Diet changes due to urbanization in South Africa are linked to microbiome and metabolome signatures of Westernization and colorectal cancer.

Transition from traditional high-fiber to Western diets in urbanizing communities of Sub-Saharan Africa is associated with increased risk of non-communicable diseases (NCD), exemplified by colorectal cancer (CRC) risk. To investigate how urbanization gives rise to microbial patterns that may be amenable by dietary intervention, we analyzed diet intake, fecal 16 S bacteriome, virome, and metabolome in a cross-sectional study in healthy rural and urban Xhosa people (South Africa). Urban Xhosa individuals had higher intakes of energy (urban: 3,578 ± 455; rural: 2,185 ± 179 kcal/d), fat and animal protein. This was associated with lower fecal bacteriome diversity and a shift from genera favoring degradation of complex carbohydrates (e.g., Prevotella) to taxa previously shown to be associated with bile acid metabolism and CRC. Urban Xhosa individuals had higher fecal levels of deoxycholic acid, shown to be associated with higher CRC risk, but similar short-chain fatty acid concentrations compared with rural individuals. Fecal virome composition was associated with distinct gut bacterial communities across urbanization, characterized by different dominant host bacteria (urban: Bacteriodota; rural: unassigned taxa) and variable correlation with fecal metabolites and dietary nutrients. Food and skin microbiota samples showed compositional differences along the urbanization gradient. Rural-urban dietary transition in South Africa is linked to major changes in the gut microbiome and metabolome. Further studies are needed to prove cause and identify whether restoration of specific components of the traditional diet will arrest the accelerating rise in NCDs in Sub-Saharan Africa.

Environmental Consequences of Intensive Aquaculture Practices at Moyna Purba Medinipur West Bengal India with Special Reference to Carbon Footprint and Carbon Sequestration.

Moyna of Purba Medinipur district is widely known as an aquaculture hub of West Bengal, India. Though very good production is achievable from this fish culture system, management practices are inappropriate, which could create the sustainability problem of this culture system. The present study was thus undertaken for the estimation of plankton population, water quality, carbon footprint and carbon sequestration of this intensive aquaculture practices. Information on spawn to fry, fry to fingerlings and grow-out culture were collected through the structured questionnaire from the fish farmers. The plankton density, primary productivity, carbon footprint and carbon sequestration were analyzed using standard procedures. The phytoplankton, zooplankton and primary productivity were maximum at the stocking period and minimum during the middle of culture period. The lowest feed conversion ratio (FCR) was noticed with the minimum amount of feed applied in the pond. The CO2-e emission ranged from 0.56 to 4.89 kg CO2-e/kg fish (av. 2.13) for the production levels of 5.0 to 10.7 t/ha/yr. The pond water developed salinity and ammonium-N increased from 0.01 to 0.50 mg/l. The ponds with high feed loading (28 to 32 t/ha/yr) had the highest average sediment accumulation rate (11.0 ± 3.0 cm/yr) and carbon sequestration (704 ± 30 g C/m2/yr).

Dementia Symptoms among Senior Citizens Living in Geriatric Homes of Kathmandu Valley.

Background With increasing age, the older population becomes more susceptible to mental disorders. It is important to recognize and develop an understanding of psychiatric morbidity particularly among the residents of geriatric homes in resource-poor settings. Objective To assess the prevalence and associated factors of dementia symptoms among Nepalese senior citizens living in geriatric homes of Kathmandu valley. Method A cross-sectional study was conducted among 304 senior citizens living in geriatric homes of Kathmandu valley. Cognitive Impairment Test (CIT), was used to assess dementia symptoms. Bivariate and multivariate logistic regressions were performed. All the variables that were significant at p < 0.05 level in the bivariate analysis were included in the multivariate regression model and statistical significance was declared at p < 0.05 with a 95.00% confidence interval (CI). Result This study showed 75.65%, of the participants, had dementia symptoms. In the multivariate logistic regression analysis, female respondents (AOR=2.94, 95% CI=1.31-6.57), respondents never received geriatric allowances (AOR=2.46, 95% CI=1.22-4.98), respondent's history of alcohol consumption habits (AOR=2.04, 95% CI=1.01-4.11) and non-vegetarian diet habits (AOR= 2.31, 95% CI=1.12-4.76) were found more likely to had higher dementia symptoms whereas, literate participants (AOR=0.19, 95% CI=0.08-0.43) were less likely to had dementia symptoms. Conclusion The high prevalence of dementia symptoms among senior citizens living in geriatric homes in the Kathmandu valley indicates an urgent need for early diagnosis and treatment of mental disorders among senior citizens to improve their quality of life and well-being.

Variants of SARS-CoV-2, their effects on infection, transmission and neutralization by vaccine-induced antibodies.

OBJECTIVE: The current study reviewed Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) variants for their effects on infection, transmission and neutralization by vaccine-induced antibodies. MATERIALS AND METHODS: The research articles for the current study were searched over PubMed, Google Scholar, EMBASE and Web of Science online databases. The keywords used were: (("SARS-CoV-2" OR "COVID-19") AND ("mutation" OR "variant") AND ("death" OR "hospitalization" OR "infection" OR "transmission") AND ("antibody" OR "neutralize" OR "vaccine")). A total of 333 research articles were retrieved through online-database search. These articles were further scrutinized for their relevancy. Additionally, searches were performed to find the latest relevant information over Google search engine and relevant news browsers. Finally, around 35 germane articles were considered for scripting the current report. RESULTS: The mutations have changed amino acids at key positions in spike protein viz. S477N, E484K, Q677H, E484Q, L452R, K417T, K417N and N501Y. These mutations are relevant for different characteristics and are present in newly evolved strains of SARS-CoV-2 like E484K in B.1.526, B.1.525, P.2, B.1.1.7, P.1 and B.1.351. Mutations have increased the immune escape potential leading to 3.5-6.5-folds decrease in neutralization of antibodies (Pfizer and Moderna vaccines). The variant, B.1.617 circulating in India and many other countries (double variant) having E484Q and L452R mutations, has raised the infection rate and decreased the neutralization capacity of the vaccine-induced antibodies. Deadly K417N+E484K+N501Y triplet mutations found in B.1.351 and P.1 have increased the transmission ability of these strains by 50% leading to greater COVID-19 hospitalization, ICU admissions and deaths. CONCLUSIONS: The new SARS-CoV-2 variants have compromised the neutralization potential of the currently used vaccines, but still, they have considerable efficacy to reduce infection and mortality. GRAPHICAL ABSTRACT: https://www.europeanreview.org/wp/wp-content/uploads/Graphical_Abstract.jpg.

Allyl piperidine-1-carbodiothioate and benzyl 1H-imidazole 1 carbodithioate: two potential agents to combat against mycobacteria.

AIMS: The emergence of multidrug resistant strains of Mycobacterium tuberculosis has made tuberculosis more difficult to manage clinically. With the aim of obtaining new and effective anti-mycobacterial agent(s), this study investigated the anti-mycobacterial activity of several imidazole and piperidine derivatives. METHODS AND RESULTS: Towards obtaining new anti-mycobacterial agents, Mycobacterium smegmatis cells were treated with different compounds for their growth inhibitory activity. Among these, benzyl 1H-imidazole-1-carbodithioate and allyl piperidine-1-carbodiothioate exhibited better inhibition than the others. Thereafter, anti-biofilm property of these two was examined by treating M. smegmatis with these agents before and after the formation of biofilm. The result showed that both the compounds at their sublethal dose inhibited the formation of biofilm as well as dispersed preformed biofilm. Consistently, they augmented the activity of isoniazid or rifampicin against biofilm-encapsulated cells. MTT assay was performed to examine the toxic effects of this combinatorial therapy on different cell lines. Results exhibited a low cytotoxicity for this combinatorial treatment. The activity of these two was also verified against dormant mycobacterial cells and was found to be effective. CONCLUSION: The present study identified two compounds that exhibited anti-mycobacterial activities against both planktonic and dormant cells. These two also exhibited anti-biofilm activity at their sublethal dose and augmented the activity of isoniazid and rifampicin against biofilm encapsulated cells. SIGNIFICANCE AND IMPACT OF THE STUDY: The current study provides two new agents that have the potential to be used in anti-mycobacterial therapy and may help in public health management.

Detection of Vascular Changes in Systemic Lupus Erythematosus by Carotid Duplex Study in A Tertiary Cardiac Hospital.

Systemic lupus erythematosus (SLE) is a common autoimmune connective tissue disorder and mainly affected female patients. This cross sectional study was performed in the department of Cardiology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from July 2008 to June 2012. A total fifty (50) SLE patients were diagnosed on the basis of ACR criteria, having no cardiovascular symptoms. Another 50 age-matched normal individuals were included to compare with SLE group. Congenital vascular disease, ischaemic heart disease, congenital heart disease, rheumatic heart disease, hypothyroidism and any other inflammatory disease along with SLE were excluded from study. All patients were evaluated by Carotid duplex study. Mean age of SLE was 26.70±7.3 and mean age of normal subject was 25.64±8.01. Most of the SLE patients were female (about 92%) and male (about 8%). And about 94% was female in normal group and 6% was male. In Right common carotid arteries (RCCA), mean Intema medial thickness (IMT) was 0.86±0.10 IN SLE group and 0.73±0.06 in normal group. In LCCA, mean IMT was 0.89±0.14 in SLE group and 0.76±0.10 in normal group. IMT in SLE group was increased than control group. There was a significant difference (p=0.001) in both right and left side. The percentage rate of change in PSV and EDV of Carotid arteries of the SLE group was significantly higher than the control group (Both left and right side p=0.001). In RCCA, the PSV was 91.72±19.46 in SLE group and 62.60±6.66 in normal group (p=0.001). And EDV was 27.02±8.23 in SLE group and 16.48±2.32 in normal group (p=0.001). In LCCA, the PSV was 82.06±22.28 in SLE group and 60.36±7.54 in normal group (p=0.001). And EDV was 27.82±6.61 in SLE group and 18.08±2.69 in normal group (p=0.001). In LICA, mean PSV was 83.46±23.54 in SLE group and 60.36±7.54 in normal group (p=0.001). And EDV was 29.36±8.56 in SLE group and 18.08±2.69 in normal group (p=0.001). In RICA, mean PSV was 61.56±7.66 in SLE group and 62.16±5.35 in normal group (p=0.651) which was not significant. And EDV was 26.36±2.26 in SLE group and 19.00±2.17 in normal group (p=0.001). But majority of the vessels showed significant P value which signifies that vascular changes were more evident in SLE group than normal control group. SLE patients with carotid artery blood flow velocity and structural changes in endothelial function changes more evident than control group. Compared with the normal control group, IMT, PSV and EDV were significantly higher in SLE group, the difference was statistically significant (P<0.05). Vascular changes are common in SLE when clinically asymptomatic. Carotid duplex study is a non invasive tool for early detection of vascular changes to prevent stroke in SLE patients.

Urinary metabolomics fingerprinting around parturition identifies metabolites that differentiate lame dairy cows from healthy ones.

Lameness is a very important disorder of periparturient dairy cows with implications on milk production and composition as well as with consequences on reproductive performance. The aetiology of lameness is not clear although there have been various hypotheses suggested over the years. The objective of this study was to metabotype the urine of dairy cows prior to, during and after the onset of lameness by evaluating at weeks -8, -4 pre-calving, the week of lameness diagnosis, and +4 and +8 weeks post-calving. We used a metabolomics approach to analyse urine samples collected from dairy cows around calving (6 cows with lameness v. 20 healthy control cows). A total of 153 metabolites were identified and quantified using an in-house MS library and classified into 6 groups including: 11 amino acids (AAs), 39 acylcarnitines (ACs), 3 biogenic amines (BAs), 84 glycerophospholipids, 15 sphingolipids and hexose. A total of 23, 36, 40, 23 and 49 metabolites were observed to be significantly different between the lame and healthy cows at -8 and -4 weeks pre-calving, week of lameness diagnosis as well as at +4 and +8 weeks post-calving, respectively. It should be noted that most of the identified metabolites were elevated; however, a few of them were also lower in lame cows. Overall, ACs and glycerophospholipids, specifically phosphatidylcholines (PCs), were the metabolite groups displaying the strongest differences in the urine of pre-lame and lame cows. Lysophosphatidylcholines (LysoPCs), although to a lesser extent than PCs, were altered at all time points. Alterations in urinary AA concentrations were also observed during the current study for four time points. During the pre-calving period, there was an observed elevation of arginine (-8 week), tyrosine (-8 week) and aspartate (-4 week), as well as a depression of urinary glutamate (-4 weeks). In the current study, it was additionally observed that concentrations of several sphingomyelins and one BA were altered in pre-lame and lame cows. Symmetric dimethylarginine was elevated at both -8 weeks pre-calving and the week of lameness diagnosis. Data showed that urinary fingerprinting might be a reliable methodology to be used in the future to differentiate lame cows from healthy ones.

Gamma-aminobutyric acid-producing lactobacilli positively affect metabolism and depressive-like behaviour in a mouse model of metabolic syndrome.

Metabolic and neuroactive metabolite production represents one of the mechanisms through which the gut microbiota can impact health. One such metabolite, gamma-aminobutyric acid (GABA), can modulate glucose homeostasis and alter behavioural patterns in the host. We previously demonstrated that oral administration of GABA-producing Lactobacillus brevis DPC6108 has the potential to increase levels of circulating insulin in healthy rats. Therefore, the objective of this study was to assess the efficacy of endogenous microbial GABA production in improving metabolic and behavioural outcomes in a mouse model of metabolic dysfunction. Diet-induced obese and metabolically dysfunctional mice received one of two GABA-producing strains, L. brevis DPC6108 or L. brevis DSM32386, daily for 12 weeks. After 8 and 10 weeks of intervention, the behavioural and metabolic profiles of the mice were respectively assessed. Intervention with both L. brevis strains attenuated several abnormalities associated with metabolic dysfunction, causing a reduction in the accumulation of mesenteric adipose tissue, increased insulin secretion following glucose challenge, improved plasma cholesterol clearance and reduced despair-like behaviour and basal corticosterone production during the forced swim test. Taken together, this exploratory dataset indicates that intervention with GABA-producing lactobacilli has the potential to improve metabolic and depressive- like behavioural abnormalities associated with metabolic syndrome in mice.

Artificial intelligence and amniotic fluid multiomics: prediction of perinatal outcome in asymptomatic women with short cervix.

OBJECTIVE: To evaluate the application of artificial intelligence (AI), i.e. deep learning and other machine-learning techniques, to amniotic fluid (AF) metabolomics and proteomics, alone and in combination with sonographic, clinical and demographic factors, in the prediction of perinatal outcome in asymptomatic pregnant women with short cervical length (CL). METHODS: AF samples, which had been obtained in the second trimester from asymptomatic women with short CL (< 15 mm) identified on transvaginal ultrasound, were analyzed. CL, funneling and the presence of AF 'sludge' were assessed in all cases close to the time of amniocentesis. A combination of liquid chromatography coupled with mass spectrometry and proton nuclear magnetic resonance spectroscopy-based metabolomics, as well as targeted proteomics analysis, including chemokines, cytokines and growth factors, was performed on the AF samples. To determine the robustness of the markers, we used six different machine-learning techniques, including deep learning, to predict preterm delivery < 34 weeks, latency period prior to delivery < 28 days after amniocentesis and requirement for admission to a neonatal intensive care unit (NICU). Omics biomarkers were evaluated alone and in combination with standard sonographic, clinical and demographic factors to predict outcome. Predictive accuracy was assessed using the area under the receiver-operating characteristics curve (AUC) with 95% CI, sensitivity and specificity. RESULTS: Of the 32 patients included in the study, complete omics, demographic and clinical data and outcome information were available for 26. Of these, 11 (42.3%) patients delivered ≥ 34 weeks, while 15 (57.7%) delivered < 34 weeks. There was no statistically significant difference in CL between these two groups (mean ± SD, 11.2 ± 4.4 mm vs 8.9 ± 5.3 mm, P = 0.31). Using combined omics, demographic and clinical data, deep learning displayed good to excellent performance, with an AUC (95% CI) of 0.890 (0.810-0.970) for delivery < 34 weeks' gestation, 0.890 (0.790-0.990) for delivery < 28 days post-amniocentesis and 0.792 (0.689-0.894) for NICU admission. These values were higher overall than for the other five machine-learning methods, although each individual machine-learning technique yielded statistically significant prediction of the different perinatal outcomes. CONCLUSIONS: This is the first study to report use of AI with AF proteomics and metabolomics and ultrasound assessment in pregnancy. Machine learning, particularly deep learning, achieved good to excellent prediction of perinatal outcome in asymptomatic pregnant women with short CL in the second trimester. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Defect mediated magnetic transitions in Fe and Mn doped MoS2.

We report single-phase syntheses of undoped 2H-MoS2 as well as Mn and Fe doped MoS2 by a facile hydrothermal route. The formation of the 2H-MoS2 phase was confirmed by XRD and was corroborated with Raman spectra. The morphology of the doped and undoped MoS2 nanostructures comprised sheets, as revealed by TEM and STEM images. The fine granular structure was observed by high resolution TEM micrographs. The STEM-EDS results show dopant concentrations of ∼1 atom% corresponding to Mn and Fe in doped MoS2. The undoped MoS2 revealed diamagnetic behavior at room temperature and paramagnetic behavior in the range (100 to 300 K). The Mn-MoS2 sample displayed ferromagnetism below 20 K with a coercive field of ∼50 Oe. Such a sample may be utilized for magnetic switching purposes at low temperatures. The onset of the antiferromagnetic interaction was observed below 145 K in Fe-MoS2 samples. They have been understood in terms of long-range magnetic interactions amongst the dipole moments mediated via surface defects as well as the interaction between the dipoles and the surface charges. The findings are corroborated with the help of EPR studies.

Indian childhood cirrhosis - down but not out: Report of a rare case with a practical clinicopathological diagnostic approach.

Indian childhood cirrhosis is an entity believed to be on the verge of extinction. We present the case of a 13-month-old girl presenting acutely with jaundice, fever, and persistently increasing bilirubin. Investigations revealed direct hyperbilirubinemia, elevated transaminases, anemia, a blood with few schistocytes, positive direct coombs test, and deranged prothrombin time. Viral, autoimmune, and metabolic workup was unremarkable. Ultrasonography showed chronic liver disease, portal hypertension, and ascites. Due to numerous confounding factors and a low index of suspicion, the diagnosis of Indian childhood cirrhosis remained elusive and was clinched only on liver biopsy, albeit more than three weeks later, shortly after which the child expired. The timing and technique of the liver biopsy may have profound impact on the ultimate clinical outcome. Close coordination between the clinical and pathological teams is essential for deciphering acute presentations where the etiology is uncertain. We highlight the clinical considerations, varied morphological pointers, and offer a diagnostic algorithm facilitating the consideration of this disease.

Haptoglobin and serum amyloid A as putative biomarker candidates of naturally occurring bovine respiratory disease in dairy calves.

Bovine respiratory disease (BRD) is one of the leading causes of morbidity and mortality in dairy calves. Identification of reliable biomarkers of naturally occurring BRD is essential for ensuring early diagnosis and treatment of calves and monitoring treatment efficacy. This need is punctuated, especially in mild to moderate cases that would greatly help to decrease recurrence and the overall prevalence of BRD. The present study was conducted to investigate the changes in serum concentrations of haptoglobin (Hpt) and serum amyloid A (SAA) and association between oxidative stress and acute phase proteins (APPs) in BRD. Hpt and SAA levels significantly increased (P < .01) in BRD stressed calves as compared to healthy subjects. There was a significant decrease (P < .01) in serum albumin (Alb) concentration of infected calves as compared to controls. The oxidative stress markers revealed a significant (P < .01) increase in lipid peroxidation (LPO) and a concurrent decrease in activities of superoxide dismutase (SOD), reduced glutathione (R-GSH) and catalase (CAT) in BRD. A significant correlation among APPs, extent of oxidative stress and clinical score (CS) of calves was depicted. A stepwise decrease in Hpt and SAA and increase in Alb was observed in infected calves post-treatment. These results suggest implication of oxidative stress in enhancing APPs and monitoring of APPs as a potential complement to clinical assessment of treatment in calves with naturally occurring BRD. Hpt may be useful as the most sensitive biomarker in BRD. However, the combined use of Hpt and oxidative stress biomarkers would greatly improve the diagnostic accuracy.

Effect of non-ß-lactams on stable variants of inhibitor-resistant TEM ß-lactamase in uropathogenic Escherichia coli: implication for alternative therapy.

AIMS: ß-lactamase inhibitor resistance (BLIR) among the uropathogenic Escherichia coli (UPEC) minimizes treatment options. This study aimed to identify inhibitor-resistant TEM (IRT) ß-lactamase that impart BLIR phenotype and explore non-ß-lactams as alternative therapeutics. METHODS AND RESULTS: Thirty BLIR UPEC isolates were detected by Kirby-Bauer disc diffusion technique using ß-lactam-ß-lactamase inhibitor combination. Conjugal transfer of BLIR was successful from 17 isolates. PCR and sequencing of the TEM ß-lactamases from the transconjugants indicated 14 TEM-84 (IRT) and three novel IRT variants (pUE184TEM, pUE203TEM, pUE210TEM). Three-dimensional models of the latter were predicted and validated. Molecular docking of selected non-ß-lactams (morin, catechin, naringenin triacetate) with the variants using AutoDock 4.2 showed comparable docking scores with significant hydrogen bond and hydrophobic interactions. Molecular dynamics simulation study confirmed stability of the non-ß-lactams inside the catalytic pocket of the enzymes. Moreover, all three non-ß-lactams were found to inhibit the purified TEM ß-lactamase variants in vitro. Microbroth dilution method indicated naringenin triacetate 64 µg ml-1 in combination with ceftazidime (CAZ) 30 µg ml-1 to be most effective against the BLIR transconjugants. CONCLUSIONS: BLIR phenotypes were primarily attributed to the production of IRT ß-lactamases. Administration of the non-ß-lactams with CAZ demonstrated an alternative therapeutic strategy against the IRT ß-lactamase producers. SIGNIFICANCE AND IMPACT OF THE STUDY: This study indicates high risk of transmission of IRT ß-lactamases and suggests ß-lactam-non-ß-lactam combination therapy to combat BLIR.

Targeted metabolomics: new insights into pathobiology of retained placenta in dairy cows and potential risk biomarkers.

A targeted quantitative metabolomics approach was used to study temporal changes of serum metabolites in cows that normally released their fetal membranes and those that retained the placenta. We identified and measured serum concentrations of 128 metabolites including amino acids, acylcarnitines, biogenic amines, glycerophospholipids, sphingolipids and hexose at -8 and -4 weeks before parturition, during the week of retained placenta (RP) diagnosis, and at +4 and +8 weeks after parturition. In addition, we aimed at identifying metabolite signatures of pre-RP in the serum that might be used as predictive biomarkers for risk of developing RP in dairy cows. Results revealed major alterations in the metabolite fingerprints of pre-RP cows starting as early as -8 weeks before parturition and continuing as far as +8 weeks after calving. Biomarker candidates found in this study are mainly biomarkers of inflammation which might not be specific to RP. Therefore, the relevance of serum Lys, Orn, acetylornithine, lysophophatidylcholine LysoPC a C28:0, Asp, Leu and Ile as potential serum biomarkers for prediction of risk of RP in dairy cows will have to be tested in the future. In addition, lower concentrations of LysoPCs, Trp, and higher kynurenine in the serum during prepartum and the week of occurrence of RP suggest involvement of inflammation in the pathobiology of RP.

Urine metabolic fingerprinting can be used to predict the risk of metritis and highlight the pathobiology of the disease in dairy cows.

INTRODUCTION: Metritis is an uterine pathology that causes economic losses for the dairy industry. It is associated with lower reproductive efficiency, increased culling rates, decreased milk production and increased veterinary costs. OBJECTIVES: To gain a more detailed view of the urine metabolome and to detect metabolite signature in cows with metritis. In addition, we aimed to identify early metabolites which can help to detect cows at risk to develop metritis in the future. METHODS: We used nuclear magnetic resonance spectroscopy starting at 8 and 4 weeks prior to the expected day of parturition, during the week of diagnosis of metritis, and at 4 and 8 weeks after diagnosis of metritis in Holstein dairy cows. RESULTS: At 8 weeks before parturition, pre-metritic cows had a total of 30 altered metabolites. Interestingly, 28 of them increased in urine when compared with control cows (P < 0.05). At 4 weeks before parturition, 34 metabolites were altered. At the week of diagnosis of metritis a total of 20 metabolites were altered (P < 0.05). The alteration continued at 4 and 8 weeks after diagnosis. CONCLUSIONS: The metabolic fingerprints in the urine of pre-metritic and metritic cows point toward excretion of multiple amino acids, tricarboxylic acid cycle metabolites and monosaccharides. Combination of galactose, leucine, lysine and panthotenate at 8 weeks before parturition might serve as predictive biomarkers for metritis.

Metabolomic identification of diagnostic serum-based biomarkers for advanced stage melanoma.

INTRODUCTION: Melanoma is a highly aggressive malignancy and is currently one of the fastest growing cancers worldwide. While early stage (I and II) disease is highly curable with excellent prognosis, mortality rates rise dramatically after distant spread. We sought to identify differences in the metabolome of melanoma patients to further elucidate the pathophysiology of melanoma and identify potential biomarkers to aid in earlier detection of recurrence. METHODS: Using 1H NMR and DI-LC-MS/MS, we profiled serum samples from 26 patients with stage III (nodal metastasis) or stage IV (distant metastasis) melanoma and compared their biochemical profiles with 46 age- and gender-matched controls. RESULTS: We accurately quantified 181 metabolites in serum using a combination of 1H NMR and DI-LC-MS/MS. We observed significant separation between cases and controls in the PLS-DA scores plot (permutation test p-value = 0.002). Using the concentrations of PC-aa-C40:3, DL-carnitine, octanoyl-L-carnitine, ethanol, and methylmalonyl-L-carnitine we developed a diagnostic algorithm with an AUC (95% CI) = 0.822 (0.665-0.979) with sensitivity and specificity of 100 and 56%, respectively. Furthermore, we identified arginine, proline, tryptophan, glutamine, glutamate, glutathione and ornithine metabolism to be significantly perturbed due to disease (p < 0.05). CONCLUSION: Targeted metabolomic analysis demonstrated significant differences in metabolic profiles of advanced stage (III and IV) melanoma patients as compared to controls. These differences may represent a potential avenue for the development of multi-marker serum-based assays for earlier detection of recurrences, allow for newer, more effective targeted therapy when tumor burden is less, and further elucidate the pathophysiologic changes that occur in melanoma.

Cumulative Risk of Metabolic Syndrome Correlated with the Coexistence of (-1306C/T) and Altered Circulating MMP2 level.

BACKGROUND: Interindividual genetic variations and environmental factors both play pivotal roles in the pathogenesis of metabolic syndrome (MetS). The rationale of this study conducted was to analyze the association of Matrix Metalloproteinase (MMP) gene variants, MMP-1 (-1607 1G/2G) and MMP-2 (-1306 C/T) with susceptibility to MetS and its effect on serum MMP level. METHODS: Study involved 370 subjects with 1:1 distribution of cases and controls. Patients were recruited according to modified NCEP-ATP III criteria for MetS. Clinical, biochemical analysis, PCR-RFLP and ELISA methods were employed for genotyping and estimation of serum MMP level. RESULTS: Significantly (p<0.001) higher Serum MMP-2 (39.13±19.96 ng/ml) was detected in cases as compared to controls. The MMP-2 (-1306 C/T) was significantly associated with the risk of MetS. The variant genotype TT was significantly associated with increased risk of MetS. (p=0.032; OR=2.31; 95%CI=1.07-4.97). No significant association of MMP-1(-1607 1G/2G) was found with risk of MetS. CONCLUSION: Our study concluded that presence of MMP-2 (-1306 C/T) might be associated the risk of MetS. Serum MMP2 level was significantly higher in patients and correlated with clinical parameters of MetS. Clinical implication of the work may help to identify the individuals with high risk of MetS and further complications.

Stamping out RAF and MEK1/2 to inhibit the ERK1/2 pathway: an emerging threat to anticancer therapy.

The RAS-RAF-MEK1/2-ERK1/2 pathway is a key signal transduction pathway in the cells. Critically, it remains constitutively active in approximately 30% of human cancers, having key roles in cancer development, maintenance and progression, while being responsible for poorer prognosis and drug resistance. Consequently, the inhibition of this pathway has been the subject of intense research for >25 years. The advent of better patient screening techniques has increasingly shown that upstream regulators like RAS and RAF remain persistently mutated in many cancer types. These gain-of-function mutations, such as KRAS-4B(G12V/G13D/Q61K), NRAS(Q61L/Q61R) or BRAF(V600E), lead to tremendous increase in their activities, resulting in constitutively active extracellular signal-regulated kinase 1/2 (ERK1/2). They were not efficiently targeted by the first-generation inhibitors such as Lonafarnib or Sorafenib, which were essentially broad spectrum inhibitors targeting pan-RAS and pan-RAF, respectively. This triggered the development of the second-generation inhibitors selective against the mutated proteins. Second generation inhibitors such as Vemurafenib (Zelboraf) and Dabrafenib (Tafinlar) targeting BRAF(V600E), Trametinib (Mekinist) targeting MEK1/2 and the first generation pan-RAF inhibitor Sorafenib (Nexavar) have already been approved for treating renal, hepatocellular, thyroid cancers and BRAF(V600E/K) harboring metastatic melanoma. Others against RAF and MEK1/2 are presently undergoing clinical trials. Their success would depend on the better understanding of the acquired resistance mechanisms to these drugs in the cancer cells and the identification of predictive biomarkers for the proper administration of suitable inhibitor(s).