Miracle-dz/UniFAR-FTUs huggingface dataset:
Restoration of absent in melanoma 2 (AIM2) induces G2/M cell cycle arrest and promotes invasion of colorectal cancer cells

Absent in melanoma 2 (AIM2) is a member of the interferon‐inducible HIN‐200 protein family. Recent findings point to a role of AIM2 function in both inflammation and cancer. In response to foreign cytoplasmic DNA, AIM2 forms an inflammasome, resulting in caspase activation in inflammatory cells. Moreover, AIM2 reduces breast cancer cell proliferation and mammary tumor growth in a mouse model and shows a high frequency of frameshift mutations in microsatellite unstable (MSI‐H) gastric, endometrial and colorectal cancers. However, the consequences of AIM2 restoration in AIM2‐deficient colon cancer cells have not yet been examined. Using different constructs for expression of AIM2 fusion proteins, we found that AIM2 restoration clearly suppressed cell proliferation and viability in HCT116 cells as well as in cell lines derived from other entities. In contrast to previous reports from breast cancer cells, our cell cycle analyses of colon cancer cells revealed that AIM2‐mediated inhibition of cell proliferation is associated with accumulation of cells at late S‐phase, resulting in G2/M arrest. The latter correlated well with upregulation of cyclin D3 and p21Waf1/Cip1 as well as with inhibition of cdc2 activity through Tyr‐15 phosphorylation. Furthermore, AIM2 restoration affected the adhesion of colorectal cancer cells to fibronectin and stimulated the invasion through extracellular matrix‐coated membrane in transwell assays. Consistent with this phenotype, AIM2 induced the expression of invasion‐associated genes such as VIM and MCAM, whereas ANXA10 and CDH1 were downregulated. Our data suggest that AIM2 mediates reduction of cell proliferation by cell cycle arrest, thereby conferring an invasive phenotype in colon cancer cells.
GSTT1 and GSTM1 polymorphisms and myelodysplastic syndrome risk: a systematic review and meta‐analysis

Glutathione‐S‐transferace polymorphisms may make hematopoietic lineage cells susceptible to genotoxicity following exposure to heavy metals or benzene. We conducted a systematic review and meta‐analysis to define the effect of GSTM1 and GSTT1 null polymorphisms on MDS risk. We searched the PubMed and SCOPUS databases to identify peer‐reviewed published case‐control studies investigating the association between GSTT1 and/or GSTM1 null genotypes and development of MDS. Between‐study heterogeneity was assessed using Cochran's Q statistic and the I2 statistic. Odds ratios from individual studies were pooled using fixed and random effects models. Thirteen studies were considered eligible for the GSTT1 meta‐analysis (1471 cases, 1907 controls) and 10 were considered eligible for the GSTM1 meta‐analysis (1161 cases, 1668 controls). For the GSTT1 polymorphism, there was moderate between study heterogeneity (pQ = 0.01; I2 = 52.3%) and the null genotype was significantly associated with increased risk of MDS development, random effects OR = 1.43 (95% CI, 1.09–1.89); p = 0.01. For the GSTM1 polymorphisms there was moderate between‐study heterogeneity (p = 0.07; I2 = 43.1%) and the random effects OR = 1.02 (95% CI, 0.82–1.28) was non‐significant (p = 0.85). The GSTT1 null genotype is a significant risk factor for MDS development. Gene‐environment interactions need to be further explored.
A Comparative Study of α‐Dystroglycan Glycosylation in Dystroglycanopathies Suggests that the Hypoglycosylation of α‐Dystroglycan Does Not Consistently Correlate with Clinical Severity

Hypoglycosylation of α‐dystroglycan underpins a subgroup of muscular dystrophies ranging from congenital onset of weakness, severe brain malformations and death in the perinatal period to mild weakness in adulthood without brain involvement. Mutations in six genes have been identified in a proportion of patients. POMT1, POMT2 and POMGnT1 encode for glycosyltransferases involved in the mannosylation of α‐dystroglycan but the function of fukutin, FKRP and LARGE is less clear. The pathological hallmark is reduced immunolabeling of skeletal muscle with antibodies recognizing glycosylated epitopes on α‐dystroglycan. If the common pathway of these conditions is the hypoglycosyation of α‐dystroglycan, one would expect a correlation between clinical severity and the extent of hypoglycosylation. By studying 24 patients with mutations in these genes, we found a good correlation between reduced α‐dystroglycan staining and clinical course in patients with mutations in POMT1, POMT2 and POMGnT1. However, this was not always the case in patients with defects in fukutin and FKRP, as we identified patients with mild limb–girdle phenotypes without brain involvement with profound depletion of α‐dystroglycan. These data indicate that it is not always possible to correlate clinical course and α‐dystroglycan labeling and suggest that there might be differences in α‐dystroglycan processing in these disorders.
Four‐Year Follow‐Up of a Meditation‐Based Program for the Self‐Regulation of Chronic Pain: Treatment Outcomes and Compliance

Two hundred twenty-five chronic pain patients were studied following training in mindfulness meditation. Large and significant overall improvements were recorded post-intervention in physical and psychological status. These gains were maintained at follow-up in the majority of subjects. Follow-up times ranged from 2.5–48 months. Status on the McUill Melzack Fain Rating Index (PRI). however, tended to revert to preintervention levels following the intervention. Most subjects reported a high degree of adherence with the meditation techniques, maintenance of improved status over time, and a high degree of importance attributed to the training program. We conclude that such training can have long-term benefit for chronic pain patients.
BMP2 rescues deficient cell migration in Tgfbr3−/− epicardial cells and requires Src kinase

ABSTRACT During embryogenesis, the epicardium undergoes proliferation, migration, and differentiation into several cardiac cell types which contribute to the coronary vessels. The type III transforming growth factor-β receptor (TGFβR3) is required for epicardial cell invasion and development of coronary vasculature in vivo. Bone Morphogenic Protein-2 (BMP2) is a driver of epicardial cell migration. Utilizing a primary epicardial cell line derived from Tgfbr3+/+ and Tgfbr3−/− mouse embryos, we show that Tgfbr3−/− epicardial cells are deficient in BMP2 mRNA expression. Tgfbr3−/− epicardial cells are deficient in 2-dimensional migration relative to Tgfbr3+/+ cells; BMP2 induces cellular migration to Tgfbr3+/+ levels without affecting proliferation. We further demonstrate that Src kinase activity is required for BMP2 driven Tgfbr3−/− migration. BMP2 also requires Src for filamentous actin polymerization in Tgfbr3−/− epicardial cells. Taken together, our data identifies a novel pathway in epicardial cell migration required for development of the coronary vessels.
All 4 di‐leucine motifs in the first hydrophobic domain of the E5 oncoprotein of human papillomavirus type 16 are essential for surface MHC class I downregulation activity and E5 endomembrane localization

The E5 oncoprotein of human papillomavirus type 16 downregulates surface MHC Class I and interacts with the heavy chain of the MHC complex via the first hydrophobic domain, believed to form the first helical transmembrane region (TM1) of E5. TM1 contains 4 equally spaced di‐leucine (LL1‐LL4) motifs. Di‐leucine motifs have been implicated in protein–protein interactions and as localization signals. To see if any of the 4 di‐leucine motifs of TM1 are involved in MHC downregulation by E5, we mutated each LL pair into valine pairs (VV1‐VV4), as mutation of leucine to valine is not expected to cause major structural alterations in E5. We found that all 4 mutations disrupted the intracellular location of E5 and abrogated its MHC I downregulating activity; however VV2 and VV4 mutants were still able to interact physically with the MHC I heavy chain (HC) in vitro, while VV1 and VV3 mutants had lost this activity. We conclude that LL1 and LL3 are necessary for the interaction with HC, but LL2 and LL4 are not. However all 4 LL motifs are responsible for the proper localization of E5 in the Golgi/ER, and the displacement of E5 from this location contributes to the abrogation of MHC I downregulation. LL1 and LL3 motifs are expected to be on one face of the TM1 helix and LL2 and LL4 on the opposite face. We propose that E5 interacts with HC via LL1 and LL3 and that all 4 di‐leucine motifs act as a targeting signal.
In vitro formation of neuroclusters in microfluidic devices and cell migration as a function of stromal-derived growth factor 1 gradients

ABSTRACT Central nervous system (CNS) cells cultured in vitro as neuroclusters are useful models of tissue regeneration and disease progression. However, the role of cluster formation and collective migration of these neuroclusters to external stimuli has been largely unstudied in vitro. Here, 3 distinct CNS cell types, medulloblastoma (MB), medulloblastoma-derived glial progenitor cells (MGPC), and retinal progenitor cells (RPC), were examined with respect to cluster formation and migration in response to Stromal-Derived Growth Factor (SDF-1). A microfluidic platform was used to distinguish collective migration of neuroclusters from that of individual cells in response to controlled concentration profiles of SDF-1. Cell lines were also compared with respect to expression of CXCR4, the receptor for SDF-1, and the gap junction protein Connexin 43 (Cx43). All cell types spontaneously formed clusters and expressed both CXCR4 and Cx43. RPC clusters exhibited collective chemotactic migration (i.e. movement as clusters) along SDF-1 concentration gradients. MGPCs clusters did not exhibit adhesion-based migration, and migration of MB clusters was inconsistent. This study demonstrates how controlled microenvironments can be used to examine the formation and collective migration of CNS-derived neuroclusters in varied cell populations.
The Functional Reach Test in 3- to 5-Year-Old Children Without Disabilities

Purpose: The purposes of this study were to describe normal values and variability of the Functional Reach Test (FRT) scores in young children and to examine the relationship between anthropometric measures and FRT scores. Methods: One hundred twenty-one children aged 3 to 5 years without known disabilities participated in this study. The mean of three successful FRT trials was analyzed. Results: Three-year-old children reached 11.4 ± 2.6 cm (mean ± SD), 4-year-old children 13.6 ± 3.0 cm, and 5-year-old children 15.7 ± 4.4 cm. The 95% confidence intervals for the mean and the cutoff reach value for 2 standard deviations below the mean are reported. Weight was the only significant anthropometric measure that predicted FR (R2 = 0.34). Conclusion: The FRT is a feasible test to examine the balance of 4- to 5-year-old children and should be used with caution for 3-year-old children.
Pet's Presence and Owner's Blood Pressures during the Daily Lives of Pet Owners with Pre- to Mild Hypertension

ABSTRACT As the population ages the number of older adults living with hypertension (HTN) is rising dramatically. Uncontrolled HTN increases cardiovascular and renal mortality. Ambulatory (A) blood pressure (BP) is a better predictor of HTN-related morbidity and mortality than office BP. Lower BP is the most important therapeutic goal in treating HTN. Any reduction in BP has significant benefits for older adults. The current study was designed to evaluate the impact of the presence of pet dogs and cats on ABP during the daily lives of independently living, older pet owners with pre- to mild HTN. A repeated measures observational study of ABP of 32 pet owners (21 dogs, 8 cats, 3 cat and dog; 29 women) aged 50–83 years with BP 120–150/80–100 mmHg or < 150/100 with anti-hypertensive medication was conducted. Owner's ABPs were recorded every 20 minutes for one day during waking hours at study entry, one month, and three months. Activity monitors and diaries were used to obtain information about activity, mood, and whether the pet and/or another person was present in the room (indoors) or in close proximity (outdoors) with the owner at each assessment. Generalized estimating equation (GEE) analyses for hierarchical data (unstructured correlations) were performed for systolic and diastolic ABP. Mean ABPs were significantly (systolic BP/diastolic BP: dog p = 0.008/ p = 0.002; cat p < 0.009/ p < 0.001) different (systolic BP/diastolic BP mmHg: dog 3.1/1.5; cat –3.0/2.2) when pets were present after controlling for participant's mood (p > 0.05/ p < 0.001), activity intensity (p = 0.026/ p = 0.441), location (p = 0.013/ p = 0.004), and the presence of other people (p = 0.947/ p = 0.723). The presence of a dog was associated with lower systolic and diastolic BP and of a cat was associated with lower diastolic BP and higher systolic BP during their owners' normal daily lives. This finding suggests that pets, especially dogs, may be effective as an adjunctive intervention to slow the development or progression of HTN in older adults. Comparison of ABPs of pet owners with non-owners during their daily lives is warranted and underway.
Efeito das terapias associadas de imagem motora e de movimento induzido por restrição na hemiparesia crônica: estudo de caso

This study assessed the efficacy of the association of motor imagery and constraint-induced movement therapies in functional rehabilitation of the upper limb in a patient with somatosensory and motor deficits following stroke. Motor imagery (MI) therapy, i.e., mental simulation of body image, consisted in: 1st, mirror visual stimulus, at three 30-60-minute weekly sessions for four weeks; and 2nd, MI with mental practice, at three 15-minute sessions per week for three weeks. Lastly, constraint-induced movement therapy was applied for 14 days, in 10 of which the patient underwent 6 hours daily of paretic limb functional training. The patient was assessed at baseline and at the end of each therapy modality as to clinical examination of sensation; hand grip strength; shoulder, elbow and wrist range of motion; and the motor assessment scale (MAS) was applied. Scores obtained at the four assessment moments were statistically compared. Results showed significant differences (p<0.05) after treatment: increased range of motion at all upper limb joints, increased hand grip strength, decrease in time of task performance at MAS, and recovery of clinical sensation, especially tactile detection and pressure sense. The association of IM and constraint-induced therapies thus proved effective in functional rehabilitation of the upper limb of the poststroke patient with chronic hemiparesis.
Tip off the HAT– Epigenetic control of learning and memory by Drosophila Tip60

Disruption of epigenetic gene control mechanisms involving histone acetylation in the brain causes cognitive impairment, a debilitating hallmark of most neurodegenerative disorders. Histone acetylation regulates cognitive gene expression via chromatin packaging control in neurons. Unfortunately, the histone acetyltransferases (HATs) that generate such neural epigenetic signatures and their mechanisms of action remain unclear. Our recent findings provide insight into this question by demonstrating that Tip60 HAT action is critical for morphology and function of the mushroom body (MB), the learning and memory center in the Drosophila brain. We show that Tip60 is robustly produced in MB Kenyon cells and extending axonal lobes and that targeted MB Tip60 HAT loss results in axonal outgrowth disruption. Functional consequences of loss and gain of Tip60 HAT levels in the MB are evidenced by defects in memory. Tip60 ChIP-Seq analysis reveals enrichment for genes that function in cognitive processes and accordingly, key genes representing these pathways are misregulated in the Tip60 HAT mutant fly brain. Remarkably, increasing levels of Tip60 in the MB rescues learning and memory deficits resulting from Alzheimer's disease associated amyloid precursor protein (APP) induced neurodegeneration. Our studies highlight the potential of HAT activators as a therapeutic option for cognitive disorders.
Ultrasonographic assessment of liver size in the dog

A simple ultrasonographic method of estimating liver size in the dog was evaluated in this study. A single linear measurement from the tip of the ventral liver lobes to the diaphragm was made, using both transverse and longitudinal planes of section, Assuming careful technique, this measurement proved to be highly reproducible. There was good correlation between the measurements taken on the two planes of section. This measurement was shown to provide a good indicator of liver mass, irrespective of the size or breed of dog. It was concluded that ultrasound provides a simple, quantitative method of assessing liver size in the dog.
Use of nonsteroidal anti‐inflammatory drugs and prostate cancer risk: A meta‐analysis

The association between use of aspirin and other nonsteroidal anti‐inflammatory drugs (NSAIDs) and the risk of prostate cancer remains controversial despite many observational epidemiological studies. We conducted a systematic meta‐analysis of these studies to examine both the strength and the consistency of the association, and to explore sources of variability between studies. We searched 12 computerized literature databases for reports published before June 2008 and included any epidemiologic studies where the outcome was prostate cancer incidence or mortality, and the exposure was use of NSAIDs. Studies that met the inclusion criteria comprised 10 case–control and 14 cohort studies with a total of 24,230 prostate cancer cases. Studies that assessed the effect of aspirin use on total prostate cancer had a pooled odds ratio (POR) of 0.83 (95%CI: 0.77–0.89), whereas those that assessed the effect of aspirin on advanced prostate cancer had a POR of 0.81 (0.72–0.92). Studies that examined the effects of non‐aspirin NSAIDs or all NSAIDs were less consistent but still suggestive of reduced risks. However, most reviewed studies were limited by exposure and disease misclassification, by inadequate information on dose and duration of use and by the possibility of screening and other biases. In conclusion, the epidemiologic evidence for a protective effect of aspirin and other NSAID use against prostate cancer is suggestive but not conclusive. There is a need for well‐designed observational studies with adequate exposure measurements, accurate case definition, attention to latency effects, and careful adjustment for screening and other biases.
Kinesthetic Sensitivity and Related Measures of Hand Sensitivity in Children With Nonproficient Handwriting

Purpose: This study compared measures of hand sensitivity and handwriting quality in children aged 10 to 12 years identified by their teachers as having nonproficient or proficient handwriting. We hypothesized that children with nonproficient handwriting have decreased kinesthetic sensitivity of the hands and digits. Methods: Sixteen subjects without documented motor or cognitive concerns were tested for kinesthetic sensitivity, discriminate tactile awareness, diadochokinesia, stereognosis, and graphesthesia. Eight children were considered to have nonproficient handwriting; 8 had proficient handwriting. Nonparametric Mann-Whitney U tests were used to identify differences between groups on sensory tests. Results: The 2 groups showed a statistically significant difference in handwriting legibility (P = .018). No significant difference was found on tests of kinesthetic sensitivity or other measures of sensation. Conclusions: Children presenting with handwriting difficulty as the only complaint have similar sensitivity in hands and digits as those with proficient handwriting. Failure to detect differences may result from a small sample size.
Adjuvant effects of formalin‐inactivated HSV through activation of dendritic cells and inactivation of myeloid‐derived suppressor cells in cancer immunotherapy

Use of adequate adjuvant is necessary for induction of effective antitumor immune responses. To develop an effective adjuvant for cancer immunotherapy, we selected formalin‐inactivated (f)‐HSV as an adjuvant component, and analyzed the mechanisms underlying its adjuvant effects. First, we found that f‐HSV can induce the tumor antigen‐specific CTLs by enhancing antigen cross‐presentation by dendritic cells (DCs), mainly through TLR2, but not TLR9. Next, f‐HSV was also found to prevent the accumulation of myeloid‐derived suppressor cells (MDSCs). We demonstrated that the expansion of MDSCs in the blood and spleen during tumor progression required B cells producing the inflammatory angiogenesis factors, vascular endothelial growth factor (VEGF)‐A and neuropilin‐1 (NRP‐1), a co‐receptor for VEGF receptor‐2 (VEGFR‐2). Interestingly, the transmembrane‐type NRP‐1 on B cells changed to soluble‐type NRP‐1 (sNRP‐1) by f‐HSV treatment. We further showed that the sNRP‐1 and VEGF‐A secreted from B cells by f‐HSV treatment could abrogate the immunosuppressive ability of MDSCs. These results suggest that f‐HSV can enhance antitumor immune responses as an adjuvant, not only through activation of DCs, but also inactivation of MDSCs via B cells.
Protein kinase C enhances plasma membrane expression of cardiac L-type calcium channel, CaV1.2

ABSTRACT L-type-voltage-dependent Ca2+ channels (L-VDCCs; CaV1.2, α1C), crucial in cardiovascular physiology and pathology, are modulated via activation of G-protein-coupled receptors and subsequently protein kinase C (PKC). Despite extensive study, key aspects of the mechanisms leading to PKC-induced Ca2+ current increase are unresolved. A notable residue, Ser1928, located in the distal C-terminus (dCT) of α1C was shown to be phosphorylated by PKC. CaV1.2 undergoes posttranslational modifications yielding full-length and proteolytically cleaved CT-truncated forms. We have previously shown that, in Xenopus oocytes, activation of PKC enhances α1C macroscopic currents. This increase depended on the isoform of α1C expressed. Only isoforms containing the cardiac, long N-terminus (L-NT), were upregulated by PKC. Ser1928 was also crucial for the full effect of PKC. Here we report that, in Xenopus oocytes, following PKC activation the amount of α1C protein expressed in the plasma membrane (PM) increases within minutes. The increase in PM content is greater with full-length α1C than in dCT-truncated α1C, and requires Ser1928. The same was observed in HL-1 cells, a mouse atrium cell line natively expressing cardiac α1C, which undergoes the proteolytic cleavage of the dCT, thus providing a native setting for exploring the effects of PKC in cardiomyocytes. Interestingly, activation of PKC preferentially increased the PM levels of full-length, L-NT α1C. Our findings suggest that part of PKC regulation of CaV1.2 in the heart involves changes in channel's cellular fate. The mechanism of this PKC regulation appears to involve the C-terminus of α1C, possibly corroborating the previously proposed role of NT-CT interactions within α1C.