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The interaction between gut microbes and gastrointestinal (GI) tract carcinogenesis has always attracted researchers' attention to identify therapeutic targets or potential prognostic biomarkers. Various studies have suggested that the microbiota do show inflammation and immune dysregulation, which led to carcinogenesis in GI tract. In this review, we have focused on the role of microbes present in the gut, intestine, or faeces in GI tract cancers, including esophageal cancer, gastric cancer, and colorectal cancer. Herein, we have discussed the importance of the microbes and their metabolites, which could serve as diagnostic biomarkers for cancer detection, especially in the early stage, and prognostic markers. To maximize the effect of the treatment strategies, an accurate evaluation of the prognosis is imperative for clinicians. There is a vast difference in the microbiota profiles within a population and across the populations depending upon age, diet, lifestyle, genetic makeup, use of antibiotics, and environmental factors. Therefore, the diagnostic efficiency of the microbial markers needs to be further validated. A deeper understanding of the GI cancer and the host microbiota is needed to acquire pivotal information about disease status.

Neurodegenerative disorders occur when nerve cells in the brain or peripheral nervous system partial or complete fail in their functions and sometimes even die due to some injuries or aging. Neurodegenerative disorders such as Alzheimer's Disease (AD) and Parkinson's Disease (PD), have been majorly resulted due to degeneration of neurons and neuroinflammation progressively. There are many similarities that correlates both AD and PD on a cellular and sub-cellular level. Therefore, a hope for therapeutic advancement for simultaneous upgradation in both the diseases are directly depending on the discovery of common mechanism at molecular and cellular level. Recent and past evidences from scientific literature supporting the efficacy of plants flavonoids in treatment and protection of both AD and PD. Further, dietary flavones, specially Heptamethoxyflavone, Kaempferitrin, Vitexin and Amentoflavone gains recently much more attention for producing many health beneficiary effects including neuroprotection. Despite of these evidence a detailed updated overview of neuroprotective effects against both AD and PD by Heptamethoxyflavone, Kaempferitrin, Vitexin and Amentoflavone are still missing. In this context several published studies were assessed by using various online electronic search engines/databases to meet the objective from 1981 to 2021 (Approx. 224). Therefore, present review was designed to deliver the detailed description on these flavones including therapeutic benefits in AD, PD and other CNS complications with critical analysis on underlying mechanisms.

The aim of the present study is to evaluate the neuroprotective effect of methanol extract of Garcinia morella Desr leaves in monosodium glutamate (MSG) induced neurotoxicity in rats. The MSG 2 g/kg, i.p. was used to induce the neurotoxicity. The rats were administrated with methanol extract of Garcinia morella Desr leaves (MEGM) 200 and 400 mg/kg, p.o. and Dextromethorphan 30 mg/kg, p.o. after 1 h injection of MSG. The animals were evaluated for its behavioural factors such as muscle grip and locomotor activity. At the end of the study, the antioxidant enzymes levels, neurotransmitter levels, TNFα, ß-amyloid and mineral levels were estimated in brain homogenate. The MEGM treated group shows significant improvement of behavioural and locomotor activity and muscle strength against MSG induced neurotoxicity. The glutathione, SOD, catalase and total protein levels were significantly increased in MEGM treated group. However, significant reduction within the level of varied neurotransmitters like AChE, Dopamine, TNFα, ß-amyloid were observed on treatment with MEGM extract. Further, MEGM also significantly decrease the MSG induced toxicity through declined levels of Ca+2 and Na+ with increased levels of K+. In conclusion, the present study suggests that the MEGM has significant neuroprotective activity against MSG induced neurotoxic rats.

Background: Thalassemia is a hereditary autosomal recessive haemoglobinopathy that remains a major health problem throughout the world. Aims and Objectives: The aim of this study was to evaluate knowledge of the relatives of Thalassemia patients regarding different aspects of Thalassemia with special emphasis on the role of splenectomy. Material and Methods: This was a cross-sectional study conducted at a Government Tertiary Thalassemia day care centre. Initially, 131 relatives of Thalassemia patients were interviewed. Excluding 10 relatives, 87 (66.4 %) relatives having knowledge of splenectomy were further interviewed regarding various aspects of splenectomy. Result: In our survey, 67.2 % relatives had knowledge about the congenital origin of the disease. The knowledge about premarriage counselling, risk of consanguineous marriage, antenatal screening and medical termination of pregnancy was 55%, 29.8%, 70.2% and 64.1% respectively. Although all (100%) relatives knew about regular blood transfusion and iron chelation, only 74% and 63.4% of the relatives had the knowledge about splenectomy and bone marrow transplant as a treatment modality, respectively. In 87 relatives interviewed further, 37.9 % came to know about splenectomy from other relatives. The indications of splenectomy known were: splenomegaly (98.8%), increased blood transfusion (68.9%), low platelet count (20.6%) and low TLC (4.6%). Only 47.1% were aware about the optimal age of splenectomy. Awareness about serious complication of OPSI, its prevention by preoperative vaccinations and postoperative chemoprophylaxis was only 48.3%, 62% and 46% respectively. Around 59% knew about role of blood transfusion and 74.7% were aware about the need of regular follow up after splenectomy

Significance Although the overwhelming majority of COVID-19-related deaths are due to respiratory failure, little is known about the host response to SARS-CoV-2 in lung parenchyma. By profiling the lung and colon transcriptome and lung proteome of nine patients who died of COVID-19 during the first wave of the pandemic in Wuhan, China, we obtained molecular insights into the host response to severe SARS-CoV-2 infection. Interestingly, all samples had a low viral burden, a finding that suggests the patients’ deaths may be due to uncontrolled host inflammatory processes rather than an active viral infection. Taken together, our findings shed light on COVID-19 pathophysiology and offer potential therapeutic targets for severe COVID-19 disease., Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, has resulted thus far in greater than 933,000 deaths worldwide; yet disease pathogenesis remains unclear. Clinical and immunological features of patients with COVID-19 have highlighted a potential role for changes in immune activity in regulating disease severity. However, little is known about the responses in human lung tissue, the primary site of infection. Here we show that pathways related to neutrophil activation and pulmonary fibrosis are among the major up-regulated transcriptional signatures in lung tissue obtained from patients who died of COVID-19 in Wuhan, China. Strikingly, the viral burden was low in all samples, which suggests that the patient deaths may be related to the host response rather than an active fulminant infection. Examination of the colonic transcriptome of these patients suggested that SARS-CoV-2 impacted host responses even at a site with no obvious pathogenesis. Further proteomics analysis validated our transcriptome findings and identified several key proteins, such as the SARS-CoV-2 entry-associated protease cathepsins B and L and the inflammatory response modulator S100A8/A9, that are highly expressed in fatal cases, revealing potential drug targets for COVID-19.

Decline in insulin sensitivity due to dysfunction of adipose tissue (AT) is one of the earliest pathogenic events in type 2 diabetes. We hypothesize that differential DNA methylation (DNAm) controls insulin sensitivity and obesity by modulating transcript expression in AT. Integrating AT DNAm profiles with transcript profile data measured in a cohort of 230 African Americans (AAs) from the African American Genetics of Metabolism and Expression cohort, we performed cis-expression quantitative trait methylation (cis-eQTM) analysis to identify epigenetic regulatory loci for glucometabolic trait–associated transcripts. We identified significantly associated cytosine-guanine dinucleotide regions for 82 transcripts (false discovery rate [FDR]-P < 0.05). The strongest eQTM locus was observed for the proopiomelanocortin (POMC; ρ = −0.632, P = 4.70 × 10−27) gene. Epigenome-wide association studies (EWAS) further identified 155, 46, and 168 cytosine-guanine dinucleotide regions associated (FDR-P < 0.05) with the Matsuda index, SI, and BMI, respectively. Intersection of EWAS, transcript level to trait association, and eQTM results, followed by causal inference test identified significant eQTM loci for 23 genes that were also associated with Matsuda index, SI, and/or BMI in EWAS. These associated genes include FERMT3, ITGAM, ITGAX, and POMC. In summary, applying an integrative multiomics approach, our study provides evidence for DNAm-mediated regulation of gene expression at both previously identified and novel loci for many key AT transcripts influencing insulin resistance and obesity.

Idiopathic hypoparathyroidism leads to hypocalcemia and hyperphosphatasemia and usually has a genetic aetiology. The variable but often subtle signs and symptoms usually lead to a misdiagnosis of hypoparathyroidism. Case records of 32 patients of idiopathic hypoparathyroidism admitted over a period of five years were analysed. There was a lag period of 5.94 years from the onset of symptoms to the diagnosis. Carpopedal spasm was the most common indication for admission to the hospital. Trivial symptoms such as fatigue (84%) and paresthesia (62.5%) were the most common reported symptoms. A sum of 46.5% of the patients were on antiepileptic drugs before the correct diagnosis of hypoparathyroidism was made. This observation emphasized that Calcium profile should be obtained in patients with history of paresthesia and seizure to avoid the long delay in diagnosis of hypoparathyroidism.

Mycobacterium tuberculosis, responsible for Tuberculosis (TB), remains the leading cause of mortality among infectious diseases worldwide from a single infectious agent, with an estimated 1.7 million deaths in 2016. Biotin is an essential cofactor in M. tuberculosis that is required for lipid biosynthesis and gluconeogenesis. M. tuberculosis relies on de novo biotin biosynthesis to obtain this vital cofactor since it cannot scavenge sufficient biotin from a mammalian host. The biotin biosynthetic pathway in M. tuberculosis has been well studied and rigorously genetically validated providing a solid foundation for medicinal chemistry efforts. This review examines the mechanism and structure of the enzymes involved in biotin biosynthesis and ligation, summarizes the reported genetic validation studies of the pathway, and then analyzes the most promising inhibitors and natural products obtained from structure-based drug design and phenotypic screening.

Background: Insulin resistance (IR) is a pre-diabetic condition and has been reported in patients with acanthosis nigricans (AN) and acrochordon. AN and acrochordon are claimed to be cutaneous markers of IR. Aim: The purpose of this paper was to study the association of AN and acrochordon with IR. Methods: It was a cross-sectional hospital-based study. Both groups were assessed for IR by using homeostatic model assessment of insulin resistance (HOMA-IR) formula. Results: A total of 70 cases and an equal number of controls were studied. IR was observed more in cases (41.4%) compared to controls (17.1%) (P < 0.01). Mean HOMA-IR value was also significantly higher in cases (4.32 ± 4.44) compared to controls (2.27 ± 0.90) (P < 0.05). Limitations: Low number of cases and controls were taken in the study. Association with hyperlipidemia and metabolic syndrome was not elicited. Conclusions: AN and acrochordons were found to be associated with IR.

PURPOSE: The Consumer Assessment of Healthcare Providers and Systems (CAHPS) Cancer Care Survey is a systematic assessment of health care experiences of patients with cancer. It supports comparisons among all cancer treatment settings and modalities. METHODS: Formative research included 16 focus groups with patients receiving treatment and family members; advice from a panel of oncology and quality improvement experts; and interviews with stakeholders representing oncology associations, accredited cancer centers, and community oncology practices. We conducted cognitive tests of the instrument and field tests at six cancer centers and four community oncology practices, after which the survey was finalized and obtained the CAHPS trademark. RESULTS: The survey includes 56 questions that form six core composite measures (Getting Timely Care; Supporting Patient Self-Management; Available to Provide Care and Information; Provider Communication; Care Coordination; and Courteous Office Staff); two single-item measures of family participation in care and interpreter services; and two global ratings of cancer care and the treatment team. Sixteen additional items form three supplemental composite measures: Shared Decision-Making, Keeping Patients Informed, and Access to Care. CONCLUSION: Mail-only, mail-telephone mixed-mode, and Web-mail mixed-mode data collection methods are recommended. The questionnaires and instructions for use are free and available in English and Spanish on the CAHPS Website ( www.ahrq.gov/cahps ).

Compelling evidence suggest that germs cells are predominantly sensitive to DNA damaging agents in comparison to other cells. High fidelity DNA repair in testicular cells thus becomes indispensable to preserve the genomic integrity for passing on to the progeny. Compromised DNA repair machinery in the testicular cells may result in impaired spermatogenesis and infertility. It remains unclear if the alterations in the expression of DNA repair genes correlate with azoospermia and male infertility. In the present study, 54 non-obstructive azoospermic infertile patients with hypospermatogenesis (HS, n = 26), maturation arrest (MA, n = 15), Sertoli cell only syndrome (SCOS, n = 13) and 14 controls with obstructive azoospermia, but normal spermatogenesis were recruited. Expression profiling of 84 DNA repair genes in testicular biopsy samples was performed using PCR array. Out of 84 genes, 27, 64 and 28 genes showed >5 fold down-regulation in the HS, MA and SCOS groups, respectively. On the basis of differential expression and their functional significance in spermatogenesis, ten genes (MSH2, BRIP1, CCNH, LIG4, MGMT, NTHL1, PMS1, DMC1, POLB and XPA) were selected for validation of transcript levels in a higher number of cases using RT-PCR, which corroborated the findings of array. Four genes (MSH2, LIG4, PMS1 and DMC1) were analyzed for protein levels using immunohistochemistry, which further validated the loss of DNA repair gene expression. Caspase-3 immunostaining showed that the loss of DNA repair correlated with increased testicular apoptosis in patients. Maturation arrest showed the highest apoptotic index with maximum number of downregulated genes. We conclude that the loss of DNA repair genes expression in testis correlates with increased apoptosis, azoospermia and infertility.

Background: Shankhpushpi is an Ayurvedic drug, widely used for its actions on the central nervous system, especially to improve intellect and boost memory. Four botanicals viz. Canscora decussata Schult. (CD), Clitorea ternatea Linn. (CT), Convolvulus pluricaulis Choisy. (CP) and Evolvulus alsinoides Linn. (EA) are considered as sources of Shankhpushpi by Indian practitioners on the basis of their morphological descriptions given in ancient texts. Objective: The present study was undertaken to evaluate the neuropharmacological effect of four herbs commonly identified as source of Shankhpushpi. Materials and methods: Methanol extracts of all four varieties were tested and evaluated in vitro and in vivo for their neuropharmacological effects. Experiments such as protection against β-amyloid induced neurotoxicity on brain cell line (Neuro 2A), antioxidant potential, AchE (acetylcholinesterase enzyme) inhibition, and 5-LOX (lipoxygenase) enzyme inhibition were conducted for in vitro evaluation. For in vivo evaluation, scopolamine (0.3 mg/kg i.p.) induced memory retrieval using pole climbing apparatus and Morris water maze were performed in rat models. Results: It was found that protective effects of EA and CD against β-amyloid induced neurotoxicity in Neuro 2A cells were significantly higher than CT and CP. EA proved to be superior than other varieties on the basis of antioxidant activity, AchE inhibitory and LOX inhibitory activities. The preventive activity of EA on scopolamine induced memory retrieval in pole climbing and Morris water maze task in rats was found to be higher than that of CD, CT and CP. Conclusion: EA has remarkable neuropharmacological effect as compared to other three varieties of Shankhpushpi. This effect may be attributed due to the presence of steroids (stigmasterol and betulinic acid), coumarins (scopoletin) and flavonoids (β-carotene and chlorogenic acid). Hence it can be used as a promising lead in development and management of neuronal disorders including Alzheimer's disease. Keywords: Neuroprotection, Lipoxygenase, Enzyme inhibition, Memory, Shankhpushpi

Background: Use of sunscreens on the face is becoming popular, and patients with melasma are prescribed sunscreen for use on the face. Results of a few Western studies on the effect of sunscreen use on serum vitamin D concentration are not applicable to Indian conditions. Aims: To examine the effect of use of a high sun protection factor (SPF 50+, PA++++) sunscreen on face in patients with melasma on serum concentration of 25-hydroxyvitamin D. Methods: Forty-five Indian patients (Fitzpatrick skin types III and IV) with melasma were advised to use a sunscreen with SPF 50 + for 3 months, 43 (33 female, 10 male; age 32.9 ± 8 years) completed the study. Patients staying outdoor for 4 hours reapplied sunscreen 4 hours after first application. Patients were provided a container to measure the amount of sunscreen for use, which was approximately equal to recommended thickness. Compliance was tested by weighing the used tubes and tubes in use during monthly visits. Serum concentration of 25-hydroxyvitamin D was tested before and after the study period. Results: Amount of sunscreen advised (100.5 ± 29.2 ml) and the actual amount used (96.6 ± 27.9 ml) were similar (P = 0.53, t-test). The difference between serum concentrations of 25-hydroxyvitamin D at the baseline (19.20 ± 9.06 ng/ml) and at 3 months (18.91 ± 8.39 ng/ml) was not significant (P = 0.87, paired t-test, 95% confidence interval of difference −3.33 to 3.92). No correlation was found between the amount of sunscreen used and the percentage change in serum 25-hydroxyvitamin D concentration at 3 months (rho = 0.099, P = 0.528, Spearman's rank correlation). Limitations: Longer duration of application and a larger sample size may detect minor differences in vitamin D concentration. Conclusion: Using a high SPF sunscreen on the face, along with physical photoprotection advice, in patients with melasma for 3 months does not influence serum 25-hydroxyvitamin D concentration in Indian conditions.

Subcutaneous insulin therapy is associated with important injection site complications, which can influence insulin pharmacokinetics resulting in glycemic fluctuations above and below target levels for blood glucose.Our objective was to assess the prevalence and risk factors of cutaneous complications including insulin derived amyloidosis in insulin-injecting diabetes patients and to study the role of ultrasonography (in comparison to gel-assisted palpation) in early diagnosis of lipohypertrophy (LH).This was a cross-sectional study conducted at a tertiary care center in India, wherein 500 patients injecting insulin for ≥2 years were randomly enrolled and evaluated for the presence of cutaneous complications of insulin therapy through clinical examination, ultrasonography and punch biopsy of skin.Clinical examination detected LH in 44.6% of patients. Ultrasonography diagnosed additional 13.4% of patients with LH which were missed on clinical examination. Incorrect rotation of sites (P0.001) and insulin syringe reusage for more than five times (P0.001) significantly increased the risk of LH. Skin biopsy was performed in 100 cases, out of which two patients showed apple green birefringence and its association with insulin was confirmed by positive staining with anti insulin antibody in these two patients.Improper rotation of sites and reuse of needles were the leading causes of LH in Indian diabetic patients. Ultrasonography is more objective and reliable method of detecting LH. Insulin-derived amyloidosis may be a more common complication of insulin therapy than previously thought.

Interleukin-3 (IL-3) is produced during infections caused by parasites, bacteria and viruses, but its contribution to immunity in this context remains largely unknown. In mouse models of parasitic infections, in which the effects of IL-3 have been most extensively studied, IL-3 has been variously reported as protective, detrimental or inconsequential. Similarly, mixed results have been reported in viral and bacterial infection models. Here, we investigated the effects of IL-3 in mouse models of Mycobacterium tuberculosis and herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections by assessing the pathogen burden, disease manifestations and survival following infection. After infection with M. tuberculosis, IL-3 deficient mice showed higher bacillary burden, increased lung pathology and reduced survival compared to wild type mice. After infection with HSV-1 through cutaneous route and HSV-2 through vaginal route, IL-3 deficient mice showed higher viral burden, increased disease manifestations and reduced survival compared to wild type mice. Our results show that IL-3 makes a subtle but significant contribution to protective immunity in these mouse models of bacterial and viral infections.

Introduction: Numerous doctors have been infected while treating the patients of Coronavirus Disease (COVID-2019). Expecting doctors to treat without any regard to their safety is an extreme and unrealistic approach. Apart from professional obligations, doctors have personal obligations to their families too. Aim: To understand the barriers of willingness and ability to serve during pandemics for Indian doctors. Materials and Methods: This cross-sectional study, Peer-tested web-based questionnaire was carried out at the King George’s Medical University, Lucknow, India, along with informed consent form incorporated into Google form, was posted on a WhatsApp group. Study was conducted from April to June 2020. The group included 400 Indian medical practitioners, selected randomly. It comprised of total 49 questions, including open and close ended type, in English language. Out of these, 14 questions were pertaining to the present study. The exploratory data analysis was used to analyse and interpret the data. Results: Responses were submitted by 256 (64% response rate) doctors out of which 121 were from males, 134 from females and 1 person preferred not to disclose the gender. Majority (64.8%) of the responses were obtained from doctors in age group of 20-40 years and 49% of the total responses were from faculty in government medical college. It was revealed that 9% doctors were willing to quit medical profession and 23% doctors preferred not to serve patients during pandemic of contagious disease. As many as 58.6% expressed that incidences of doctors facing public harassments abuse and social discrimination dissuaded them from serving COVID-19 patients. A 59.4% and 58.2% of doctors had responsibility of child-care and elderly-care respectively which was acting barrier to ability to serve during the pandemic. As many as 49.2% brought it to light that the infrastructure at their workplace was not up to the mark to deal with COVID-19 patients. Conclusion: This study has brought into light that fear of contracting the disease due to lack of Personal Protective Equipment (PPE), risking one’s family for getting infected, responsibility of child-care and elderly-care along with social ostracism as untouchables are the major deterrents for willingness to work. Distance from workplace, one’s illness and lack of proper infrastructure at workplace are barriers to ability to work during COVID-19 for Indian doctors.

The interaction of host cells with mycobacteria is complex and can lead to multiple outcomes ranging from bacterial clearance to progressive or latent infection. Autophagy is recognized as one component of host cell responses that has an essential role in innate and adaptive immunity to intracellular bacteria. Many microbes, including Mycobacterium tuberculosis, have evolved to evade or exploit autophagy, but the precise mechanisms and virulence factors are mostly unknown. Through a loss-of-function screening of an M. tuberculosis transposon mutant library, we identified 16 genes that contribute to autophagy inhibition, six of which encoded the PE/PPE protein family. Their expression in Mycobacterium smegmatis confirmed that these PE/PPE proteins inhibit autophagy and increase intracellular bacterial persistence or replication in infected cells. These effects were associated with increased mammalian target of rapamycin (mTOR) activity and also with decreased production of tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β). We also confirmed that the targeted deletion of the pe/ppe genes in M. tuberculosis resulted in enhanced autophagy and improved intracellular survival rates compared to those of wild-type bacteria in the infected macrophages. Differential expression of these PE/PPE proteins was observed in response to various stress conditions, suggesting that they may confer advantages to M. tuberculosis by modulating its interactions with host cells under various conditions. Our findings demonstrated that multiple M. tuberculosis PE/PPE proteins are involved in inhibiting autophagy during infection of host phagocytes and may provide strategic targets in developing therapeutics or vaccines against tuberculosis.

BACKGROUND: Rhino-orbito-cerebral mucormycosis(ROCM) is an uncommon yet potentially fatal fungal infection predominantly seen in immunocompromised individuals. However, there is very limited data available from India regarding outcome of patients with ROCM and diabetes mellitus. OBJECTIVE: To ascertain clinical parameters and factors in the final outcome of patients with diabetes mellitus and ROCM. MATERIALS AND METHODS: This series included retrospective analysis of medical records of 91 patients with diabetes mellitus who were diagnosed with ROCM from january 2007 to june 2019 at a tertiary care hospital in Punjab. RESULTS: The mean age of patients was 52.6 years (range 18–82 years), with men constituting the majority (71.4 %). Ophthalmoplegia was the most frequent presenting feature seen in 77 % of patients followed by proptosis (71 %). Intracranial involvement was seen in 20 % of the patients and cavernous sinus thrombosis was diagnosed in 9(10 %) patients. Out of 91 patients, 81 patients were subjected to appropriate surgical procedure depending upon site and extent of involvement by mucorales. A total of 53 (58.2 %) patients survived while 38(41.8 %) patients succumbed. Delay in presentation to hospital, intracranial extension and loss of vision at presentation adversely affected the outcome (p

Cancer cells hijack autophagy pathway to evade anti-cancer therapeutics. Many molecular signaling pathways associated with drug-resistance converge on autophagy induction. Honokiol (HNK), a natural phenolic compound purified from Magnolia grandiflora, has recently been shown to impede breast tumorigenesis and, in the present study, we investigated whether breast cancer cells evoke autophagy to modulate therapeutic efficacy and functional networks of HNK. Indeed, breast cancer cells exhibit increased autophagosomes-accumulation, MAP1LC3B-II/LC3B-II-conversion, expression of ATG proteins as well as elevated fusion of autophagosomes and lysosomes upon HNK treatment. Breast cancer cells treated with HNK demonstrate significant growth inhibition and apoptotic induction, and these biological processes are blunted by macroautophagy/autophagy. Consequently, inhibiting autophagosome formation, abrogating autophagosome-lysosome fusion or genetic-knockout of BECN1 and ATG7 effectively increase HNK-mediated apoptotic induction and growth inhibition. Next, we explored the functional impact of tumor suppressor STK11 in autophagy induction in HNK-treated cells. STK11-silencing abrogates LC3B-II-conversion, and blocks autophagosome/lysosome fusion and lysosomal activity as illustrated by LC3B-Rab7 co-staining and DQ-BSA assay. Our results exemplify the cytoprotective nature of autophagy invoked in HNK-treated breast cancer cells and put forth the notion that a combined strategy of autophagy inhibition with HNK would be more effective. Indeed, HNK and chloroquine (CQ) show synergistic inhibition of breast cancer cells and HNK-CQ combination treatment effectively inhibits breast tumorigenesis and metastatic progression. Tumor-dissociated cells from HNK-CQ treated tumors exhibit abrogated invasion and migration potential. Together, these results implicate that breast cancer cells undergo cytoprotective autophagy to circumvent HNK and a combined treatment with HNK and CQ can be a promising therapeutic strategy for breast cancer.

The present study was designed to develop pH-sensitive lipid polymer hybrid nanoparticles (pHS-LPHNPs) for specific cytosolic-delivery of docetaxel (DTX). The pHS-LPHNPs-DTX formulation was prepared by self-assembled nano-precipitation technique and characterized for zeta potential, particle size, entrapment efficiency, polydispersity index (PDI), and in vitro drug release. In vitro cytotoxicity of pHS-LPHNPs-DTX was assessed on breast cancer cells (MDA-MB-231 and MCF-7) and compared with DTX-loaded conventional LPHNPs and bare DTX. In vitro cellular uptake in MDA-MB-231 cell lines showed better uptake of pHS-LPHNPs. Further, a significant reduction in the IC50 of pHS-LPHNPs-DTX against both breast cancer cells was observed. Flow cytometry results showed greater apoptosis in case of pHS-LPHNPs-DTX treated MDA-MB-231 cells. Breast cancer was experimentally induced in BALB/c female mice, and the in vivo efficacy of the developed pHS-LPHNPs formulation was assessed with respect to the pharmacokinetics, biodistribution in the vital organs (liver, kidney, heart, lungs, and spleen), percentage tumor burden, and survival of breast cancer-bearing animals. In vivo studies showed improved pharmacokinetic and target-specificity with minimum DTX circulation in the deep-seated organs in the case of pHS-LPHNPs-DTX compared to the LPHNPs-DTX and free DTX. Mice treated with pHS-LPHNPs-DTX exhibited a significantly lesser tumor burden than other treatment groups. Also, reduced distribution of DTX in the serum was evident for pHS-LPHNPs-DTX treated mice compared to the LPHNPs-DTX and free DTX. In essence, pHS-LPHNPs mediated delivery of DTX presents a viable platform for developing therapeutic-interventions against breast-cancer.

Dyslipidaemia has a prominent role in the onset of notorious atherosclerosis, a disease of medium to large arteries. Atherosclerosis is the prime root of cardiovascular events contributing to the most considerable number of morbidity and mortality worldwide. Factors like cellular senescence, genetics, clonal haematopoiesis, sedentary lifestyle-induced obesity, or diabetes mellitus upsurge the tendency of atherosclerosis and are foremost pioneers to definitive transience. Accumulation of oxidized low-density lipoproteins (Ox-LDLs) in the tunica intima triggers the onset of this disease. In the later period of progression, the build-up plaques rupture ensuing thrombosis (completely blocking the blood flow), causing myocardial infarction, stroke, and heart attack, all of which are common atherosclerotic cardiovascular events today. The underlying mechanism is very well elucidated in literature but the therapeutic measures remains to be unleashed. Researchers tussle to demonstrate a clear understanding of treating mechanisms. A century of research suggests that lowering LDL, statin-mediated treatment, HDL, and lipid-profile management should be of prime interest to retard atherosclerosis-induced deaths. We shall brief the Ox-LDL-induced atherogenic mechanism and the treating measures in line to impede the development and progression of atherosclerosis.

Objective Little is known about factors affecting medical care experiences of cancer survivors. This study examined experience of care among cancer survivors and assessed associations of survivors' characteristics with their experience. Materials and Methods We used a newly-developed, unique data resource, SEER-CAHPS (NCI's Surveillance Epidemiology and End Results [SEER] data linked to Medicare Consumer Assessment of Healthcare Providers and Systems [CAHPS] survey responses), to examine experiences of care among breast, colorectal, lung, and prostate cancer survivors age > 66 years who completed CAHPS > 1 year after cancer diagnosis and survived ≥ 1 year after survey completion. Experience of care was assessed by survivor-provided scores for overall care, health plan, physicians, customer service, doctor communication, and aspects of care. Multivariable logistic regression models assessed associations of survivors' sociodemographic and clinical characteristics with care experience. Results Among 19,455 cancer survivors with SEER-CAHPS data, higher self-reported general-health status was significantly associated with better care experiences for breast, colorectal, and prostate cancer survivors. In contrast, better mental-health status was associated with better care experience for lung cancer survivors. College-educated and Asian survivors were less likely to indicate high scores for care experiences. Few differences in survivors' experiences were observed by sex or years since diagnosis. Conclusions The SEER-CAHPS data resources allows assessment of factors influencing experience of cancer among U.S. cancer survivors. Higher self-reported health status was associated with better experiences of care; other survivors' characteristics also predicted care experience. Interventions to improve cancer survivors' health status, such as increased access to supportive care services, may improve experience of care.

Objective: This case report will highlight the importance of histopathologic analysis of the gonads to differentiate ovotesticular disorder of sexual development (OT-DSD) from mixed gonadal dysgenesis. Both disorders may have the same clinical and cytogenetic presentation, but the latter presents high risk for gonadal malignancy, hence there is usually a need for early gonadectomy, while the former has a low risk for malignancy. Therefore OT-DSD patients may have the opportunity for spontaneous pubertal development and fertility with regular tumor surveillance.Methods: We report the case of a 22-year-old patient reared as a male with a 46,XY karyotype diagnosed as OT-DSD by gonadal biopsy. The patient presented with microphallus with chordee, penoscrotal hypospadias, poor virilization, and development of gynecomastia at puberty.Results: Histopathologic examination of the single tubule biopsy of the left gonad showed seminiferous tubules lined by Sertoli cells and Leydig cells in the interstitial space. Biopsy of the right gonad showed an ovary with Graafian follicles and fallopian tubes. There was also a uterus with the endometrium in the proliferative phase.Conclusion: OT-DSD is a rare disorder of sexual development characterized by the presence of both ovarian tissue with mature ovarian follicles as well as testicular tissue with distinct seminiferous tubules. These may present either in the same gonad or separately as opposite-side gonads in the same individual. It is associated with variable genotypes of which the most common karyotype is 46,XX with the 46,XY karyotype found in only 10% of cases.Abbreviations: DSD Disorder of sexual development OT-DSD ovotesticular disorder of sexual development

Lipid metabolism forms the heart and soul of Mycobacterium tuberculosis life cycle. Starting from macrophage invasion at cholesterol rich micro-domains to a sustainable survival for infection by utilizing cholesterol, Mycobacterium displays the nexus of metabolic pathways around host derived lipids. mce4 operon acts as cholesterol import system in M. tuberculosis and here we demonstrate role of mce4A gene of this operon in cholesterol catabolism. Here M. tuberculosis H37Rv overexpressing Rv3499c (mce4A) recombinant was used as a model to decipher the metabolic flux during intake and utilization of host lipids by mycobacteria. We analysed the impact of mce4A expression on carbon shift initiated during cholesterol utilization necessary for long term survival of mycobacterium. Through transcriptional analysis, upregulation in methylcitrate cycle (MCC) and methylmalonyl pathway (MMP) genes was observed in Rv3499c overexpressing recombinants of M. tuberculosis H37Rv. Up-regulation of methylmalonyl pathway associated enzyme encoding genes increased accumulation of virulence associated mycobacterial lipids phthiocerol dimycocerates (PDIM) and sulfolipid (SL1). We demonstrate that MCC and MMP associated enzyme encoding genes are upregulated upon mce4A overexpression and lead to enhanced accumulation of PDIM and SL1 which are responsible for pathogenicity of M. tuberculosis.

Background and Objectives: Type 2 diabetes is a multifactorial disorder that results from the interaction between genetic predisposition and environmental factors. Different Prakriti (body constitution) individuals have different susceptibility for the diseases, and this Prakriti is determined by both genetic and environmental factor. This study was undertaken to determine the association status of Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C with type 2 diabetes and Prakriti. Materials and Methods: After informed consent, 54 patients with type 2 diabetes and 56 individuals as normal controls were analyzed. Their constitution and pathological data were collected and MTHFR C677T and A1298C genotypes were determined. Results: Kapha/Kapha-Pittaja Prakriti were associated and found to be strong risk factors (Chi-square test = 39.67, P < 0.00001, odds ratio [OR] = 16.133, 95% confidence interval [CI] = 6.32–41.20) for type 2 diabetes. MTHFR C677T was associated (Chi-square test = 7.743, P = 0.02) with type 2 diabetes where the major CC genotype was found to be a risk for type 2 diabetes (OR = 3.78, 95% CI = 1.14–12.45). A1298C was not associated with type 2 diabetes (Chi-square test = 2.264, P = 0.322). None of the Prakriti was associated with C677T and A1298C variants. Interpretation and Conclusion: In the present study, an extremely strong association between Prakriti (Kaphaja/Kapha-Pittaja) and type 2 diabetes (P < 0.00001) was detected. The present study gives a strong clue for the association of Prakriti (body constitutional) and clinical phenotype.

Tumor suppressor and upstream master kinase Liver kinase B1 (LKB1) plays a significant role in suppressing cancer growth and metastatic progression. We show that low-LKB1 expression significantly correlates with poor survival outcome in breast cancer. In line with this observation, loss-of-LKB1 rendered breast cancer cells highly migratory and invasive, attaining cancer stem cell-like phenotype. Accordingly, LKB1-null breast cancer cells exhibited an increased ability to form mammospheres and elevated expression of pluripotency-factors (Oct4, Nanog and Sox2), properties also observed in spontaneous tumors in Lkb1−/− mice. Conversely, LKB1-overexpression in LKB1-null cells abrogated invasion, migration and mammosphere-formation. Honokiol (HNK), a bioactive molecule from Magnolia grandiflora increased LKB1 expression, inhibited individual cell-motility and abrogated the stem-like phenotype of breast cancer cells by reducing the formation of mammosphere, expression of pluripotency-factors and aldehyde dehydrogenase activity. LKB1, and its substrate, AMP-dependent protein kinase (AMPK) are important for HNK-mediated inhibition of pluripotency factors since LKB1-silencing and AMPK-inhibition abrogated, while LKB1-overexpression and AMPK-activation potentiated HNK’s effects. Mechanistic studies showed that HNK inhibited Stat3-phosphorylation/activation in an LKB1-dependent manner, preventing its recruitment to canonical binding-sites in the promoters of Nanog, Oct4 and Sox2. Thus, inhibition of the coactivation-function of Stat3 resulted in suppression of expression of pluripotency factors. Further, we showed that HNK inhibited breast tumorigenesis in mice in an LKB1-dependent manner. Molecular analyses of HNK-treated xenografts corroborated our in vitro mechanistic findings. Collectively, these results present the first in vitro and in vivo evidence to support crosstalk between LKB1, Stat3 and pluripotency factors in breast cancer and effective anticancer modulation of this axis with HNK treatment.

Aim: The aim of present research was to complex aceclofenac with lysine (LYS) and the developed aceclofenac–LYS cocrystal was encapsulated in lipid bilayers of liposomes by employing dual carrier approach for the treatment of pain-related disorders in rheumatoid arthritis (RA). Materials & methods: The developed carriers were characterized for particle size, drug release, ex vivo and in vivo studies, dermatokinetic modeling, complete freund's adjuvant (CFA)-induced RA rat model, radiant heat tail-flick method, formalin-induced paw-licking model, paw edema model and xylene-induced ear edema model in mice. Results: The developed nanoliposomes offered nanometric size, controlled drug release and enhanced drug permeation. Further, hydrogel incorporated nanoproduct was found to be rheologically acceptable and substantially compatible with rodent skin. Conclusion: The studies indicated the superiority of LYS-conjugated liposome-entrapped nanocarriers for improved management of conditions like RA over the marketed product.

The p53 inhibitor Mdm4 is present at high levels in multiple human cancers. Overexpression of Mdm4 in mice drives the spontaneous development of mostly lymphomas and sarcomas. In this study, we explored the ability of Mdm4 to cooperate with lesions in tumour development. The Mdm4 transgene contributed to mammary tumour development in a BALB/cJ background. High levels of Mdm4 enhanced tumour development in a mutant p53R172H heterozygous background, and reduced the need to lose the wild-type p53 allele, as compared with mice heterozygous only for the p53R172H mutation. Additionally, high levels of Mdm4 cooperated with an oncogenic K-ras mutation to drive lung tumourigenesis in vivo. Finally, we examined p53-independent functions of Mdm4 by studying the contribution of Mdm4 to tumour development in the absence of p53. Whereas the overall survival times of p53-null mice with and without the Mdm4 transgene were similar, male mice with both alterations showed significantly shorter survival than p53-null male mice, and showed differences in tumour spectrum, demonstrating a p53-independent function of Mdm4 in tumourigenesis. Furthermore, p53-null mice with the highest level of Mdm4 tended to have multiple tumours. Thus, a detailed analysis of Mdm4 transgenic mice in various genetic backgrounds shows synergy in tumour development in vivo. Mdm4 may thus serve as a therapeutic target in cancers. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

PURPOSE Pain, fatigue, and distress are common among patients with cancer but are often underassessed and undertreated. We examine the prevalence of pain, fatigue, and emotional distress among patients with cancer, as well as patient perceptions of the symptom care they received. PATIENTS AND METHODS Seventeen Commission on Cancer–accredited cancer centers across the United States sampled patients with local/regional breast (82%) or colon (18%) cancer. We received 2,487 completed surveys (61% response rate). RESULTS Of patients, 76%, 78%, and 59% reported talking to a clinician about pain, fatigue, and distress, respectively, and 70%, 61%, and 54% reported receiving advice. Sixty-one percent of patients experienced pain, 74% fatigue, and 46% distress. Among those patients experiencing each symptom, 58% reported getting the help they wanted for pain, 40% for fatigue, and 45% for distress. Multilevel logistic regression models revealed that patients experiencing symptoms were significantly more likely to have talked about and received advice on coping with these symptoms. In addition, patients who were receiving or recently completed curative treatment reported more symptoms and better symptom care than did those who were further in time from curative treatment. CONCLUSION In our sample, 30% to 50% of patients with cancer in community cancer centers did not report discussing, getting advice, or receiving desired help for pain, fatigue, or emotional distress. This finding suggests that there is room for improvement in the management of these three common cancer-related symptoms. Higher proportions of talk and advice among those experiencing symptoms imply that many discussions may be patient initiated. Lower rates of talk and advice among those who are further in time from treatment suggest the need for more assessment among longer-term survivors, many of whom continue to experience these symptoms. These findings seem to be especially important given the high prevalence of these symptoms in our sample.

Dicer1 functions as a tumor suppressor in mouse models. In humans, somatic mutations are associated with many cancers in adults, and patients with DICER1 syndrome with DICER1 germline mutations are susceptible to childhood cancers. Dicer is phosphorylated by the ERK-MAP kinase pathway and because this pathway is activated in human cancers, we asked whether phosphorylated Dicer1 contributed to tumor development. In human endometrioid cancers, we discovered that phosphorylated DICER1 is significantly associated with invasive disease. To test a direct involvement of Dicer1 phosphorylation in tumor development, we studied mice with phosphomimetic alterations at the two conserved serines phosphorylated by ERK and discovered that a phosphomimetic Dicer1 drives tumor development and dissemination in two independent murine cancer models (KRas+/LA1 and p53+/−). Our findings demonstrate that phosphomimetic Dicer1 promotes tumor development and invasion. Significance: This work highlights the relevance of Dicer1 phosphorylation in mammalian tumor development and dissemination.

The prognosis in breast cancer is worse in younger patients, invasive papillary, classic lobular and medullary cancers, tumors more than 1 cm in diameter, four or more positive axillary node and es...

Rheumatoid arthritis (RA), an autoimmune and inflammatory pathology, is resulted due to the disruption of immune-homeostasis and failure of host immune-surveillance mechanism leading to cartilage degradation and bone erosion. Orally and parenterally administered methotrexate (MTX) have had adverse systemic complications in RA therapeutics. Therefore, transdermal application of MTX is recommended for the treatment of RA [1]. Present study is designed to develop MTX loaded nanostructured lipid carriers and chemical enhancer co-incorporated hydrogel (gel-(MTX-NLCs+CE)) for an efficient transdermal delivery of MTX in a Freund's adjuvants induced experimental animal model of RA. A gel-(MTX-NLCs+CE) was formulated and evaluated for its biocompatibility in hyper keratinocytes (HaCaT) and human monocytic cells (U937). Further, systemic and local inflammation was assessed by the estimation of pro-inflammatory cytokines & joint-destructive enzymes (TNF-α, IL-6, MMP-1 & IL-1β,; iNOS & COX-2) in the serum and synovial fluid, respectively in an experimentally induced RA animal model. Prepared formulations were also evaluated with respect to arthritis index, arthritis score and histopathology of paw and ankle bones. The biocompatibility study of formulation on U937 and HaCaT is suggestive of safe and greater therapeutic efficacy of the developed formulations. Our results show that transcutaneous ability of MTX loaded nanostructured lipid carries (NLCs) and chemical enhancer (CE) co-incorporated hydrogel significantly (p

The present study was designed to engineer surface-anchored and methotrexate loaded lipobrid nano-constructs for targeting breast cancer. Ligands (fucose, galactose and mannose) anchored lipobrid nano-constructs were used to compare and assess delivery efficiency in breast cancer cell lines as well as in DMBA induced breast cancer animal model. The developed and characterized formulations were used to comparatively assess cellular uptake, cell-viability, apoptosis, lysosomal membrane permeability, bioavailability, bio-distribution, changes in tumor volume and animal survival. Our results show greater cellular uptake, cytotoxicity at low IC50, apoptosis with altered lysosomal membrane permeability and greater rate of degradation of lysosomal membrane. We saw better bioavailability and tumor targeting efficiency with minimum secondary organ drug distribution. The significant reduction was seen in tumor burden with ligand anchored lipobrids in comparison to plain and MTX-lipobrid formulations. In conclusion, fucose anchored MTX-lipobrid formulation showed promising results, and warrants to explore the development of therapeutic interventions for breast cancer.

In May 2015, the Cancer and Aging Research Group, in collaboration with the National Cancer Institute and the National Institute on Aging through a U13 grant, convened a conference to identify research priorities to help design and implement intervention studies to improve the quality of life and survivorship of older, frailer adults with cancer. Conference attendees included researchers with multidisciplinary expertise and advocates. It was concluded that future intervention trials for older adults with cancer should: 1) rigorously test interventions to prevent the decline of or improve health status, especially interventions focused on optimizing physical performance, nutritional status, and cognition while undergoing cancer treatment; 2) use standardized care plans based on geriatric assessment findings to guide targeted interventions; and 3) incorporate the principles of geriatrics into survivorship care plans. Also highlighted was the need to integrate the expertise of interdisciplinary team members into geriatric oncology research, improve funding mechanisms to support geriatric oncology research, and disseminate high-impact results to the research and clinical community. In conjunction with the 2 prior U13 meetings, this conference provided the framework for future research to improve the evidence base for the clinical care of older adults with cancer. Cancer 2016;122:2459-68. © 2016 American Cancer Society.

Type 2 diabetes mellitus (T2DM) is characterized by persistent hyperglycemia which causes a chain of abrupt biochemical and physiological changes. Immune dys-regulation is the hallmark of T2DM that could contribute to prolonged inflammation causing transformation of wounds into non-healing chronic ulcers. Toll like receptor -9 (TLR9) is a major receptor involved in innate immune regulation. TLR9 activation induces release of pro-inflammatory molecules like S100A8 and interleukin-8 (IL-8) by myeloid cells causing migration of myeloid cells to the site of inflammation. We hypothesized that pro-inflammatory S100A8 and IL-8 proteins could cause persistent inflammation in chronic wounds like diabetic foot ulcer (DFU) and may contribute to impaired wound healing in T2DM patients.Expression of TLR9 and its downstream effector molecules S100A8, and IL-8 were analyzed in chronic diabetic wound and non-diabetic control wound tissue samples by semiquantitative reverse transcriptase - polymerase chain reaction (RT-PCR), quantitative RT-PCR, western blot and immunofluorescence. CD11b(+)CD33(+) myeloid cells were analyzed by flow cytometry.TLR9 message and protein were higher in diabetic wounds compared to control wounds (p=0.03, t=2.21 for TLR9 mRNA; p=0.001, t=4.21 for TLR9 protein). TLR9 down-stream effector molecules S100A8 and IL-8 were also increased in diabetic wounds (p=0.003, t=3.1 for S100A8 mRNA; p=0.04, t=2.04 for IL-8). CD11b(+) CD33(+) myeloid cells were decreased in T2DM as compared to non-diabetic controls (p=0.001, t=3.6). DFU subjects had higher levels of CD11b(+) CD33(+) myeloid cells as compared to non-DFU T2DM control (p=0.003, t=2.8). Infection in the wound microenvironment could be the cause of increase in CD11b(+)CD33(+) myeloid cells in DFU (p=0.03, t=2.5).The up-regulation of myeloid cell-derived pro-inflammatory molecules S100A8 and IL-8 in combination with lower levels of CD11b(+) CD33(+) myeloid cells may cause the impairment of wound healing in T2DM subjects leading to chronic ulcers.

Under a Creative Commons license.-- Review.-- et al., Targeted therapies and the consequent adoption of >personalized> oncology have achieved notablesuccesses in some cancers; however, significant problems remain with this approach. Many targetedtherapies are highly toxic, costs are extremely high, and most patients experience relapse after a fewdisease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistantimmortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are notreliant upon the same mechanisms as those which have been targeted). To address these limitations, aninternational task force of 180 scientists was assembled to explore the concept of a low-toxicity >broad-spectrum> therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspectsof relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a widerange of high-priority targets (74 in total) that could be modified to improve patient outcomes. For thesetargets, corresponding low-toxicity therapeutic approaches were then suggested, many of which werephytochemicals. Proposed actions on each target and all of the approaches were further reviewed forknown effects on other hallmark areas and the tumor microenvironment. Potential contrary or procar-cinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixedevidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of therelationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. Thisnovel approach has potential to be relatively inexpensive, it should help us address stages and types ofcancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for futureresearch is offered., Amr Amin was funded by Terry Fox Foundation Grant # TF-13-20 and UAEU Program for Advanced Research (UPAR) #31S118; Jack Arbiser was funded by NIHAR47901; Alexandra Arreola was funded by NIH NRSA Grant F31CA154080; Alla Arzumanyan was funded by NIH (NIAID) R01: Combination therapies for chronic HBV, liver disease, and cancer (AI076535); Work in the lab of Asfar S. Azmi is supported by NIH R21CA188818 as well as from Sky Foundation Inc. Michigan; Fabian Benencia was supported by NIH Grant R15 CA137499-01; Alan Bilsland was supported by the University of Glasgow, Beatson Oncology Centre Fund, CRUK (www.cancerresearchuk.org) Grant C301/A14762; Amancio Carnero was supported by grants from the Spanish Ministry of Economy and Competitivity, ISCIII (Fis: PI12/00137, RTICC: RD12/0036/0028) co-funded by FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion (CTS-6844 and CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0135-2010 and PI-0306-2012). His work on this project has also been made possible thanks to the Grant PIE13/0004 co-funded by the ISCIII and FEDER funds; Stephanie C. Casey was supported by NIH Grant F32CA177139; Mrinmay Chakrabarti was supported by the United Soybean Board; Rupesh Chaturvedi was supported by an NIH NCCAM Grant (K01AT007324); Georgia Zhuo Chen was supported by an NIH NCI Grant (R33 CA161873-02); Helen Chen acknowledges financial support from the Michael Cuccione Childhood Cancer Foundation Graduate Studentship; Sophie Chen acknowledges financial support from the Ovarian and Prostate Cancer Research Trust, UK; Yi Charlie Chen acknowledges financial support from the West Virginia Higher Education Policy Commission/Division of Science Research, his research was also supported by NIH grants (P20RR016477 and P20GM103434) from the National Institutes of Health awarded to the West Virginia IDeA Network of Biomedical Research Excellence; Maria Rosa Ciriolo was partially supported by the Italian Association for Cancer Research (AIRC) Grants #IG10636 and #15403; Helen M. Coley acknowledges financial support from the GRACE Charity, UK and the Breast Cancer Campaign, UK; Marisa Connell was supported by a Michael Cuccione Childhood Cancer Foundation Postdoctoral Fellowship; Sarah Crawford was supported by a research grant from Connecticut State University; Charlotta Dabrosin acknowledges financial support from the Swedish Research Council and the Swedish Research Society; Giovanna Damia gratefully acknowledges the generous contributions of The Italian Association for Cancer Research (IG14536 to G.D.), Santanu Dasgupta gratefully acknowledges the support of the University of Texas Health Science Centre at Tyler, Elsa U. Pardee Foundation; William K. Decker was supported in part by CPRIT, the Cancer Prevention and Research Institute of Texas; Anna Mae E. Diehl was supported by NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the NIH National Institute on Alcohol Abuse and Alcoholism (NIAAA), Gilead and Shire Pharmaceuticals; Q. Ping Dou was partially supported by NIH/NCI (1R01CA20009, 5R01CA127258-05 and R21CA184788), and NIH P30 CA22453 (to Karmanos Cancer Institute); Janice E. Drew was supported by the Scottish Government's Rural and Environment Science and Analytical Services Division; Eyad Elkord thanks the National Research Foundation, United Arab Emirates University and the Terry Fox Foundation for supporting research projects in his lab; Bassel El-Rayes was supported by Novartis Pharmaceutical, Aveo Pharmaceutical, Roche, Bristol Myers Squibb, Bayer Pharmaceutical, Pfizer, and Kyowa Kirin; Mark A. Feitelson was supported by NIH/NIAID Grant AI076535, Dean W. Felsher was supported by NIH grants (R01CA170378, U54CA149145, and U54CA143907); Lynnette R Ferguson was financially supported by the Auckland Cancer Society and the Cancer Society of New Zealand; Gary L. Firestone was supported by NIH Public Service Grant CA164095 awarded from the National Cancer Institute; Christian Frezza “would like to acknowledge funding from a Medical Research Council CCU-Program Grant on cancer metabolism, and a unique applicant AICR project grant”; Mark M. Fuster was supported by NIH Grant R01-HL107652; Alexandros G. Georgakilas was supported by an EU Marie Curie Reintegration Grant MC-CIG-303514, Greek National funds through the Operational Program ‘Educational and Lifelong Learning of the National Strategic Reference Framework (NSRF)-Research Funding Program THALES (Grant number MIS 379346) and COST Action CM1201 ‘Biomimetic Radical Chemistry’; Michelle F. Green was supported by a Duke University Molecular Cancer Biology T32 Training Grant; Brendan Grue was supported by a National Sciences Engineering and Research Council Undergraduate Student Research Award in Canada; Dorota Halicka was supported by by NIH NCI grant NCI RO1 28704; Petr Heneberg was supported by the Charles University in Prague projects UNCE 204015 and PRVOUK P31/2012, by the Czech Science Foundation projects 15-03834Y and P301/12/1686, by the Czech Health Research Council AZV project 15-32432A, and by the Internal Grant Agency of the Ministry of Health of the Czech Republic project NT13663-3/2012; Matthew D. Hirschey wishes to acknowledge Duke University Institutional Support, the Duke Pepper Older Americans Independence Center (OAIC) Program in Aging Research supported by the National Institute of Aging (P30AG028716-01) and NIH/NCI training grants to Duke University (T32-CA059365-19 and 5T32-CA059365), Lorne J. Hofseth was supported by NIH grants (1R01CA151304, 1R03CA1711326, and 1P01AT003961); Kanya Honoki was supported in part by the grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan (No. 24590493); Hsue-Yin Hsu was supported in part by grants from the Ministry of Health and Welfare (CCMP101-RD-031 and CCMP102-RD-112) and Tzu-Chi University (61040055-10) of Taiwan; Lasse D. Jensen was supported by Svenska Sallskapet for Medicinsk Forskning, Gosta Fraenkels Stiftelse, Ak.e Wibergs Stiftelse, Ollie och Elof Ericssons Stiftelse, Linkopings Universitet and the Karolinska Institute, Sweden; Wen G. Jiang wishes to acknowledge the support by Cancer Research Wales, the Albert Hung Foundation, the Fong Family Foundation, and Welsh Government A4B scheme; Lee W. Jones was supported in part by grants from the NIH NCI; W Nicol Keith was supported by the University of Glasgow, Beatson Oncology Centre Fund, CRUK (www.cancerresearchuk.org) Grant C301/A14762; Sid P. Kerkar was supported by the NIH Intramural Research Program; Rob J. Kulathinal was supported by the National Science Foundation, and the American Cancer Society; Byoung S. Kwon was supported in part by National Cancer Center (NCC-1310430-2) and National Research Foundation (NRF-2005-0093837); Anne Le was supported by Sol Goldman Pancreatic Cancer Research Fund Grant 80028595, a Lustgarten Fund Grant 90049125 and Grant NIHR21CA169757 (to Anne Le); Michael A. Lea was funded by the The Alma Toorock Memorial for Cancer Research; Ho-Young Lee., This work was supported by grants from the National Research Foundation of Korea (NRF), the Ministry of Science, ICT & Future Planning (MSIP), Republic of Korea (Nos. 2011-0017639 and 2011-0030001) and by a NIH Grant R01 CA100816; Liang-Tzung Lin was supported in part by a grant from the Ministry of Education of Taiwan (TMUTOP103005-4); Jason W. Locasale acknowledges support from NIH awards (CA168997 and AI110613) and the International Life Sciences Institute; Bal L. Lokeshwar was supported in part by United States’ Public Health Services Grants: NIH R01CA156776 and VA-BLR&D Merit Review Grant No. 5I01-BX001517-02; Valter D. Longo acknowledges support from NIH awards (P01AG034906 and R01AG020642) and from the V Foundation; Costas A. Lyssiotis was funded in part by the Pancreatic Cancer Action Network as a Pathway to Leadership Fellow and through a Dale F. Frey Breakthrough award from the Damon Runyon Cancer Research Foundation; Karen L. MacKenzie wishes to acknowledge the support from the Children's Cancer Institute Australia (affiliated with the University of New South Wales, Australia and the Sydney Children's Hospital Network); Maria Marino was supported by grant from University Roma Tre to M.M. (CLA 2013) and by the Italian Association for Cancer Research (AIRC-Grant #IG15221), Ander Matheu is funded by Carlos III Health Institute (AM: CP10/00539), Basque Foundation for Science (IKERBASQUE) and Marie Curie CIG Grant (AM: 2012/712404); Christopher Maxwell was supported by funding from the Canadian Institutes of Health Research, in partnership with the Avon Foundation for Women (OBC-134038) and the Canadian Institutes of Health Research New Investigator Salary Award (MSH-136647); Eoin McDonnell received Duke University Institutional Support; Kapil Mehta was supported by Bayer Healthcare System G4T (Grants4Targets); Gregory A. Michelotti received support from NIH NIDDK, NIH NIAAA, and Shire Pharmaceuticals; Vinayak Muralidhar was supported by the Harvard-MIT Health Sciences and Technology Research Assistantship Award; Elena Niccolai was supported by the Italian Ministry of University and the University of Italy; Virginia R. Parslow gratefully acknowledges the financial support of the Auckland Cancer Society Research Centre (ACSRC); Graham Pawelec was supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF) Grant number 16SV5536K, and by the European Commission (FP7 259679 “IDEAL”); Peter L. Pedersen was supported by NIH Grant CA-10951; Brad Poore was supported by Sol Goldman Pancreatic Cancer Research Fund Grant 80028595, the Lustgarten Fund Grant 90049125, and Grant NIHR21CA169757 (to Anne Le); Satya Prakash was supported by a Canadian Institutes of Health Research Grant (MOP 64308); Lizzia Raffaghello was supported by an NIH Grant (P01AG034906-01A1) and Cinque per Mille dell’IRPEF–Finanziamento della Ricerca Sanitaria; Jeffrey C. Rathmell was supported by an NIH Grant (R01HL108006); Swapan K. Ray was supported by the United Soybean Board; Domenico Ribatti received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under Grant agreement n°278570; Luigi Ricciardiello was supported by the AIRC Investigator Grants 10216 and 13837, and the European Community's Seventh Framework Program FP7/2007–2013 under Grant agreement 311876; Francis Rodier acknowledges the support of the Canadian Institute for Health Research (FR: MOP114962, MOP125857), Fonds de Recherche Québec Santé (FR: 22624), and the Terry Fox Research Institute (FR: 1030), Gian Luigi Russo contributed to this effort while participating in the Fulbright Research Scholar Program 2013–14; Isidro Sanchez-Garcia is partially supported by FEDER and by MICINN (SAF2012-32810), by NIH Grant (R01 CA109335-04A1), by Junta de Castilla y León (BIO/SA06/13) and by the ARIMMORA project (FP7-ENV-2011, European Union Seventh Framework Program). Isidro Sanchez-Garcia's lab is also a member of the EuroSyStem and the DECIDE Network funded by the European Union under the FP7 program; Andrew J. Sanders wishes to acknowledge the support by Cancer Research Wales, the Albert Hung Foundation, the Fong Family Foundation, and Welsh Government A4B scheme; Neeraj K. Saxena was supported by grant funding from NIH NIDDK (K01DK077137, R03DK089130); Dipali Sharma was partially funded by NIH NCI grants (R01CA131294, R21 CA155686), the Avon Foundation and a Breast Cancer Research Foundation Grant (90047965); Markus David Siegelin received funding from National Institute of Health, NINDS Grant K08NS083732, and the 2013 AACR-National Brain Tumor Society Career Development Award for Translational Brain Tumor Research, Grant Number 13-20-23-SIEG; Neetu Singh was supported by funds from the Department of Science and Technology (SR/FT/LS-063/2008), New Delhi, India; Carl Smythe was supported by Yorkshire Cancer Research and The Wellcome Trust, UK; Carmela Spagnuolo was supported by funding from Project C.I.S.I.A., act n. 191/2009 from the Italian Ministry of Economy and Finance Project CAMPUS-QUARC, within program FESR Campania Region 2007/2013, objectives 2.1, 2.2; Diana M. Stafforini was supported by grants from the National Cancer Institute (5P01CA073992), IDEA Award W81XWH-12-1-0515 from the Department of Defense, and by the Huntsman Cancer Foundation; John Stagg was supported by the Canadian Institutes of Health Research; Pochi R. Subbarayan was supported by the University of Miami Clinical and Translational Science Institute (CTSI) Pilot Research Grant (CTSI-2013-P03) and SEEDS You Choose Awards; Phuoc T. Tran was funded by the DoD (W81XWH-11-1-0272 and W81XWH-13-1-0182), a Kimmel Translational Science Award (SKF-13-021), an ACS Scholar award (122688-RSG-12-196-01-TBG) and the NIH (R01CA166348); Kathryn E. Wellen receives funding from the National Cancer Institute, Pancreatic Cancer Action Network, Pew Charitable Trusts, American Diabetes Association, and Elsa U. Pardee Foundation; Huanjie Yang was partially supported by the Scientific Research Foundation for the Returned Oversea Scholars, State Education Ministry and Scientific and Technological Innovation Project, Harbin (2012RFLXS011), Paul Yaswen was supported by funding from the United States National Institutes of Health (ES019458) and the California Breast Cancer Research Program (17UB-8708); Clement Yedjou was supported by a grant from the National Institutes of Health (Grant # G1200MD007581), through the RCMI-Center for Environmental Health; Xin Yin was supported by NIH/National Heart, Lung, and Blood Institute Training Grant T32HL098062.; Jiyue Zhu was supported by NIH Grant R01GM071725; Massimo Zollo was supported by the European FP7-TuMIC HEALTH-F2-2008-201662, the Italian Association for Cancer research (AIRC) Grant IG # 11963 and the Regione Campania L.R:N.5, the European National Funds PON01-02388/1 2007-2013.

Background Bacillus species are known to cause severe infection in immunocompromised hosts. The incidence of Bacillus bloodstream infections and characteristics of infection among children with cancer or indication for hematopoietic cell transplant (HCT) is unknown. Methods We performed a retrospective medical record review of all cases of Bacillus bacteremia between January 1, 2005, and December 31, 2014, at Boston Children's Hospital. We report average incidences from 2012 to 2014. We performed a detailed review of infections among children with cancer or undergoing HCT and a case-control study to evaluate whether neutropenia at diagnosis caries higher risk of Bacillus infection for children with acute lymphoblastic leukemia (ALL). Results One hundred fourteen children developed Bacillus bacteremia during the study period, with an estimated incidence of 0.27/1,000 patients. Among children treated for cancer or undergoing HCT, there were 37 bloodstream infections (2.0/1,000 patients). Of the 37 oncology/HCT patients, oncologic diagnoses included ALL (18), acute myeloid leukemia (3), myelodysplastic syndrome (1), solid tumors (8), and 7 children were undergoing HCT. The incidence of infection among children with ALL was 34/1,000 patients and all central nervous system (CNS) infections (6) and deaths (3) occurred in this population. Neutropenia at time of diagnosis in children with ALL was not associated with risk of infection (P = 0.17). Discussion We report the first hospital-wide analysis of Bacillus infection and found that immunocompromised children experience a significant proportion of Bacillus infections. Children with ALL have a high incidence of infection and are at higher risk of CNS involvement and death.

Insulin resistance (IR) is a harbinger of type 2 diabetes (T2D) and partly determined by genetic factors. However, genetically regulated mechanisms of IR remain poorly understood. Using gene expression, genotype, and insulin sensitivity data from the African American Genetics of Metabolism and Expression (AAGMEx) cohort, we performed transcript-wide correlation and expression quantitative trait loci (eQTL) analyses to identify IR-correlated cis-regulated transcripts (cis-eGenes) in adipose tissue. These IR-correlated cis-eGenes were tested in the European ancestry individuals in the Metabolic Syndrome in Men (METSIM) cohort for trans-ethnic replication. Comparison of Matsuda index–correlated transcripts in AAGMEx with the METSIM study identified significant correlation of 3,849 transcripts, with concordant direction of effect for 97.5% of the transcripts. cis-eQTL for 587 Matsuda index–correlated genes were identified in both cohorts. Enoyl-CoA hydratase domain-containing 3 (ECHDC3) was the top-ranked Matsuda index–correlated cis-eGene. Expression levels of ECHDC3 were positively correlated with Matsuda index, and regulated by cis-eQTL, rs34844369 being the top cis-eSNP in AAGMEx. Silencing of ECHDC3 in adipocytes significantly reduced insulin-stimulated glucose uptake and Akt Ser473 phosphorylation. RNA sequencing analysis identified 691 differentially expressed genes in ECHDC3-knockdown adipocytes, which were enriched in γ-linolenate biosynthesis, and known IR genes. Thus, our studies elucidated genetic regulatory mechanisms of IR and identified genes and pathways in adipose tissue that are mechanistically involved in IR.

Ethnopharmacological relevance Ensete superbum (Roxb.) Cheesman. (Family: Musaceae), commonly known as “Wild Banana” is well recorded as popular ethnomedicine for medicinal and nutritional uses by different people and communities native to India, Ethiopia, Thailand, Myanmar and Vietnam. Aim of the review Despite the wide ethnomedicinal and pharmacological studies on E. superbum, there are no concise elaborated article comprising reviews of published literature. So, herein we designed this review article to discuss the current ethnopharmacology, pharmacognosy, phytochemistry, pharmacology and intellectual property status of E. superbum. Materials and methods Exhaustive literature searches were performed on E. superbum through various scientific and patent search engines such as Google Scholar, Scopus, PubMed, USPTO, Google patents, and Espacenet, using different keywords for screening of relevant information. Results E. superbum was recorded in different regions of the world for ailments such as dog bite, calculi, semen production, abortion, leucorrhoea, stomachache, immune response, pain, diabetes, psychosomatic, contraceptive, umbilical cord care, convulsions, pneumonia, cholera, labor and delivery pain, dehydration, appendicitis, chickenpox, measles, urinary problems, food poisoning, snake bites, diarrhoea, dysentery, jaundice, bone fracture, infections, fever, asthma, hiccups and leucoderma. Major bioactive phytochemicals such as triterpenoid esters, proanthocyanidin, pro-pelargonidin glucosides, pelargonidin, anigorufone, hydroxyanigorufone, β-carboline alkaloids and fractions such as VIDR-2T, VIDR-2GC, VIDR-2GD were reported. Pharmacologically, E. superbum was found to be non-toxic (LD50 = 3235.9 mg/kg) and has been reported to possesses antiurolithiatic, antidiabetic, antifertility, anti-estrogenic, antiviral, cardiovascular and anti-inflammatory activities. Conclusions E. superbum could be an excellent source of safe and effective medicinal and nutritional herbal remedies for human and animal consumption.

CONTEXT: Excessive body iron stores are a risk factor for decreased insulin sensitivity (S(I)) and diabetes. We hypothesized that transcriptional dysregulation of genes involved in iron metabolism in adipocytes causes insulin resistance. OBJECTIVE AND DESIGN: To define the genetic regulation of iron metabolism and its role in S(I), we used gene expression, genotype, and S(I) data from an African American cohort (N = 256). Replication studies were performed in independent European ancestry cohorts. In vitro studies in human adipocytes were performed to define the role of a selected gene in causing insulin resistance. RESULTS: Among 62 transcripts representing iron homeostasis genes, expression of 30 in adipose tissue were correlated with S(I). Transferrin (TF) and ferritin heavy polypeptide were most positively and negatively associated with S(I), respectively. These observations were replicated in two independent European ancestry adipose data sets. The strongest cis-regulatory variant for TF expression (rs6785596; P = 7.84 × 10(−18)) was identified in adipose but not muscle or liver tissue. Variants significantly affected the normal relationship of serum ferritin to insulin resistance. Knockdown of TF in differentiated Simpson-Golabi-Behmel syndrome adipocytes by short hairpin RNA decreased intracellular iron, reduced maximal insulin-stimulated glucose uptake, and reduced Akt phosphorylation. Knockdown of TF caused differential expression of 465 genes, including genes involved in glucose transport, mitochondrial function, Wnt-pathway/ S(I), chemokine activity, and obesity. Iron chelation recapitulated key changes in the expression profile induced by TF knockdown. CONCLUSION: Genetic regulation of TF expression in adipose tissue plays a novel role in regulating S(I).

Study question Do methylation changes in sperm DNA correlate with infertility? Study answer Loss of spermatogenesis and fertility was correlated with 1680 differentially-methylated CpGs (DMCs) across 1052 genes. What is known already Methylation changes in a number of genes have been correlated with reduced sperm count and motility. Study design, size, duration This case-control study used spermatozoal DNA from 38 oligo-/oligoastheno-zoospermic infertile patients and 26 normozoospermic fertile men. Participants/materials, settings, methods Genome-wide methylation analysis was undertaken using 450 K BeadChip on spermatozoal DNA from six infertile and six fertile men to identify DMCs. This was followed by deep sequencing of spermatozoal DNA from 32 infertile patients and 20 fertile controls. Main results and the role of chance A total of 1680 DMCs were identified, out of which 1436 were hypermethylated and 244 were hypomethylated. Classification of DMCs according to the genes identified BCAN, CTNNA3, DLGAP2, GATA3, MAGI2 and TP73 among imprinted genes, SPATA5, SPATA7, SPATA16 and SPATA22 among spermatogenesis-associated genes, KDM4C and JMJD1C, EZH2 and HDAC4 among genes which regulate methylation and gene expression, HLA-C, HLA-DRB6 and HLA-DQA1 among complementation and immune response genes, and CRISPLD1, LPHN3 and CPEB2 among other genes. Genes showing significant differential methylation in deep sequencing, i.e. HOXB1, GATA3, EBF3, BCAN and TCERG1L, are strong candidates for further investigations. The role of chance was ruled out by deep sequencing of select genes. Large-scale data N/A. Limitations, reason for caution Genome-wide analyses are fairly accurate, but may not be exactly validated in replication studies across all DMCs. We used the 't' test in the genome-wide methylation analysis, whereas other tests could provide a more robust and powerful analysis. Wider implications of the findings DMCs can serve as markers for inclusion in infertility screening panels, particularly those in the genes showing differential methylation consistent with previous studies. The genes validated by deep sequencing are strong candidates for investigations of their roles in spermatogenesis. Study funding/competing interest(s) The study was funded by the Council of Scientific and Industrial Research (CSIR), Govt. of India with grant number BSC0101 awarded to Rajender Singh. None of the authors has any competing interest to declare.

The new generation of nanoparticles (NPs) encompass attributes of lipids and polymers and are referred to as 'lipid-polymer hybrid nanoparticles' (LPHNPs). LPHNPs have helped shed light on the mechanisms involved in targeted and non-specific drug delivery. Research has also highlighted the opportunities and challenges faced by the use of nanomedicine as personalized therapies in oncology. Here, we review the development of LPHNPs as cancer therapeutics, focusing on the methods deployed for enhancing the targeting efficiency and applications of LPHNPs.

Objective: To analyze global DNA methylation along with DNA methyltransferases (DNMTs) expression at transcript level in patients with impaired spermatogenesis to dissect its role in pathophysiology of human male infertility. Method: The content of Global methylated cytosine (mC) was determined using ELISA system (Imprint Methylated DNA Quantification Kit, Sigma–Aldrich) in 31 testicular biopsies showing impaired spermatogenesis and 8 with normal spermatogenesis. Real-time reverse transcription-polymerase chain reaction was done to analyze DNMTs (DNMT1, DNMT3A, DNMT3B and DNMT3L) mRNA levels in biopsies with different testicular phenotypes. Results: There was significant increase in levels of global methylation in different impaired testicular phenotypes as compared to normal. Expression analysis revealed significantly increased expression of DNMT1 and its positive correlation with global DNA methylation. Conclusion: In conclusion, increased levels of global methylation in impaired cases might be the one of the contributing factors for aberrant gene expression in infertile patients.

Patient-reported outcomes (PROs) measure quality of life, symptoms, patient functioning, and patient perceptions of care; they are essential for gaining a full understanding of cancer care and the impact of cancer on people's lives. Repeatedly captured facility-level and/or population-level PROs (PRO surveillance) could play an important role in quality monitoring and improvement, benchmarking, advocacy, policy making, and research. This article describes the rationale for PRO surveillance and the methods of the Patient Reported Outcomes Symptoms and Side Effects Study (PROSSES), which is the first PRO study to use the American College of Surgeons Commission on Cancer's Rapid Quality Reporting System to identify patients and manage study data flow. The American Cancer Society, the National Cancer Institute, the Commission on Cancer, and RTI International collaborated on PROSSES. PROSSES was conducted at 17 cancer programs that participated in the National Cancer Institute Community Cancer Centers Program among patients diagnosed with locoregional breast or colon cancer. The methods piloted in PROSSES were successful as demonstrated by high eligibility (93%) and response (61%) rates. Differences in clinical and demographic characteristics between respondents and nonrespondents were mostly negligible, with the exception that non-white individuals were somewhat less likely to respond. These methods were consistent across cancer centers and reproducible over time. If repeated and expanded, they could provide PRO surveillance data from patients with cancer on a national scale.