Studying the molecular mechanism of hepatocellular carcinoma

Background: Hepatocellular carcinoma (HCC) has a poor prognosis due to ineffective therapeutic modality and lack of early diagnostic marker. Accumulating studies have shown that elevated expression of mucin 13 as potential oncogene and predictive biomarker for various cancer. However, very little is known about its expression and function for development and progression of HCC. Objective: To investigate mucin 13 expression in chemically induced hepatocellular carcinoma model. Methodology: Diethyl nitrosamine (DEN) and 2-Acetylaminofluorene (2-AAF) induced method was employed for the development of hepatocellular carcinoma in Male Wistar rats. Serum and tissues were collected at regular intervals of time and routinely validated for liver cancer stages. Immunohistochemistry and in situ hybridization were performed on formalin-fixed, paraffin-embedded tissues. Molecular docking studies were performed to study the interaction of mucin 13 and DEN. Results: Our results demonstrate hepatocellular adenoma as observed by histopathological analysis. Biochemical analysis showed a progressive increase in the levels of serum ALT, AST, and ALP, suggesting the development and progression of hepatocellular damage. Notably, mucin 13 expression gradually elevated during consecutive stages of hepatocellular carcinoma. Interestingly, an increase in nuclear localization of mucin 13 was observed in the treated group as compared to control group. In situ hybridization analysis showed that a decrease in miR-132 and miR-145, which are inversely related with mucin 13 expression. Moreover, DEN efficiently binds mucin 13 with high affinity and thus stabilize it as demonstrated by molecular docking analysis. Conclusion: These results suggest that mucin 13 expression is closely associated with hepatocarcinogenesis and could serve as a predictive candidate biomarker for HCC

Piii‐37

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109838/1/cptclpt2006257.pd

Risk for opioid misuse in chronic pain patients is associated with endogenous opioid system dysregulation

µ-Opioid receptors (MOR) are a major target of endogenous and exogenous opioids, including opioid pain medications. The µ-opioid neurotransmitter system is heavily implicated in the pathophysiology of chronic pain and opioid use disorder and, as such, central measures of µ-opioid system functioning are increasingly being considered as putative biomarkers for risk to misuse opioids. To explore the relationship between MOR system function and risk for opioid misuse, 28 subjects with chronic nonspecific back pain completed a clinically validated measure of opioid misuse risk, the Pain Medication Questionnaire (PMQ), and were subsequently separated into high (PMQ > 21) and low (PMQ ≤ 21) opioid misuse risk groups. Chronic pain patients along with 15 control participants underwent two separate [11C]-carfentanil positron emission tomography scans to explore MOR functional measures: one at baseline and one during a sustained pain-stress challenge, with the difference between the two providing an indirect measure of stress-induced endogenous opioid release. We found that chronic pain participants at high risk for opioid misuse displayed higher baseline MOR availability within the right amygdala relative to those at low risk. By contrast, patients at low risk for opioid misuse showed less pain-induced activation of MOR-mediated, endogenous opioid neurotransmission in the nucleus accumbens. This study links human in vivo MOR system functional measures to the development of addictive disorders and provides novel evidence that MORs and µ-opioid system responsivity may underlie risk to misuse opioids among chronic pain patients.publishedVersionPeer reviewe

Reduced basal ganglia μ-opioid receptor availability in trigeminal neuropathic pain: A pilot study

Abstract Background Although neuroimaging techniques have provided insights into the function of brain regions involved in Trigeminal Neuropathic Pain (TNP) in humans, there is little understanding of the molecular mechanisms affected during the course of this disorder. Understanding these processes is crucial to determine the systems involved in the development and persistence of TNP. Findings In this study, we examined the regional μ-opioid receptor (μOR) availability in vivo (non-displaceable binding potential BPND) of TNP patients with positron emission tomography (PET) using the μOR selective radioligand [11C]carfentanil. Four TNP patients and eight gender and age-matched healthy controls were examined with PET. Patients with TNP showed reduced μOR BPND in the left nucleus accumbens (NAc), an area known to be involved in pain modulation and reward/aversive behaviors. In addition, the μOR BPND in the NAc was negatively correlated with the McGill sensory and total pain ratings in the TNP patients. Conclusions Our findings give preliminary evidence that the clinical pain in TNP patients can be related to alterations in the endogenous μ-opioid system, rather than only to the peripheral pathology. The decreased availability of μORs found in TNP patients, and its inverse relationship to clinical pain levels, provide insights into the central mechanisms related to this condition. The results also expand our understanding about the impact of chronic pain on the limbic system.http://deepblue.lib.umich.edu/bitstream/2027.42/112555/1/12990_2012_Article_533.pd

Comorbid anxiety increases cognitive control activation in Major Depressive Disorder

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134086/1/da22541.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134086/2/da22541_am.pd

Arterial/venous plasma nicotine concentrations following nicotine nasal spray

Background and objectives : Arterial (A) and venous (V) plasma nicotine and cotinine concentrations were measured after nasal nicotine spray in tobacco smokers of both genders. The hypothesis for this research was that a greater A/V difference in plasma nicotine would be present in males than females because males have greater skeletal muscle mass to bind nicotine.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42031/1/228-55-9-639_90550639.pd

Future therapeutic targets in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches

PySAGES: flexible, advanced sampling methods accelerated with GPUs

Molecular simulations are an important tool for research in physics, chemistry, and biology. The capabilities of simulations can be greatly expanded by providing access to advanced sampling methods and techniques that permit calculation of the relevant underlying free energy landscapes. In this sense, software that can be seamlessly adapted to a broad range of complex systems is essential. Building on past efforts to provide open-source community supported software for advanced sampling, we introduce PySAGES, a Python implementation of the Software Suite for Advanced General Ensemble Simulations (SSAGES) that provides full GPU support for massively parallel applications of enhanced sampling methods such as adaptive biasing forces, harmonic bias, or forward flux sampling in the context of molecular dynamics simulations. By providing an intuitive interface that facilitates the management of a system's configuration, the inclusion of new collective variables, and the implementation of sophisticated free energy-based sampling methods, the PySAGES library serves as a general platform for the development and implementation of emerging simulation techniques. The capabilities, core features, and computational performance of this new tool are demonstrated with clear and concise examples pertaining to different classes of molecular systems. We anticipate that PySAGES will provide the scientific community with a robust and easily accessible platform to accelerate simulations, improve sampling, and enable facile estimation of free energies for a wide range of materials and processes

No association between chronic musculoskeletal complaints and Val158Met polymorphism in the Catechol-O-methyltransferase gene. The HUNT study

BACKGROUND: The Catechol-O-methyltransferase (COMT) gene contains a functional polymorphism, Val158Met, that has been found to influence human pain perception. In one study fibromyalgia was less likely among those with Val/Val genotype. METHODS: In the 1995–97 Nord-Trøndelag Health Study (HUNT), the association between Val/Met polymorphism at the COMT gene and chronic musculoskeletal complaints (MSCs) was evaluated in a random sample of 3017 individuals. RESULTS: The distribution of the COMT Val158Met genotypes and alleles were similar between controls and the twelve different chronic MSCs groups. Even when the Met/Met and Val/Met genotypes were pooled, the distribution of the Val/Val genotype and other genotypes were similar between controls and the chronic MSCs groups. CONCLUSION: In this population-based study, no significant association was found between Val/Met polymorphism at the COMT gene and chronic MSCs

Genetic variation in human NPY expression affects stress response and emotion

Understanding inter- individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y ( NPY) is anxiolytic(1,2) and its release is induced by stress(3). NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories(4-6). Here we show that haplotype- driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in postmortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype- driven NPY expression predicted higher emotion- induced activation of the amygdala, as well as diminished resiliency as assessed by pain/ stress- induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism ( SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter- individual variation in resiliency to stress, a risk factor for many diseases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62768/1/nature06858.pd