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ObjectiveThe optimal diet to improve glycemia in patients with type 2 diabetes remains unclear. Low carbohydrate, high fat (LCHF) diets can improve glycemic control, but have not been investigated in real-world settings.Research design and methodsWe investigated effects of the LCHF diet compared with usual care in a community-based cohort of patients with type 2 diabetes by performing a retrospective study of 49 patients who followed the LCHF diet for ≥3 months, and compared glycemic outcomes with age-matched and body mass index (BMI)-matched controls who received usual care (n=75). The primary outcome was change in A1C from baseline to the end of follow-up.ResultsCompared with the usual care group, the LCHF group showed a significantly greater reduction in A1C (−1.29% (95% CI −1.75 to −0.82; pConclusionsIn a community-based cohort of type 2 diabetes, the LCHF diet was associated with superior A1C reduction, greater weight loss and significantly more patients discontinuing or reducing antihyperglycemic therapies suggesting that the LCHF diet may be a metabolically favorable option in the dietary management of type 2 diabetes.

We present a rare case of autoimmune diabetes mellitus and hypothyroidism in an elderly man initiated on nivolumab two months prior to admission for treatment of a high-grade neuroendocrine rectal tumor. This patient presented to a local community hospital with one-week history of severe nausea, thirst, and bilateral leg edema. Biochemical studies confirmed the diagnosis of diabetic ketoacidosis in the setting of autoimmune diabetes mellitus and primary hypothyroidism, likely due to nivolumab use. This case illustrates an acute complication due to secondary diabetes mellitus in the setting of a novel anticancer agent. There are three key takeaways for physicians managing patients on nivolumab. First, there should be a discussion of the benefits and risks of immunomodulatory therapy. Second, patients should be tested for immunological and other markers before being started on checkpoint inhibitors. Third, oncologists must be aware of the signs and symptoms of life-threatening hyperglycemia and severe hypothyroidism. Additional studies are needed to identify those patients at highest risk for autoimmune complications.

Purpose: Differentiated thyroid cancer (DTC) responds to VEGF receptor inhibitors. VEGF signals through RAS/RAF/MEK signaling. We evaluated the safety and efficacy of the VEGF receptor inhibitor pazopanib and MEK inhibitor trametinib in advanced solid tumors and DTC. Patients and Methods: Patients with advanced solid tumors were enrolled in a phase I, multicenter trial with a DTC expansion cohort. Patients received pazopanib 400–800 mg and trametinib 1–2 mg daily. Efficacy in the expansion cohort was assessed with objective response (OR) at 6 months of treatment. Results: Twenty-six patients were enrolled in five dose levels. MTD was not reached; the recommended phase II dose was pazopanib 800 mg orally and trametinib 2 mg orally every day. There was one dose-limiting toxicity on dose level 1 with grade 3 fatigue and muscle weakness. Common grade 3 adverse events were elevated transaminases (19%), diarrhea (15%), hypertension (12%), and fatigue (8%). Thirteen patients were enrolled in the DTC cohort; OR was 33% (95% confidence interval, 9.9, 65.1%) and median progression-free survival was 10.7 months. The cohort was terminated after planned interim analysis suggested insufficiently increased activity against the historical control of pazopanib alone. Reduction in tumor diameter negatively correlated with p-ERK change in tumor (Spearman ρ = −0.71; P = 0.05). NRAS mutation was associated with response (Fisher exact P = 0.008). Conclusions: Pazopanib + trametinib was tolerable at full single-agent doses with clinical activity in DTC but did not achieve the prespecified response rate target.

Autism Spectrum Disorder (ASD) is a clinically heterogenous condition with a wide range of etiological factors and causing significant public health burden. ASD poses a serious developmental disadvantage to the child in the form of poor schooling, social function and adult productivity. Thus, framing evidence-based national guidelines is a pressing need. The meeting on formulation of national consensus guidelines on neurodevelopmental disorders was organized by Indian Academy of Paediatrics in Mumbai on 18th and 19th December 2015. The invited experts included Pediatricians, Developmental Pediatricians, Psychiatrists, Remedial Educators, Pediatric Neurologists and Clinical Psychologists. The participants framed guidelines after extensive discussions. Thereafter, a committee was established to review the points discussed in the meeting. To provide consensus guidelines on evaluation and management of ASD in children in India. Intervention should begin as early as possible. A definitive diagnosis is not necessary for commencing intervention. Intervention should target core features of autism i.e. deficits in social communication and interaction, and restricted repetitive patterns of behavior, activities and/ or interests. Intervention should be specific, evidence-based, structured and appropriate to the developmental needs of the child. Management of children should be provided through interdisciplinary teams, coordinated by the Pediatrician. Management of co-morbidities is critical to effectiveness of treatment. Pharmacotherapy may be offered to children when there is a specific target symptom or co-morbid condition.

Background: We completed a phase I clinical trial to test the safety and toxicity of combined treatment with cixutumumab (anti-IGF-1R antibody) and selumetinib (MEK 1/2 inhibitor). Methods: Patients with advanced solid tumours, refractory to standard therapy received selumetinib hydrogen sulphate capsules orally twice daily, and cixutumumab intravenously on days 1 and 15 of each 28-day cycle. The study used a 3+3 design, with a dose-finding cohort followed by an expansion cohort at the maximally tolerated dose that included pharmacokinetic and pharmacodynamic correlative studies. Results: Thirty patients were enrolled, with 16 in the dose-finding cohort and 14 in the expansion cohort. Grade 3 or greater toxicities included nausea and vomiting, anaemia, CVA, hypertension, hyperglycaemia, and ophthalmic symptoms. The maximally tolerated combination dose was 50 mg twice daily of selumetinib and 12 mg kg−1 every 2 weeks of cixutumumab. Two patients achieved a partial response (one unconfirmed), including a patient with BRAF wild-type thyroid carcinoma, and a patient with squamous cell carcinoma of the tongue, and six patients achieved time to progression of >6 months, including patients with thyroid carcinoma, colorectal carcinoma, and basal cell carcinoma. Comparison of pre- and on-treatment biopsies showed significant suppression of pERK and pS6 activity with treatment. Conclusions: Our study of anti-IGF-1R antibody cixutumumab and MEK 1/2 inhibitor selumetinib showed that the combination is safe and well-tolerated at these doses, with preliminary evidence of clinical benefit and pharmacodynamic evidence of target inhibition.

Autism is a neurodevelopmental disorder with early manifestation. It is a multifactorial disorder and several susceptible chromosomal regions for autism are identified through genome scan studies. The gene coding for glutamate receptor 6 (GluR6 or GRIK2) has been suggested as a candidate gene for autism based on its localization in the autism specific region on chromosome 6q21 and the involvement of receptor protein in cognitive functions like learning and memory. Despite its importance, so far no studies have been carried out on possible involvement of GluR6 with autism in the Indian population. Therefore in the present study, we have performed genetic analysis of three markers of GluR6 (SNP1: rs2227281, SNP2: rs2227283, SNP3: rs2235076) for possible association with autism through population, and family-based (TDT and HHRR) approaches. DSM-IV criteria and CARS/ADI-R have been utilized for diagnosis. Genotyping analysis for the SNPs has been carried out in 101 probands with autism spectrum disorder, 180 parents and 152 controls from different regions of India. Since the minor allele frequency of SNP3 was too low, the association studies have been carried out only for SNP1 and SNP2. Even though two earlier studies have shown association of these markers with autism, the present case-control and TDT, as well as HHRR analyses have not demonstrated any biased transmission of alleles or haplotypes to the affected offspring. Thus our results suggest that these markers of GluR6 are unlikely to be associated with autism in the Indian population.

Several studies suggest involvement of serotoninergic system in the pathophysiology of Autism Spectrum Disorder (ASD). The 5-HT receptor binding studies using (3)H-lysergic acid diethylamide ((3)H-LSD) and linkage analysis provided evidences to consider HTR2A as a potential candidate gene for ASD. The three SNPs, -1438A/G (rs6311), 102T/C (rs6313) and 1354C/T (rs6314) of HTR2A have been well studied in the etiology of various neuropsychiatric disorders. But studies on association of this gene with ASD are limited to two reports from American and Korean populations. Additionally there are reports, which demonstrated paternal imprinting of HTR2A with expression from only one allele. So far no reports are available on HTR2A and its association with any neuropsychiatric disorders from Indian population. Therefore, the present study investigates association of the above mentioned three markers of HTR2A with ASD in Indian population using population and family-based approaches. The study also deals with allelic expression pattern of HTR2A in Peripheral Blood Leukocytes (PBLs) to understand the parental imprinting status. The genotyping analyses were carried out for probands, parents and controls. The subsequent association analyses did not show association of these markers with ASD. So, HTR2A is unlikely to be a genetic marker for ASD in Indian population. The expression analyses showed absence of monoallelic expression, suggesting lack of parental imprinting of HTR2A gene. However, we noticed methylation of the CpG sites at -1438A/G and 102T/C loci of HTR2A gene. Further bioinformatics analysis revealed absence of CpG islands in the promoter of the gene supporting biallelic expression pattern of HTR2A in PBLs.

Involvement of reelin with Autism spectrum disorder (ASD) has been implicated through several biochemical as well as genetic studies. Reelin is an extracellular signaling protein, which plays a significant role in cytoarchitectonic pattern formation of different brain areas during development. Reelin gene (RELN) is located on chromosome 7q22; an important autism critical region identified through several genome-wide scans. A number of genetic studies have been carried out to investigate the association of reelin with autism. Recently we reported possible paternal effect in the transmission of CGG repeat alleles of RELN in the susceptibility towards autism. Further analysis on other polymorphisms is warranted to validate the status of RELN as a candidate for autism. Therefore in the present study, we have investigated six more SNPs (rs727531, rs2072403, rs2072402, rs362691, rs362719, rs736707) in 102 patients, 182 parents and 101 healthy controls. We have followed DSM-IV criteria and the screening for autism was carried out using CARS. Genomic DNA isolated from blood was used for PCR and subsequent RFLP analysis. Finally, case-control and family-based association studies were carried out to examine the genetic association of these SNP markers with ASD in the Indian population. But, we failed to detect either preferential parental transmission of any alleles of the markers to affected offspring or any biased allelic or genotypic distribution between the cases and controls. Thus the present study suggests that these SNPs of RELN are unlikely to be associated with ASD in the Indian population.

Autism is a neurodevelopmental disorder with high heritability factor and the reelin gene, which codes for an extracellular matrix protein involved with neuronal migration and lamination is being investigated as a positional and functional candidate gene for autism. It is located on chromosome 7q22 within the autism susceptible locus (AUTS1); identified in earlier genome scans and several investigations have been carried out on various ethnic groups to assess possible association and linkage of the gene with autism. However, the findings are still inconclusive. In the present study which represents the first report of such a study on the Indian population, genotyping analyses of CGG repeat polymorphism at 5′UTR, two single nucleotide polymorphisms (SNP) at exon 6 and exon 50 were performed in 73 autistic subjects, 129 parents, and 80 controls. The allelic distributions of the repeat polymorphism and exon 50 T/C SNP were quite different from earlier reports in other populations. Allelic and genotypic distribution of the markers did not show any differences between the cases and controls. While our preliminary data on family-based association studies on 58 trios showed no preferential transmission of any allele from the parents to the affected offspring, TDT and HHRR analyses revealed significant paternal transmission distortions for 10- and ≥11-repeat alleles of CGG repeat polymorphism. Thus, the present study suggests that 5′UTR of reelin gene may have a role in the susceptibility towards autism with the paternal transmission and non-transmission respectively of 10- and ≥11-repeat alleles, to the affected offspring. © 2006 Wiley-Liss, Inc.

Serotonin transporter (5-HTT) is a transmembrane protein belonging to Na + /Cl − dependent membrane transporter family and transports 5-HT across the membranes of presynaptic neurons. 5-HTT-linked polymorphic region (5-HTTLPR) gained much interest because of the differential regulation of expression and activity of 5-HTT by its various genotypes. A population-based study has been conducted on 5-HTTLPR with 358 individuals, which included 79 autistic probands, 136 parents, and 143 controls from two subpopulations of east and northeast regions of India. The genotypic frequencies of all the groups conform to Hardy–Weinberg equilibrium. With the finding of efficacy of serotonin reuptake inhibitors in ameliorating ritualistic behavior in autistic disorder, 5-HTT emerged as a putative candidate gene for autism and association studies have been carried out in different ethnic populations. But these studies were inconclusive due to conflicting results on association. Because such a study has never been performed in the Indian population, we have tested the possible involvement of 5-HTTLPR polymorphism with autism. The present study failed to establish any association or linkage of 5-HTTLPR with autism in the Indian population by case–control studies ( χ 2 = 1.314, P = 0.63) and family-based approaches (TDT χ 2 = 0.22, P = 0.64 and HHRR- χ 2 = 0.25, P = 0.61). However, when a meta-analysis of all the available TDT data, inclusive of the present study is carried out, we observed a significant preferential transmission of S-allele from parents to the affected offspring ( χ 2 = 7.51, P = 0.006) indicating an association of 5-HTTLPR with autism.

Background: P is a small molecule tyrosine kinase inhibitor that selectively inhibits VEGFR1-3, PDGFR-α, PDGFR-β, c-kit, and FGFR 1-3 and is approved for renal cancer and STS. T is a potent, highly selective, allosteric inhibitor of MEK1/2 approved for BRAF-mutated advanced melanoma. Increased signaling of growth factor receptor tyrosine kinases have been shown to be important to cell survival in multiple tumor types, and their inhibition has been effective therapeutically in STS, DTC, and ChCa. In addition, increased RAS/RAF/MEK/ERK signaling plays a critical role in the development of many different types of cancers, including ChCA and DTC. We hypothesized that combination therapy with P and T would be tolerable and effective for this range of tumor types. Methods: We designed a phase I, open label, dose escalation trial with P+T open to patients with advanced solid tumors. The study was a standard 3+3 design with an expansion cohort of 25 pts each for advanced DTC, STS, and ChCA for correlative endpoints and PK studies. Pts were treated with T held constant at 1 mg QD and P at 400 mg QD (DL1), 600 mg QD (DL2)and 800 mg QD (DL3); T was then escalated to 1.5 mg QD (DL4) and 2 mg QD (DL5). Eligibility included adequate end organ function, PS 0-1, and PD within 6 months in the expansion cohort of DTC. The primary objective was to determine the safety and tolerability of P+T and to find the MTD. Secondary objectives include assessing preliminary efficacy and exploration of PK/PD endpoints with tumor biopsies. Results: We report the results of the dose escalation component of the study. 26 pts were accrued to 5 dose levels and treated for a median of 3 cycles (range Conclusions: P+T is a tolerable combination with some preliminary signs of efficacy. Accrual to expansion cohorts in DTC, STS, and ChCA for further exploration of efficacy and correlative endpoints is ongoing. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support provided by GlaxoSmithKline. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B279. Citation Format: Nilofer Azad, Douglas Ball, Steven Sherman, Michelle Rudek, Gerald Falchook, Barry Nelkin, Filip Janku, Nicholas Papadopoulos, Ashley O'Conner, Shabina Ahmed, Breelyn Wilky, Susan Markus, Jing Gong, David Cosgrove, Marianna Zahurak, Ralph Zinner, Razelle Kurzrock. A phase I study determining the safety and tolerability of combination therapy with Pazopanib (P), a VEGFR/PDGFR/Raf inhibitor, and GSK1120212 (Trametinib: T), a MEK inhibitor, in advanced solid tumors with expansion cohorts in advanced differentiated thyroid cancer (DTC), cholangiocarcinoma (ChCA), and soft tissue sarcoma (STS). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B279.