62), and AST (WMD = -2.90 IU/L; 95 % CI -9.77, 3.98; P = 0.40) concentrations. Subgroup analysis revealed a significant reduction in serum ALT and AST concentrations in the participants with mean age <45 years, and studies with intervention dosage <1000 mg/day. In addition, ALT and AST levels were decreased significantly in studies with duration >12 weeks and participants with BMI < 30 kg/m

, respectively.

The overall results indicated that resveratrol supplementation did not affect liver enzymes in patients with NAFLD. More studies examining the effect of resveratrol supplementation on liver enzymes are needed in the future.

The overall results indicated that resveratrol supplementation did not affect liver enzymes in patients with NAFLD. More studies examining the effect of resveratrol supplementation on liver enzymes are needed in the future.

The aim of this study was to evaluate the effect of hypocaloric high-protein, low-carbohydrate weight loss diet supplemented with fennel on anthropometric and androgen indices in overweight and obese women with polycystic ovary syndrome (PCOS).

A randomized controlled trial with a factorial design was performed on sixty-four overweight/obese women with PCOS. Participants were randomly allocated to four groups (n = 16 per group) as follows 1) hypocaloric standardize diet + fennel (2 capsule/day) (HSDF), 2) hypocaloric high-protein diet + fennel (2 capsule/day) (HHPF), 3) hypocaloric standardize diet + placebo (HSDP), and 4) hypocaloric high-protein diet + placebo (HHPP).

The mean (SD) age of the participants was 28.54 (6.80) years and body mass index was 32.24 (4.65) kg/m

. At the end of intervention, protein intake was 20.43 % in the groups that received a high-protein diet versus 16.37 % in the standard diet groups (P < 0.001). Combination of hypocaloric high-protein diet and fennel capsule did not significantly affect change in outcomes compared with groups not receiving them. There was a significant interaction between hypocaloric high-protein diet and fennel on weight (P = 0.019).

A hypocaloric high-protein diet along with fennel supplementation could not provide additional improvements in anthropometric and androgen indices among PCOS women. Further studies are required to more precisely elucidate these findings.

A hypocaloric high-protein diet along with fennel supplementation could not provide additional improvements in anthropometric and androgen indices among PCOS women. Further studies are required to more precisely elucidate these findings.

The objective of this review is to trace the evolution of the art and science of allergy immunotherapy (AIT).

Original reports relating to the evolution of the concept of respiratory allergy and its specific treatment were identified by following references in journal articles, review articles, and allergy textbooks from the mid-20th century to the present.

Studies highlighting substantial milestones in the evolution of the practice of allergy immunotherapy were included.

The story of AIT begins with the recognition of hay fever as a distinct entity and subsequent studies that established grass pollen as one of the causes. This knowledge led several investigators, most notable Leonard Noon and John Freeman who worked at St. Mary’s Hospital in London, to attempt to induce tolerance giving grass pollen extract by injection to their patients. After the publication of the work of Noon and Freeman in 1911, the practice of AIT spread rapidly and was applied to many other pollen allergens besides grass and for perennial rhinitis and asthma. The early studies were largely anecdotal, but over the past 60 to 70 years, studies of AIT have been conducted with increasingly sophisticated scientific methods. Nowadays, not only is the practice of AIT based on carefully conducted studies, but the underlying immunologic basis of allergy and the response to AIT have also been and still are being firmly established.

Both the art and the science behind the practice of AIT have been established by a solid base of clinical and immunologic studies.

Both the art and the science behind the practice of AIT have been established by a solid base of clinical and immunologic studies.Both hereditary and sporadic breast cancer are suggested to develop from a stem cell subcomponent retaining most key stem cell properties but with dysregulation of self-renewal pathways, which drives tumorigenic differentiation and cellular heterogeneity. Cancer stem cells (CSCs), characterized by their self-renewal and differentiation potential, have been reported to contribute to chemo-/radio-resistance and tumor initiation and to be the main reason for the failure of current therapies in breast cancer and other CSC-bearing cancers. Thus, CSC-targeted therapies, such as those inducing CSC apoptosis and differentiation, inhibiting CSC self-renewal and division, and targeting the CSC niche to combat CSC activity, are needed and may become an important component of multimodal treatment. To date, the understanding of breast cancer has been extended by advances in CSC biology, providing more accurate prognostic and predictive information upon diagnosis. Recent improvements have enhanced the prospect of targeting breast cancer stem cells (BCSCs), which has shown promise for increasing the breast cancer remission rate. However, targeted therapy for breast cancer remains challenging due to tumor heterogeneity. One major challenge is determining the CSC properties that can be exploited as therapeutic targets. Another challenge is identifying suitable BCSC biomarkers to assess the efficacy of novel BCSC-targeted therapies. This review focuses mainly on the characteristics of BCSCs and the roles of BCSCs in the formation, maintenance and recurrence of breast cancer; self-renewal signaling pathways in BCSCs; the BCSC microenvironment; potential therapeutic targets related to BCSCs; and current therapies and clinical trials targeting BCSCs.Aldosterone, the main mineralocorticoid hormone, plays a fundamental role in maintaining blood pressure (BP)and volume under hypovolemic conditions. However, in numerous diseases, where it is produced in excess, it plays a detrimental role and contributes to cardiovascular events and ultimately to death in a multitude of patients. The seminal observation that the fungicide-derivative fadrozole blunted steroidogenesis has led to develop several agents to inhibit aldosterone synthase (AS, CYP11B2), the mitochondrial NADH-dependent enzyme that is necessary for aldosterone biosynthesis. Aldosterone synthase inhibitors (ASI) have, thereafter, been conceived and investigated in phase I and phase II studies. We herein reviewed the ASIs available so far considering their chemical structure, the related aldosterone synthase binding and pharmacodynamic properties. We also examined the promising results obtained with ASIs that have already been tested in phase II human studies.

Premenstrual dysphoric disorder (PMDD) is the most severe form for premenstrual distress. This study’s objective was to understand the association among PMDD, premenstrual syndrome (PMS), and eating behaviors.

Cross-sectional design. The survey was composed of validated measures.

Female students at a nursing school.

PMDD and PMS diagnoses were made using the Premenstrual Symptoms Screening Tool (PSST). Eating behaviors were assessed using the Eating Attitudes Test (EAT-26) and the Three-Factor Eating Questionnaire-Revised 18 (TFEQ-R18).

Of the 504 participants, according to the PSST, 80 (15.9%) met the criteria for PMDD, 222 (44%) had moderate-to-severe PMS, and the remaining 202 (40%) participants showed mild or no premenstrual symptoms. The total EAT-26 scores were significantly higher in the PMDD group than in the other groups (P<.001). According to the cut-off value (20 points) of EAT-26, the total prevalence of disordered eating behaviors was also significantly higher in the PMDD group (45.5%) compared with the moderate-to-severe PMS group (16.5%) and the no/mild PMS group (13.6%) (P<.001). According to the TFEQ-R18 scores, significantly higher scores for emotional eating and uncontrolled eating were found in the PMDD group than in the other groups (P<.001 for each).

Given that PMDD is defined as a more severe form of PMS with more strict criteria, the findings in this study reflect that as the severity of premenstrual symptoms increase, disordered eating behaviors also increase. To the best of our knowledge, this is the first study to compare eating behaviors among PMDD, moderate-to-severe PMS, and no/mild PMS groups.

Given that PMDD is defined as a more severe form of PMS with more strict criteria, the findings in this study reflect that as the severity of premenstrual symptoms increase, disordered eating behaviors also increase. To the best of our knowledge, this is the first study to compare eating behaviors among PMDD, moderate-to-severe PMS, and no/mild PMS groups.

To evaluate the diagnostic performance of a Volume and Solid Vascular Tissue Score (VSVTS) for preoperative risk assessment of pediatric and adolescent adnexal masses.

A retrospective cohort study comprised of all female individuals who presented with an adnexal mass that was managed surgically between April 2011 and March2016.

The Hospital for Sick Children (Toronto, Ontario, Canada).

Female individuals 1-18years of age who presented to a large tertiary pediatric hospital with an adnexal mass that was managed surgically.

Main outcome measures included diagnostic performance of the VSVTS for malignancy via sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+), negative likelihood ratio (LR-), and receiver operating characteristic area-under-the-curve (AUC) analysis.

A total of 179 masses in 169 subjects were included. The malignancy rate was 10.6%. The AUC for the VSTVS was 0.919. A VSTVS cut-off value of 4 achieved a sensitivity of 79% (95% CI 0.54-0.93), specificity of 88% (95% CI 0.82-0.93), PPV of 0.44 (95% CI 0.33-0.56), NPV of 0.97 (95% CI 0.94-0.99), LR+ of 6.77 (95% CI 4.18-10.97), and LR- of 0.24 (95% CI 0.10-0.57).

A sonographic scoring system based on the volume and presence of solid vascular tissue improves PPV for preoperative risk stratification of adnexal masses in the pediatric and adolescent population compared to existing ultrasound-only approaches. Further prospective research is needed to determine how best to incorporate components of such scoring systems into clinical management algorithms.

A sonographic scoring system based on the volume and presence of solid vascular tissue improves PPV for preoperative risk stratification of adnexal masses in the pediatric and adolescent population compared to existing ultrasound-only approaches. Further prospective research is needed to determine how best to incorporate components of such scoring systems into clinical management algorithms.We report two cases of Corona Virus Disease-19 (COVID-19) in patients with Down Syndrome (DS) and describe the identification, diagnosis, clinical course and management of the infection. Down Syndrome, which is caused by trisomy 21, is characterized by immune dysregulation, anatomical differences in the upper respiratory tract and higher rate of comorbidities. All these risk factors can contribute to more severe clinical presentations of COVID-19 in this population. It is essential to raise awareness of the clinical relevance of SARS-COV-2 infection in DS patients, as well as in other most vulnerable patients, in order to improve their management and treatment and to encourage vaccinating these individuals early, once a vaccination is available.

Meta-analysis is a statistical method with the ability to increase the power for statistical inference, while it may still face the problem of being underpowered. In this study, we investigated the power to detect certain true effects for published meta-analyses of rare events.

We extracted data from the Cochrane Database of Systematic Reviews for meta-analyses of rare events from January 2003 to May 2018. We retrospectively estimated the power to detect a 10-50% relative risk reduction (RRR) of eligible meta-analyses. The proportion of meta-analyses achieved a sufficient power (≥0.8) were estimated.

We identified 4,177 meta-analyses. The median power to detect 10%, 30%, and 50% RRR were 0.06 (interquartile range [IQR] 0.05 to 0.06), 0.08 (IQR 0.06 to 0.15), and 0.17 (IQR 0.10 to 0.42), respectively); the corresponding proportion of meta-analyses that reached sufficient power were 0.32%, 3.68%, and 11.81%. Meta-analyses incorporating data from more studies had higher probability to achieve a sufficient power (rate ratio=2.49, 95% CI 1.76, 3.52, P<0.001).

Most of the meta-analyses of rare events in Cochrane systematic reviews were underpowered. Future meta-analysis of rare events should report the power of the results to support informative conclusions.

Most of the meta-analyses of rare events in Cochrane systematic reviews were underpowered. Future meta-analysis of rare events should report the power of the results to support informative conclusions.A duration of parturition beyond 300 min negatively impacts the health of the sow and the survival of piglets during parturition. Hence, oxytocin is widely used to speed up the parturition. However, oxytocin’s negative side effects raise the need of finding alternative treatments such as those already implemented in human medicine. The aim of this study was to evaluate the efficacy of Prostaglandin E2 (PGE2) applied intravaginally (PGE2-V) (1.0 mg) or intramuscularly (PGE2-M) (2.5 mg) to improve the parturition process after expulsion of the fourth piglet compared to a placebo (P-V), which was sterile intravaginal gel or intramuscular oxytocin application (OXY-M) (20 iu) in free farrowing systems.In total, 201 eutocic sows were examined after stratification by parity and random allocation into groups 54 (P-V), 48 (OXY-M), 50 (PGE2-V), 49 (PGE2-M). Farrowing duration (time between first piglet and last piglet), piglet interval and placenta expulsion duration (time between first and last placenta) were recordedoved.

To identify predictors of visual outcomes in children with open globe injuries.

The medical records of patients (≤18years of age) with open globe injury from 2012 to 2020 at a single institution were retrospectively reviewed. The Pediatric Ocular Trauma Scores (POTS) and Toddler Ocular Trauma Scores (TOTS) were assessed against our cohort. Univariate and multivariate linear regression analysis was performed to identify predictors of visual outcome.

A total of 85 eyes of 85 pediatric patients (63 males [74%]) were included. Median patient age was 8.9years. Final best-corrected visual acuity was significantly associated with presenting vision (P=0.0001), age at injury (P=0.02), lens involvement (P<0.0001), retinal detachment (P<0.0001), and location of injury (P<0.0001). In a multivariate linear regression model, only presenting visual acuity and retinal detachment were independent predictors of outcome. When visual acuity was unknown, age at injury, lens involvement, and retinal detachment were independently associated with final visual acuity. POTS and TOTS scores moderately correlated with final best-corrected visual acuity (R

=0.51 and R

=0.53, resp.).

We identified patient characteristics predicting visual outcomes in a large US-based cohort of pediatric open globe injuries. POTS and TOTS scores moderately correlated with final visual acuity; however, the small study sizes from which they were derived preclude our identifying which predictors are most important. Development of a more predictive model will require a large multicenter study population or registry.

We identified patient characteristics predicting visual outcomes in a large US-based cohort of pediatric open globe injuries. POTS and TOTS scores moderately correlated with final visual acuity; however, the small study sizes from which they were derived preclude our identifying which predictors are most important. Development of a more predictive model will require a large multicenter study population or registry.

Systemic therapy agents targeting immune checkpoint inhibitors have been approved for use since 2011. This type of therapy aims to trigger a patient’s immune response to attack tumor cells, rather than acting against the tumor directly. Radiomics is an automated method of medical image analysis that is now being actively investigated for predictive markers of treatment response in immunotherapy.

To conduct an early systematic review determining the current status of radiomic features as potential predictive markers of immunotherapy response. Provide a detailed critical appraisal of methodological quality of models, as this informs the degree of confidence about current reports of model performance. In addition, to offer some recommendations for future studies that could establish robust evidence for radiomic features as immunotherapy response markers.

A PubMed citation search was conducted for publications up to and including April 2020, followed by full-text screening. A total of seven articles meetingll number of studies to date prevents any conclusive remarks to be made. We recommended future improvements in regards to prospective study registration, clinical utility, methodological procedure and data sharing.

Radiomics has a potentially significant role for predicting immunotherapy response. Additional multi-institutional studies with robust methodological underpinning and repeated external validations are required to establish the (added) value of radiomics within the pantheon of clinical tools for decision-making in immunotherapy.

Radiomics has a potentially significant role for predicting immunotherapy response. Additional multi-institutional studies with robust methodological underpinning and repeated external validations are required to establish the (added) value of radiomics within the pantheon of clinical tools for decision-making in immunotherapy.Bacteria can form a biofilm composed of diverse bacterial microorganism, which work as a barrier to protect from threats, such as antibiotics and host immunity system. The formation of biofilms significantly impairs the efficacy of antibiotics against pathogenic bacteria. It is also a serious problem to be solved that the emergence of multidrug-resistant bacteria (such as methicillin-resistant Staphylococcus aureus, MRSA) accelerated by the overuse of antibiotics. Therefore, the usage of biofilm inhibition agents has attracted immense interest as a novel strategy for treatment of diseases related to bacterial infection. From the difference of mode of action against bacterial cells, biofilm inhibition agents are expected to circumvent the emergence of multidrug-resistant bacteria. In this study, we have developed the derivatives of c-di-GMP, a kind of cyclic dinucleotide that is expected to have the effect of inhibiting bacterial biofilm formation. Some of the synthesized derivatives were found to inhibit biofilm formation of Gram-positive bacteria.Phthalates are reproductive toxicants in experimental animal studies and exposure has been associated with infertility in human populations, although the results have been inconsistent. To help to address the data gap, we conducted a hypothesis-generating investigation of associations between urinary phthalate metabolites and reproductive outcomes among women (n = 56) and their male partners (n = 43) undergoing in vitro fertilization (IVF). Urine was collected from participants on the day of oocyte retrieval. Samples were analyzed for a series of phthalates, MEP, MBP, MPP, MHxP, MEHP, MEHHP, MECPP, MiNP, MiDP, MCHP, and MBzP, using liquid chromatography-tandem mass spectrometry. We employed Poisson regression with robust variance estimation to estimate associations between urinary phthalate levels and biochemical pregnancy and live birth, adjusted for partner’s concentration and confounding factors. Doublings in women’s MBP (relative risk (RR) = 0.32, 95 % CI 0.13, 0.78), and men’s MEHP (RR = 0.28, 95 % CI 0.09, 0.83), were associated with a lower likelihood for pregnancy. Doublings in women’s (RR = 0.08, 95 % CI 0.01, 0.67) and men’s (RR = 0.13, 95 % CI 0.02, 0.92) MHxP were associated with a lower likelihood of live birth. Our results suggest that phthalate exposure may impact IVF outcomes, and underscore the importance of including male partners when investigating the impact of phthalate exposure on IVF. These results also suggest that clinical recommendations should include male partners for limiting phthalate exposure. Still, a larger and more comprehensive investigation is necessary to more definitively assess the risks.Epigenetic modifications influence gene expression programs ultimately dictating physiological outcomes. In the past decades, an increasing body of work has demonstrated that the enzymes that deposit and/or remove epigenetic marks on DNA or histones use metabolites as substrates or co-factors, rendering the epigenome sensitive to metabolic changes. In this context, acetyl-CoA and α-ketoglutarate have been recognized as critical for epigenetics, impinging on histone marks and nuclear DNA methylation patterns. Given that these metabolites are primarily generated in the mitochondria through the tricarboxylic acid cycle (TCA), the requirement of proper mitochondrial function for maintenance of the epigenetic landscape seems obvious. Nevertheless, it was not until recently when the epigenomic outcomes of mitochondrial dysfunction were tested, revealing mitochondria’s far-reaching impact on epigenetics. This review will focus on data that directly tested the role of mitochondria on the epigenetic landscape, the mechanisms by which mitochondrial dysfunction may dysregulate the epigenome and gene expression, and their potential implications to health and disease.Endothelial cell (EC) glycocalyx (GLX) comprise a multicomponent layer of proteoglycans and glycoproteins. Alteration of its integrity contributes to chronic vascular inflammation and leads to the development of cardiovascular diseases. Myeloperoxidase (MPO), a highly abundant enzyme released by polymorphonuclear neutrophils, binds to the GLX and deleteriously affects vascular EC functions. The focus of this study was to elucidate the mechanisms of MPO-mediated alteration of GLX molecules, and to unravel subsequent changes in endothelial integrity and function. MPO binding to GLX of human ECs and subsequent internalization was mediated by cell surface heparan sulfate chains. Moreover, interaction of MPO, which is carrying a cationic charge, with anionic glycosaminoglycans (GAGs) resulted in reduction of their relative charge. By means of micro-viscometry and atomic force microscopy, we disclosed that MPO can crosslink GAG chains. MPO-dependent modulation of GLX structure was further supported by alteration of wheat germ agglutinin staining. Increased expression of ICAM-1 documented endothelial cell activation by both catalytically active and also inactive MPO. Furthermore, MPO increased vascular permeability connected with reorganization of intracellular junctions, however, this was dependent on MPO’s catalytic activity. Novel proteins interacting with MPO during transcytosis were identified by proteomic analysis. Altogether, these findings provide evidence that MPO through interaction with GAGs modulates overall charge of the GLX, causing modification of its structure and thus affecting EC function. Importantly, our results also suggest a number of proteins interacting with MPO that possess a variety of cellular localizations and functions.Myocardial infarction (MI) is an irreversible event caused by cardiac ischemia and may be fatal. Studies reported that increased intake of n-3 polyunsaturated fatty acids (PUFA) namely, eicosapentaenoic acid and docosahexaenoic acid reduce the risk of cardiovascular disease and lower the incidence of MI. Nonetheless, the cardioprotective effect of plant n-3-PUFA such as α-linolenic acid (ALA) in the diet is not conclusive. In this study, Sprague Dawley rats were supplemented with isocaloric diets enriched with ALA rich flaxseed (FS) and flaxseed oil (FSO), and normal chow (Control) for 4 weeks. MI was induced by isoproterenol (ISO) injection. Results showed that all ALA-enriched diets displayed cardioprotection against MI. The heart to body weight ratio, plasma LDH activity and plasma cTnI were reduced compared to ISO and was prominent in FS diet. ALA and EPA were up-regulated in both tissues and plasma by ALA-diets compared to Control and remained higher than ISO groups. Notably, LOX-mediated HETEs decreased whereas LOX-mediated HDHAs were elevated in both tissues and plasma of ALA-enriched diets compared to ISO. In addition, non-enzymatic oxidized products from arachidonic acid including 15-F2t-IsoP were reduced in both tissues and plasma of MI rats supplemented with ALA-enriched diets while those from n-3 PUFAs including F4-NeuroPs, PhytoPs and PhytoFs were elevated compared to control. ALA-enriched diets particularly flaxseed reduced gene expressions of inflammatory cytokines namely IL-1β, IL-6 and TNFα and prevented the down regulation of antioxidant catalase in the heart tissues. In conclusion ALA-enriched diets potentially exerted cardioprotection through the regulation of anti-inflammatory and anti-oxidative mediators from n-3 PUFA autooxidation.Available evidences point to methionine metabolism as a key target to study the molecular adaptive mechanisms underlying differences in longevity. The plasma methionine metabolic profile was determined using a LC-MS/MS platform to systematically define specific phenotypic patterns associated with genotypes of human extreme longevity (centenarians). Our findings demonstrate the presence of a specific plasma profile associated with human longevity characterized by an enhanced transsulfuration pathway and tricarboxylic acid (TCA) cycle intermediates, as well as a reduced content of specific amino acids. Furthermore, our work reveals that centenarians maintain a strongly correlated methionine metabolism, suggesting an improved network integrity, homeostasis and more tightly regulated metabolism. We have discovered a particular methionine signature related to the condition of extreme longevity, allowing the identification of potential mechanisms and biomarkers of healthy aging.

Antegrade superficial femoral artery (SFA) access for peripheral artery disease reduces the time, radiation, and contrast required with contralateral common femoral access (CFA). Yet, this technique remains underutilized in the treatment of SFA, popliteal and tibial disease, and there remains limited data on the safety and effectiveness of antegrade SFA access in the outpatient setting.

A retrospective review of lower extremity peripheral arterial interventions in our office-based endovascular suite was conducted from 2013 to 2018. Interventions necessitating CFA access such as iliac, common femoral, or deep femoral artery revascularization were excluded (n=206). In addition, interventions potentially requiring large sheaths not amenable to SFA access (e.g., popliteal aneurysm) were excluded. Relevant demographic and treatment variables including postoperative complications were abstracted.

We identified 718 patients, who underwent revascularization of the SFA, popliteal and tibial arteries. Antegrade Suoroscopy and contrast.

Percutaneous antegrade SFA access can be performed safely in the outpatient setting and remains an effective alternative to retrograde CFA access with significantly less utilization of fluoroscopy and contrast.

The aim of this study was to form hydrophobic ion-pairs of proteinase with cationic surfactants and to incorporate them into self-emulsifying drug delivery systems (SEDDS) to improve their mucus permeating properties.

Proteinase was ion-paired with benzalkonium chloride (BAK), hexadecylpyridinium chloride (HDP), alkyltrimethylammonium bromide (ATA) and hexadecyltrimethylammonium bromide (HDT) at pH 8.5-9.0, and subsequently incorporated into SEDDS consisting of Cremophor EL, propylene glycol, and Capmul 808-G (40/20/40). Mucus permeation of SEDDS containing proteinase complexes was evaluated via rotating tube technique and cell-free Transwell® insert system. Additionally, enzymatic activity of proteinase complexes as well as their potential cytotoxicity was evaluated.

Among all tested hydrophobic ion-pairs, proteinase/BAK showed highest potential. Mucus diffusion of SEDDS containing proteinase/BAK complex yielded in 2.3-fold and 2.5-fold higher mucus permeability with respect to blank SEDDS at Transwell® insert system and rotating tube technique, respectively. Furthermore, proteinase/BAK complex maintained the highest enzymatic activity of 50.5 ± 5.6% compared to free proteinase. At a SEDDS concentration as low as 0.006% cell viability was just 80%. The addition of proteinase complexes to SEDDS increased cytotoxicity on Caco-2 cells in a concentration-dependent manner.

SEDDS loaded with proteinase/BAK complexes are promising nanocarriers because of enhanced mucus permeating properties.

SEDDS loaded with proteinase/BAK complexes are promising nanocarriers because of enhanced mucus permeating properties.Conventional treatment options for lung cancer treatment were restricted due to non-specific nature and side effects, with this associated problem and to overcome this we had developed lumefantrine with nano calcium phosphate loaded lipid nanoparticles (LF- CaP- Ls) affording pH sensitive mechanism. Herein, the present study the in vivo anti-cancer property of LF-CaP-Ls was checked in mice models. Further, reduced lung cancer progression of lumefantrine with nano calcium phosphate loaded lipid nanoparticles (LF-CaP-Ls) treated mice were assessed by measuring the 5-methyltetrahydrofolate (MTHF) in serum. Moreover, LF-CaP-Ls showed substantially a anticancer effect compared to that of lumefantrine loaded lipid nanoparticles (LF-Ls) and free lumefantrine (LF) by exhibiting higher effects in lung tumor bearing mice model as confirmed by reduced tumor progression. Histopathological examination of lungs supported with H&E staining proved the reduced tumor vasculature and reduced inflammatory cells for LF-CaP-Ls compared to that of free LF and LF-Ls. Further, visual inspection with acetic acid test confirmed the reduced tumor progression for LF-CaP-Ls compared to that of free LF and LF-Ls. Altogether, the overall results suggested that the developed LF-CaP-Ls may acts as a better therapeutic molecule for lung cancer due to its maintenance of increased level of 5-MTHF levels, reduced tumor weight. Further, hematological and biochemical parameters were measured and supports our in-vivo therapeutic effect of LF-CaP-Ls.

Electrical pulmonary vein isolation (PVI) is used for the invasive treatment of atrial fibrillation (AF). However, despite the procedure’s technical evolution, the rate of AF recurrence due to electrical reconnection of the PVs is high. The aims of this study was to assess the influence of left common pulmonary venous ostium (LCO) on clinical outcomes following PVI.

Retrospective cohort of 254 patients who underwent the first procedure of PVI from the years 2013-2018 was assessed. Patients with persistent AF of long duration and extra-pulmonary focus associated with triggers for arrhythmia were excluded. Patients were stratified into two groups according to the presence of a LCO and received follow up for atrial tachyarrhythmia-free survival. The mean follow-up period was 28±1.73 months.

The majority were men (68.5%), with a mean age of 54±12 years. With respect to the atrial anatomy, LCO occurred in 23.6% of cases after pulmonary venous angiotomography. The arrhythmia-free survival rate was 79.5% in the follow-up period. The Cox regression model was utilized and the adjusted hazard ratio for LCO was 0.36 (95% CI 0.15-0.87; p=0.02) in terms of age, body mass index, left atrium diameter, bi-directional blocking of the cavotricuspid isthmus, persistent AF, left ventricular ejection fraction adjusted model.

Anatomic abnormality with the presence of the LCO is present in a quarter of patients undergoing AF ablation, which is associated with a lower rate of arrhythmia recurrence in our population.

Anatomic abnormality with the presence of the LCO is present in a quarter of patients undergoing AF ablation, which is associated with a lower rate of arrhythmia recurrence in our population.Permanent pacemaker (PPM) malfunction due to electrical connection problems such as a loose set screw or lead-header malapposition is extremely rare. We present a patient with complete heart block (CHB) who had PPM malfunction and recurrent syncope, late (14 months) after initial implantation, which was caused by the ventricular lead pin disengagement from the header resulting in oversensing due to noise, pacing inhibition and recurrent syncope. PPM due to lead-header malapposition this late after device implantation has previously not been reported.Microglia cells are versatile players coordinating inflammatory and regenerative processes in the central nervous system in which sphingosine-1-phosphate (S1P)-mediated migration is essential. We investigated the involved signaling cascade by means of voltage clamp, measurement of ATP secretion, and wound healing assay in murine microglial BV-2 cells. S1P and extracellular hypoosmolar solution evoked an anion conductance of the cell membrane. The corresponding ion currents were inhibited by intracellular hypoosmolar solution and by the anion channel antagonists NPPB, tamoxifen, and carbenoxolone, pointing to the activation of volume-regulated anion channels (VRAC). The knockdown by siRNA indicates the involvement of LRRC8A subunits. The S1PR1-antagonist W123 and pertussis-toxin prevented the S1P-induced currents, showing the involvement of the Gi-protein-coupled S1P receptor 1 (S1PR1). Furthermore, S1P and hypoosmolar extracellular solution induced an increase of ATP levels in the supernatants of BV-2 cells, which was inhibited by NPPB, tamoxifen, and W123. S1P, ATP, and ADP stimulated cell migration into the scratch area. The inhibition of S1PR1 and the downstream Gi proteins hampered cell migration. Antagonists of VRAC were also able to diminish the migration of BV-2 cells. Furthermore, direct inhibition of ATP-gated P2X4 or P2X7 receptors or ADP-stimulated P2Y12 receptors blocked the stimulating effects of S1P on BV-2 cell migration. We conclude that there is an interaction between S1P receptors and purinergic receptors mediated by an S1P-induced ATP release via VRAC and that the amount of released ATP is capable of stimulating cell migration of BV-2 microglia cells via activation of P2X4, P2X7, and P2Y12 receptors.APE1 is a multi-functional protein with a redox function in its N-terminal domain and an apurinic/apyrimidinic endonuclease activity in the C-terminal domain. APE1 redox function plays an important role in regulating cell proliferation and survival through activating specific transcriptional activators. APE1 redox function is also found to be associated with some cancer occurrence. In this study, we demonstrated that APE1 redox function is essential for Epstein-Barr virus (EBV) lytic replication as the silencing of APE1 expression or treatment with APE1 redox inhibitors C10 and E3330 can inhibit EBV lytic replication and virion production. Furthermore, C10 and E3330 also inhibit MHV-68 replication in vitro and in vivo. C10 and E3330 were able to significantly reduce the loss of pulmonary alveoli and thickening of alveolar septa in mice caused by MHV-68 infection. Altogether, (i) APE1 redox function is validated as a new antiviral target; (ii) APE1 redox inhibitors, especially C10, have potentials to be used for the treatment of γ-herpesvirus infection and associated diseases; (iii) MHV-68 is validated to be a surrogate for the study of the pathogenesis and therapy of EBV and KSHV infection in vivo.Simultaneous magnetic resonance and positron emission tomography provides an opportunity to measure brain haemodynamics and metabolism in a single scan session, and to identify brain activations from multimodal measurements in response to external stimulation. However, there are few analysis methods available for jointly analysing the simultaneously acquired blood-oxygen-level dependant functional MRI (fMRI) and 18-F-fluorodeoxyglucose functional PET (fPET) datasets. In this work, we propose a new multimodality concatenated ICA (mcICA) method to identify joint fMRI-fPET brain activations in response to a visual stimulation task. The mcICA method produces a fused map from the multimodal datasets with equal contributions of information from both modalities, measured by entropy. We validated the method in silico, and applied it to an in vivo visual stimulation experiment. The mcICA method estimated the activated brain regions in the visual cortex modulated by both BOLD and FDG signals. The mcICA provides a fully data-driven analysis approach to analyse cerebral haemodynamic response and glucose uptake signals arising from exogenously induced neuronal activity.A key aspect of human cognitive flexibility concerns the ability to convert complex symbolic instructions into novel behaviors. Previous research proposes that this transformation is supported by two neurocognitive states an initial declarative maintenance of task knowledge, and an implementation state necessary for optimal task execution. Furthermore, current models predict a crucial role of frontal and parietal brain regions in this process. However, whether declarative and procedural signals independently contribute to implementation remains unknown. We report the results of an fMRI experiment in which participants executed novel instructed stimulus-response associations. We then used a pattern-tracking procedure to quantify the contribution of format-unique signals during instruction implementation. This revealed independent procedural and declarative representations of novel S-Rs in frontoparietal areas, prior to execution. Critically, the degree of procedural activation predicted subsequent behavioral performance. Altogether, our results suggest an important contribution of frontoparietal regions to the neural architecture that regulates cognitive flexibility.Fiber tractography based on diffusion-weighted MRI provides a non-invasive characterization of the structural connectivity of the human brain at the macroscopic level. Quantification of structural connectivity strength is challenging and mainly reduced to „streamline counting” methods. These are however highly dependent on the topology of the connectome and the particular specifications for seeding and filtering, which limits their intra-subject reproducibility across repeated measurements and, in consequence, also confines their validity. Here we propose a novel method for increasing the intra-subject reproducibility of quantitative estimates of structural connectivity strength. To this end, the connectome is described by a large matrix in positional-orientational space and reduced by Principal Component Analysis to obtain the main connectivity „modes”. It was found that the proposed method is quite robust to structural variability of the data.While the function of most biological systems is tightly constrained by their structure, current evidence suggests that coupling between the structure and function of brain networks is relatively modest. We aimed to investigate whether the modest coupling between connectome structure and function is a fundamental property of nervous systems or a limitation of current brain network models. We developed a new deep learning framework to predict an individual’s brain function from their structural connectome, achieving prediction accuracies that substantially exceeded state-of-the-art biophysical models (group R=0.9±0.1, individual R=0.55±0.1). Crucially, brain function predicted from an individual’s structural connectome explained significant inter-individual variation in cognitive performance. Our results suggest that structure-function coupling in human brain networks is substantially tighter than previously suggested. We establish the margin by which current brain network models can be improved and demonstrate how deep learning can facilitate investigation of relations between brain function and behavior.Looking at the eyes informs us about the thoughts and emotions of those around us, and impacts our own emotional state. However, it is unknown how perceiving direct and averted gaze impacts our ability to share the gazer’s positive and negative emotions, abilities referred to as positive and negative affective empathy. We presented 44 participants with contextual sentences describing positive, negative and neutral events happening to other people (e.g. „Her newborn was saved/killed/fed yesterday afternoon.”). These were designed to elicit positive, negative, or little to no empathy, and were followed by direct or averted gaze images of the individuals described. Participants rated their affective empathy for the individual and their own emotional valence on each trial. Event-related potentials time-locked to face-onset and associated with empathy and emotional processing were recorded to investigate whether they were modulated by gaze direction. Relative to averted gaze, direct gaze was associated with increased positive valence in the positive and neutral conditions and with increased positive empathy ratings. A similar pattern was found at the neural level, using robust mass-univariate statistics. The N100, thought to reflect an automatic activation of emotion areas, was modulated by gaze in the affective empathy conditions, with opposite effect directions in positive and negative conditions.. The P200, an ERP component sensitive to positive stimuli, was modulated by gaze direction only in the positive empathy condition. Positive and negative trials were processed similarly at the early N200 processing stage, but later diverged, with only negative trials modulating the EPN, P300 and LPP components. These results suggest that positive and negative affective empathy are associated with distinct time-courses, and that perceived gaze direction uniquely modulates positive empathy, highlighting the importance of studying empathy with face stimuli.Adult cognitive neuroscience has guided the study of human brain development by identifying regions associated with cognitive functions at maturity. The activity, connectivity, and structure of a region can be compared across ages to characterize the developmental trajectory of the corresponding function. However, developmental differences may reflect both the maturation of the function and also its organization across the brain. That is, a function may be present in children but supported by different brain regions, leading its maturity to be underestimated. Here we test the presence, maturity, and localization of adult functions in children using shared response modeling, a machine learning approach for functional alignment. After learning a lower-dimensional feature space from fMRI activity as adults watched a movie, we translated these shared features into the anatomical brain space of children 3-12 years old. To evaluate functional maturity, we correlated this reconstructed activity with children’s actual fMRI activity as they watched the same movie. We found reliable correlations throughout cortex, even in the youngest children. The strength of the correlation in the precuneus, inferior frontal gyrus, and lateral occipital cortex predicted chronological age. These age-related changes were driven by three types of developmental trajectories emergence from absence to presence, consistency in anatomical expression, and reorganization from one anatomical region to another. We also found evidence that the processing of pain-related events in the movie underwent reorganization across childhood. This data-driven, naturalistic approach provides a new perspective on the development of functional neuroanatomy throughout childhood.Neuroblastoma (NBL), the most frequent and lethal pediatric cancer of children in pre-school age, is considered enigmatic in view of its extreme heterogeneity, from spontaneous regression in the IV-S form to incurable disease in approx. 40% of cases (High Risk, HR-NBL). It has an embryonal origin and a very heterogeneous genomic landscape, hampering the success of targeted strategies. The glycosphingolipid GD2 was shown to be expressed on NBL cells and utilized as target for passive immunotherapy with anti-GD2 antibodies (GD2-IMT). An international protocol was established with GD2-IMT, which increases remission length and survival in HR-NBL. By reviewing the different biological and molecular aspects of NBL and GD2-IMT, this mini-review questions the present lack of association between GD2-IMT and the underlying molecular landscape. The alternative model of Micro-Foci inducing virus (MFV) is presented, since MFV infection can induce extensive genomic aberrations (100X NMYC DNA-amplification). Since this family of viruses uses molecules for cell penetration similar to GD2 (i.e., GM2), it is hypothesized that GD2 is the port-of-entry for MFV and that success of anti-GD2 therapies is also associated to inhibition of this clastogenic virus in HR-NBL.Pancreatic ductal adenocarcinoma(PDAC) is resistant to the PD-1/PD-L1 blockade therapy. Previously, the combination of PD-1 blockade and vaccine therapy was shown to have a modest antitumor activity in murine models of PDAC. We used a murine syngeneic model of metastatic PDAC to identify, among multiple T cell modulators tested, which therapeutic agents in combination with the GVAX cancer vaccine and an anti-PD-1 antagonist antibody(αPD-1) are able to improve the survival. We found that an anti-CD137 agonist antibody(αCD137) most significantly improved survival in the mouse PDAC model. Moreover, αPD-1 and αCD137 together in combination with vaccine therapy more significantly increased the expression of costimulatory molecules CD137 and OX40 on CD4+PD-1+ and CD8+PD-1+ T cells comparing to αPD-1 or αCD137, respectively, suggesting that T cell activation within PDACs were enhanced by a synergy of αCD137 and αPD-1. On another hand, αCD137 treatment led to an increase in effector memory T cells independent of αPD-1. Although αCD137 does not increase the cytotoxic effector T cell function, the addition of αCD137 to GVAX+αPD-1 increased expression of IFNγ in EOMES + exhausted tumor-infiltrating T cells. Taken together, this preclinical study established the mechanism of targeting CD137 to enhance effector memory and activated T cells in PDAC. Immunohistochemistry analysis of resected human PDACs following the neo-adjuvant GVAX treatment showed increased levels of CD8+ T cells in those with high levels of CD137 expression, supporting an ongoing clinical trial of testing CD137 as a potential target in treating PDACs that are inflamed with T cells by vaccine therapy.Protocadherin 10 (PCDH10) is identified as a tumor suppressor in multiple cancers. The molecular mechanisms that mediate the functions of PCDH10 have yet to be fully elucidated. Here, we demonstrated that ectopic expression of PCDH10 in colorectal cancer (CRC) cells induced cell cycle retardation and increased apoptosis through regulation of the p53/p21/Rb axis and Bcl-2 expression. Overexpression of PCDH10 reversed the epithelial-mesenchymal transition (EMT) process with morphological changes and EMT marker alterations. Mechanistic study revealed that PCDH10 inhibited AKT/GSK3β signaling pathway which in turn reduced β-catenin activity and thus attenuated Snail and Twist1 expression. Furthermore, PCDH10 inhibited the stemness of CRC cells, including spheroid formation and stem cell markers. A proteomics approach revealed that PCDH10 could interact with EGFR, which was further verified by co-immunoprecipitation. Moreover, restoration of PCDH10 expression reduced EGFR phosphorylation. Accordingly, our work proposes a novel pathway by which PCDH10 directly engages in the negative regulation of EGFR/AKT/β-catenin signaling pathway, resulting in tumor suppression.Spices are susceptible to mycotoxin contamination which can cause gastrointestinal and adverse central nervous symptoms in humans, which highlights the importance of assessing the risk of their consumption on a daily basis. The aim of this study was to assess the risk of mycotoxin intake from spices in routinely prepared Lebanese dishes. 150 households were interviewed about their usage of 27 type of spices and 6 routinely prepared Lebanese dishes. Results showed a high variability in consumption levels. Among the investigated dishes, the minimum number of spices that were consumed in a dish was 13 while the maximum was 18. The mean intake of one spice ranged from 0.26 g/portion observed for cloves to 5.37 g/portion for cinnamon, with its intake per portion more than 1 g in 2/3 of dishes. 20% of portion sizes of coriander, cinnamon and fennel, had an intake exceeding 5 g/portion. Ochratoxin A (OTA) Probable Daily Intake (PDI) had a mean of 0.11 ng/kg-bw/day. Mean PDI of fumonisin B1 (FB1) was 79.3 ng/kg-bw/day. Aflatoxin B1 (AFB1) PDI had a mean of 1.55 ng/kg-bw/day. The Margin of Exposure (MOE) of AFB1 ranged from 108.10 to 4444.44. The present study showed that the risk of AFB1 from spices is a matter of concern while the risk of OTA and FB1 is limited with the exception of FB1 from garlic and onion.Poly (ADP-ribose) polymerases (PARPs) play a key role in DNA repair. In this study we designed a novel small-molecular compound, (E)-2-(2,3-dibromo-4,5-dimethoxybenzylidene)hydrazine-1-carbothioamide (DHC-1), which was a potent and selective PARP-1 inhibitor. DHC-1 selectively inhibited PARP-1 activity with an IC50 value of 41.12 ± 13.28 nM. Cytotoxicity results showed that DHC-1 selectively inhibited the proliferation of BRCA1-deficient breast cancer HCC-1937 and BRCA2-deficient pancreatic cancer Capan-1 cells. Mechanism studies found that DHC-1 stabilized PARP-1-DNA complexes and inhibited PAR formation in BRCA2-/- Capan-1 cells. Further experiments found that DHC-1 induced DNA double-strand damage in BRCA2-/- Capan-1 cells, which was demonstrated by accumulation of γ-H2AX foci. Flow cytometry experiments revealed that DHC-1 induced G2/M phase arrest and activate mitochondrial-induced apoptotic pathways. Interestingly, we also found that DHC-1 enhanced cell proliferation inhibitory effect of oxaliplatin (OXA). The further in vivo nude mouse studies showed that DHC-1 inhibited the growth of Capan-1 xenografts and showed a similar mechanism to that in vitro. Collectively, our results demonstrate that DHC-1 may be an excellent candidate for treatment of BRCA-deficient pancreatic cancers.