Towards precision medicine in bariatric surgery prescription

Obesity is a complex, multifactorial and chronic disease. Bariatric surgery is a safe and effective treatment intervention for obesity and obesity-related diseases. However, weight loss after surgery can be highly heterogeneous and is not entirely predictable, particularly in the long-term after intervention. In this review, we present and discuss the available data on patient-related and procedure-related factors that were previously appointed as putative predictors of bariatric surgery outcomes. In addition, we present a critical appraisal of the available evidence on which factors could be taken into account when recommending and deciding which bariatric procedure to perform. Several patient-related features were identified as having a potential impact on weight loss after bariatric surgery, including age, gender, anthropometrics, obesity co-morbidities, eating behavior, genetic background, circulating biomarkers (microRNAs, metabolites and hormones), psychological and socioeconomic factors. However, none of these factors are sufficiently robust to be used as predictive factors. Overall, there is no doubt that before we long for precision medicine, there is the unmet need for a better understanding of the socio-biological drivers of weight gain, weight loss failure and weight-regain after bariatric interventions. Machine learning models targeting preoperative factors and effectiveness measurements of specific bariatric surgery interventions, would enable a more precise identification of the causal links between determinants of weight gain and weight loss. Artificial intelligence algorithms to be used in clinical practice to predict the response to bariatric surgery interventions could then be created, which would ultimately allow to move forward into precision medicine in bariatric surgery prescription

Estimating capital investment and facility footprint in cell therapy facilities

Estimations of the facility footprint and fixed capital investment (FCI) of cell therapy (CT) facilities need to consider the unique features of the single-use technologies (SUTs) selected for CT manufacture (e.g. cleanroom containment requirement, capacity, automation) and the product nature that impacts scale-out versus scale-up approaches. A novel detailed factorial methodology is proposed for estimating FCI and footprint for bespoke stick-built cell therapy facilities that accounts for technology-specific factors for key cell culture technologies as well as the implications of SUTs, open versus closed operations and the commercialisation scenario selected. This was used to derive benchmark values for short-cut cost and area factors for typical cell therapy facilities according to the technologies selected. The results provide project-specific ratios for equipment purchase costs to facility footprint (area factor) and for FCI to total equipment purchase costs (cost factor or “Lang” factor). Area factors ($/m2) were 675-6,815 and the cost factors were 2.3–8.5 for a greenfield project in a medium-developed country. The case study shows that for the same output, facility footprints and FCI values are on average 6 times higher for autologous processes than allogeneic processes. This is attributed to economies of scale achieved with scale-up for allogeneic cell therapy manufacture. This study can be used to predict the commercial FCI and facility footprint during early stages of process development

Apoptosis regulation in adrenocortical carcinoma

Apoptosis evading is a hallmark of cancer. Tumor cells are characterized by having an impaired apoptosis signaling, a fact that deregulates the balance between cell death and survival, leading to tumor development, invasion and resistance to treatment. In general, patients with adrenocortical carcinomas (ACC) have an extremely bad prognosis, which is related to disease progression and significant resistance to treatments. In this report, we performed an integrative review about the disruption of apoptosis in ACC that may underlie the characteristic poor prognosis in these patients. Although the apoptosis has been scarcely studied in ACC, the majority of the deregulation phenomena already described are anti-apoptotic. Most importantly, in a near future, targeting apoptosis modulation in ACC patients may become a promising therapeutic.The work was supported by the Foundation for Science and Technology (FCT) (PTDC/MEC-ONC/31384/2017). Unit for Multidisciplinary Research in Biomedicine (UMIB) is funded by grants from FCT (UID/Multi/00215/2013)

Angiogenesis in the Normal Adrenal Fetal Cortex and Adrenocortical Tumors

Simple Summary Pharmacological angiogenesis modulation was robustly demonstrated to be a powerful clinical resource in oncotherapy. Adrenocortical carcinomas (ACC) often have a poor prognosis for which therapeutic options are limited. Understanding the mechanisms that regulate adrenocortical angiogenesis both under physiological conditions and in ACC could provide important clues on how these processes could be modulated for clinical purposes. This report summarizes the current knowledge on adrenal cortex angiogenesis regulation in physiological conditions and ACC. Embryonic adrenal angiogenesis is regulated by VEGF and Ang-Tie signaling pathways. VEGF angiogenic pathway was initially considered a promising therapeutic target for improving ACC prognosis. However, every single VEGF pathway-targeting clinical trial in ACC so far conducted yielded disappointing results. In contrast, the potential of Ang-Tie pathway-targeting in ACC is yet to be explored. Therefore, further investigation on the role and efficacy of modulating both Ang-Tie and VEGF pathways in ACC is still an unmet need. Angiogenesis plays an important role in several physiological and pathological processes. Pharmacological angiogenesis modulation has been robustly demonstrated to achieve clinical benefits in several cancers. Adrenocortical carcinomas (ACC) are rare tumors that often have a poor prognosis. In addition, therapeutic options for ACC are limited. Understanding the mechanisms that regulate adrenocortical angiogenesis along the embryonic development and in ACC could provide important clues on how these processes could be pharmacologically modulated for ACC treatment. In this report, we performed an integrative review on adrenal cortex angiogenesis regulation in physiological conditions and ACC. During embryonic development, adrenal angiogenesis is regulated by both VEGF and Ang-Tie signaling pathways. In ACC, early research efforts were focused on VEGF signaling and this pathway was identified as a good prognostic factor and thus a promising therapeutic target. However, every clinical trial so far conducted in ACC using VEGF pathway- targeting drugs, alone or in combination, yielded disappointing results. In contrast, although the Ang-Tie pathway has been pointed out as an important regulator of fetal adrenocortical angiogenesis, its role is yet to be explored in ACC. In the future, further research on the role and efficacy of modulating both Ang-Tie and VEGF pathways in ACC is needed

Renal Dysfunction Phenotypes in Patients Undergoing Obesity Surgery

Obesity surgery candidates are at an increased risk of kidney injury, but pre-operative evaluation usually neglects kidney function assessment. This study aimed to identify renal dysfunction in candidates for bariatric surgery. To reduce the sources of bias, subjects with diabetes, prediabetes under metformin treatment, neoplastic or inflammatory diseases were excluded. Patients' (n = 192) average body mass index was 41.7 +/- 5.4 kg/m(2). Among these, 51% (n = 94) had creatinine clearance over 140 mL/min, 22.4% (n = 43) had proteinuria over 150 mg/day and 14.6% (n = 28) albuminuria over 30 mg/day. A creatinine clearance higher than 140 mL/min was associated with higher levels of proteinuria and albuminuria. Univariate analysis identified sex, glycated hemoglobin, uric acid, HDL and VLDL cholesterol as being associated with albuminuria, but not with proteinuria. On multivariate analysis, glycated hemoglobin and creatinine clearance as continuous variables were significantly associated with albuminuria. In summary, in our patient population prediabetes, lipid abnormalities and hyperuricemia were associated with albuminuria, but not with proteinuria, suggesting different disease mechanisms might be implicated. Data suggest that in obesity-associated kidney disease, tubulointerstitial injury precedes glomerulopathy. A significant proportion of obesity surgery candidates present clinically relevant albuminuria and proteinuria along with renal hyperfiltration, suggesting that routine pre-operative assessment of these parameters should be considered

Are SADI-S and BPD/DS bariatric procedures identical twins or distant relatives?-A case report

Given the common anatomical features and similar short-term weight loss outcomes, Biliopancreatic Diversion with Duodenal Switch (BPD/DS) and Single-Anastomosis Duodenoileal bypass with Sleeve gastrectomy (SADI-S) are considered identical bariatric procedures, apart from technical complexity being lower for SADI-S. In the absence of prospective randomized trials or long-term comparative studies the rationale for choosing between procedures is hampered. Post-bariatric hormonal profiles could contribute to understand the underlying mechanisms and potentially be used as a decision aid when choosing between procedures. The main aim of this study was to compare the outcomes of BPD/DS and SADI-S, in genetically identical individuals exposed to similar environmental factors. Two identical twin (T) female patients, one submitted to BPD/DS (T_BPD/DS) and another to SADIS-S (T_SADI-S) were followed up to one year after surgery. Before surgery and at 3, 6 and 12 months after surgery, both patients underwent mixed meal tolerance tests (MMTT) to evaluate postprandial glucose, glucagon and GLP-1 response. In addition, 3 months after surgery, glucose dynamics were assessed using a Flash Glucose Monitoring (FGM) system for 14 days. The percentage of total weight loss (%TWL) was higher for T_BPD/DS compared to T_SADI-S (34.03 vs 29.03 %). During MMTT, T_BPD/DS presented lower glucose, glucagon, insulin and C-peptide excursions at all timepoints when compared to SADI-S; along with a greater percentage of time within the low glucose range (55.97 vs 39.93 %) and numerically lower glucose variability indexes on FGM (MAG change:0.51 vs 0.63 mmol/lxh- 1). In patients with the same genetic background, BPD/DS was shown to result in greater weight loss than SADI-S. The differences in glucose and enteropancreatic hormone profiles observed after BPD/DS and SADI-S suggest that different mechanisms underlie weight loss

FORMULATION AND CHARACTERIZATION OF POLOXAMER 407 (R): THERMOREVERSIBLE GEL CONTAINING POLYMERIC MICROPARTICLES AND HYALURONIC ACID

The influence of the composition and preparation method on the sol-gel transition temperature (Tsol-gel) and rheological response of poloxamer-based formulations was determined. Manual and more complex mechanical stirring were found to provide similar results. In addition, a linear dependence of Tsol-gel on the poloxamer content was observed in the range of concentrations analyzed, and a Poloxamer 407® concentration of 18% was selected. The addition of hyaluronic acid did not lead to significant changes in the Tsol-gel values. In contrast, the addition of microparticles caused a reduction in Tsol-gel without a significant reduction in gel strength, and pseudoplastic characteristics were observed, indicating that a thermoreversible gel was obtained with a rheology suitable for application in the treatment of burn wounds

Visceral Adipose Tissue Bioenergetics Varies According to Individuals' Obesity Class

Obesity is associated with complex adipose tissue energy metabolism remodeling. Whether AT metabolic reprogramming differs according to body mass index (BMI) and across different obesity classes is unknown. This study's purpose was to evaluate and compare bioenergetics and energy substrate preference of visceral adipose tissue (VAT) pertaining to individuals with obesity class 2 and class 3. VAT obtained from patients with obesity (n = 15) class 2 (n = 7; BMI 37.53 +/- 0.58 kg/m(2)) or class 3 (n = 8; BMI 47.79 +/- 1.52 kg/m(2)) was used to assess oxygen consumption rate (OCR) bioenergetics and mitochondrial substrate preferences. VAT of patients with obesity class 3 presented significantly higher non-mitochondrial oxygen consumption (p < 0.05). In VAT of patients with obesity class 2, inhibition of pyruvate and glutamine metabolism significantly decreased maximal respiration and spare respiratory capacity (p < 0.05), while pyruvate and fatty acid metabolism inhibition, which renders glutamine the only available substrate, increased the proton leak with a protective role against oxidative stress (p < 0.05). In conclusion, VAT bioenergetics of patients with obesity class 2 depicts a greater dependence on glucose/pyruvate and glutamine metabolism, suggesting that patients within this BMI range are more likely to be responsive to interventions based on energetic substrate modulation for obesity treatment

Efeitos antiangiogênicos in vivo convalidam a atividade antineoplásica potencial do metiljasmonato

Molecular plant components have long been aimed at the angiogenesis and anti-angiogenesis pathways, and have been tested as sources for antineoplasic drugs with promising success. The present work deals with the anti-angiogenic effects of Methyl Jasmonate. Jasmonate derivatives were demonstrated to selectively damage the mitochondria of cancer cells. In vitro, 1-10 mM Methyl Jasmonate induced the cell death of the human umbilical vein endothelial cells (HUVEC) and the Murine melanoma cells (B16F10), while micromolar concentrations were ineffective. In vivo, comparable concentrations were toxic and reduced the vessel density of the Chorioallantoic Membrane of the Chicken Embryo (CAM). However, 1-10 µM concentrations produced a complex effect. There was increased capillary budding, but the new vessels were leakier and less organised than corresponding controls. It is suggested that not only direct toxicity, but also the drug effects upon angiogenesis are relevant to the antineoplasic effects of Methyl Jasmonate.Moléculas de origem vegetal são, há muito, conhecidas como substâncias ativas sobre as vias de angiogênese e antiangiogênese e foram testadas como fonte de drogas antineoplásicas com sucesso promissor. Este trabalho trata dos efeitos antiangiogênicos do Metiljasmonato, um protótipo da família dos derivados do ácido jasmônico, que danificam seletivamente a mitocôndria de células neoplásicas. In vitro, metiljasmonato 1-10 mM promoveu a morte celular de células endoteliais humanas de cordão umbilical (HUVEC) e de melanoma murino (B16F10); concentrações micromolares foram inócuas. In vivo, concentrações equivalentes foram tóxicas e reduziram a densidade de vasos em membranas corioalantoicas de embrião de galinha (CAM). Entretanto, concentrações entre 1-10 µM produziram um efeito complexo. Ocorreu aumento no brotamento capilar, mas os novos vasos apresentaram-se frágeis e menos organizados que os controles correspondentes. Sugere-se que, além da toxicidade direta contra as células tumorais, a ação do metiljasmonato sobre a angiogênese seja relevante para seu efeito antineoplásico

Accuracy of prediction models for long-term type 2 diabetes remission after gastric bypass

AimTo evaluate the accuracy of DiaBetter, DiaRem, Ad-DiaRem and 5y-Ad-DiaRem scores' at predicting T2D remission 10 or more years after surgery.MethodsPatients with obesity and T2D (n = 126) submitted to RYGB with 10 or more years of follow-up. It was a unicentric trial. Pre-operative anthropometric and clinical data was retrieved to calculate DiaRem, DiaBetter, Ad-DiaRem and 5y-Ad-DiaRem scores, while a hospital visit was conducted to assess current diabetes status. The area under the receiver operating characteristic (AUROC) curve was calculated as estimate of the scores' accuracy to predict long-term T2D remission.ResultsAmong the entire cohort (n = 126), 70 subjects (55.6%) achieved and maintained T2D remission 10 or more years after RYGB. The 5y-Ad-DiaRem score was the one that depicted the highest discriminative power (AUROC = 0.838) to predict long-term T2D remission when compared to DiaBetter (AUROC = 0.735), DiaRem (AUROC = 0.721) and Ad-DiaRem (AUROC = 0.720).ConclusionThe score with highest accuracy to predict long-term T2D remission after RYGB surgery was the 5y-Ad-DiaRem. Yet, the available scores accuracy to predict T2D remission in the long term is still suboptimal, highlighting the unmet need for a better scoring system