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Purpose: The purpose of this study was to conduct a systematic review evaluating the reported complications and outcomes of bone-anchored prostheses in digit and partial hand amputees., Methods: A literature review of primary research articles on osseointegration and bone-anchored prostheses for digit and partial amputees was performed. The Medline, Embase, Scopus, and Cochrane Library databases were queried. Inclusion criteria were journal articles that evaluated osseointegration and bone-anchored prostheses in digit and partial hand amputees. The main outcome measures were reported complications and the need for revision surgery. Secondary outcomes included all reported outcome assessments., Results: Fifteen articles were included with publication dates ranging from 1996 to 2022. The sample sizes ranged from single-patient case reports to a 13-patient retrospective study. Overall, 33 men and 16 women were reported with a mean age of 33.6 years (range: 12-68) and a total of 71 amputated digits. The median follow-up was 2.1 years (IQR: 1.1-6.8 years). A total of 24 complications were reported in 14 digits (19.7%). Complications included superficial infection in 6 digits (8.5%), abutment loosening or failure in 5 (7%), fixture aseptic loosening in 4 (5.6%), deep infection in 1 (1.4%), and soft tissue instability in 1 (1.4%). Sixteen revision surgeries or component changes were reported., Conclusions: Bone-anchored prostheses using osseointegrated implants in the hand are associated with favorable outcomes in the limited number of low-quality studies available for review. Superficial infections and implant-related failures were the most frequently reported complications., Type of Study/level of Evidence: Systematic review IV., Competing Interests: Conflicts of Interest No benefits in any form have been received or will be received related directly to this article. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of Defense or the U.S. Government., (Copyright © 2024 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Background and Aim: The Dysfunctional Adiposity Index (DAI) is a clinical surrogate for evaluating adipose tissue functionality and cardiometabolic health. However, its association with Pericardial Fat Volume (PFV) has not been tested. The aim of this study was to evaluate DAI- PFV association, stratified by type 2 diabetes (T2D) status, and identify DAI thresholds for detecting increased PFV among patients without premature CVD., Methods and Results: Participants from the GEA-Mexican study underwent a computed tomography scan to measure PFV. Adjusted logistic regression analyses tested the association between DAI and PFV. AUROC curves evaluated DAI's ability to identify elevated PFV (≥57.57 cm³), and the Youden method determined DAI thresholds, along with diagnostic metrics. The study analyzed 997 participants (women: 55%; mean age: 54 ± 9 years; median PFV: 42 cm³ [IQR: 29-58]), with a 13% prevalence of T2D. DAI was positively associated with elevated PFV (OR: 1.33, 95% CI: 1.07-1.70), which was more pronounced among subjects with T2D (OR: 3.01, 95% CI: 1.41-6.40). DAI thresholds were established for all participants (>1.176), individuals without T2D (>1.003), and with T2D (>1.936), yielding sensitivities of 71%, 81%, and 57%, and specificities of 48%, 38%, and 75%, respectively. The adjusted logistic regression tied DAI thresholds to a 1.68-fold elevation in PFV for all, 2.06-fold for those without T2D, and 6.81-fold for those with T2D., Conclusion: DAI was positively associated with increased PFV, particularly among participants with T2D. Established DAI thresholds demonstrated good diagnostic values for detecting increased PFV. DAI could serve as an accessible marker to identify PF in clinical settings., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Phosphatidylcholine (PC) derived from eggs has been shown to beneficially modulate T cell response and intestinal permeability under the context of a high-fat diet., Objectives: The objective of this study was to determine whether there is a differential effect of plant and animal-derived sources of PC on immune function., Methods: Four-week-old male Wistar rats were randomly assigned to consume 1 of 4 diets (n = 10/group) for 12 wk, all containing 1.5 g of total choline/kg of diet but differing in choline forms: 1-Control Low-Fat [CLF, 20% fat, 100% free choline (FC)]; 2-Control High-Fat (CHF, 50% fat, 100% FC); 3-High-Fat Egg-derived PC (EPC, 50% fat, 100% Egg-PC); 4-High-Fat Soy-derived PC (SPC, 50% fat, 100% Soy-PC). Immune cell functions and phenotypes were measured in splenocytes by ex vivo cytokine production after mitogen stimulation and flow cytometry, respectively., Results: The SPC diet increased splenocyte IL-2 production after PMA+I stimulation compared with the CHF diet. However, the SPC group had a lower proportion of splenocytes expressing the IL-2 receptor (CD25+, P < 0.05). After PMA+I stimulation, feeding EPC normalized splenocyte production of IL-10 relative to the CLF diet, whereas SPC did not (P < 0.05). In mesenteric lymph node lymphocytes, the SPC diet group produced more IL-2 and TNF-α after PMA+I stimulation than the CHF diet, whereas the EPC diet group did not., Conclusions: Our results suggest that both egg- and soy-derived PC may attenuate high-fat diet-induced T cell dysfunction. However, egg-PC enhances, to a greater extent, IL-10, a cytokine involved in promoting the resolution phase of inflammation, whereas soy-PC appears to elicit a greater effect on gut-associated immune responses., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Dual inhibition with a T-cell immunoreceptor with immunoglobulin and ITIM domains plus programmed death (ligand)-1 (PD[L]-1) inhibitors, with or without chemotherapy, is an emerging therapeutic strategy in metastatic non-small cell lung cancer (mNSCLC). The STAR-121 (NCT05502237) phase III, global, randomized, open-label study will investigate first-line domvanalimab (anti-TIGIT) and zimberelimab (anti-PD-1) plus chemotherapy versus pembrolizumab plus chemotherapy in mNSCLC with no actionable gene alterations., Participants and Methods: Approximately 720 participants (≥18 years old) with untreated mNSCLC and no EGFR and ALK mutations will be randomized into 3 groups (A, B, or C) in a 4:4:1 ratio and stratified by baseline PD-L1 expression (tumor cells <50% vs. ≥50%), histology (squamous vs. nonsquamous), and geographic region (East Asia vs. non-East Asia). Group A will receive domvanalimab 1200 mg plus zimberelimab 360 mg plus platinum-doublet chemotherapy (PT), group B will receive pembrolizumab 200 mg plus PT, and group C will receive zimberelimab 360 mg plus PT, every 3 weeks. Treatment will be administered until disease progression or intolerable toxicity. Dual primary endpoints are progression-free survival (by blinded independent central review [BICR]) and overall survival for group A versus B. Key secondary endpoints comprise overall response rate (by BICR), safety, and quality of life. Exploratory endpoints include efficacy and safety between groups A and C, pharmacokinetics, patient-reported outcomes, and biomarkers., Conclusion: Enrollment in the STAR-121 study commenced on October 12, 2022, and is currently ongoing with completion planned by September 2024. The study completion is expected by December 2027., Competing Interests: Disclosure DR-A has provided consulting services to Roche, Bristol-Myers Squibb, MSD, AstraZeneca, and Novartis; participated in a speaker's bureau for Roche, Bristol-Myers Squibb, and MSD; and received travel accommodations from Roche, Bristol-Myers Squibb, MSD, and Novartis. JB-B reports grants and personal fees from Roche and Pfizer; personal fees from MSD, BMS, AstraZeneca, Vifor, and Sanofi, outside the submitted work; and has received support for attending meetings and/or travel from Takeda, MSD, and Roche. JEG has received honoraria from Jazz Pharmaceuticals, Merck, and Oncocyte; has provided consulting services to AstraZeneca, Blueprint Medicines, Bristol-Myers Squibb, EMD Serono, Eli Lilly, Sanofi, Merck, Loxo, Jazz Pharmaceuticals, Novartis, MedImmune, Janssen, and the National Comprehensive Cancer Network; and has received travel accommodations from Novartis, Oncocyte, Jazz Pharmaceuticals, and Merck. MJA has provided consulting services to AstraZeneca, Eli Lilly, MSD, Takeda, Alpha Pharmaceutical, Amgen, Merck, Pfizer, and Yuhan and has received honoraria from AstraZeneca, Eli Lilly, MSD, Takeda, Merck, and Yuhan. Her institution has received research funding from Yuhan. MJ has provided consulting services to Genentech/Roche, AstraZeneca, Calithera Biosciences, Merck, Sanofi, Mirati Therapeutics, Ribon Therapeutics, Abbvie, GlaxoSmithKline, Gristone Bio, Janssen, Eli Lilly, Amgen, Daiichi Sankyo, Eisai, Axelia Oncology, Black Diamond Therapeutics, CytomX Therapeutics, EcoR1 Capital, Editas Medicine, Genmab, IDEAYA Biosciences, ITeos Therapeutics, Oncorus, Regeneron, Turning Point Therapeutics, Astellas Pharma, Checkpoint Therapeutics, Genocea Biosciences, Molecular Axiom, Novartis, Revolution Medicines, Takeda, VBL Therapeutics, ArriVent Biopharma, Pyramid Biosciences, and Seagen and has received travel accommodations from Abbvie, AstraZeneca, Genentech, Incyte, Merck, Pfizer, and Sanofi. Her institution has received research funding from EMD Serono, Kadmon, Janssen, Mirati Therapeutics, Genmab, Pfizer, AstraZeneca, Stem CentRX, Novartis, Array Biopharma, Regeneron, Merck, Hengrui Pharmaceutical, Lycera, BeiGene, Tarveda Therapeutics, Loxo, Abbvie, Boehringer Ingelheim, Guardant Health, Daiichi Sankyo, Sanofi, CytomX Therapeutics, Dynavax Technologies, Corvus Pharmaceuticals, Incyte, Genocea Biosciences, Gristone Bio, Amgen, Genentech/Roche, Adaptimmune, Syndax, Neovia Oncology, Acerta Pharma, Takeda, Shattuck Labs, GlaxoSmithKline, Apexigen, Atreca, OncoMed, Eli Lilly, Immunocore, University of Michigan, TCR2 Therapeutics, Arcus Biosciences, Ribon Therapeutics, BerGenBio, Calithera Biosciences, Tmunity Therapeutics, Seven and Eight Biopharmaceuticals, Curis, Silicon Therapeutics, Dracen, PMV Pharma, Artios, BioAtla, Elicio Therapeutics, Erasca Inc., Harpoon, Helsinn Healthcare, Hutchinson MediPharma, IDEAYA Biosciences, IGM Biosciences, Memorial Sloan-Kettering Cancer Center, NeoImmuneTech, Numab, Relay Therapeutics, Revolution Medicines, Tempest Therapeutics, Tizona Therapeutics Inc., Turning Point Therapeutics, Vyriad, Y-mAbs Therapeutics, Exelixis, Fate Therapeutics, Merus, Black Diamond Therapeutics, Kartos Therapeutics, Carisma Therapeutics, Rain Therapeutics, Nuvalent Inc., Palleon Pharmaceuticals, EQRx, and Immunitas. XY is a current employee of, and receives stock options from, Gilead Sciences, Inc. SM is a current employee of, and receives stock options from, Gilead Sciences, Inc. XC is a previous employee of Novartis and Innovent Biologics, and a current employee of Gilead Sciences, Inc. and has received stock options from Novartis and Gilead Sciences, Inc. TT is a current employee of, and receives stock options from, Arcus Biosciences. JK is a current employee of, and receives stock options from, Gilead Sciences, Inc. MR has provided consulting services to Eli Lilly, MSD Oncology, Merck Serono, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Genentech/Roche, Abbvie, Amgen, Mirati Therapeutics, Samsung Bioepis, Sanofi, Regeneron, and Daiichi Sankyo and has also participated in a speaker's bureau for Genentech/Roche, Eli Lilly, MSD Oncology, Merck Serono, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Pfizer, Novartis, Amgen, Mirati Therapeutics, and Sanofi/Aventis., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: The LIPI, based on pretreatment derived neutrophils/[leukocytes-neutrophils] ratio (dNLR) and LDH, is associated with immune checkpoint inhibitors (ICI) outcomes in advanced non-small-cell lung cancer (NSCLC). We aimed to assess baseline LIPI correlation with durvalumab consolidation outcomes in the locally advanced setting., Material and Methods: Multicentre retrospective study (330 patients) with stage III unresectable NSCLC treated with durvalumab after chemo-radiotherapy between April 2015 and December 2020; 65 patients treated with chemo-radiotherapy only. Baseline LIPI characterized 3 groups: good (dNLR≤3+LDH≤ULN), intermediate (dNLR>3/LDH>ULN) and poor (dNLR>3+LDH>ULN). Primary endpoint was overall survival (OS)., Results: In the durvalumab cohort, median age was 67 years, 95% smokers, 98% with a performance status of 0-1; 60% had nonsquamous histology and 16% a PD-L1 expression <1%. Radiotherapy was delivered concurrently in 81%. LIPI was evaluable in 216 patients: 66% good, 31% intermediate, 3% poor. LIPI significantly correlated with median OS (median follow-up: 19 months): 18.1 months vs. 47.0 months vs. not reached in poor, intermediate and good LIPI groups, respectively (P = .03). A trend between objective response rate and LIPI groups was observed: 0% vs. 41% vs. 45%, respectively (P = .05). The pooled intermediate/poor LIPI group was associated with shorter OS (HR 1.97; P = .03) and higher risk of progressive disease (OR 2.68; P = .047). Survivals and response were not influenced in the control cohort., Conclusion: Baseline LIPI correlated with outcomes in patients with locally advanced NSCLC treated with durvalumab consolidation, but not in those who only received chemo-radiotherapy, providing further evidence of its prognostic and potential predictive role of ICI benefit in NSCLC., Competing Interests: Disclosure VAA: Lectures and educational activities: Bristol-Myers Squibb, AstraZeneca, MSD; Travel, Accommodations, Expenses: Takeda, Sanofi, Janssen; RL: Personal fees: AstraZeneca, Bristol-Myers Squibb. Travel, Accommodations: Roche, Italfarmaco; RLC: Consulting, advisory role or lectures: Amgen, Bristol-Myers Squibb, Pierre-Fabre, Boehringer Ingelheim, Novartis, Roche. Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Pierre-Fabre, MSD, Novartis, Pfizer, Roche, Takeda. Clinical trials research: AstraZeneca, Roche. Travel, Accommodations, Expenses: Roche, Novartis, Takeda, Boehringer Ingelheim; JBB: Reports grants and personal fees from Roche and Pfizer, and personal fees from MSD, BMS, AstraZeneca, Boehringer-Ingelheim, Sanofi, and Novartis, outside the submitted work; SP: Consulting, advisory role or lectures: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Roche, Amgen, Takeda (outside the submitted manuscript); MT: Travel, accommodation, expenses: Roche, Bristol-Myers Squibb, AstraZeneca, Takeda, Eli Lilly. Honoraria as medical writer: Novartis, Amgen, MSD. None related to the current manuscript; MS: Speaker, Advisory Role: Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi Avemtis, Siemens Healthineers, Takeda; Research support (institutional): Amgen, BMS, Dracen Pharmaceuticals, Janssen, Novartis, Pfizer, Siemens Healthiness; EN: has participated in lectures and advisory boards from Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Pfizer, Lilly, Amgen, Boehringer Ingelheim, AstraZeneca, Takeda, Sanofi and Bayer. E. N. has received research funding support from Pfizer, Roche, Merck Serono, Bristol Myers Squibb and Nanostring; GL: Honorary from Boehringer Ingelheim, Blueprint Medicines, AstraZeneca, Merck, Janssen; Consulting and advisory role from Pfizer and AstraZeneca; Research funding from AstraZeneca, Lucence, Xilis, Merck Sharp and Dohme, EMD Serono, Blueprint Medicines, Tesaro, Vavarian Nordic, Novartis, G1 Therapeutics. AdaptImmune, BMS, GSK, Abbvie, Rgenix, Pfizer, Roche, Genentech, Lilly, Janssen; travel, accommodations and expenses from Boehringer Ingelheim, Pfizer, Squibb Sons, Janssen, Seattle Genetics, Celgene, Ibsen, Pharmacyclocs, Merck, AstraZeneca, Seagen; DS: Consulting, advisory role: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Sanofi. Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Roche, Merck Sharp & Dohme. Principal Investigator in clinical trial sponsored by Bristol-Myers Squibb, Merck Sharp & Dohme, Eli Lilly. Travel, Accommodations: AstraZeneca, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer; RGC: Consulting, advisory role or lectures from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Takeda, Janseen, MSD, Roche, Pfizer, Eli Lilly, Amgen, Sanofi; honoraria (self) from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Pfizer, Roche, MSD, Takeda, Eli Lilly, Novartis; clinical trials research from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis; VB: Consulting, advisory role: AstraZeneca, Bristol-Myers Squibb, MSD, Merck, Novartis, Pfizer, Roche. Clinical trials research: AstraZeneca, MSD, Roche; MC: Advisory or Consultancy role: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, EUSA Pharma, Lilly, Roche. Honoraria, lectures: Abbot, AstraZeneca, Bristol-Myers Squibb, EUSA Pharma, Ipsen, Merck, Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, Takeda. Travel expenses: Ipsen, Lilly, Merck, Pfizer, Pierre Fabre. Institutional financial interests: Astra Zeneca, Merck, Pfizer, Roche; BB: Sponsored Research at Gustave Roussy Cancer Center, Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma; DP: Consulting, advisory role or lectures: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche. Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche. Clinical trials research: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo. Travel, Accommodations, Expenses: AstraZeneca, Roche, Novartis, prIME Oncology, Pfizer; LM: Research grant/Funding (self): Bristol Myers Squibb, Boehringer Ingelheim, Amgen, Stilla, Inivata; Advisory/Consultancy: Roche Diagnostics, Takeda; Honoraria (self): Bristol Myers Squibb, Tecnofarma, Roche; Travel/Accommodation/Expenses: Roche, Boehringer Ingelheim, Takeda, AstraZeneca. The remaining authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Obesity is associated with increased intestinal permeability and a diminished immune response. Phosphatidylcholine (PC), a form of choline found in eggs, has been shown to beneficially modulate T-cell response in the context of obesity when provided as the sole form of choline in the diet., Objective: This study aimed to determine the impact of varying doses of PC as part of a high-fat diet (HFD) on immune cell function and intestinal permeability., Methods: Male Wistar rats 4 wk of age were randomly assigned to consume 1 of 6 diets for 12 wk containing the same amount of total choline but differing in the forms of choline: 1-control low-fat (CLF, 20% fat, 100% free choline [FC]); 2-control high-fat (CHF, 50% fat, 100% FC); 3-100% PC (100PC, 50% fat, 100% egg-PC); 4-75% PC (75PC, 50% fat, 75% egg-PC+25% FC); 5-50% PC (50PC, 50% fat, 50% egg-PC+50% FC); and 6-25% PC (25PC; 50% fat, 25% egg-PC+75% FC). Intestinal permeability was measured by fluorescein isothiocyanate-dextran. Immune function was assessed by ex vivo cytokine production of splenocytes and cells isolated from the mesenteric lymph node (MLN) after stimulation with different mitogens., Results: Feeding the CHF diet increased intestinal permeability compared with the CLF diet, and doses of PC 50% or greater returned permeability to levels similar to that of the CLF diet. Feeding the CHF diet lowered splenocyte production of interleukin (IL)-1β, IL-2, IL-10, and tumor necrosis factor-alpha, and MLN production of IL-2 compared with the CLF group. The 50PC diet most consistently significantly improved cytokine levels (IL-2, IL-10, tumor necrosis factor-alpha) compared with the CHF diet., Conclusions: Our results show that a dose of 50% of total choline derived from egg-PC can ameliorate HFD-induced intestinal permeability and immune cell dysfunction., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background: Dostarlimab is an anti-programmed cell death protein-1 antibody being evaluated in recurrent/advanced solid tumors, including non-small cell lung cancer (NSCLC), in the ongoing Phase I, multi-center, open-label, 2-part (dose escalation and cohort expansion) GARNET study (NCT02715284)., Materials and Methods: Here, we report an interim analysis of patients with recurrent/advanced NSCLC who progressed following platinum-based chemotherapy. Patients received dostarlimab (500 mg IV every 3 weeks [Q3W] for Cycles 1-4, then 1000 mg Q6W) until disease progression or unacceptable toxicity for > 2 years. The primary endpoints were immune-related objective response rate (irORR) per investigator-assessed irRECIST and safety., Results: As of 8, July 2019, 67 patients with recurrent/advanced NSCLC were enrolled and treated with dostarlimab; the majority had programmed death ligand 1 (PD-L1) tumor proportion score (TPS) < 1% (35.8% of patients) or PD-L1 TPS 1%-49% (29.9% of patients); 7.5% had PD-L1 TPS ≥ 50%, and 26.9% had unknown PD-L1 TPS status. Median follow-up was 13.8 months (range: 0.0-22.6). irORR was 26.9%, including 2 complete and 16 partial responses. The median duration of response of 11.6 months (range: 2.8-19.4). Responses were observed in 2 of 24 (16.7%) patients with PD-L1 TPS < 1%, 4 of 20 (20.0%) patients with PD-L1 TPS 1%-49% and 2 of 5 (40.0%) patients with PD-L1 TPS ≥ 50%. Fatigue (4.5%) was the most common Grade ≥ 3 treatment-related treatment-emergent adverse event (TRAE). Immune-related TRAEs (any grade) were observed in 28.4% of patients., Conclusion: Dostarlimab demonstrated promising antitumor activity in advanced/recurrent NSCLC that progressed following platinum-based chemotherapy, including across all PD-L1 subgroups, and has an acceptable safety profile., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In humans, the development of gut-associated lymphoid tissue (GALT) occurs in the first years of life and can be influenced by diet., Objectives: The objective of this study was to determine the effect of dietary choline on the development of gut-associated lymphoid tissue (GALT)., Methods: Three feeding trials were conducted in female Sprague-Dawley rats. Beginning 3 d before parturition (studies 1 and 3) or at day 10 of gestation (study 2), control dams consumed a 100% free choline (FC) diet until the end of the lactation period. In studies 1 and 3, test dams consumed a high-glycerophosphocholine (HGPC) diet [75% glycerophosphocholine (GPC), 12.5% phosphatidylcholine (PC), 12.5% FC] and a 100% PC diet, respectively (both 1 g of choline/kg diet). In study 2, test dams consumed a high-sphingomyelin (SM) and PC (SMPC) diet (34% SM, 37% PC, 17% GPC, 7% FC, 5% phosphocholine) or a 50% PC diet (50% PC, 25% FC, 25% GPC), both 1.7 g of choline/kg diet. Immune cell phenotypes and ex vivo cytokine production by mitogen-stimulated immune cells were measured., Results: Feeding of the HGPC diet lowered T-cell IL-2 (44%), IFN-γ (34%), and TNF-α (55%) production in mesenteric lymph nodes (MLNs) compared with control. Feeding both SMPC and 50% PC diets during the lactation and weaning periods increased IL-2 (54%) and TNF-α (46%) production after T-cell stimulation compared with control. There was a lower production of IL-2 (46%), IL-6 (66%), and TNF-α (45%), and a higher production of IL-10 (44%) in both SMPC and 50% PC groups following ovalbumin stimulation compared with control in MLNs. Feeding a diet containing 100% PC increased the production of IFN-γ by 52% after T-cell stimulation compared with control., Conclusion: Feeding a diet containing a mixture of choline forms with a high content of lipid-soluble forms during both the lactation and weaning periods enhances ex vivo immune responses from the GALT in female Sprague-Dawley offspring., (Copyright © 2022 American Society for Nutrition.)

Background and Aims: Coronary artery disease (CAD) is the leading cause of death around the world, and its rate of presentation is increasing at young ages. Despite the evidence that secondary prevention in CAD reduces the risk of recurrent major adverse cardiovascular events (MACE), no studies have analyzed the composite control of blood pressure, lipids, and glucose control in premature CAD., Methods and Results: This was a real-world prospective cohort study of patients with premature CAD. The composite control in blood pressure <140/80 mmHg, LDL-C <70 mg/dL, non-HDL-C <100 mg/dL, and Hemoglobin A1c <8% was considered as metabolic control. The primary endpoint was the occurrence of non-fatal and fatal MACE. The data included 1042 patients with premature CAD. The mean age of the patients was 54.1 ± 8.1 years, 18.5% were women, and had a median follow-up of 59.1 ± 11.8 months. Of them, 7% had non-fatal MACE, and 4% had a fatal MACE. Overall, 21.3% achieved metabolic control, and 3.0% did not achieve any target. Cox regression analysis showed that percutaneous coronary intervention (Hazzard ratio = 1.883 [95% CI, 1.131-3.136]), C-reactive protein (1.046 [1.020-1.073]), blood pressure >140/90 mmHg (2.686 [1.506-4.791]), fibrates (2.032 [1.160-3.562]), calcium channel blockers (2.082 [1.158-3.744]) had greater risk to present a recurrent non-fatal MACE; whereas familial history of premature CAD (2.419 [1.240-4.721]), heart failure (2.139 [1.032-4.433]), LDL-C >70 mg/dL (4.594 [1.401-15.069]), and diuretics (3.328 [1.677-6.605]) were associated with cardiovascular mortality., Conclusions: The composite goal achievement in lipids, blood pressure and glucose, reduced the risk for recurrent MACE in 80%., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Studies have focused on the search of novel biomarkers that allow to easily identify dysfunctional adipose tissue (AT). Uric acid (UA) could be produced and reabsorbed by AT. It has been suggested that the increases of UA concentrations participates in AT dysfunction. We investigated the association of UA with morpho-functional adipose tissue markers in apparently healthy subjects., Methods: Forty apparently healthy individuals were included. Dietary habits and anthropometrical features were evaluated. Circulating concentrations of UA, adiponectin, leptin, and plasminogen activator inhibitor-1 (PAI-1) were quantified. Periumbilical subcutaneous AT samples were obtained and adipocyte number, adipocyte area, and macrophages content were assessed., Results: The present study included 40 healthy subjects (67% women) with an average age of 57 ± 9 y, BMI of 26 ± 4 (kg/m 2 ). UA showed a significant association with the number and mean area of adipocytes, macrophages number, adiponectin, and PAI-1. Although UA was independently associated with the number and mean area of adipocytes, macrophages number, adiponectin into the adjusted multivariable model., Conclusion: UA concentrations are associated with morpho-functional adipose tissue markers. Our results underscore the importance of UA as one earlier instigator of adipose tissue dysfunction in subjects without metabolic abnormalities., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Immune function is altered during obesity. Moreover, males and females across different species demonstrate distinct susceptibility to several diseases. However, less is known regarding the interplay between high-fat diet (HFD) and sex in the context of immune function., Objectives: The objective was to determine sex differences on immune function in response to an HFD compared with a control low-fat diet (LFD) in Wistar rats., Methods: At 5 wk of age, male and female Wistar rats were randomly assigned to 1 of 2 diets for 9 wk: ad libitum control LFD (20 kcal% fat, 53 kcal% carbohydrate, and 27 kcal% protein) or HFD (50 kcal% fat, 23 kcal% carbohydrate, and 27 kcal% protein). At 13 wk of age, rats were killed and splenocytes were isolated. Immune cell subsets were determined by flow cytometry. Immune cell function was determined by measuring the ex vivo cytokine production following stimulation with mitogens. Two-factor ANOVA was used to assess the main effect of sex, diet, and their interaction., Results: Males gained more weight than females (410 ± 46 vs. 219 ± 45 g), independently of diet (P-sex < 0.01). The HFD led to a lower production of IL-2 while increasing the production of IL-10 (both P-diet ≤ 0.05), independently of sex. HFD-fed females had increased production of cytokines (IL-2 and IL-6) after stimulation with phorbol 12-myristate 13-acetate plus ionomycin (PMA+I), as well as a higher T-helper (Th) 1:Th2 balance compared with HFD-fed males (all P < 0.05). Males fed the HFD had significantly lower production of IL-2 upon stimulation compared with all other groups., Conclusions: Female Wistar rats developed a milder obesity phenotype and maintained enhanced cytokine production compared with males fed the HFD. Sex differences modulate immune function in the context of high-fat feeding and it should be considered in research design to establish personalized health-related recommendations., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Young oncologists are at particular risk of professional burnout, and this could have a significant impact on their health and care of their patients. The coronavirus disease 2019 (COVID-19) pandemic has forced rapid changes in professionals' jobs and training, with the consequent physical and psychological effects. We aimed to characterize burnout levels and determinants in young oncologists, and the effects of the pandemic on their training and health., Methods: Two online surveys were conducted among oncology residents and young oncology specialists in Spain. The first addressed professional burnout and its determinants before the COVID-19 pandemic, while the second analyzed the impact of the pandemic on health care organization, training, and physical and psychological health in the same population., Results: In total, 243 respondents completed the first survey, and 263 the second; 25.1% reported significant levels of professional burnout. Burnout was more common among medical oncology residents (28.2%), mainly in their second year of training. It was significantly associated with a poor work-life balance, inadequate vacation time, and the burnout score. Nearly three-quarters of respondents (72%) were reassigned to COVID-19 care and 84.3% of residents missed part of their training rotations. Overall, 17.2% of this population reported that they had contracted COVID-19, 37.3% had scores indicating anxiety, and 30.4% moderate to severe depression. Almost a quarter of young oncologists (23.3%) had doubts about their medical vocation., Conclusions: Burnout affects a considerable number of young oncologists. The COVID-19 pandemic has had a profound impact on causes of burnout, making it even more necessary to periodically monitor it to define appropriate detection and prevention strategies., Competing Interests: Disclosure The authors have declared no conflict of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: To assess the efficacy and safety of a metronomic schedule of oral vinorelbine (mVNR) in advanced non-small-cell lung cancer (NSCLC) in patients unfit for platinum-based combination chemotherapy., Patients and Methods: This was a multicenter, prospective, randomized, open-label phase II study in treatment-naive patients with TNM stage IIIB/IV NSCLC. Patients received mVNR at a fixed dose of 50 mg × 3 or standard schedule 60-80 mg/m 2 weekly until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) without grade 4 toxicity (G4PFS; NCI-CTC v4). Main secondary objectives were safety, disease control rate (DCR) without grade 4 toxicity (G4DCR), DCR, PFS, overall survival (OS) and quality of life (QoL)., Results: A total of 167 patients were included, 83 and 84 patients in the mVNR and standard arms, respectively. The median G4PFS was 4.0 months [95% confidence interval (CI): 2.6-4.3] and 2.2 months (95% CI: 1.5-2.9), hazard ration (HR) = 0.63 (95% CI: 0.45-0.88), P = 0.0068 in favor of metronomic arm; G4DCR was 45.8% and 26.8% in the mVNR and standard arms, respectively. Grade 3-4 treatment-related adverse events were less frequent in the mVNR arm (25.3% versus 54.4%) mainly owing to a reduction in all grades (15.7% versus 51.9%) and grade 3-4 neutropenia (10.8% versus 42%). PFS was 4.3 (95% CI: 3.3-5.1) and 3.9 months (95% CI: 2.8-5.2) in mVNR and standard arms, respectively. No difference in median OS was observed. QoL was comparable between arms., Conclusions: Metronomic oral vinorelbine significantly prolonged median G4PFS in advanced NSCLC patients unfit for platinum combinations as first-line treatment. It was associated with a clear reduction in toxicity and may be considered as an important option in this challenging population., Competing Interests: Disclosure AC has disclosed expert testimony (Pierre Fabre), travel accommodations/expenses (Roche, Pierre Fabre). A Morabito has disclosed speaker's bureau (Pfizer, BMS, Boehringer, MSD, Roche, AstraZeneca). FG has disclosed advisory boards/consultations (Eli Lilly, Roche, Boehringer Ingelheim, AstraZeneca, Pierre Fabre, BMS, MSD, Novartis); honoraria: seminar/talks to industry (Eli Lilly, Roche, Boehringer Ingelheim, AstraZeneca, Pierre Fabre, Amgen, Celgene, BMS, MSD); research funding (AstraZeneca, BMS, MSD). RR has disclosed consulting/advisory (Roche, MSD, Pfizer, Novartis, Boehringer Ingelheim). G-LC has disclosed consulting/advisory (Pfizer, Boehringer Ingelheim, Astellas). JB-B reports grants and personal fees from Roche-Genentech, grants from Pfizer, personal fees from MSD, personal fees from BMS, personal fees from AstraZeneca, personal fees from Novartis and grants from Pierre Fabre outside the submitted work. PL is an employee of Pierre Fabre Médicament. CTTM is an employee of Pierre Fabre Médicament. SG, biostatistician, is an employee of Pierre Fabre Médicament (IRPF). DK has disclosed consultancy and advisory board: Pfizer, AstraZeneca, Roche/Genentech, BMS, MSD. T-EC reports consulting/advisory, personal fees from Astellas Pharma, Janssen, BMS, Merck Serono, Amgen, Roche, Pfizer, Boehringer Ingelheim, Servier, A-D Pharm, Lilly, AstraZeneca and Novartis; non-financial support from Pfizer, Sanofi, Boehringer Ingelheim, Merck, Servier, Ipsen, Amgen, Adpharm, AstraZeneca, Roche, BMS, Lilly, Janssen, Novartis and Astellas Pharma. All other authors declare no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This report covers the methodology for generation of stable heterohybridoma clones producing Foot-and-mouth disease virus (FMDV) reactive porcine monoclonal antibodies (mAbs). Swine received five inoculations of an inactivated O1 Manisa FMDV vaccine prior to the harvest of splenocytes. Due to the lack of a species-specific hybridoma fusion partner, the Sp2/0 murine myeloma cell line was utilized for the formation of porcine-murine heterohybridoma clones. Twenty-nine FMDV-reactive parental clones were generated. Following sub-cloning and monitoring of reactivity over 20 serial passages, eleven subclones derived from unique parental origins were characterized and are reported herein. This methodology demonstrated the production of porcine mAbs by fusion of porcine splenocytes from immunized pigs with murine myeloma cells to generate heterohybridomas. The porcine immune response may differ from the murine immune response in relation to recognized epitopes. Therefore, application of this methodology may provide valuable resources for swine immunology and enhance the understanding of the mechanisms for antibody based protection from diseases in swine., (Copyright © 2020. Published by Elsevier B.V.)

Background: Brain metastases are frequent complications in patients with non-small-cell lung cancer (NSCLC) associated with significant morbidity and poor prognosis. Our goal is to give a global overlook on clinical efficacy from immune checkpoint inhibitors in this setting and to review the role of biomarkers and molecular interactions in brain metastases from patients with NSCLC., Methods: We reviewed clinical trials reporting clinical outcomes of patients with NSCLC with brain metastases as well as publications assessing the tumor microenvironment and the complex molecular interactions of tumor cells with immune and resident cells in brain metastases from NSCLC biopsies or preclinical models., Results: Although limited data are available on immunotherapy in patients with brain metastases, immune checkpoint inhibitors alone or in combination with chemotherapy have shown promising intracranial efficacy and safety results. The underlying mechanism of action of immune checkpoint inhibitors in the brain niche and their influence on tumor microenvironment are still not known. Lower PD-L1 expression and less T CD8 + infiltration were found in brain metastases compared with matched NSCLC primary tumors, suggesting an immunosuppressive microenvironment in the brain. Reactive astrocytes and tumor associated macrophages are paramount in NSCLC brain metastases and play a role in promoting tumor progression and immune evasion., Conclusions: Discordances in the immune profile between primary tumours and brain metastases underscore differences in the tumour microenvironment and immune system interactions within the lung and brain niche. The characterization of immune phenotype of brain metastases and dissecting the interplay among immune cells and resident stromal cells along with cancer cells is crucial to unravel effective immunotherapeutic approaches in patients with NSCLC and brain metastases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. E. Nadal has received honoraria for participating in advisory boards from Bristol Myers Squibb, Merck Sharpe & Dohme, Lilly, Roche, Pfizer, Takeda, Boehringer Ingelheim and AstraZeneca. E. Nadal has received research funding from Roche and Pfizer.J. Bosch-Barrera serves on advisory boards and/or accepted honoraria for giving lectures from Bristol Myers-Squibb (BMS), Roche, Merck Sharp & Dohme (MSD), AstraZeneca, Novartis and Boehringer-Ingelheim. J. Bosch-Barrera has also received grants for research from Pfizer and Roche. All remaining authors have declared no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Biological differences between the sexes have a major impact on disease and treatment outcome. In this paper, we evaluate the prognostic value of sex in stage IV non-small-cell lung cancer (NSCLC) in the context of routine clinical data, and compare this information with other external datasets., Methods: Clinical data from stage IV NSCLC patients from Hospital Puerta de Hierro (HPH) were retrieved from electronic health records using big data analytics (N = 397). In addition, data from the Spanish Lung Cancer Group (GECP) Tumor Registry (N = 1382) and from a published study available from the cBioPortal (MSK) (N = 601) were analyzed. Survival curves were estimated using the Kaplan-Meier method. A Cox proportional hazards regression model was used to assess the prognostic value of sex. A meta-analysis to compare the outcome for males and females in terms of overall survival (OS) and progression free survival (PFS) was performed., Results: The median OS time was 12 months for males and 19 months for females (overall HR = 0.77; 95% CI: 0.68-0.87; P < 0.001). Similarly, females with stage IV NSCLC harboring an EGFR-sensitizing mutation lived significantly longer than males (median OS: males, 19 months; females, 32 months) with a lower risk of death compared with males (overall HR = 0.75; 95% CI: 0.67-0.84). In addition, female patients benefited more from EGFR inhibitors in terms of PFS and OS (overall HR = 0.45; 95% CI: 0.32-0.64, and HR = 0.62; 95% CI: 0.48-0.80, respectively). Median PFS was 21 months in females and 12 months in males (P < 0.001)., Conclusions: Using routine clinical data we confirmed the previous finding that among stage IV NSCLC patients, females had a significantly better prognosis than males. The effect size of the sex was notable, highlighting the fact that survival rates are usually estimated and patients are generally managed without considering the sexes separately, which may lead to suboptimal results., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Buttermilk contains a mixture of choline forms; it is high in phosphatidylcholine (PC) and sphingomyelin (SM), which could have an impact on immune system development and function., Objectives: We aimed to determine the effect of feeding buttermilk-derived choline forms during pregnancy and lactation on maternal immune function., Methods: Sprague Dawley dams (n = 8 per diet) were randomly assigned midway through pregnancy (10 d of gestation) to 1 of 3 experimental diets, containing 1.7 g/kg choline: control [100% free choline (FC)]; buttermilk [37% PC, 34% SM, 17% glycerophosphocholine (GPC), 7% FC, 5% phosphocholine]; or placebo (50% PC, 25% FC, 25% GPC). Dams consumed the same diet until the end of the lactation period (21 d after parturition). Cell phenotypes and cytokine production by mitogen-stimulated splenocytes were measured and compared using 1-factor ANOVA test in order to asses the effect of diet on immune fuction of lactating dams (main outcome)., Results: After ConA stimulation, splenocytes from dams in the buttermilk group produced more IL-2 (30%), TNF-α (30%), and IFN-γ (42%) compared with both the placebo and control diets. Placebo-fed dams had a higher proportion of CD8+ cells expressing CD152+ (22%) in spleen, and splenocytes from dams that were fed the buttermilk and the placebo diets produced about 50% and 53% more IL-10 after LPS and OVA stimulation, respectively, compared with the control group., Conclusions: Feeding buttermilk-derived choline forms during pregnancy and lactation had a beneficial impact on the immune system of Sprague Dawley rat dams, especially on T-cell function., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Injury to the skin from severe burns can cause debilitating physical and psychosocial distress to the patients. Upon healing, deep dermal burns often result in devastating hypertrophic scar formation. For many decades, stem cell-based therapies have shown significant potential in improving wound healing. However, current cell delivery methods are often insufficient to maintain cell viability in a harmful burn wound environment to promote skin regeneration. In this study, we developed an enhanced approach to deliver adipose-derived stem cells (ASCs) for the treatment of burn wounds, using an in-situ-formed hydrogel system comprised of a hyperbranched poly(ethylene glycol) diacrylate (HB-PEGDA) polymer, a commercially available thiol-functionalized hyaluronic acid (HA-SH) and a short RGD peptide. Stable hydrogels with tunable swelling and mechanical properties form within five minutes under physiological conditions via the Michael-type addition reaction. Combining with RGD peptide, as a cell adhesion motif, significantly alters the cellular morphology, enhances cell proliferation, and increases the paracrine activity of angiogenesis and tissue remodeling growth factors and cytokines. Bioluminescence imaging of luciferase + ASCs indicated that the hydrogel protected the implanted cells from the harmful wound environment in burns. Hydrogel-ASC treatment significantly enhanced neovascularization, accelerated wound closure and reduced the scar formation. Our findings suggest that PEG-HA-RGD-based hydrogel provides an effective niche capable of augmenting the regenerative potential of ASCs and promoting burn wound healing. STATEMENT OF SIGNIFICANCE: Burn injury is one of the most devastating injures, and patients suffer from many complications and post-burn scar formation despite modern therapies. Here, we designed a conformable hydrogel-based stem cell delivery platform that allows rapid in-situ gelation upon contact with wounds. Adipose-derived stem cells were encapsulated into a PEG-HA-RGD hydrogels. Introducing of RGD motif significantly improved the cellular morphology, proliferation, and secretion of angiogenesis and remodeling cytokines. A deep second-degree burn murine model was utilized to evaluate in-vivo cell retention and therapeutic effect of the hydrogel-ASC-based therapy on burn wound healing. Our hydrogel remarkably improved ASCs viability in burn wounds and the hydrogel-ASC treatment enhanced the neovascularization, promoted wound closure, and reduced scar formation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Detection of ALK and ROS1 gene rearrangements in non-small-cell lung cancer is required for directing patient care. Although fluorescence in situ hybridization (FISH) and immunohistochemistry have been established as gold standard methods, next-generation sequencing (NGS) platforms are called to be at least equally successful. Comparison of these methods for translation into daily use is currently under investigation., Patients and Methods: Forty non-small-cell lung cancer paraffin-embedded samples with previous ALK (n = 33) and ROS1 (n = 7) FISH results were examined with the Oncomine Focus Assay and tested for ALK and ROS1 immunoreactivity. Clinical implications of concurrent molecular alterations and concordance between methods were evaluated., Results: NGS was successful in 32 (80%) cases: 25 ALK and 7 ROS1. Few concomitant alterations were detected: 1 ALK rearranged case had an ALK p.L1196M-resistant mutation, 4 had CDK4, MYC, and/or ALK amplifications, and 1 ROS1 rearranged case showed a FGFR4 amplification. Comparison between techniques revealed 5 (16%) discordant cases that had lower progression-free survival than concordant cases: 7.6 (95% confidence interval, 2.2-13) versus 19.4 (95% confidence interval, 10.1-28.6). Remarkably, 4 of these cases had isolated 3' signal FISH pattern (P = .026)., Conclusion: Our data support that the identification of 3' isolated signal FISH pattern in ALK and ROS1 cases might suggest a false-positive result. NGS seems a reliable technique to assess ALK and ROS1 rearrangements, offering the advantage over immunohistochemistry of detecting other molecular alterations with potential therapeutic implications., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cats are definitive hosts and reservoirs for several parasites, some of which are responsible for serious zoonotic diseases. We conducted a case-control study of data from a trap-neuter-return (TNR) programme (years 2014-2017) designed to examine the prevalence of zoonotic parasites in free-roaming cats living in urban areas of central Spain. In the animal population tested (n = 263), we detected a 29.2% prevalence of endoparasites, including high rates of cestodes (12.9%) and Toxocara cati (11.7%). While faecal samples showed no Toxoplasma gondii oocysts, the seroprevalence of T. gondii infection was 24.2%. Antibodies to Leishmania infantum were detected in 4.8% of the animals, though all skin and blood samples analyzed were PCR negative for this parasite. Ectoparasites (ticks and fleas) were found in 4.6% of the cat population, and 10.6% of the cats were detected with Otodectes cynotis. Finally, 6.3% and 7.9% cats tested positive for feline leukaemia virus and feline immunodeficiency virus, respectively. Our study provides useful information for animal-welfare and public-health, as the parasites detected can affect native wild animals through predation, competition and disease transmission. Our detection of zoonotic parasites such as L. infantum, T. gondii, T. cati, Giardia duodenalis and several ectoparasites prompts an urgent need for health control measures in stray cats., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Signal transducer and activator of transcription 3 (STAT3) has a prominent role in mediating resistance to conventional chemo-/radio-therapies and modern targeted drugs. While a number of STAT3 inhibitors have been shown to enhance the efficacy of therapeutic agents in vitro, the majority of them have yet to enter clinical evaluation mostly because of lack of efficacy issues. Silibinin is the main component of the silymarin complex, a standardized extract obtained from the seeds of the milk thistle herb Silybum marianum. This review summarizes current evidence supporting the ability of silibinin to function as a natural down-modulator of STAT3 activity. We examine the reported capacity of silibinin to reduce the toxicity of cancer treatments and to reverse tumor cell resistance via STAT3 inhibition. We also briefly review our clinical data in cancer patients treated with oral nutraceutical products containing silibinin. The beneficial effects of silibinin might accelerate the design of strategies aimed to overcome and prevent the emergence of STAT3-mediated cancer drug resistance in clinical settings., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: There is a widening range of antidiabetic medications available; however changes in consumption patterns remain poorly documented. The aim of this study is to analyze the evolution of consumption of antidiabetic medications during the period 2001-2014 in an Andalusian region., Methods: All antidiabetic medicines on the market were selected for analysis. Consumption data were obtained for the 15-year period and were expressed in defined daily doses (DDD) per 1000 inhabitants per day (DHD)., Results: During the study period consumption of insulins grew only a 2.2%, from 17.9 DHD to 18.3 DHD, while oral agents increased a 27.6%, from 41.3 DHD to 52.7 DHD. Consumption of sulfonylureas was gradually reduced from 30.1 DHD to 16.4 DHD but metformin (alone) usage increased from 4.3 DHD to 23.7 DHD, and was the most consumed agent in 2014. A rise in consumption of dipeptidyl peptidase-4 inhibitors and "other hypoglycemic agents" was also noticed. Overall expenditure in antidiabetic medications increased notably from 4.5 in 2001 to 14.4 million euros in 2014., Conclusion: We highlight the market uptake of antidiabetic drugs commercialized during the last decade; despite further exploration is needed to clarify the cost-benefit ratio of these new antidiabetic medicines., (Copyright © 2017 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Background: Clopidogrel has provided beneficial effects in acute coronary syndrome and percutaneous coronary intervention. Different polymorphisms have been associated with differences in clopidogrel response. The aim of this study was to check if CYP2C19/ABCB1-genotype-guided strategy reduces the rates of cardiovascular events and bleeding., Methods: This experimental study included patients undergoing percutaneous coronary intervention with stent. The prospective genotype-guided strategy (intervention group) was compared against a retrospective non-tailored strategy (control group). Primary efficacy endpoint was the composite of cardiovascular death, acute coronary syndrome or stroke during 12months after intervention. Secondary endpoint was to compare the efficacy of the different antiplatelet therapies used in genotyping conditions., Results: The study included 719 patients undergone stent, more than 86% with acute coronary syndrome. The primary endpoint occurred in 32 patients (10.1%) in the genotyping group and in 59 patients (14.1%) in the control group (HR 0.63, 95% CI (0.41-0.97), p =0.037). There was no difference in The Thrombolysis in Myocardial Infarction major and minor bleeding criteria between the two groups (4.1% vs. 4.7%, HR=0.80, 95% CI (0.39-1.63), p=0.55). In intervention group, there was no difference in the rate of events in patients treated with clopidogrel versus patients treated with other antiplatelet treatments (9.1% vs 11.5% p=0.44), or bleeding (3.7% vs 4.6%, p=0.69)., Conclusions: The genotype-guided strategy could reduce the rates of composite of cardiovascular events and bleeding during 12months after percutaneous coronary intervention compared to a non-genotype-guide strategy., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

(210)Pb is a radioactive lead isotope present in the environment as member of the (238)U decay chain. Since it is a relatively long-lived radionuclide (T1/2 = 22.2 years), its analysis is of interest in radiation protection and the geochronology of sediments and artwork. Here, we present a method for analysing (210)Pb using plastic scintillation resins (PSresins) packaged in solid-phase extraction columns (SPE cartridge). The advantages of this method are its selectivity, the low limit of detection, as well as reductions in the amount of time and reagents required for analysis and the quantity of waste generated. The PSresins used in this study were composed of a selective extractant (4',4″(5″)-Di-tert-butyldicyclohexano-18-crown-6 in 1-octanol) covering the surface of plastic scintillation microspheres. Once the amount of extractant (1:1/4) and medium of separation (2 M HNO3) were optimised, PSresins in SPE cartridges were calibrated with a standard solution of (210)Pb. (210)Pb could be fully separated from its daughters, (210)Bi and (210)Po, with a recovery value of 91(3)% and detection efficiency of 44(3)%. Three spiked water samples (one underground and two river water samples) were analysed in triplicates with deviations lower than 10%, demonstrating the validity of the PS resin method for (210)Pb analysis., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Technetium is a synthetic element with no stable isotopes, produced as waste in nuclear power plants and in cyclotrons used for nuclear medicine. The element has high mobility, in the form of TcO4(-); its determination is therefore important for environmental protection. Technetium is found in low concentrations and therefore common methods for its analysis include long treatments in several steps and require large amounts of reagents for its purification and preconcentration. Plastic scintillation resins (PSresin) are novel materials used to separate, preconcentrate and measure radionuclides in a single step. The objective of this study is to prepare and characterise a PSresin for the preconcentration and measurement of (99)Tc. The study first evaluates the reproducibility of the production of PSresins between batches and over time; showing good reproducibility and storage stability. Next, we studied the effect of some common non-radioactive interferences, showing small influences on measurement, and radioactive interferences ((36)Cl and (238)U/(234)U). (36)Cl can be removed by a simple treatment with 0.5 M HCl and (238)U/(234)U can be removed from the column by cleaning with a mixture of 0.1 M HNO3 and 0.1 M HF. In the latter case, a slight change in the morphology of the PSresin caused an increase in detection efficiency. Finally, the PSresin was applied to the measurement of real spiked samples (sea water and urine) with deviations lower than 10% in all cases., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many different types of cancer and plays a pivotal role in tumor growth and metastasis. Retrospective studies have established that STAT3 expression or phospho-STAT3 (pSTAT3 or activated STAT3) are poor prognostic markers for breast, colon, prostate and non-small cell lung cancer. Silibinin or silybin is a natural polyphenolic flavonoid which is present in seed extracts of milk thistle (Silybum marianum). Silibinin has been shown to inhibit multiple cancer cell signaling pathways in preclinical models, demonstrating promising anticancer effects in vitro and in vivo. This review summarizes evidence suggesting that silibinin can inhibit pSTAT3 in preclinical cancer models. We also discuss current strategies to overcome the limitations of oral administration of silibinin to cancer patients to translate the bench results to the bed side. Finally, we review the ongoing clinical trials exploring the role of silibinin in cancer., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: Patients with non-small cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) rearrangement selectively respond to ALK inhibitors. Thus, identification of ALK rearrangements has become a standard diagnostic test in advanced NSCLC patients. Our institution has been a referral center in Spain for ALK determination by Fluorescent in situ hybridization (FISH). The aim of our study was to assess the feasibility and the FISH patterns of the ALK gene and to evaluate the clinical and pathological features of patients with ALK alterations., Methods: Between 2010 and 2014, 1092 samples were evaluated for ALK using FISH technique (927 histological samples, 165 cytological samples). Correlation with available clinical-pathological information was assessed., Results: ALK rearrangement was found in 35 patients (3.2%). Cytological samples (using either direct smears or cell blocks), were more frequently non-assessable than histological samples (69% versus 89%, respectively) (p < 0.001). Within the ALK-rearranged cases the majority were female, non-smokers, and stage IV., Conclusions: Although assessable in cytological samples, biopsies are preferred when available for ALK evaluation by FISH. The ALK translocation prevalence and the associated clinico-pathological features in Spanish NSCLC patients are similar to those previously reported.

Background: In a Spanish Lung Cancer Group (SLCG) phase II trial, the combination of BRCA1 and receptor-associated protein 80 (RAP80) expression was significantly associated with outcome in Caucasian patients with nonsmall-cell lung cancer (NSCLC). The SLCG therefore undertook an industry-independent collaborative randomized phase III trial comparing nonselected cisplatin-based chemotherapy with therapy customized according to BRCA1/RAP80 expression. An analogous randomized phase II trial was carried out in China under the auspices of the SLCG to evaluate the effect of BRCA1/RAP80 expression in Asian patients., Patients and Methods: Eligibility criteria included stage IIIB-IV NSCLC and sufficient tumor specimen for molecular analysis. Randomization to the control or experimental arm was 1 : 1 in the SLCG trial and 1 : 3 in the Chinese trial. In both trials, patients in the control arm received docetaxel/cisplatin; in the experimental arm, patients with low RAP80 expression received gemcitabine/cisplatin, those with intermediate/high RAP80 expression and low/intermediate BRCA1 expression received docetaxel/cisplatin, and those with intermediate/high RAP80 expression and high BRCA1 expression received docetaxel alone. The primary end point was progression-free survival (PFS)., Results: Two hundred and seventy-nine patients in the SLCG trial and 124 in the Chinese trial were assessable for PFS. PFS in the control and experimental arms in the SLCG trial was 5.49 and 4.38 months, respectively [log rank P = 0.07; hazard ratio (HR) 1.28; P = 0.03]. In the Chinese trial, PFS was 4.74 and 3.78 months, respectively (log rank P = 0.82; HR 0.95; P = 0.82)., Conclusion: Accrual was prematurely closed on the SLCG trial due to the absence of clinical benefit in the experimental over the control arm. However, the BREC studies provide proof of concept that an international, nonindustry, biomarker-directed trial is feasible. Thanks to the groundwork laid by these studies, we expect that ongoing further research on alternative biomarkers to elucidate DNA repair mechanisms will help define novel therapeutic approaches., Trial Registration: NCT00617656/GECP-BREC and ChiCTR-TRC-12001860/BREC-CHINA., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Patterns have been widely used in Computer Science. A pattern describes a generic solution to an existing problem in a more readable and accessible form. A pattern-oriented process specification consists of a generic and abstract description of a process. This paper presents a pattern-oriented specification of a genetic regulatory network inference process performed from microarray data and prior biological knowledge. The proposed specification was conceived based on prior work on gene inference networks. The adequacy of the proposed solution was then evaluated with respect to modern tendencies of the genes network inference literature., (© 2013 Elsevier Ltd. All rights reserved.)

A potential new Ni-free Ti alloy for biomedical applications was assessed in order to investigate the superelastic behavior, corrosion resistance and the biocompatibility. The alloy studied was Ti19.1Nb8.8Zr. The chemical composition was determined by X-ray microanalysis, the thermoelastic martensitic transformation was characterized by high sensitivity calorimeter. The critical stresses were determined by electromechanical testing machine and the corrosion behavior was analyzed by potentiostatic equipment in artificial saliva immersion at 37°C. The results were compared with six different NiTi orthodontic archwire brands. The biocompatibility was studied by means of cultures of MG63 cells. Ni-free Ti alloy exhibits thermoelastic martensitic transformation with Ms=45°C. The phase present at 37°C was austenite which under stress can induce martensite. The stress-strain curves show a superelastic effect with physiological critical stress (low and continuous) and a minimal lost of the recovery around 150 mechanical cycles. The corrosion resistance improves the values obtained by different NiTi alloys avoiding the problem of the Ni adverse reactions caused by Ni ion release. Cell culture results showed that adhered cell number in new substrate was comparable to that obtained in a commercially pure Ti grade II or beta-titanium alloy evaluated in the same conditions. Consequently, the new alloy presents an excellent in-vitro response., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Metastatic non-small-cell lung cancer is generally not considered to be curable, and the overall 5-year survival rate is less than 1%. Despite this poor prognosis, palliative chemotherapy can increase time and quality of life in the advanced-disease setting. New chemotherapy treatments and targeted therapies are available for this stage of disease, but their high costs are an important issue. In this perspective article, we discuss the hospital costs of antitumor drug administration and the ethical principles involved, the roles of drug agencies and oncologists, and relevant current research on these topics. These considerations have been examined from the perspective of a national public healthcare system., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Interactions between extracellular matrix proteins and prostate carcinoma cells change dramatically during prostate tumor progression. We have concentrated on two key modifications that occur in the hemidesmosome in prostate carcinoma: loss of laminin-5 protein expression and altered basal cell polarity of the alpha6beta4 integrin. We previously demonstrated two cell line-specific isoforms (beta3A and beta3B) of the LAMB3 message. Cells expressing only the beta3B isoform did not translate the beta3 protein and were unable to assemble the laminin-5 trimer. One such cell line, LNCaP, was selected to determine whether restoration of the laminin-5 beta3A isoform would cause expression of a functional laminin-5 beta3 chain, assembly and secretion of the laminin-5 trimer, and reversion to a non-neoplastic phenotype. Laminin-5 beta3A cDNA was cloned and stably transfected into LNCaP cells. We observed the restoration of the beta3 protein, but a laminin-5 trimer was not secreted. Moreover, increased cell migration was demonstrated, and tumorigenicity was increased in SCID mice. A microarray analysis, performed between transfected and nontransfected LNCaP cells, showed most changing genes to be associated with signal transduction. The beta3 chain of laminin-5 may thus play an important role in signal transduction, which may enhance cell motility and tumorigenesis.

This paper describes a data mining environment for knowledge discovery in bioinformatics applications. The system has a generic kernel that implements the mining functions to be applied to input primary databases, with a warehouse architecture, of biomedical information. Both supervised and unsupervised classification can be implemented within the kernel and applied to data extracted from the primary database, with the results being suitably stored in a complex object database for knowledge discovery. The kernel also includes a specific high-performance library that allows designing and applying the mining functions in parallel machines. The experimental results obtained by the application of the kernel functions are reported., (Copyright 2003 Elsevier Ltd.)

To visualize the accumulation of chromosome abnormalities in head and neck squamous cell carcinomas (HNSCC) and investigate the extension of the abnormal field, we applied the fluorescence in situ hybridization (FISH) technique to tumor cells and cells collected from a large extension of clinically normal buccal mucosa distant from the tumor in 10 patients. DNA probes specific for 14 human chromosomes (1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 15, 17, X, and Y) were used in dual-target, dual-color FISH assays. Control specimens were collected from oral mucosa of 10 healthy non-smokers, in order to define the tolerance limits for abnormalities, and from 10 healthy smokers. Extensive aneuploidy was detected in most of tumor specimens, more frequently represented by chromosome gains than losses. Interestingly, the clinically normal distant oral regions displayed chromosomal aneuploidies in seven out of the 10 patients tested. These findings support the occurrence of field cancerization in HNSCC. In addition, interphase FISH is demonstrated as an effective technique for detecting chromosome aneuploidy associated with malignancy and a potential tool for non-invasive screening of individuals at high-risk for HNSCC., (Copyright 1999 Elsevier Science B.V.)

Quercitol, five saponins and 3-O-(6'-O-palmitoyl) beta-D-glucopyranosyl stigmasterol were isolated from the stem bark of Myrisine pellucida. These compounds are described for the first time in this plant and their structures were determined using a combination of 1H and 13C NMR, and mass spectroscopy. The two saponins are new compounds, 3-O-(alpha-L-rhamnopyranosyl (1-->2) beta-D-glucopyranosyl (1-->4) alpha-L-arabinopyranosyl) cyclamiretin A and 3-O-(beta-D-xylopyranosyl) (1-->2) beta-D-glucopyranosyl (1-->4) [beta-D-glucopyranosyl (1-->2)] alpha-L-arabinopyranosyl) cyclamiretin D.

The causes of liver disease, ranging from fatty changes to cirrhosis and hepatocellular carcinoma, in porphyria cutanea tarda (PCT) remain unclear. We tested 100 consecutive PCT patients for antibodies to hepatitis C virus (HCV) by enzyme-linked immunosorbent assay and a recombinant immunoblot assay. 75 (79%) patients with sporadic PCT but none of 5 with familial PCT were positive. HCV RNA was found in serum of all 18 anti-HCV-positive patients tested. There were no significant differences in the prevalence of anti-HCV between treated and untreated patients or between those with and without various HCV risk factors. The frequency of anti-HCV increased with the severity of liver histology. These findings implicate HCV in the aetiology of PCT-associated liver disease.

To assess the risk to hospital personnel of acquiring an hepatitis C virus (HCV) infection as a result of occupational exposure to needle-stick injuries, 81 employees who had parenteral exposure to an anti-HCV-positive source were followed for 12 months. None developed hepatitis and anti-HCV testing by a second-generation ELISA system of serum samples collected on the day of exposure and at 3, 6 and 12 months was negative. Consequently, a low efficacy of needle-stick injuries in the transmission of HCV in hospital personnel may be suggested.