Notes

Elegance associated with Two-Class Generator Imagery in a fNIRS Centered Brain Laptop or computer Software.
The acquisition of DNA damage is an early driving event in tumorigenesis. Premalignant lesions show activated DNA damage responses and inactivation of DNA damage checkpoints promotes malignant transformation. However, DNA damage is also a targetable vulnerability in cancer cells. This requires a detailed understanding of the cellular and molecular mechanisms governing DNA integrity. Here, we review current work on DNA damage in tumorigenesis. We discuss DNA double strand break repair, how repair pathways contribute to tumorigenesis, and how double strand breaks are linked to the tumor microenvironment. Next, we discuss the role of oncogenes in promoting DNA damage through replication stress. Finally, we discuss our current understanding on DNA damage in micronuclei and discuss therapies targeting these DNA damage pathways.Neuroendocrine neoplasms (NENs) are relatively rare neoplasms with 6.4-times increasing age-adjusted annual incidence during the last four decades. NENs arise from neuroendocrine cells, which release hormones in response to neuronal stimuli and they are distributed into organs and tissues. The presentation and biological behaviour of the NENs are highly heterogeneous, depending on the organ. The increased incidence is mainly due to increased awareness and improved detection methods both in the majority of sporadic NENs (non-inherited), but also the inherited groups of neoplasms appearing in at least ten genetic syndromes. The most important one is multiple endocrine neoplasia type 1 (MEN-1), caused by mutations in the tumour suppressor gene MEN1. MEN-1 has been associated with different tumour manifestations of NENs e.g. pancreas, gastrointestinal tract, lungs, thymus and pituitary. Pancreatic NENs tend to be less aggressive when arising in the setting of MEN-1 compared to sporadic pancreatic NENs. There have been very important improvements over the past years in both genotyping, genetic counselling and family screening, introduction and validation of various relevant biomarkers, as well as newer imaging modalities. Alongside this development, both medical, surgical and radionuclide treatments have also advanced and improved morbidity, quality of life and mortality in many of these patients. Despite this progress, there is still space for improving insight into the genetic and epigenetic factors in relation to the biological mechanisms determining NENs as part of MEN-1. This review gives a comprehensive update of current evidence for co-occurrence, diagnosis and treatment of MEN-1 and neuroendocrine neoplasms and highlight the important progress now finding its way to international guidelines in order to improve the global management of these patients.CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental disorder caused by pathogenic variants in the Cyclin-dependent kinase-like 5 (CDKL5) gene, resulting in dysfunctional CDKL5 protein. It predominantly affects females and causes seizures in the first few months of life, ultimately resulting in severe intellectual disability. In the absence of targeted therapies, treatment is currently only symptomatic. CDKL5 is a serine/threonine kinase that is highly expressed in the brain, with a critical role in neuronal development. Evidence of mitochondrial dysfunction in CDD is gathering, but has not been studied extensively. We used human patient-derived induced pluripotent stem cells with a pathogenic truncating mutation (p.Arg59*) and CRISPR/Cas9 gene-corrected isogenic controls, differentiated into neurons, to investigate the impact of CDKL5 mutation on cellular function. Quantitative proteomics indicated mitochondrial defects in CDKL5 p.Arg59* neurons, and mitochondrial bioenergetics analysis confirmed decreased activity of mitochondrial respiratory chain complexes. Additionally, mitochondrial trafficking velocity was significantly impaired, and there was a higher percentage of stationary mitochondria. We propose mitochondrial dysfunction is contributing to CDD pathology, and should be a focus for development of targeted treatments for CDD.The present study was aimed to evaluate the isoxanthanol against Staphylococcus aureus chronic obstructive pulmonary disease (COPD) in rat model. The isoxanthanol decreased the parasitic load by almost 99% in the Staphylococcus aureus infected rats. It significantly (P less then 0.05) decreased mortality rate of the rats, prevented pulmonary tissue damage and aggregation of inflammatory cytokines. In Staphylococcus aureus infected rats, isoxanthanol treatment inhibited production of interleukin-18, interleukin-1β and TNF-α significantly (P less then 0.05) in the BALF and pulmonary tissues. Treatment of the Staphylococcus aureus-infected rats with isoxanthanol inhibited up-regulation of NLRP3, ASC and caspase-1 expression. In Staphylococcus aureus-infected rats the expression of miR-145-5p was remarkably increased on treatment with isoxanthanol. In summary, isoxanthanol prevents Staphylococcus aureus-induced COPD in rats through up-regulation of miR-145-5p and suppression of inflammatory cytokines. Therefore, isoxanthanol can be of therapeutic importance for the treatment of Staphylococcus aureus induced COPD.
Cancer results in a hypercoagulable state that is associated with both venous and arterial thromboses. However, little is known about the effects of acute limb ischemia (ALI) in this cohort of patients. In the present systematic review and meta-analysis, we analyzed the available clinical data on cancer and its association with ALI and evaluated the outcomes in these patients after a diagnosis of ALI.

Three databases, including PubMed, EMBASE, and the Cochrane Library, were queried. Studies that met the inclusion criteria were included regardless of the publication year, language, sample size, or follow-up length. All the steps of the meta-analysis were conducted in accordance with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) and MOOSE (meta-analysis of observational studies in epidemiology) guidelines.

Seven studies from 6222 references with a total of 2899 patients were included. Of the 2899 patients, 1195 (41%) had had a diagnosis of ALI before their cancer diagnosiof ALI in patients with cancer was >50%. For patients presenting with ALI of unclear etiology, the presence of an underlying cancer should be considered.
50%. For patients presenting with ALI of unclear etiology, the presence of an underlying cancer should be considered.
Patients with critical limb-threatening ischemia (CLTI) have had poor long-term survival after lower extremity revascularization owing to coexistent coronary artery disease. A new cardiac diagnostic test, coronary computed tomography-derived fractional flow reserve (FFR
), can identify patients with ischemia-producing coronary stenosis who might benefit from coronary revascularization. We sought to determine whether the diagnosis of silent coronary ischemia before limb salvage surgery with selective postoperative coronary revascularization can reduce the incidence of adverse cardiac events and improve the survival of patients with CLTI compared with standard care.

Patients with CLTI and no cardiac history or symptoms who had undergone preoperative testing to detect silent coronary ischemia with selective postoperative coronary revascularization (group I) were compared with patients with standard preoperative cardiac clearance and no elective postoperative coronary revascularization (group II). Both group in two of every three patients. Selective coronary revascularization of patients with silent coronary ischemia after recovery from limb salvage surgery resulted in fewer CV deaths and MIs and improved 2-year survival compared with patients with CLTI who had received standard cardiac evaluation and care. Prospective controlled studies are required to further define the role of FFRCT in the evaluation and treatment of patients with CLTI.Transdermal delivery of nucleic acid therapeutics has been demonstrated to be effective for psoriasis treatment. We previously reported the utility of iontophoresis (IP) using weak electric current (0.3-0.5 mA/cm2) for intradermal delivery of nucleic acid therapeutics via weak electricity-mediated intercellular junction cleavage, and subsequent exertion of nucleic acid function. However, the thickened pathological skin in psoriasis hampers permeation of IP-administered macromolecules. Thus, approaches are needed to more strongly cleave intercellular spaces and overcome the psoriatic skin barrier. Herein, we applied a combination of tight junction-opening peptide AT1002 with IP, as synergistic effects of weak electricity-mediated intercellular junction cleavage and the tight junction-opening ability of AT1002 may help overcome thickened psoriatic skin and facilitate macromolecule delivery. Pretreatment with IP of an AT1002 analog exhibiting positively-charged moieties before fluorescence-labeled oligodeoxynucleotide IP resulted in the oligodeoxynucleotide permeation into psoriatic skin, whereas IP of the oligodeoxynucleotide alone did not. Moreover, psoriasis-induced upregulation of inflammatory cytokine mRNA levels was significantly suppressed by NF-κB decoy oligodeoxynucleotide IP combined with the AT1002 analog, resulting in amelioration of epidermis hyperplasia. These results suggest that synergistic effects of IP and an AT1002 analog can overcome thickened psoriatic skin and enable intradermal delivery of NF-κB decoy oligodeoxynucleotide for psoriasis treatment.Methyl aminolevulinate (MAL) is a photosensitizer topically used for photodynamic diagnosis (PDD) and photodynamic therapy (PDT) of skin pre-cancers and cancers. In this study, our goal is to expand the application of MAL to dual intraoperative PDD and PDT of peritoneal carcinomatosis. A new liposomal MAL formulation (lipMAL) designed for systemic or intraperitoneal administration was developed. LipMALs prepared by ammonium sulfate gradient technique achieved MAL payload up to 18% (w/w) with drug encapsulation efficiency in the range of 15.1-31.5%. All lipMALs demonstrated controlled MAL release behavior, and achieved strong fluorescence in cancer cells (SKOV3) but minimal fluorescence in non-cancer peritoneal cells (B14FAF28-G3). LipMALs led to significantly higher fluorescence levels than free MAL groups (P less then 0.05), up to 6.8-fold of the free MAL fluorescence levels in SKOV3 cells. The PDD performance of lipMALs was also compared with free MAL in SKOV3/ B14FAF28-G3 co-cultures simulating ovarian cancer micrometastases on peritoneal surface. The lipMAL-treated cancer colonies glew more brightly than the free MAL treated colonies and were clearly distinguishable from the dim peritoneum background with unaided eyes. LipMAL also achieved significantly stronger anticancer PDT effects than free MAL both in terms of cell viability and colony-formation (P less then 0.05) while demonstrating minimal dark toxicity. To conclude, a new promising aid for the surgeons to achieve more complete resection of tumors and PC micrometastases and clean up any residual cancer cells undetected was developed.Cardiometabolic diseases (CMDs) are metabolic diseases (e.g., obesity, diabetes, atherosclerosis, rare genetic metabolic diseases, etc.) associated with cardiac pathologies. Pathophysiology of most CMDs involves increased production of reactive oxygen species and impaired antioxidant defense systems, resulting in cardiac oxidative stress (OxS). To alleviate OxS, various antioxidants have been investigated in several diseases with conflicting results. Here we review the effect of CMDs on cardiac redox homeostasis, the role of OxS in cardiac pathologies, as well as experimental and clinical data on the therapeutic potential of natural antioxidants (including resveratrol, quercetin, curcumin, vitamins A, C, and E, coenzyme Q10, etc.), synthetic antioxidants (including N-acetylcysteine, SOD mimetics, mitoTEMPO, SkQ1, etc.), and promoters of antioxidant enzymes in CMDs. As no antioxidant indicated for the prevention and/or treatment of CMDs has reached the market despite the large number of preclinical and clinical studies, a sizeable translational gap is evident in this field.
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