures, improvements are necessary. Improvements could include the introduction of innovative injectable adjuvants or novel delivery methods, such as mucosal immunization. Protection against infections that infect mucosal areas may necessitate mucosal delivery. Alternatively, innovative techniques for delivery, such as intradermal administration using self-administrable devices or the use of microneedle technology to bypass the stratum corneum's skin penetration barrier and aid in the transport of antigens, could be utilized to increase vaccine compliance. Needle-free delivery systems are of particular relevance for safer mass immunization programs, as they would prevent problems caused by needles reuse in several regions of the world, as well as needle-stick accidents. Based on this information, future vaccine development will mainly concentrate on rational antigen, adjuvant, and, most importantly, delivery mechanism design, resulting in new and improved vaccinations. In addition, this study discusses the current state and prospects of vaccine delivery via a variety of channels, including non- or minimally invasive approaches.

Genomic landscape of metastatic breast cancer (MBC) patients with methylthioadenosine phosphorylase (MTAP) loss.

INTRODUCTION: Homozygous deletion of MTAP upregulates de novo synthesis of purine (DNSP) and increases the proliferation of neoplastic cells. This increases the sensitivity of breast cancer cells to DNSP inhibitors such as methotrexate, L-alanosine and pemetrexed. MATERIALS AND METHODS: 7,301 cases of MBC underwent hybrid-capture based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Tumor cell PD-L1 expression was determined by IHC (Dako 22C3). RESULTS: 208 (2.84%) of MBC featured MTAP loss. MTAP loss patients were younger (p = 0.002) and were more frequently ER- (30% vs. 50%; p < 0.0001), triple negative (TNBC) (47% vs. 27%; p < 0.0001) and less frequently HER2+ (2% vs. 8%; p = 0.0001) than MTAP intact MBC. Lobular histology and CDH1 mutations were more frequent in MTAP intact (14%) than MTAP loss MBC (p < 0.0001). CDKN2A (100%) and CDKN2B (97%) loss (9p21 co-deletion) were significantly associated with MTAP loss (p < 0.0001). Likely associated with the increased TNBC cases, BRCA1 mutation was also more frequent in MTAP loss MBC (10% vs. 4%; p < 0.0001). As for immune checkpoint inhibitors biomarkers, higher TMB >20 mut/Mb levels in the MTAP intact MBC (p < 0.0001) and higher PD-L1 low expression (1-49% TPS) in the MTAP loss MTAP (p = 0.002) were observed. CONCLUSIONS: MTAP loss in MBC has distinct clinical features with genomic alterations (GA) affecting both targeted and immunotherapies. Further efforts are necessary to identify alternative means of targeting PRMT5 and MTA2 in MTAP-ve cancers to benefit from the high-MTA environment of MTAP-deficient cancers.

Recent Advancements and Patents on Buccal Drug Delivery Systems: A Comprehensive Review.

The major requirement for a dosage form to be successful is its ability to penetrate the site of application and the bioavailability of the drug released from the dosage form. The buccal drug delivery is an influential route to deliver the drug into the body. Here, in this context, various novel approaches that include lipoidal carriers like ethosomes, transferosomes, niosomes etc. and electrospun nanofibers are discussed, with respect to buccal drug delivery. These carriers can be easily incorporated into buccal dosage forms like patches and gels that are responsible for increased permeation across the buccal epithelium. The in vivo methods of evaluation on animal models are conscribed here. The novel biocarriers of lipoidal and non-lipoidal nature can be utilized by loading the drug into them, which are helpful in preventing drug degradation and other drawbacks as compared to conventional formulations. The globally patented buccal formulations give us a wide context in literature about the patents filed and granted in the recent years. When it comes to patient compliance, age is an issue, which is also solved by the buccal route. The pediatric buccal formulations are researched for the customization to be delivered to children. Diseases like mouth ulcers, oral cancer, Parkinson's disease, aphthous stomatitis etc. have been successfully treated through the buccal route, which infers that the buccal drug delivery system is an effective and emerging area for formulation and development in the field of pharmaceutics.

Lupus Cerebritis Refractory to Guideline-Directed Therapy: A Case Report.

Systemic lupus erythematosus is an autoimmune disease that affects multiple organs and organ systems, subsequently requiring an elaborate regimen for management. We present the case of a 63-year-old female who developed unrelenting symptoms of drug-induced lupus, which persisted even after the offending agent was withdrawn, unmasking her underlying systemic lupus erythematosus. She continued to develop neuropsychiatric symptoms, including mania and hallucinations, which complicated the management of her disease. After exhausting the bank of anti-inflammatory and immunomodulators recommended by current guidelines, we found that a combination of rituximab infusions with thiothixene, an antipsychotic agent, significantly improved our patient's neuropsychiatric symptoms. Further research should be conducted to determine the efficacy of rituximab in the treatment of resistant lupus cerebritis, and to validate the use of thiothixene in the management of neuropsychiatric symptoms secondary to lupus.

Accidental Ixazomib Overdose in a Patient With Multiple Myeloma.

Multiple myeloma is the second most common hematological malignancy. Ixazomib is the first oral proteasome inhibitor approved in the United States for the management of multiple myeloma who have received at least one prior treatment. The availability of oral chemotherapeutic agents for the management of multiple myeloma has made it easier for patients who do not have to come to the hospital for chemotherapy infusions. However, many barriers are associated with oral chemotherapy, and one of them is a misinterpretation of instruction which can have deleterious effects. In this case report, we present a case of a 69-year-old male with multiple myeloma who accidentally took ixazomib daily for 3 days instead of the weekly regimen and thus coming into the hospital with an overdose. In this report, we focus on the adverse effects associated with ixazomib toxicity and how to manage the adverse reactions. Although there is no antidote available for ixazomib, supportive care is very essential in these patients.

An Uncommon Presentation of DRESS Syndrome Secondary to Leflunomide Use: A Case Report.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a constellation of symptoms that manifest as a result of certain medications. Several antipsychotics, antibiotics, and sulfa-containing drugs are known to be implicated in the etiology of DRESS syndrome. The clinical presentation of this disorder consists of a diffuse rash, lymphadenopathy, and systemic organ damage. Our patient presented with symptoms consistent with DRESS syndrome after being started on leflunomide, which is not commonly associated with DRESS. The diagnostic workup comprised of monitoring inflammatory markers on laboratory work, an excisional lymph node biopsy (to rule out malignancy), and a skin biopsy (to assess the etiology of the rash). Our patient received systemic steroids, dose-adjusted based on expert opinion. Further research is required to explore the association between leflunomide and DRESS and address guidelines for the management of DRESS.

A unified scaling model for flow through a lattice of microfabricated posts.

A scaling model is presented for low Reynolds number viscous flow within an array of microfabricated posts. Such posts are widely used in several lab-on-a-chip applications such as heat pipes, antibody arrays and biomolecule separation columns. Finite element simulations are used to develop a predictive model for pressure driven viscous flow through posts. The results indicate that the flow rate per unit width scales as approximately h1.17g1.33/d0.5 where h is the post height, d post diameter and g is the spacing between the posts. These results compare favorably to theoretical limits. The scaling is extended to capillary pressure driven viscous flows. This unified model is the first report of a scaling that incorporates both viscous and capillary forces in the microfabricated post geometry. The model is consistent with Washburn dynamics and was experimentally validated to within 8% using wetting on microfabricated silicon posts.

Fully integrated microfluidic platform enabling automated phosphoprofiling of macrophage response.

The ability to monitor cell signaling events is crucial to the understanding of immune defense against invading pathogens. Conventional analytical techniques such as flow cytometry, microscopy, and Western blot are powerful tools for signaling studies. Nevertheless, each approach is currently stand-alone and limited by multiple time-consuming and labor-intensive steps. In addition, these techniques do not provide correlated signaling information on total intracellular protein abundance and subcellular protein localization. We report on a novel phosphoFlow Chip (pFC) that relies on monolithic microfluidic technology to rapidly conduct signaling studies. The pFC platform integrates cell stimulation and preparation, microscopy, and subsequent flow cytometry. pFC allows host-pathogen phosphoprofiling in 30 min with an order of magnitude reduction in the consumption of reagents. For pFC validation, we monitor the mitogen-activated protein kinases ERK1/2 and p38 in response to Escherichia coli lipopolysaccharide (LPS) stimulation of murine macrophage cells (RAW 264.7). pFC permits ERK1/2 phosphorylation monitoring starting at 5 s after LPS stimulation, with phosphorylation observed at 5 min. In addition, ERK1/2 phosphorylation is correlated with subsequent recruitment into the nucleus, as observed from fluorescence microscopy performed on cells upstream of flow cytometric analysis. The fully integrated cell handling has the added advantage of reduced cell aggregation and cell loss, with no detectable cell activation. The pFC approach is a step toward unified, automated infrastructure for high-throughput systems biology.

Microfluidic pressure sensing using trapped air compression.

We have developed a microfluidic method for measuring the fluid pressure head experienced at any location inside a microchannel. The principal component is a microfabricated sealed chamber with a single inlet and no exit; the entrance to the single inlet is positioned at the location where pressure is to be measured. The pressure measurement is then based on monitoring the movement of a liquid-air interface as it compresses air trapped inside the microfabricated sealed chamber and calculating the pressure using the ideal gas law. The method has been used to measure the pressure of the air stream and continuous liquid flow inside microfluidic channels (d approximately 50 microm). Further, a pressure drop has also been measured using multiple microfabricated sealed chambers. For air pressure, a resolution of 700 Pa within a full-scale range of 700-100 kPa was obtained. For liquids, pressure drops as low as 70 Pa were obtained in an operating range from 70 Pa to 10 kPa. Since the method primarily uses a microfluidic sealed chamber, it does not require additional fabrication steps and may easily be incorporated in several lab-on-a-chip fluidic applications for laminar as well as turbulent flow conditions.

Electronic drop sensing in microfluidic devices: automated operation of a nanoliter viscometer.

We describe three droplet sensing techniques: a digital electrode, an analog electrode, and a thermal method. All three techniques use a single layer of metal lines that is easy to microfabricate and an electronic signal can be produced using low DC voltages. While the electrode methods utilize changes in electrical conductivity when the air/liquid interface of the droplet passes over a pair of electrodes, the thermal method is based on convective heat loss from a locally heated region. For the electrode method, the analog technique is able to detect 25 nL droplets while the digital technique is capable of detecting droplets as small as 100 pL. For thermal sensing, temperature profiles in the range of 36 degrees C and higher were used. Finally, we have used the digital electrode method and an array of electrodes located at preset distances to automate the operation of a previously described microfluidic viscometer. The viscometer is completely controlled by a laptop computer, and the total time for operation including setup, calibration, sample addition and viscosity calculation is approximately 4 minutes.

Depression during pregnancy: Prevalence and obstetric risk factors among pregnant women attending a tertiary care hospital in Navi Mumbai.

CONTEXT: Depression affects about 20% of women during their lifetime, with pregnancy being a period of high vulnerability. Prevalence of depression during pregnancy ranges from 4% to 20%. Several risk factors predispose to depression during pregnancy including obstetric factors. Depression during pregnancy is not only the strongest risk factor for post-natal depression but also leads to adverse obstetric outcomes. AIMS: To study the prevalence of depression during pregnancy and its associated obstetric risk factors among pregnant women attending routine antenatal checkup. SETTINGS AND DESIGN: Cross-sectional observational survey done at the outpatient department (OPD) of the department of obstetrics of a tertiary care hospital in Navi Mumbai. MATERIALS AND METHODS: One hundred and eighty-five pregnant women were randomly administered the Beck Depression Inventory (BDI) for detecting depression. Additional socio-demographic and obstetric history was recorded and analyzed. RESULTS: Prevalence of depression during pregnancy was found to be 9.18% based upon BDI, and it was significantly associated with several obstetric risk factors like gravidity (P = 0.0092), unplanned pregnancy (P = 0.001), history of abortions (P = 0.0001), and a history of obstetric complications, both present (P = 0.0001) and past (P = 0.0001). CONCLUSIONS: Depression during pregnancy is prevalent among pregnant women in Navi-Mumbai, and several obstetric risk factors were associated to depression during pregnancy. Future research in this area is needed, which will clearly elucidate the potential long-term impact of depression during pregnancy and associated obstetric risk factors so as to help health professionals identify vulnerable groups for early detection, diagnosis, and providing effective interventions for depression during pregnancy.

Microfluidically-unified cell culture, sample preparation, imaging and flow cytometry for measurement of cell signaling pathways with single cell resolution.

We have developed a microfluidic platform that enables, in one experiment, monitoring of signaling events spanning multiple time-scales and cellular locations through seamless integration of cell culture, stimulation and preparation with downstream analysis. A combination of two single-cell resolution techniques-on-chip multi-color flow cytometry and fluorescence imaging provides multiplexed and orthogonal data on cellular events. Automated, microfluidic operation allows quantitatively- and temporally-precise dosing leading to fine time-resolution and improved reproducibility of measurements. The platform was used to profile the toll-like receptor (TLR4) pathway in macrophages challenged with lipopolysaccharide (LPS)-beginning with TLR4 receptor activation by LPS, through intracellular MAPK signaling, RelA/p65 translocation in real time, to TNF-α cytokine production, all in one small macrophage population (< 5000 cells) while using minute reagent volume (540 nL/condition). The platform is easily adaptable to many cell types including primary cells and provides a generic platform for profiling signaling pathways.