Colorectal cancer (CRC) screening programs help diagnose cancer precursors and early cancers and help reduce CRC mortality. However, currently recommended tests, the fecal immunochemical test (FIT) and colonoscopy, have low uptake. There is therefore a pressing need for screening strategies that are minimally invasive and consequently more acceptable to patients, most likely blood based, to increase early CRC identification. MicroRNAs (miRNAs) released from cancer cells are detectable in plasma in a remarkably stable form, making them ideal cancer biomarkers. Using plasma samples from FIT-positive (FIT+) subjects in an Italian CRC screening program, we aimed to identify plasma circulating miRNAs that detect early CRC. miRNAs were initially investigated by quantitative real-time PCR in plasma from 60 FIT+ subjects undergoing colonoscopy at Fondazione IRCCS Istituto Nazionale dei Tumori, then tested on an internal validation cohort (IVC, 201 cases) and finally in a large multicenter prospective series (external validation cohort [EVC], 1121 cases). For each endoscopic lesion (low-grade adenoma [LgA], high-grade adenoma [HgA], cancer lesion [CL]), specific signatures were identified in the IVC and confirmed on the EVC. A two-miRNA-based signature for CL and six-miRNA signatures for LgA and HgA were selected. In a multivariate analysis including sex and age at blood collection, the areas under the receiver operating characteristic curve (95% confidence interval) of the signatures were 0.644 (0.607-0.682), 0.670 (0.626-0.714) and 0.682 (0.580-0.785) for LgA, HgA and CL, respectively. A miRNA-based test could be introduced into the FIT+ workflow of CRC screening programs so as to schedule colonoscopies only for subjects likely to benefit most.

We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women.

Although the adhesion molecules-mediated leukocyte adherence and infiltration into tissues is an important step of inflammation, the post-translational regulation of these proteins on the endothelial cells is poorly understood. Here, we report that TRIM65, an ubiquitin E3 ligase of tripartite protein family, selectively targets vascular cell adhesion molecule 1 (VCAM-1) and promotes its ubiquitination and degradation, by which it critically controls the duration and magnitude of sepsis-induced pulmonary inflammation. TRIM65 is constitutively expressed in human vascular endothelial cells. During TNFα-induced endothelial activation, the protein levels of TRIM65 and VCAM-1 are inversely correlated. Expression of wild-type TRIM65, but not expression of a TRIM65 mutant that lacks E3 ubiquitin ligase function in endothelial cells, promotes VCAM-1 ubiquitination and degradation, whereas small interference RNA-mediated knockdown of TRIM65 attenuates VCAM-1 protein degradation. Further experiments show that TRIM65 directly interacts with VCAM-1 protein and directs its polyubiquitination, by which TRIM65 controls monocyte adherence and infiltration into tissues during inflammation. Importantly, TRIM65-deficient mice are more sensitive to lipopolysaccharide-induced death, due to sustained and severe pulmonary inflammation. Taken together, our studies suggest that TRIM65-mediated degradation of VCAM-1 represents a potential mechanism that controls the duration and magnitude of inflammation.

The Pax6 gene encodes a regulatory transcription factor that is key in brain development. The molecular structure of Pax6, the roles it plays and its patterns of expression in the brain have been highly conserved during vertebrate evolution. As neurodevelopment proceeds, the Pax6 expression changes from the mitotic germinal zone in the ventricular zone to become distributed in cell groups in the adult brain. Studies in various vertebrates, from fish to mammals, found that the Pax6 expression is maintained in adults in most regions that express it during development. Specifically, in amphibians, Pax6 is widely expressed in the adult brain and its distribution pattern serves to highlight regional organization of the brain. In the present study, we analyzed the detailed distribution of Pax6 cells in the adult central nervous system of lungfishes, the closest living relatives of all tetrapods. Immunohistochemistry performed using double labeling techniques with several neuronal markers of known distribution patterns served to evaluate the actual location of Pax6 cells. Our results show that the Pax6 expression is maintained in the adult brain of lungfishes, in distinct regions of the telencephalon (pallium and subpallium), diencephalon, mesencephalon, hindbrain, spinal cord, and retina. The pattern of Pax6 expression is largely shared with amphibians and helps to understand the primitive condition that would have characterized the common ancestors to all sarcopterygians (lobe-finned fishes and tetrapods), in which Pax6 would be needed to maintain specific entities of subpopulations of neurons.

Even though the majority of population studies in environmental health focus on a single factor, environmental exposure in the real world is a mixture of many chemicals. The concept of "exposome" leads to an intellectual framework of measuring many exposures in humans, and the emerging metabolomics technology offers a means to read out both the biological activity and environmental impact in the same dataset. How to integrate exposome and metabolome in data analysis is still challenging. Here, we employ a hierarchical community network to investigate the global associations between the metabolome and mixed exposures including DDTs, PFASs and PCBs, in a women cohort with sera collected in California in the 1960s. Strikingly, this analysis revealed that the metabolite communities associated with the exposures were non-specific and shared among exposures. This suggests that a small number of metabolic phenotypes may account for the response to a large class of environmental chemicals.

Gene panel testing has become the norm for assessing breast cancer (BC) susceptibility, but actual cancer risks conferred by genes included in panels are not established. Contrarily, deciphering the missing hereditability on BC, through identification of novel candidates, remains a challenge. We aimed to investigate the mutation prevalence and spectra in a highly selected cohort of Greek patients with BC, questioning an extensive number of genes, implicated in cancer predisposition and DNA repair, while calculating gene-specific BC risks that can ultimately lead to important associations.

Neuroinflammation is a major contributor to secondary neuronal injury that accounts for a significant proportion of final brain cell loss in neonatal hypoxic-ischemic encephalopathy (HIE). However, the immunological mechanisms that underlie HIE remain unclear. MicroRNA-210 (miR-210) is the master "hypoxamir" and plays a key role in hypoxic-ischemic tissue damage. Herein, we report in an animal model of neonatal rats that HIE significantly upregulated miR-210 expression in microglia in the neonatal brain and strongly induced activated microglia. Intracerebroventricular administration of miR-210 antagomir effectively suppressed microglia-mediated neuroinflammation and significantly reduced brain injury caused by HIE. We demonstrated that miR-210 induced microglial M1 activation partly by targeting SIRT1, thereby reducing the deacetylation of the NF-κB subunit p65 and increasing NF-κB signaling activity. Thus, our study identified miR-210 as a novel regulator of microglial activation in neonatal HIE, highlighting a potential therapeutic target in the treatment of infants with hypoxic-ischemic brain injury.

Influenza causes a substantial burden worldwide, and current seasonal influenza vaccine has suboptimal effectiveness. To develop better, more broadly protective vaccines, a more thorough understanding is needed of how antibodies that target the influenza virus surface antigens, hemagglutinin (HA) (including head and stalk regions) and neuraminidase (NA), impact influenza illness and virus transmission.

The goal of this study was to compare dysphagia phenotypes in low and high copy number (LCN and HCN) transgenic superoxide dismutase 1 (SOD1) mouse models of ALS to accelerate the discovery of novel and effective treatments for dysphagia and early amyotrophic lateral sclerosis (ALS) diagnosis. Clinicopathological features of dysphagia were characterized in individual transgenic mice and age-matched controls utilizing videofluoroscopy in conjunction with postmortem assays of the tongue and hypoglossal nucleus. Quantitative PCR accurately differentiated HCN-SOD1 and LCN-SOD1 mice and nontransgenic controls. All HCN-SOD1 mice developed stereotypical paralysis in both hindlimbs. In contrast, LCN-SOD1 mice displayed wide variability in fore- and hindlimb involvement. Lick rate, swallow rate, inter-swallow interval, and pharyngeal transit time were significantly altered in both HCN-SOD1 and LCN-SOD1 mice compared to controls. Tongue weight, tongue dorsum surface area, total tongue length, and caudal tongue length were significantly reduced only in the LCN-SOD1 mice compared to age-matched controls. LCN-SOD1 mice with lower body weights had smaller/lighter weight tongues, and those with forelimb paralysis and slower lick rates died at a younger age. LCN-SOD1 mice had a 32% loss of hypoglossal neurons, which differed significantly when compared to age-matched control mice. These novel findings for LCN-SOD1 mice are congruent with reported dysphagia and associated tongue atrophy and hypoglossal nucleus pathology in human ALS patients, thus highlighting the translational potential of this mouse model in ALS research.

China is the largest producer and consumer of tobacco products worldwide. While direct marketing and advertisement of tobacco products is restricted, indirect marketing still exists under the guise of sponsorship and corporate social responsibility (CSR). This case study is focused on tobacco industry-sponsored elementary schools in Chinese rural areas.

To show the characteristics and outcomes of patients with neovascular age-related macular degeneration (nAMD) who had extended remission (ER) while on a pro re nata (PRN) treatment protocol.

Three-dimensional scanning technology was used to measure the expansion of the area and size of auricular skin to meet the normal standard of the external ear before ear reconstruction among microtia patients.

We attempted to train and validate a model of deep learning for the preoperative prediction of the response of patients with intermediate-stage hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE).

Experimental studies have shown that the progesterone metabolite, allopregnanolone, is endowed with promyelinating effects. The mechanisms underlying these promyelinating effects are not well understood. Therefore, we explored the impact of allopregnanolone's synthetic analogue, ganaxolone, on remyelination and microglial activation following focal demyelination in the corpus callosum of ovariectomized rats.

FA-SAT is a highly conserved satellite DNA sequence transcribed in many Bilateria species. To disclose the cellular and functional profile of FA-SAT non-coding RNAs, a comprehensive experimental approach, including the transcripts location in the cell and in the cell cycle, the identification of its putative protein interactors, and silencing/ectopic expression phenotype analysis, was performed. FA-SAT non-coding RNAs play a nuclear function at the G1 phase of the cell cycle and the interactomic assay showed that the PKM2 protein is the main interactor. The disruption of the FA-SAT non-coding RNA/PKM2 protein complex, by the depletion of either FA-SAT or PKM2, results in the same phenotype-apoptosis, and the ectopic overexpression of FA-SAT did not affect the cell-cycle progression, but promotes the PKM2 nuclear accumulation. Overall, our data first describe the importance of this ribonucleoprotein complex in apoptosis and cell-cycle progression, what foresees a promising novel candidate molecular target for cancer therapy and diagnosis.

The second generation antipsychotic drug clozapine is a psychotherapeutic agent with superior efficacy for treatment-resistant schizophrenia. Clozapine is associated with a low likelihood of neurological side-effects, but a high propensity to induce weight gain and metabolic dysregulation. The primary metabolite of clozapine is norclozapine (N-Desmethylclozapine), which has psychoactive properties itself, but its effects on metabolic function remains unknown. The goal of the present study was to determine whether directly administered norclozapine could cause metabolic dysregulation, similar to clozapine.

Astrocytes are major glial cells critically in maintaining stability of the central nervous system and functional activation of astrocytes occurs rapidly in various diseased or traumatic events. We are interested in functional changes of astrocytes during the spinal cord injury, and studied expression of nerve growth factor (NGF) in activated astrocytes by mouse model of contused spinal cord injury and cell culture experiment. It revealed that the spinal cord injury resulted in apparent activation of astrocytes and microglial cells and decreased BMS scores. A larger number of astrocytes showed immunoreactivity to proNGF in the injured spinal cord areas, and proNGF expression increased and remained high level at 7 to 14dpi, which was coincided with upregulation of glial fibrillary acidic protein. The proNGF was clearly localized in both exosome-like vesicles and cytoplasm of astrocytes in culture. Electron microscopy confirmed exosome-like vesicles with proNGF-immunoreactivity in diameter sizes of 50-100 nm. Finally, cell culture with lipopolysaccharide (LPS) experiment indicated increasing expression and release of proNGF in the astrocytes with LPS exposure. This study demonstrated that reactive astrocytes increased proNGF expression after spinal cord injury, also suggesting involvement of exosome-like proNGF transport or release in triggering neuronal apoptosis and aggravating progression of spinal cord injury.

Differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs) is a key event for axonal myelination in the central nervous system (CNS). Several growth factors and neurotransmitters like GABA are postulated as important regulators of that process, and different protein kinases may also participate in OL differentiation and myelination. However, the molecular mechanisms underlying the regulation of myelination by neurotransmitters are only partially known. In the present study, we provide evidence showing that GABA receptors (GABARs) play an important role in OL differentiation. First, we observed that OPCs and OLs synthesize GABA and expressed GABAR and transporters, both in vitro and in vivo and, in contrast to GABAARs, the subunits GABAB1R and GABAB2R are expressed in OLs over time. Then, we found that exogenous GABA increases the number of myelin segments and MBP expression in DRG-OPC cocultures, indicating that GABA regulates myelination when OLs are in contact with axons. Notably, in purified rat OPC cultures, chronic treatment with GABA and baclofen, specific GABABR agonist, accelerates OPC differentiation by enhancing the processes branching and myelin protein expression, effects that are reverted in presence of GABABR specific antagonist CGP55845. Exposure of OPCs to baclofen promotes the Src-phosphorylation, and the baclofen-induced maturation is attenuated in presence of the Src-family kinases inhibitor PP2. None of these effects are mediated by the GABAAR agonist muscimol. Together, these results highlight the relevance of the GABAergic system in OL differentiation, and indicate that this functional role is mediated through GABABR involving the participation of Src-family kinases. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.

Economic evaluations of tobacco control policies targeting adolescents are scarce. Few take into account real-world, large-scale implementation costs; few compare cost-effectiveness of different policies across different countries. We assessed the cost-effectiveness of five tobacco control policies (nonschool bans, including bans on sales to minors, bans on smoking in public places, bans on advertising at points-of-sale, school smoke-free bans, and school education programs), implemented in 2016 in Finland, Ireland, the Netherlands, Belgium, Germany, Italy, and Portugal.

This systematic review aimed to synthesize and quantify the associations of awareness of age-related change (AARC) with emotional well-being, physical well-being, and cognitive functioning.