Levesqueallen7404

Antigens associated with tumors have proven valuable in cancer immunotherapy. Their insufficient expression in the majority of tumors, however, limits their potential value as therapeutic markers. Aiming for a noninvasive approach applicable in clinical practice, we investigated the possibility of using focused shock waves to induce membrane expression of hidden intracellular tumor markers. Here, we studied the in vitro effect of a thousand focused shock waves at 16 MPa overpressure on the membrane expression of a cytosolic glycosphingolipid, monosialosyl-galactosyl-globoside (MSGG). Double-staining flow cytometry with propidium-iodide and monoclonal antibody RM1 revealed an immediate increase in MSGG expression on renal carcinoma cells (18% ± 0.5%) that reached its peak value (20.73% ± 0.4%) within one hour after the shock waves. The results of immunoelectron microscopy confirmed the incorporation of MSGG into newly formed cytosolic vesicles and their integration with the cell membrane. Based on the enzymatic nature of MSGG production that is not controlled directly by genes, the immediate upregulation of MSGG membrane expression implies that a chain of mechanochemical events affecting subcellular structures are responsible for the shock-wave-induced antigenic modification. Physically unmasking hidden tumor antigens and enhancing their expression by focused shock waves presents a potential noninvasive method of boosting tumor immunogenicity as a theranostic strategy in cancer immunotherapy.Theory of mind (ToM, the ability to attribute mental states to others) deficit is a frequent finding in neurodegenerative conditions, mediated by a diffuse brain network confirmed by 18F-FDG-PET and MR imaging, involving frontal, temporal and parietal areas. However, the role of hubs and spokes network regions in ToM performance, and their respective damage, is still unclear. To study this mechanism, we combined ToM testing with brain 18F-FDG-PET imaging in 25 subjects with mild cognitive impairment due to Alzheimer's disease (MCI-AD), 24 subjects with the behavioral variant of frontotemporal dementia (bvFTD) and 40 controls. Regions included in the ToM network were divided into hubs and spokes based on their structural connectivity and distribution of hypometabolism. The hubs of the ToM network were identified in frontal regions in both bvFTD and MCI-AD patients. A mediation analysis revealed that the impact of spokes damage on ToM performance was mediated by the integrity of hubs (p < 0.001), while the impact of hubs damage on ToM performance was independent from the integrity of spokes (p < 0.001). Our findings support the theory that a key role is played by the hubs in ToM deficits, suggesting that hubs could represent a final common pathway leading from the damage of spoke regions to clinical deficits.Gastric cancer (GC) remains one of the most common deadly malignancies worldwide. Recently, several targeted therapeutics for treating unresectable or metastatic GC have been developed. Comprehensive characterization of the molecular profile and of the tumor immune microenvironment of GC has allowed researchers to explore promising biomarkers for GC treatment and has enabled a new paradigm in precision-targeted immunotherapy. In this article, we review established and promising new biomarkers relevant in GC, with a focus on their clinical implications, diagnostic methods, and the efficacy of targeted agents.Lymphadenectomy is crucial for an optimal oncologic resection of colon and rectal cancers. However, without a direct visualization, an aberrant route of lymph node (LN) diffusion might remain unresected. Indocyanine-green (ICG) lymphatic mapping permits a real-time LNs visualization. We designed the GREENLIGHT trial to explore in 100 patients undergoing robotic colorectal resection the clinical significance of a D3 ICG-guided lymphadenectomy. The primary endpoint was the number of patients in whom ICG changed the extent of lymphadenectomy. We report herein the interim analysis on the first 70 patients. After endoscopic ICG injection 24 h (n = 49) or 72 h (n = 21) ahead, 19, 20, and 31 patients underwent right colectomy, left colectomy, and anterior rectal resection. The extent of lymphadenectomy changed in 35 (50%) patients, mostly (29 (41.4%)) for the identification of LNs (median two) outside the standard draining basin. Identification of such LNs was less frequent in rectal tumors that had undergone chemoradiotherapy (26.3%) (p > 0.05). A non-significant correlation between time-to-ICG injection and identification of aberrant LNs was observed (48.9% at 24 h vs. GANT61 datasheet 23.8% at 72 h). The presence of LN metastases did not affect a proper fluorescent mapping. These data indicate that ICG lymphatic mapping provides relevant information in 50% of patients, thus increasing the accuracy of potentially curative resections.Treatment with dopamine agonists in Parkinson's disease (PD) is associated with debilitating neuropsychiatric side-effects characterized by impulsive and compulsive behaviors. The vulnerability to develop such impairments is thought to involve interactions between individual vulnerability traits, types of antiparkinsonian medications, and the neurodegenerative process. We investigated the effect of the dopamine D3/D2 agonist pramipexole (PPX) and selective nigrostriatal degeneration achieved by viral-mediated expression of alpha-synuclein on the expression of repetitive and compulsive-like behaviors in rats. In a task assessing spontaneous food hoarding behavior, PPX increased the time spent interacting with food pellets at the expense of hoarding. This disruption of hoarding behavior was identical in sham and lesioned rats. In an operant post-training signal attenuation task, the combination of nigrostriatal lesion and PPX decreased the number of completed trials and increased the number of uncompleted trials. The lesion led to an increased compulsive behavior after signal attenuation, and PPX shifted the overall behavioral output towards an increased proportion of compulsive lever-presses. Given the magnitude of the behavioral effects and the lack of strong interaction between PPX and nigral degeneration, these results suggest that extra-nigral pathology may be critical to increase the vulnerability to develop compulsive behaviors following treatment with D3/D2 agonists.Polycystic ovarian syndrome (PCOS) is a complex endocrine disorder affecting females in their reproductive age. The early diagnosis of PCOS is complicated and complex due to overlapping symptoms of this disease. The most accepted diagnostic approach today is the Rotterdam Consensus (2003), which supports the positive diagnosis of PCOS when patients present two out of the following three symptoms biochemical and clinical signs of hyperandrogenism, oligo, and anovulation, also polycystic ovarian morphology on sonography. Genetic variance, epigenetic changes, and disturbed lifestyle lead to the development of pathophysiological disturbances, which include hyperandrogenism, insulin resistance, and chronic inflammation in PCOS females. At the molecular level, different proteins and molecular and signaling pathways are involved in disease progression, which leads to the failure of a single genetic diagnostic approach. The genetic approach to elucidate the mechanism of pathogenesis of PCOS was recently developed, whereby four phenotypic variances of PCOS categorize PCOS patients into classic, ovulatory, and non-hyperandrogenic types. Genetic studies help to identify the root cause for the development of this PCOS. PCOS genetic inheritance is autosomal dominant but the latest investigations revealed it as a multigene origin disease. Different genetic loci and specific genes have been identified so far as being associated with this disease. Genome-wide association studies (GWAS) and related genetic studies have changed the scenario for the diagnosis and treatment of this reproductive and metabolic condition known as PCOS. This review article briefly discusses different genes associated directly or indirectly with disease development and progression.Despite current therapeutic strategies for immunomodulation and relief of symptoms in multiple sclerosis (MS), remyelination falls short due to dynamic neuropathologic deterioration and relapses, leading to accrual of disability and associated patient dissatisfaction. The potential of cannabinoids includes add-on immunosuppressive, analgesic, neuroprotective, and remyelinative effects. This study evaluates the efficacy of medical marijuana in MS and its experimental animal models. A systematic review was conducted by a literature search through PubMed, ProQuest, and EBSCO electronic databases for studies reported since 2007 on the use of cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) in MS and in experimental autoimmune encephalomyelitis (EAE), Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), and toxin-induced demyelination models. Study selection and data extraction were performed by 3 reviewers, and 28 studies were selected for inclusion. The certainty of evidence was appraised using the Cochrane GRADE approach. In clinical studies, there was low- and moderate-quality evidence that treatment with ~11 CBD/THC mixtures as a nabiximols (Sativex®) oromucosal spray reduced numerical rating scale (NRS) scores for spasticity, pain, and sleep disturbance, diminished bladder overactivity, and decreased proinflammatory cytokine and transcription factor expression levels. Preclinical studies demonstrated decreases in disease severity, hindlimb stiffness, motor function, neuroinflammation, and demyelination. Other experimental systems showed the capacity of cannabinoids to promote remyelination in vitro and by electron microscopy. Modest short-term benefits were realized in MS responders to adjunctive therapy with CBD/THC mixtures. Future studies are recommended to investigate the cellular and molecular mechanisms of cannabinoid effects on MS lesions and to evaluate whether medical marijuana can accelerate remyelination and retard the accrual of disability over the long term.Machine perfusion (MP) allows the maintenance of liver cells in a metabolically active state ex vivo and can potentially revert metabolic perturbations caused by donor warm ischemia, procurement, and static cold storage (SCS). The present preclinical research investigated the metabolic outcome of the MP procedure by analyzing rat liver tissue, bile, and perfusate samples by means of high-field (600 MHz) nuclear magnetic resonance (NMR) spectroscopy. An established rat model of normothermic MP (NMP) was used. Experiments were carried out with the addition of an oxygen carrier (OxC) to the perfusion fluid (OxC-NMP, n = 5) or without (h-NMP, n = 5). Bile and perfusate samples were collected throughout the procedure, while biopsies were only taken at the end of NMP. Two additional groups were (1) Native, in which tissue or bile specimens were collected from rats in resting conditions; and (2) SCS, in which biopsies were taken from cold-stored livers. Generally, NMP groups showed a distinctive metabolomic signature in all the analyzed biological matrices. In particular, many of the differentially expressed metabolites were involved in mitochondrial biochemical pathways. Succinate, acetate, 3-hydroxybutyrate, creatine, and O-phosphocholine were deeply modulated in ex vivo perfused livers compared to both the Native and SCS groups. These novel results demonstrate a broad modulation of mitochondrial metabolism during NMP that exceeds energy production and redox balance maintenance.