Outcomes of Visceral Arterial Interposition Graft Reconstruction for Locally Advanced Pancreatic Cancer.

OBJECTIVE: The aim of this study is to determine perioperative outcomes and the patency of interposition conduits for visceral arterial reconstruction in this setting. SUMMARY BACKGROUND DATA: Visceral arterial encasement in locally advanced pancreatic cancer was historically a contraindication for surgery. With modern effective neoadjuvant strategies, our recent experience has made advanced vascular resection and reconstruction feasible in selected patients. METHODS: A retrospective review was performed of patients undergoing pancreatic tumor resection with en bloc arterial resection and interposition revascularization between 6/2002-10/2022. Endpoints included graft patency, vascular-related complications, reinterventions, morbidity, and mortality. RESULTS: Visceral arterial reconstruction with interposition grafting was performed in 111 patients undergoing en bloc arterial resections for pancreatic cancer. Graft types included autologous arterial conduits (n=66, 58 superficial femoral artery (SFA) and 8 splenic artery), cryopreserved arterial allografts (n=24), autologous saphenous veins (n=12), synthetic conduits (n=8), and composite autologous artery and synthetic (n=1). Perioperative 90-day mortality decreased significantly over time to 5% in the last six years. Vascular complications related to arterial reconstruction occurred in 11% (n=12) and included pseudoaneurysm (n=6), graft thrombus (n=2), stenosis requiring reintervention (n=2), hepatic failure (n=1), and hepatic and intestinal ischemia (n=1). Nine (8%) patients underwent vascular-related reinterventions. After median follow-up of 17-months, primary patency was 81% for the entire cohort and was highest in the SFA group (95%). The donor limb/harvest site complication rate was 8% with 100% primary patency. CONCLUSION: Visceral arterial resection with interposition reconstruction for locally advanced pancreatic cancer can be performed with acceptable vascular morbidity and durable patency. Autologous SFA was the most suitable conduit for reconstructions in our experience, with highest primary patency.

Interactive enhancer hubs (iHUBs) mediate transcriptional reprogramming and adaptive resistance in pancreatic cancer.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) displays a remarkable propensity towards therapy resistance. However, molecular epigenetic and transcriptional mechanisms enabling this are poorly understood. In this study, we aimed to identify novel mechanistic approaches to overcome or prevent resistance in PDAC. DESIGN: We used in vitro and in vivo models of resistant PDAC and integrated epigenomic, transcriptomic, nascent RNA and chromatin topology data. We identified a JunD-driven subgroup of enhancers, called interactive hubs (iHUBs), which mediate transcriptional reprogramming and chemoresistance in PDAC. RESULTS: iHUBs display characteristics typical for active enhancers (H3K27ac enrichment) in both therapy sensitive and resistant states but exhibit increased interactions and production of enhancer RNA (eRNA) in the resistant state. Notably, deletion of individual iHUBs was sufficient to decrease transcription of target genes and sensitise resistant cells to chemotherapy. Overlapping motif analysis and transcriptional profiling identified the activator protein 1 (AP1) transcription factor JunD as a master transcription factor of these enhancers. JunD depletion decreased iHUB interaction frequency and transcription of target genes. Moreover, targeting either eRNA production or signaling pathways upstream of iHUB activation using clinically tested small molecule inhibitors decreased eRNA production and interaction frequency, and restored chemotherapy responsiveness in vitro and in vivo. Representative iHUB target genes were found to be more expressed in patients with poor response to chemotherapy compared with responsive patients. CONCLUSION: Our findings identify an important role for a subgroup of highly connected enhancers (iHUBs) in regulating chemotherapy response and demonstrate targetability in sensitisation to chemotherapy.

LCK inhibition downregulates YAP activity and is therapeutic in patient-derived models of cholangiocarcinoma.

BACKGROUND & AIMS: There is an unmet need to develop novel, effective medical therapies for cholangiocarcinoma (CCA). The Hippo pathway effector, Yes-associated protein (YAP), is oncogenic in CCA, but has historically been difficult to target therapeutically. Recently, we described a novel role for the LCK proto-oncogene, Src family tyrosine kinase (LCK) in activating YAP through tyrosine phosphorylation. This led to the hypothesis that LCK is a viable therapeutic target in CCA via regulation of YAP activity. METHODS: A novel tyrosine kinase inhibitor with relative selectivity for LCK, NTRC 0652-0, was pharmacodynamically profiled in vitro and in CCA cells. A panel of eight CCA patient-derived organoids were characterized and tested for sensitivity to NTRC 0652-0. Two patient-derived xenograft models bearing fibroblast growth factor receptor 2 (FGFR2)-rearrangements were utilized for in vivo assessment of pharmacokinetics, toxicity, and efficacy. RESULTS: NTRC 0652-0 demonstrated selectivity for LCK inhibition in vitro and in CCA cells. LCK inhibition with NTRC 0652-0 led to decreased tyrosine phosphorylation, nuclear localization, and co-transcriptional activity of YAP, and resulted in apoptotic cell death in CCA cell lines. A subset of tested patient-derived organoids demonstrated sensitivity to NTRC 0652-0. CCAs with FGFR2 fusions were identified as a potentially susceptible and clinically relevant genetic subset. In patient-derived xenograft models of FGFR2 fusion-positive CCA, daily oral treatment with NTRC 0652-0 resulted in stable plasma and tumor drug levels, acceptable toxicity, decreased YAP tyrosine phosphorylation, and significantly decreased tumor growth. CONCLUSIONS: A novel LCK inhibitor, NTRC 0652-0, inhibited YAP signaling and demonstrated preclinical efficacy in CCA cell lines, and patient-derived organoid and xenograft models. IMPACT AND IMPLICATIONS: Although aberrant YAP activation is frequently seen in CCA, YAP targeted therapies are not yet clinically available. Herein we show that a novel LCK-selective tyrosine kinase inhibitor (NTRC 0652-0) effectively inhibits YAP tyrosine phosphorylation and cotranscriptional activity and is well tolerated and cytotoxic in multiple preclinical models. The data suggest this approach may be effective in CCA with YAP dependence or FGFR2 fusions, and these findings warrant further investigation in phase I clinical trials.

Synergistic combination of cytotoxic chemotherapy and cyclin-dependent kinase 4/6 inhibitors in biliary tract cancers.

BACKGROUND AND AIMS: Biliary tract cancers (BTCs) are uncommon, but highly lethal, gastrointestinal malignancies. Gemcitabine/cisplatin is a standard-of-care systemic therapy, but has a modest impact on survival and harbors toxicities, including myelosuppression, nephropathy, neuropathy, and ototoxicity. Whereas BTCs are characterized by aberrations activating the cyclinD1/cyclin-dependent kinase (CDK)4/6/CDK inhibitor 2a/retinoblastoma pathway, clinical use of CDK4/6 inhibitors as monotherapy is limited by lack of validated biomarkers, diffident preclinical efficacy, and development of acquired drug resistance. Emerging studies have explored therapeutic strategies to enhance the antitumor efficacy of CDK4/6 inhibitors by the combination with chemotherapy regimens, but their mechanism of action remains elusive. APPROACH AND RESULTS: Here, we report in vitro and in vivo synergy in BTC models, showing enhanced efficacy, reduced toxicity, and better survival with a combination comprising gemcitabine/cisplatin and CDK4/6 inhibitors. Furthermore, we demonstrated that abemaciclib monotherapy had only modest efficacy attributable to autophagy-induced resistance. Notably, triplet therapy was able to potentiate efficacy through elimination of the autophagic flux. Correspondingly, abemaciclib potentiated ribonucleotide reductase catalytic subunit M1 reduction, resulting in sensitization to gemcitabine. CONCLUSIONS: As such, these data provide robust preclinical mechanistic evidence of synergy between gemcitabine/cisplatin and CDK4/6 inhibitors and delineate a path forward for translation of these findings to preliminary clinical studies in advanced BTC patients.

Reference Values on Children's Hair for 28 Elements (Heavy Metals and Essential Elements) Based on a Pilot Study in a Representative Non-Contaminated Local Area.

Studies have been published, and laboratories offer services of measuring elements in hair as biomarkers of environmental exposure and/or control of essential elements (trace or macro). These reported values can have only sense if compared with adopted reference values. In this work, we propose provisional reference values based on a pilot child population. The concentrations of 28 elements were measured in children's hair samples. An observational, descriptive, cross-sectional study was conducted in a typical child population in the Mediterranean region void of excessive pollution problems to analyze 419 hair samples of children aged 3-12 years. Children were selected by a simple random method from eight primary education schools in different municipal districts, which included urban, rural and industrial areas. Samples of around 100 mg were washed and acid digested by an optimized procedure. All measures were performed using ICP-MS with Sc, Y and Re as internal standards. The statistical analysis was performed by two approaches: (a) considering all the data and (b) without outliers (second-order atypical data) to compare them with other published studies. The distribution curves in all the elements studied were asymmetric and did not fit the theoretical normality distributions. Therefore, the analysis based on percentiles was more appropriate. In most elements, only slight differences were observed with sex or age, which did not justify proposing separate reference ranges. From the results of this study, provisional reference values are proposed following two criteria: (a) simple application of the table of percentiles built by removing outlier values and (b) values after a detailed analysis case-by-case, considering other data as the distribution profile and other published data of each element. Although the pilot sample was from a limited area, it was carefully selected to be representative of a general non-contaminated population. With this limitation, the proposed reference values might be useful for researchers and physicians until a wider geographical study is available for a large number of elements.

Effects of caloric restriction on immunosurveillance, microbiota and cancer cell phenotype: Possible implications for cancer treatment.

Fasting, caloric restriction and foods or compounds mimicking the biological effects of caloric restriction, known as caloric restriction mimetics, have been associated with a lower risk of age-related diseases, including cardiovascular diseases, cancer and cognitive decline, and a longer lifespan. Reduced calorie intake has been shown to stimulate cancer immunosurveillance, reducing the migration of immunosuppressive regulatory T cells towards the tumor bulk. Autophagy stimulation via reduction of lysine acetylation, increased sensitivity to chemo- and immunotherapy, along with a reduction of insulin-like growth factor 1 and reactive oxygen species have been described as some of the major effects triggered by caloric restriction. Fasting and caloric restriction have also been shown to beneficially influence gut microbiota composition, modify host metabolism, reduce total cholesterol and triglyceride levels, lower diastolic blood pressure and elevate morning cortisol level, with beneficial modulatory effects on cardiopulmonary fitness, body fat and weight, fatigue and weakness, and general quality of life. Moreover, caloric restriction may reduce the carcinogenic and metastatic potential of cancer stem cells, which are generally considered responsible of tumor formation and relapse. Here, we reviewed in vitro and in vivo studies describing the effects of fasting, caloric restriction and some caloric restriction mimetics on immunosurveillance, gut microbiota, metabolism, and cancer stem cell growth, highlighting the molecular and cellular mechanisms underlying these effects. Additionally, studies on caloric restriction interventions in cancer patients or cancer risk subjects are discussed. Considering the promising effects associated with caloric restriction and caloric restriction mimetics, we think that controlled-randomized large clinical trials are warranted to evaluate the inclusion of these non-pharmacological approaches in clinical practice.

Early life stress induces a transient increase in hippocampal corticotropin-releasing hormone in rat neonates that precedes the effects on hypothalamic neuropeptides.

Early life stress (ELS) programs hypothalamus-pituitary-adrenal (HPA) axis activity and affects synaptic plasticity and cognitive performance in adults; however, the effects of ELS during the temporal window of vulnerability are poorly understood. This study aimed to thoroughly characterize the effects of ELS in the form of periodic maternal separation (MS180) during the time of exposure to stress. Hippocampal corticotropin-releasing hormone (CRH) gene expression and baseline HPA axis activity were analyzed at postnatal (P) days 6, 12, 15, and 21, and in adulthood (P75); these factors were correlated with plasticity markers and adult behavior. Our results indicate that MS180 induces an increase in hippocampal CRH expression at P9, P12, and P15, whereas an increase in hypothalamic CRH expression was observed from P12 to P21. Increased arginine-vasopressin expression and corticosterone levels were observed only at P21. Moreover, MS180 caused transient alterations in hypothalamic synaptophysin expression during early life. As adults, MS180 rats showed a passive coping strategy in the forced swimming test, cognitive impairments in the object location test, increased hypothalamic CRH expression, and decreased oxytocin (OXT) expression. Spearman's analysis indicated that cognitive impairments correlated with CRH and OXT expression. In conclusion, our data indicate that MS180 induces a transient increase in hippocampal CRH expression in neonates that precedes the effects on hypothalamic neuropeptides, confirming the role of increased CRH during the temporal window of vulnerability as a mediator of some of the detrimental effects of ELS on brain development and adult behavior.

The Addition of C-Reactive Protein and von Willebrand Factor to Model for End-Stage Liver Disease-Sodium Improves Prediction of Waitlist Mortality.

BACKGROUND AND AIMS: Patients with cirrhosis on the liver transplant (LT) waiting list may die or be removed because of complications of portal hypertension (PH) or infections. von Willebrand factor antigen (vWF-Ag) and C-reactive protein (CRP) are simple, broadly available markers of these processes. APPROACH AND RESULTS: We determined whether addition of vWF-Ag and CRP to the Model for End-Stage Liver Disease-Sodium (MELD-Na) score improves risk stratification of patients awaiting LT. CRP and vWF-Ag at LT listing were assessed in two independent cohorts (Medical University of Vienna [exploration cohort] and Mayo Clinic Rochester [validation cohort]). Clinical characteristics, MELD-Na, and mortality on the waiting list were recorded. Prediction of 3-month waiting list mortality was assessed by receiver operating characteristics curve (ROC-AUC). In order to explore potential mechanisms underlying the prognostic utility of vWF-Ag and CRP in this setting, we evaluated their association with PH, bacterial translocation, systemic inflammation, and circulatory dysfunction. In the exploration cohort (n = 269) vWF-Ag and CRP both improved the predictive value of MELD-Na for 3-month waitlist mortality and showed the highest predictive value when combined (AUC: MELD-Na, 0.764; MELD-Na + CRP, 0.790; MELD-Na + vWF, 0.803; MELD-Na + CRP + vWF-Ag, 0.824). Results were confirmed in an independent validation cohort (n = 129; AUC: MELD-Na, 0.677; MELD-Na + CRP + vWF-Ag, 0.882). vWF-Ag was independently associated with PH and inflammatory biomarkers, whereas CRP closely, and MELD independently, correlated with biomarkers of bacterial translocation/inflammation. CONCLUSIONS: The addition of vWF-Ag and CRP-reflecting central pathophysiological mechanisms of PH, bacterial translocation, and inflammation, that are all drivers of mortality on the waiting list for LT-to the MELD-Na score improves prediction of waitlist mortality. Using the vWFAg-CRP-MELD-Na model for prioritizing organ allocation may improve prediction of waitlist mortality and decrease waitlist mortality.

Consequences of Perioperative Serotonin Reuptake Inhibitor Treatment During Hepatic Surgery.

BACKGROUND AND AIMS: Platelet-stored serotonin critically affects liver regeneration in mice and humans. Selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenalin reuptake inhibitors (SNRIs) reduce intraplatelet serotonin. As SSRIs/SNRIs are now one of the most commonly prescribed drugs in the United States and Europe and given serotonin's impact on liver regeneration, we evaluated whether perioperative use of SSRIs/SNRIs affects outcome after hepatic resection. APPROACH AND RESULTS: Consecutive patients undergoing hepatic resection (n = 754) were retrospectively included from prospectively maintained databases from two European institutions. Further, an independent cohort of 495 patients from the United States was assessed to validate our exploratory findings. Perioperative intake of SSRIs/SNRIs was recorded, and patients were followed up for postoperative liver dysfunction (LD), morbidity, and mortality. Perioperative intraplatelet serotonin levels were significantly decreased in patients receiving SSRI/SNRI treatment. Patients treated with SSRIs/SNRIs showed a higher incidence of morbidity, severe morbidity, LD, and LD requiring intervention. Associations were confirmed in the independent validation cohort. Combined cohorts documented a significant increase in deleterious postoperative outcome (morbidity odds ratio [OR], 1.56; 95% confidence interval [CI], 1.07-2.31; severe morbidity OR, 1.86; 95% CI, 1.22-2.79; LD OR, 1.96; 95% CI, 1.23-3.06; LD requiring intervention OR, 2.22; 95% CI, 1.03-4.36). Further, multivariable analysis confirmed the independent association of SSRIs/SNRIs with postoperative LD, which was closely associated with postoperative 90-day mortality and 1-year overall survival. CONCLUSIONS: We observed a significant association of perioperative SSRI/SNRI intake with adverse postoperative outcome after hepatic resection. This indicates that SSRIs/SNRIs should be avoided perioperatively in patients undergoing hepatic resections.

Neoadjuvant Chemotherapy Switch in Borderline Resectable/Locally Advanced Pancreatic Cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is an integral part of preoperative treatment for patients with borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC). The identification of a chemotherapeutic regimen that is both effective and tolerable is critical for NAC to be of oncologic benefit. After initial first-line (FL) NAC, some patients have lack of response or therapeutic toxicities precluding further treatment with the same regimen; optimal decision making regarding this patient population is unclear. Chemotherapy switch (CS) may allow for a larger proportion of patients to undergo curative-intent resection after NAC. METHODS: We reviewed our surgical database for patients undergoing combinatorial NAC for BR/LA PDAC. Variant histologic exocrine carcinomas, intraductal papillary mucinous neoplasm-associated PDAC, and patients without research consent were excluded. RESULTS: Overall, 468 patients with BR/LA PDAC receiving FL chemotherapy were reviewed, of whom 70% (329/468) continued with FL chemotherapy followed by surgical resection. The remaining 30% (139/468) underwent CS, with 72% (100/139) of CS patients going on to curative-intent surgical resection. Recurrence-free survival (RFS) and overall survival (OS) were not significantly different between the resected FL and CS cohorts (30.0 vs. 19.1 months, p = 0.13, and 41.4 vs. 36.4 months, p = 0.94, respectively) and OS was significantly worse in those undergoing CS without subsequent resection (19 months, p < 0.0001). On multivariable analysis, carbohydrate antigen (CA) 19-9 and pathologic treatment responses were predictors of RFS and OS. CONCLUSION: CS in patients undergoing NAC for BR/LA pancreatic cancer does not incur oncologic detriment. The incorporation of CS into NAC treatment sequencing may allow a greater proportion of patients to proceed to curative-intent surgery.

FDG-PET Predicts Neoadjuvant Therapy Response and Survival in Borderline Resectable/Locally Advanced Pancreatic Adenocarcinoma.

BACKGROUND: Neoadjuvant therapy (NAT) is used in borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC). Anatomic imaging (CT/MRI) poorly predicts response, and biochemical (CA 19-9) markers are not useful (nonsecretors/nonelevated) in many patients. Pathologic response highly predicts survival post-NAT, but is only known postoperatively. Because metabolic imaging (FDG-PET) reveals primary tumor viability, this study aimed to evaluate our experience with preoperative FDG-PET in patients with BR/LA PDAC in predicting NAT response and survival. METHODS: We reviewed all patients with resected BR/LA PDAC who underwent NAT with FDG-PET within 60 days of resection. Pre- and post-NAT metabolic (FDG-PET) and biochemical (CA 19-9) responses were dichotomized in addition to pathologic responses. We compared post-NAT metabolic and biochemical responses as preoperative predictors of pathologic responses and recurrence-free survival (RFS) and overall survival (OS). RESULTS: We identified 202 eligible patients. Post-NAT, 58% of patients had optimization of CA 19-9 levels. Major metabolic and pathologic responses were present in 51% and 38% of patients, respectively. Median RFS and OS times were 21 and 48.7 months, respectively. Metabolic response was superior to biochemical response in predicting pathologic response (area under the curve, 0.86 vs 0.75; P<.001). Metabolic response was the only univariate preoperative predictor of OS (odds ratio, 0.25; 95% CI, 0.13-0.40), and was highly correlated (P=.001) with pathologic response as opposed to biochemical response alone. After multivariate adjustment, metabolic response was the single largest independent preoperative predictor (P<.001) for pathologic response (odds ratio, 43.2; 95% CI, 16.9-153.2), RFS (hazard ratio, 0.37; 95% CI, 0.2-0.6), and OS (hazard ratio, 0.21; 95% CI, 0.1-0.4). CONCLUSIONS: Among patients with post-NAT resected BR/LA PDAC, FDG-PET highly predicts pathologic response and survival, superior to biochemical responses alone. Given the poor ability of anatomic imaging or biochemical markers to assess NAT responses in these patients, FDG-PET is a preoperative metric of NAT efficacy, thereby allowing potential therapeutic alterations and surgical treatment decisions. We suggest that FDG-PET should be an adjunct and recommended modality during the NAT phase of care for these patients.

Patency rates of hepatic arterial resection and revascularization in locally advanced pancreatic cancer.

BACKGROUND: Arterial resection (AR) for pancreatic adenocarcinoma is increasingly considered at specialized centers. We aimed to examine the incidence, risk factors, and outcomes of hepatic artery (HA) occlusion after revascularization. METHODS: We included patients undergoing HA resection with interposition graft (IG) or primary end-to-end anastomoses (EE). Complete arterial occlusion (CAO) was defined as "early" (EO) or "late" (LO) before/after 90 days respectively. Kaplan-Meier and change-point analysis for CAO was performed. RESULTS: HA resection was performed in 108 patients, IG in 61% (66/108) and EE in 39% (42/108). An equal proportion (50%) underwent HA resection alone or in combination with celiac and/or superior mesenteric artery. CAO was identified in 18% of patients (19/108) with arterial IG least likely to occlude (p=0.019). Hepatic complications occurred in 42% (45/108) and correlated with CAO, symptomatic patients, venous resection, and postoperative portal venous patency. CAO-related operative mortality was 4.6% and significantly higher in EO vs LO (p = 0.046). Median CAO occlusion was 126 days. With change-point analysis, CAO was minimal beyond postoperative day 158. CONCLUSION: CAO can occur in up to 18% of patients and the first 5-month post-operative period is critical for surveillance. LO is associated with better outcomes compared to EO unless there is inadequate portal venous inflow.

Surgical Management of Metastatic Gastrointestinal Stromal Tumors.

OPINION STATEMENT: Treatment with the tyrosine kinase inhibitor (TKI), imatinib is the standard first-line treatment for metastatic gastrointestinal stromal tumors (GISTs). Unfortunately, acquired c-kit mutations cause secondary resistance to imatinib in a median of 18-24 months. Sunitinib and regorafenib are multi-kinase inhibitors that can be used as second-line or third-line therapy in imatinib-resistant or -intolerant GISTs, respectively. Ripretinib (a switch-control tyrosine kinase inhibitor) has recently been approved for fourth-line treatment in metastatic GIST. The TKI avapritinib has been approved for metastatic GIST harboring the imatinib-resistant PDGFRA exon 18 mutation. Although TKI therapies have revolutionized the treatment of metastatic GISTs, they cannot cure metastatic GISTs. Therefore, cytoreductive surgery is of considerable interest and has been accordingly investigated. Retrospective non-randomized studies demonstrated the feasibility and safety of continuous TKI therapy and surgical resection. Most studies demonstrate response to TKI therapy, completeness of resection, extent of disease, and surgical complexity as predictors of outcomes. Most TKIs can be stopped shortly before surgery and restarted shortly after. There is no known survival benefit from debulking operations or R2 resections and this should not be considered. However, debulking/palliative surgery may be necessary for patients with complications of hemorrhage, pain, or intestinal obstruction. SDH-deficient GISTs have an indolent natural history despite metastatic disease and may be another uncommon subgroup that would benefit from surgical debulking (R2 resection). At the time of operation, care should be taken to avoid tumor rupture. After surgical resection, patients should resume tyrosine kinase inhibitor (TKI) therapy as soon as possible and be monitored for disease progression. In all patients with metastatic GIST, the decision to pursue metastasectomy for GIST should be made in a multidisciplinary setting and be individualized according to patient age, comorbidities, functional status, symptoms, mutation status, extent of disease, completeness of resection, TKI response, and goals of the patient.

Pharmacological, non-pharmacological and stem cell therapies for the management of autism spectrum disorders: A focus on human studies.

In the last decade, the prevalence of autism spectrum disorders (ASD) has dramatically escalated worldwide. Currently available drugs mainly target some co-occurring symptoms of ASD, but are not effective on the core symptoms, namely impairments in communication and social interaction, and the presence of restricted and repetitive behaviors. On the other hand, transplantation of hematopoietic and mesenchymal stem cells in ASD children has been shown promising to stimulate the recruitment, proliferation, and differentiation of tissue-residing native stem cells, reducing inflammation, and improving some ASD symptoms. Moreover, several comorbidities have also been associated with ASD, such as immune dysregulation, gastrointestinal issues and gut microbiota dysbiosis. Non-pharmacological approaches, such as dietary supplementations with certain vitamins, omega-3 polyunsaturated fatty acids, probiotics, some phytochemicals (e.g., luteolin and sulforaphane), or overall diet interventions (e.g., gluten free and casein free diets) have been considered for the reduction of such comorbidities and the management of ASD. Here, interventional studies describing pharmacological and non-pharmacological treatments in ASD children and adolescents, along with stem cell-based therapies, are reviewed.

The EffectiveNess of LIfestyle with Diet and Physical Activity Education ProGram Among Prehypertensives and Stage 1 HyperTENsives in an Urban Community Setting (ENLIGHTEN) Study.

This study aims to determine the effectiveness of a monthly lifestyle education program, which included advice on nutritional changes and physical activity enhancement in the reduction of blood pressure and selected biochemical and anthropometric parameters among pre-hypertensive and stage 1 hypertensive participants in Manila, Philippines. Participants resided in two barangays (districts), in Manila, Philippines, and each barangay was assigned to either the intervention or attention-control group. The intervention group received monthly lectures on cardiovascular disease and organized classes on diet and exercise, while the attention-control group received monthly lectures on non-cardiovascular topics, with verbal advice that healthy diet and exercise are important. The primary outcome was systolic blood pressure, with secondary outcomes of BMI, waist circumference, and laboratory measures. Linear mixed effects models with an interaction between intervention group and time were used to estimate the 6-month change in each group. At 6 months, systolic blood pressure was lower in the intervention group compared to the attention-control group (- 12.7 mmHg (95% CI [- 14.5, - 10.9]) vs. - 0.24 mmHg (95% CI [- 1.87, 1.43]), p-value < 0.001). Waist circumference (p < 0.001), BMI (p < 0.001), and total cholesterol (p = 0.049) were also lower. However, no statistically significant difference in fasting glucose was observed between the two groups (p = 0.740). This study showed that participants receiving a non-pharmacological intervention, specifically a low-cost diet and active lifestyle education program, experienced a greater decrease in blood pressure, BMI, waist circumference, and total cholesterol than the attention-control group. Educational programs such as in ENLIGHTEN show promise for a developing country with limited resources to improve hypertension levels, and ultimately cardiovascular health. ENLIGHTEN deserves further study in randomized trials.

Nutritional patterns associated with the maintenance of neurocognitive functions and the risk of dementia and Alzheimer's disease: A focus on human studies.

Ample epidemiological evidence suggests a strong correlation among diet, lifestyle factors and the onset and consolidation of dementia and Alzheimer's disease (AD). It has been demonstrated that AD, diabetes, obesity, insulin resistance, and cardiovascular disease are strongly interconnected pathologies. Preventive strategies and nutritional interventions seem to be promising approaches to delay neurocognitive decline and reduce the risk of AD and other non-psychiatric co-morbidities. In this regard, healthy dietary patterns, characterized by high intake of plant-based foods, probiotics, antioxidants, soy beans, nuts, and omega-3 polyunsaturated fatty acids, and a low intake of saturated fats, animal-derived proteins, and refined sugars, have been shown to decrease the risk of neurocognitive impairments and eventually the onset of AD. Here we review the role of some nutrients and, in particular, of healthy dietary patterns, such as the Mediterranean diet and other emerging healthy diets, DASH (Dietary Approach to Stop Hypertension) and MIND (Mediterranean-DASH dietIntervention for Neurodegenerative Delay), for the maintenance of cognitive performance, focusing specifically on human studies. The beneficial effects associated with overall diet composition, rather than single nutrient supplementations, for the prevention or the delay of AD and dementia are discussed.

Alcohol and hospitalized road traffic injuries in the Philippines.

Each year, there are approximately 1.24 million deaths due to road traffic injuries, the majority of which occur in low- and middle-income countries. Since 2008, 35 countries have passed legislation to implement road safety strategies. However, many countries have yet to pass comprehensive legislation while others lack adequate enforcement of current policies. The annual global mortality rate due to road trauma remains unacceptably high and reflects the need for governments to prioritize the passage and implementation of road safety legislation. Alcohol is a leading risk factor for road trauma globally and the leading cause of death and disability in the Western Pacific region. Despite the overwhelming evidence that strict enforcement of drunk-driving policies can lead to a drastic reduction in alcohol-related road incidents, many countries in the Western Pacific lack sufficient data that could facilitate the design of appropriate drunk-driving interventions. This paper provides an analysis of the current status of policies and attitudes related to alcohol and road injuries throughout the Western Pacific region, with a specific focus on the Philippines. Following the passage of drunk-driving legislation in 2013, a medical records review of alcohol-related road trauma patients in Manila Doctors Hospital was conducted. The findings of this pilot project further highlight the pervasive problem of missing or unreliable data regarding alcohol's role in road trauma. Assessing the burden of drunk driving is an important step in designing effective interventions and systematically changing attitudes about driving under the influence.