Miracle-dz/UniFAR-FTUs huggingface dataset:
Opportunities for the Primary Prevention of Colorectal Cancer in the United States

Several studies indicate that screening in combination with lifestyle modification may produce a greater reduction in colorectal cancer rates than screening alone. To identify national opportunities for the primary prevention of colorectal cancer, we assessed the prevalence of modifiable lifestyle risk factors in the United States. We used nationally representative, cross-sectional data from 5 NHANES cycles (1999–2000, n = 2,753; 2001–2002, n = 3,169; 2003–2004, n = 2,872; 2005–2006, n = 2,993; 2007–2008, n = 3,438). We evaluated the 5 colorectal cancer risk factors deemed “convincing” by the World Cancer Research Fund (obesity, physical inactivity, intake of red meat, processed meat, alcohol), and cigarette smoking, a “suggestive” risk factor in the Surgeon General's report. We estimated the prevalence of each risk factor separately and jointly, and report it overall, and by sex, race/ethnicity, age, and year. In 2007 to 2008, 81% percent of U.S. adults, aged 20 to 69 years, had at least one modifiable risk factor for colorectal cancer. More than 15% of those younger than 50 years had 3 or more risk factors. There was no change in the prevalence of risk factors between 1999 and 2008. The most common risk factors were risk factors for other chronic diseases. Our findings provide additional support for the prioritization of preventive services in health care reform. Increasing awareness, especially among young adults, that lifestyle factors influence colorectal cancer risk, and other chronic diseases, may encourage lifestyle changes and adherence to screening guidelines. Complementary approaches of screening and lifestyle modification will likely provide the greatest reduction of colorectal cancer. Cancer Prev Res; 5(1); 138–45. ©2011 AACR.
Acute effect of Vagus nerve stimulation parameters on cardiac chronotropic, inotropic, and dromotropic responses

Vagus nerve stimulation (VNS) is an established therapy for drug-resistant epilepsy and depression, and is considered as a potential therapy for other pathologies, including Heart Failure (HF) or inflammatory diseases. In the case of HF, several experimental studies on animals have shown an improvement in the cardiac function and a reverse remodeling of the cardiac cavity when VNS is applied. However, recent clinical trials have not been able to reproduce the same response in humans. One of the hypothesis to explain this lack of response is related to the way in which stimulation parameters are defined. The combined effect of VNS parameters is still poorly-known, especially in the case of VNS synchronously delivered with cardiac activity. In this paper, we propose a methodology to analyze the acute cardiovascular effects of VNS parameters individually, as well as their interactive effects. A Latin hypercube sampling method was applied to design a uniform experimental plan. Data gathered from this experimental plan was used to produce a Gaussian process regression (GPR) model in order to estimate unobserved VNS sequences. Finally, a Morris screening sensitivity analysis method was applied to each obtained GPR model. Results highlight dominant effects of pulse current, pulse width and number of pulses over frequency and delay and, more importantly, the degree of interactions between these parameters on the most important acute cardiovascular responses. In particular, high interacting effects between current and pulse width were found. Similar sensitivity profiles were observed for chronotropic, dromotropic and inotropic effects. These findings are of primary importance for the future development of closed-loop, personalized neuromodulator technologies.
Calcitonin gene-related peptide and spinal afferents partly mediate postoperative colonic ileus in the rat.

BACKGROUND Calcitonin gene-related peptide (CGRP) is a widely distributed neuropeptide contained in intrinsic and extrinsic neurons of the gastrointestinal wall that has been shown to be released by noxious stimulation, to be involved in nociception, to inhibit gastrointestinal motility, and to partly mediate postoperative gastric ileus. We hypothesized that abdominal surgery-induced release of CGRP might inhibit postoperative colonic motility and food intake. METHODS Colonic transit, stool pellet number, stool pellet weight, and food intake were measured for 48 hours after induction of postoperative ileus in rats. CGRP was immunoneutralized by preoperative injection of CGRP monoclonal antibody, or visceral afferent nerve fibers containing CGRP were functionally ablated by topical capsaicin treatment of the vagus nerves or of the celiac/superior mesenteric ganglia before abdominal surgery. RESULTS Abdominal surgery increased colonic transit time and decreased 24-hour cumulative stool pellet number, stool pellet weight, and food intake. CGRP immunoneutralization reversed postoperative inhibition of colonic transit, 24-hour cumulative stool pellet number, stool pellet weight, and food intake by 77%, 82%, 80%, and 52%, respectively. Whereas ablation of vagal afferent nerve fibers had no effect, spinal afferent nerve fiber ablation reversed postoperative inhibition of 24-hour cumulative stool pellet number, stool pellet weight, and food intake by 41%, 38%, and 19%, respectively. CONCLUSIONS CGRP and spinal afferent nerve fibers partly mediate postoperative colonic ileus and inhibition of food intake in the rat. By the magnitude of reversal of postoperative ileus, CGRP seems to be an important mediator of postoperative colonic ileus. Our results for the first time show involvement of a neuropeptide and spinal afferents in the mediation of postoperative colonic ileus and postoperative inhibition of food intake in rats.
E4BP4/NFIL3 modulates the epigenetically repressed RAS effector RASSF8 function through histone methyltransferases

RAS proteins are major human oncogenes, and most of the studies are focused on enzymatic RAS effectors. Recently, nonenzymatic RAS effectors (RASSF, RAS association domain family) have garnered special attention because of their tumor-suppressive properties in contrast to the oncogenic potential of the classical enzymatic RAS effectors. Whereas most members of RASSF family are deregulated by promoter hypermethylation, RASSF8 promoter remains unmethylated in many cancers but the mechanism(s) of its down-regulation remains unknown. Here, we unveil E4BP4 as a critical transcriptional modulator repressing RASSF8 expression through histone methyltransferases, G9a and SUV39H1. In line with these observations, we noticed a negative correlation of RASSF8 and E4BP4 expression in primary breast tumor samples. In addition, our data provide evidence that E4BP4 attenuates RASSF8-mediated anti-proliferation and apoptosis, shedding mechanistic insights into RASSF8 down-regulation in breast cancers. Collectively, our study provides a better understanding on the epigenetic regulation of RASSF8 function and implicates the development of better treatment strategies.
Physiotherapist attitudes and practices regarding head-down and modified postural drainage in the presence of heart disease

Modification of chest physiotherapy interventions is recommended for patients with concomitant respiratory and cardiac diseases. What modifications are necessary and for whom, and what strategies physiotherapists adopt when heart disease is present, have not been investigated. Consequently, few guidelines exist. A questionnaire survey was conducted to identify attitudes and practices of senior cardiopulmonary physiotherapists (SCPP) and “other” physiotherapists (OP) regarding modified and head-down postural drainage (HDPD) when heart disease is present. The overall response rate was 44% (178/407); the response rate from SCPP (78%, 50/64) was higher than from OP (37%, 128/343). Major findings included that: postural modification in the presence of heart disease is common and is not reserved for patients with severe disease; the most commonly adopted modified position is the horizontal; and that the rationale for modification is commonly based on the assumptions that the cardiovascular load is less and, thus, adverse outcomes will be avoided. In the main, the response patterns for both groups were similar, but some between-group differences were found. The findings overall suggest physiotherapists adopt a cautious approach to HDPD when heart disease is present. Whether this approach is justified remains to be investigated.
A multicenter prospective analysis of pediatric trauma activation criteria routinely used in addition to the six criteria of the American College of Surgeons

BACKGROUND The American College of Surgeons has defined six minimum activation criteria (ACS-6) for the highest level of trauma activations at trauma centers. The verification criteria also allow for the inclusion of additional criteria at the institution’s discretion. The purpose of this prospective multicenter study was to evaluate the ACS-6 as well as commonly used activation criteria to evaluate overtriage and undertriage rates for pediatric trauma team activation. METHODS Data were prospectively collected at nine pediatric trauma centers to examine 29 commonly used activation criteria. Patients meeting any of these criteria were evaluated for the use of high-level trauma resuscitation resources according to an expert consensus list. Patients requiring a resource but not meeting any activation criteria were included to evaluate undertriage rates. RESULTS During the 1-year study, a total of 656 patients were enrolled with a mean age of 8 years, a median Injury Severity Score of 14, and mortality of 11%. Using all criteria, 55% of patients would have been overtriaged and 9% would have been undertriaged. If only the ACS-6 were used, 24% of patients would have been overtriaged and 16% would have been undertriaged. Among activation criteria with more than 10 patients, those most predictive of using a high-level resource were a gunshot wound to the abdomen (92%), blood given before arrival (83%), traumatic arrest (83%), tachycardia/poor perfusion (83%), and age-appropriate hypotension (77%). The addition of tachycardia/poor perfusion and pretrauma center resuscitation with greater than 40 mL/kg results in eight criteria with an overtriage of 39% and an undertriage of 10.5%. CONCLUSION The ACS-6 provides a reliable overtriage or undertriage rate for pediatric patients. The inclusion of two additional criteria can further improve these rates while maintianing a simplified triage list for children. LEVEL OF EVIDENCE Therapeutic study, level III.
Direct contact of fibroblasts with neuronal processes promotes differentiation to myofibroblasts and induces contraction of collagen matrix in vitro

Wound healing is often delayed in the patients whose sensory and autonomic innervation is impaired. We hypothesized that existence of neurites in the skin may promote wound healing by inducing differentiation of fibroblasts into myofibroblasts with consequent wound contraction. In the current study, we examined the effect of neurons on differentiation of fibroblasts and contraction of collagen matrix in vitro using a new co‐culture model. Neuronal cell line, PC12 cells, of which the neurite outgrowth can be controlled by adding nerve growth factor, was used. Rat dermal fibroblasts were co‐cultured with PC12 cells extending neurites or with PC12 cells lacking neurites. Then, differentiation of fibroblasts into myofibroblasts and contraction of the collagen matrix was evaluated. Finally, we examined whether direct or indirect contact with neurites of PC12 cells promoted the differentiation of fibroblasts. Our results showed that fibroblasts co‐cultured with PC12 extending neurites differentiated into myofibroblasts more effectively and contracted the collagen matrix stronger than those with PC12 lacking neurites. Direct contact of fibroblasts with neurites promoted more differentiation than indirect contact. In conclusion, direct contact of fibroblasts with neuronal processes is important for differentiation into myofibroblasts and induction of collagen gel contraction, leading to promotion of wound healing.
Differential effects of satellite RNA on the accumulation of cucumber mosaic virus RNAs and their encoded proteins in tobacco vs zucchini squash with two strains of CMV helper virus.

The presence of cucumber mosaic virus (CMV) satellite RNA usually reduces the yield of accumulated helper virus, although more so in solanaceous than in cucurbit hosts. The accumulation of viral RNA and viral-encoded proteins of two strains of CMV (Fny- and Sny-) known to differ in their ability to support satellite RNA in zucchini squash was examined in squash and tobacco to determine the effect of satellite RNA on the accumulation of viral-associated components. In the absence of satellite RNA, Fny- and Sny-CMV showed similar levels of accumulation of RNA at 7 days postinoculation (p.i.), but by 14 days p.i. the Fny-CMV RNAs accumulated to lower levels than did both strains at 7 days p.i. , in either host. The levels of accumulated Sny-CMV-encoded proteins were higher than those encoded by Fny-CMV in tobacco, but not squash plants, at 7 days p.i. At 14 days p.i. , for Fny-CMV vs Sny-CMV, there were differences in the levels of accumulation of most CMV-encoded proteins in both hosts, more exacerbated in tobacco vs squash. The effect of satellite RNA was to intensify these differences; that is, by 7 days p.i. , satellite RNA reduced the accumulation of Fny-CMV RNAs 1 and 2 and their encoded proteins in both tobacco and squash but had little or no effect on the accumulation of Sny-CMV RNAs or encoded proteins. By 14 days p.i. , the levels of accumulation of all Fny-CMV RNAs and encoded proteins were severely reduced in both hosts, and the levels of accumulation of Sny-CMV RNAs 1 and 2 and their encoded proteins were also reduced in tobacco, but not squash. Sny-CMV did not support satellite RNA accumulation in squash plants or protoplasts. Satellite RNA did not appear to have a direct effect on the movement of either CMV strain. Rather, accumulation studies in tobacco protoplasts indicated that the difference in response of Fny-CMV vs Sny-CMV to satellite RNA in tobacco was due to the extent to which satellite RNA affected the levels of RNA 1, and to a lesser extent RNA 2, and their encoded proteins, 1a and 2a, both components of the CMV replicase.
Molecular determinants of A2AR–D2R allosterism: role of the intracellular loop 3 of the D2R

In the CNS, an antagonistic interaction has been shown between adenosine A2A and dopamine D2 receptors (A2ARs and D2Rs) that may be relevant both in normal and pathological conditions (i.e., Parkinson's disease). Thus, the molecular determinants mediating this receptor–receptor interaction have recently been explored, as the fine tuning of this target (namely the A2AR/D2R oligomer) could possibly improve the treatment of certain CNS diseases. Here, we used a fluorescence resonance energy transfer‐based approach to examine the allosteric modulation of the D2R within the A2AR/D2R oligomer and the dependence of this receptor–receptor interaction on two regions rich in positive charges on intracellular loop 3 of the D2R. Interestingly, we observed a negative allosteric effect of the D2R agonist quinpirole on A2AR ligand binding and activation. However, these allosteric effects were abolished upon mutation of specific arginine residues (217–222 and 267–269) on intracellular loop 3 of the D2R, thus demonstrating a major role of these positively charged residues in mediating the observed receptor–receptor interaction. Overall, these results provide structural insights to better understand the functioning of the A2AR/D2R oligomer in living cells.
Ambient Air Pollutants and Acute Case-Fatality of Cerebro-Cardiovascular Events: Takashima Stroke and AMI Registry, Japan (1988–2004)

Background: Apart from the conventional risk factors, cerebro-cardiovascular disease (CVD) are also reported to be associated with air pollution, thus lowering the level of exposure might contribute in prevention activities to reduce the associated adverse outcomes. Though few studies conducted in Japan have reported on the CVD mortality but none have explored the effect of air pollutant exposure on the acute case-fatality of CVD. We investigated the effects of air pollution exposure on acute case-fatality of stroke and acute myocardial infarction (AMI) in a setting where pollutant levels are rather low. Methods: We leveraged the data from the Takashima Stroke and AMI Registry, which covers a population of approximately 55,000 in Takashima County located in central Japan. The study period of 6,210 days (16 years, leap years also taken into account) were divided into quartiles of daily average pollutant concentration; suspended particulate matter (SPM), sulfur dioxide (SO2), nitrogen dioxide (NO2), and photochemical oxidants (Ox). The stroke and AMI events were categorized to corresponding quartiles based on the pollution levels of the onset day. To study the effects of air pollutants, we estimated the fatality rate ratio across quartiles of the pollutants where the lowest quartile served as the reference. Results: There were 307 (men: 153 and women: 154) fatal stroke cases within 28 days of onset among the 2,038 first ever stroke during 1988–2004. In the same period, there were 142 (men: 94 and women: 54) fatal AMI cases within 28 days of onset among the 429 first ever AMI events. The mean of the measured pollutant levels were as follows: SPM 26.9 µg/m3, SO2 3.9 ppb, NO2 16.0 ppb, and Ox 28.4 ppb. Among the pollutants, higher levels of NO2 showed increased fatality risk. In multi-pollutant model, the highest quartile of NO2 was associated with 60% higher stroke case-fatality risk in comparison to lowest quartile of NO2. In the fully adjusted model the fatality-rate ratio was 1.65 (95% CI 1.06–2.57). This association was more prominent among stroke subtype of cerebral infarction. Other pollutant levels did not show any association with stroke or AMI case-fatality. Conclusion: We observed association between NO2 levels, an index of traffic related air pollution, with the acute case-fatality of stroke, especially cerebral infarction in our study population. Further studies are needed in different regions to determine the association between ambient air pollutants and acute cardiovascular fatalities.
Role of Cysteine Residues in Heme Binding to Human Heme Oxygenase-2 Elucidated by Two-dimensional NMR Spectroscopy*

Background: Heme oxygenase-2 (HO-2) containing three cysteines is involved in signaling pathways. Results: The cysteines in HO-2 interact with each other, but their redox state only modestly alters heme affinity. Conclusion: Changes in the redox state of the cysteines do not significantly control heme oxidation rates. Significance: The HO-2 cysteine residues play roles in interactions related to the role of HO-2 in regulatory processes. Human heme oxygenases 1 and 2 (HO-1 and HO-2) degrade heme in the presence of oxygen and NADPH-cytochrome P450 reductase, producing ferrous iron, CO, and biliverdin. HO-1 is an inducible enzyme, but HO-2 is constitutively expressed in selected tissues and is involved in signaling and regulatory processes. HO-2 has three cysteine residues that have been proposed to modulate the affinity for heme, whereas HO-1 has none. Here we use site-specific mutagenesis and two-dimensional NMR of l-[3-13C]cysteine-labeled proteins to determine the redox state of the individual cysteines in HO-2 and assess their roles in binding of heme. The results indicate that in the apoprotein, Cys282 and Cys265 are in the oxidized state, probably in an intramolecular disulfide bond. The addition of a reducing agent converts them to the reduced, free thiol state. Two-dimensional NMR of site-specific mutants reveals that the redox state of Cys265 and Cys282 varies with the presence or absence of other Cys residues, indicating that the microenvironments of the Cys residues are mutually interdependent. Cys265 appears to be in a relatively hydrophilic, oxidizable environment compared with Cys127 and Cys282. Chemical shift data indicate that none of the cysteines stably coordinates to the heme iron atom. In the oxidized state of the apoprotein, heme is bound 2.5-fold more tightly than in the reduced state. This small difference in heme affinity between the oxidized and reduced states of the protein is much less than previously reported, suggesting that it is not a significant factor in the physiological regulation of cellular heme levels.
The effect of supplemental vitamins and minerals on the development of prostate cancer: a systematic review and meta-analysis.

BACKGROUND Vitamin supplementation is used for many purposes with mainly alleged benefits. One of these is the use of various vitamins for the prevention of prostate cancer. METHODS We conducted a systematic review and meta-analysis on this topic. Pubmed, Embase and the Cochrane Database were searched; as well, we hand searched the references in key articles. Randomized controlled trials (RCTs), cohort studies and case-control studies were included. The review assessed the effect of supplemental vitamins on the risk of prostate cancer and on disease severity and death in men with prostate cancer. RESULTS Fourteen articles were included in the final assessment. Individually, a few of these studies showed a relationship between the ingestion of supplemental vitamins or minerals and the incidence or severity of prostate cancer, especially in smokers. However, neither the use of multivitamin supplementation nor the use of individual vitamin/mineral supplementation affected the overall occurrence of prostate cancer or the occurrence of advanced/metastatic prostate cancer or death from prostate cancer when the results of the studies were combined in a meta-analysis. We also conducted several sensitivity analyses by running meta-analysis using just the higher quality studies and just the RCTs. There were still no associations found. CONCLUSIONS There is no convincing evidence that the use of supplemental multivitamins or any specific vitamin affects the occurrence or severity of prostate cancer. There was high heterogeneity among the studies so it is possible that unidentified subgroups may benefit or be harmed by the use of vitamins.
The effects of sulfhydryl inhibitors and cytochalasin on the cytoplasmic and cytoskeletal actin of human neutrophils

To better understand the changes that occur in cytoplasmic actin during cell movement, we studied the effect of inhibitors of cell movement on the molecular conformation of actin and its incorporation into the Triton‐insoluble cytoskeleton of human neutrophils. The sulfhydryl reactive compound N‐ethylmaleimide caused an increase in cellular F‐actin as measured by uptake of the F‐actin specific fluorescent probe 7‐nitrobenz‐2‐oxadiazole‐phallacidin. However, N‐ethylmaleimide reduced the amount of actin associated with the Triton‐insoluble cytoskeleton. Dithiobisnitrobenzoic acid, a sulfhydryl reagent that does not cross cell membranes efficiently, did not alter the F‐actin content of neutrophils. The effect of N‐ethylmaleimide was blocked by the presence of dithiothreitol, a donor of sulfhydryl groups. N‐ethylmaleimide did not affect the polymerization of actin in a cell‐free system. Cytochalasin B did not alter F‐actin content of neutrophils but did decrease actin in cytoskeletons of resting neutrophils. Cytochalasin inhibited the increase in F‐actin initiated by the chemoattractant N‐formylmethionylleucylphenylalanine. We propose that N‐ethylmaleimide blocks the stabilization of G‐actin in cytoplasm, interferes with the incorporation of F‐actin polymer into the cytoskeleton, and depolymerizes the cytoskeleton. In contrast cytochalasin stabilizes G‐actin in the presence of chemotactic peptide. These data suggest that reversible conversion of G‐actin to F‐actin and incorporation of F‐actin into the Triton‐insoluble cytoskeleton are important for neutrophil movement.