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Membrane trafficking within the Golgi apparatus plays a pivotal role in the intracellular transportation of lipids and proteins. Dysregulation of this process can give rise to various pathological manifestations, including cancer. Exploiting Golgi defects, cancer cells capitalise on aberrant membrane trafficking to facilitate signal transduction, proliferation, invasion, immune modulation, angiogenesis, and metastasis. Despite the identification of several molecular signalling pathways associated with Golgi abnormalities, there remains a lack of approved drugs specifically targeting cancer cells through the manipulation of the Golgi apparatus. In the initial section of this comprehensive review, the focus is directed towards delineating the abnormal Golgi genes and proteins implicated in carcinogenesis. Subsequently, a thorough examination is conducted on the impact of these variations on Golgi function, encompassing aspects such as vesicular trafficking, glycosylation, autophagy, oxidative mechanisms, and pH alterations. Lastly, the review provides a current update on promising Golgi apparatus-targeted inhibitors undergoing preclinical and/or clinical trials, offering insights into their potential as therapeutic interventions. Significantly more effort is required to advance these potential inhibitors to benefit patients in clinical settings., Competing Interests: Declaration of competing interest The authors declare no competing financial interest and personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: The cardiac surgery-related ischemia-reperfusion-related oxidative stress triggers the release of cytotoxic reactive oxygen and nitrogen species, contributing to organ failure and ultimately influencing patients' short- and long-term outcomes. Selenium is an essential co-factor for various antioxidant enzymes, thereby contributing to the patients' endogenous antioxidant and anti-inflammatory defense mechanisms. Given these selenium's pleiotropic functions, we investigated the effect of a high-dose selenium-based anti-inflammatory perioperative strategy on functional recovery after cardiac surgery., Materials and Methods: This prospective study constituted a nested sub-study of the SUSTAIN CSX trial, a double-blinded, randomized, placebo-controlled multicenter trial to investigate the impact of high-dose selenium supplementation on high-risk cardiac surgery patients' postoperative recovery. Functional recovery was assessed by 6-min walk distance, Short Form-36 (SF-36) and Barthel Index questionnaires., Key Findings: 174 patients were included in this sub-study. The mean age (SD) was 67.3 (8.9) years, and 78.7 % of the patients were male. The mean (SD) predicted 30-day mortality by the European System for Cardiac Operative Risk Evaluation II score was 12.6 % (9.4 %). There was no difference at hospital discharge and after three months in the 6-min walk distance between the selenium and placebo groups (131 m [IQR: not performed - 269] vs. 160 m [IQR: not performed - 252], p = 0.80 and 400 m [IQR: 299-461] vs. 375 m [IQR: 65-441], p = 0.48). The SF-36 and Barthel Index assessments also revealed no clinically meaningful differences between the selenium and placebo groups., Significance: A perioperative anti-inflammatory strategy with high-dose selenium supplementation did not improve functional recovery in high-risk cardiac surgery patients., Competing Interests: Declaration of competing interest Dr. Ott received institutional research and study funds from Novartis Pharma GmbH and institutional research, study and educational grants, speaker fees and advisory board fees from Abiomed. Dr. Stoppe reported grants and nonfinancial support from Biosyn Arzneimittel Gmbh and grants from Hecht Foundation during the conduct of the study and consultant fees from B. Braun, Baxter, and Fresenius Kabi and speaker fees from Biosyn Arzneimittel Gmbh outside the submitted work. Dr. Fremes was a site investigator of the SUSTAIN study and received fees for per-patient enrollment to their institution during the conduct of the study; received grants from Medtronic and Boston Scientific as a site co-investigator for SURTAVI and Low Risk trials and received fees for per-patient enrollment to their institution; received grants from Boston Scientific as a site co–principal investigator for the NeoAccurate IDE trial and received fees for per-patient enrollment to their institution; and received grants from the Canadian Institutes of Health Research as the nominated principal investigator of the ROMA trial outside the submitted work. Dr. Heyland reported nonfinancial support from Biosyn Arzneimittel Gmbh during the conduct of the study. No other disclosures were reported. Dr. O'Brien received research funding from the British Heart Foundation and the National Institute for Health Science Research and funding for work as a consultant for Teleflex. The other authors declare no conflicts of interest related to this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Preexisting malnutrition in critically ill patients is associated with adverse clinical outcomes. Malnutrition can be diagnosed with the Global Leadership Initiative on Malnutrition using parameters such as weight loss, muscle wasting, and BMI. International critical care nutrition guidelines recommend high protein treatment to improve clinical outcomes in critically ill patients diagnosed with preexisting malnutrition. However, this recommendation is based on expert opinion., Research Question: In critically ill patients, what is the association between preexisting malnutrition and time to discharge alive (TTDA), and does high protein treatment modify this association?, Study Design and Methods: This multicenter randomized controlled trial involving 16 countries was designed to investigate the effects of high vs usual protein treatment in 1,301 critically ill patients. The primary outcome was TTDA. Multivariable regression was used to identify if preexisting malnutrition was associated with TTDA and if protein delivery modified their association., Results: The prevalence of preexisting malnutrition was 43.8%, and the cumulative incidence of live hospital discharge by day 60 was 41.2% vs 52.9% in the groups with and without preexisting malnutrition, respectively. The average protein delivery in the high vs usual treatment groups was 1.6 g/kg per day vs 0.9 g/kg per day. Preexisting malnutrition was independently associated with slower TTDA (adjusted hazard ratio, 0.81; 95% CI, 0.67-0.98). However, high protein treatment in patients with and without preexisting malnutrition was not associated with TTDA (adjusted hazard ratios of 0.84 [95% CI, 0.63-1.11] and 0.97 [95% CI, 0.77-1.21]). Furthermore, no effect modification was observed (ratio of adjusted hazard ratio, 0.84; 95% CI, 0.58-1.20)., Interpretation: Malnutrition was associated with slower TTDA, but high protein treatment did not modify the association. These findings challenge current international critical care nutrition guidelines., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT03160547; URL: www., Clinicaltrials: gov., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: D. B. received funding from Baxter Healthcare (advisory board and speaker fees), Avanos (advisor board fees), and Cardinal Health (speaker fees). None declared (C. C. H. L., Z.-Y. L., A. G. D., X. J., G. L. J., P. Y. N., L. T., A. P., D. K. H., C. C.)., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: On the basis of low-quality evidence, international critical care nutrition guidelines recommend a wide range of protein doses. The effect of delivering high-dose protein during critical illness is unknown. We aimed to test the hypothesis that a higher dose of protein provided to critically ill patients would improve their clinical outcomes., Methods: This international, investigator-initiated, pragmatic, registry-based, single-blinded, randomised trial was undertaken in 85 intensive care units (ICUs) across 16 countries. We enrolled nutritionally high-risk adults (≥18 years) undergoing mechanical ventilation to compare prescribing high-dose protein (≥2·2 g/kg per day) with usual dose protein (≤1·2 g/kg per day) started within 96 h of ICU admission and continued for up to 28 days or death or transition to oral feeding. Participants were randomly allocated (1:1) to high-dose protein or usual dose protein, stratified by site. As site personnel were involved in both prescribing and delivering protein dose, it was not possible to blind clinicians, but patients were not made aware of the treatment assignment. The primary efficacy outcome was time-to-discharge-alive from hospital up to 60 days after ICU admission and the secondary outcome was 60-day morality. Patients were analysed in the group to which they were randomly assigned regardless of study compliance, although patients who dropped out of the study before receiving the study intervention were excluded. This study is registered with ClinicalTrials.gov, NCT03160547., Findings: Between Jan 17, 2018, and Dec 3, 2021, 1329 patients were randomised and 1301 (97·9%) were included in the analysis (645 in the high-dose protein group and 656 in usual dose group). By 60 days after randomisation, the cumulative incidence of alive hospital discharge was 46·1% (95 CI 42·0%-50·1%) in the high-dose compared with 50·2% (46·0%-54·3%) in the usual dose protein group (hazard ratio 0·91, 95% CI 0·77-1·07; p=0·27). The 60-day mortality rate was 34·6% (222 of 642) in the high dose protein group compared with 32·1% (208 of 648) in the usual dose protein group (relative risk 1·08, 95% CI 0·92-1·26). There appeared to be a subgroup effect with higher protein provision being particularly harmful in patients with acute kidney injury and higher organ failure scores at baseline., Interpretation: Delivery of higher doses of protein to mechanically ventilated critically ill patients did not improve the time-to-discharge-alive from hospital and might have worsened outcomes for patients with acute kidney injury and high organ failure scores., Funding: None., Competing Interests: Declaration of interests The UK sites received support in the form of protein supplement supply from Nutrinovo (prosource tube feed [TF]) and Stanningly Pharma (Renapro Shot), and CA$20 000 from Nutricia to cover insurance and project management costs locally. Those that provided financial and product support for the trial had no role in designing the protocol, conducting the trial, or analysing the data, and did not have access to the data nor influence the content of the publication. We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Mammographic breast density (MBD) is a known risk factor for breast cancer and older women have higher incidence rates of breast cancer occurrence. The Breast Imaging Reporting and Data System (BI-RADS) is a commonly used MBD classification tool for mammogram reporting. However, they have limitations since there are reading inconsistencies between different radiologists with the visual assessment of breast density., Methods: Digitised film-screen mammographic images were extracted from the Digital Database for Screening Mammography (DDSM). A machine learning project was developed using commercially available software with several predictive models applied to classify different amount of MBD on mammograms into different density groups. The effectiveness of different predictive models used in classifying the mammograms were tested by receiver operator characteristics (ROC) curve with comparison to the gold standard of BI-RADS classification., Results: Three predictive models, Decision Tree (Tree), Support Vector Model (SVM) and k-Nearest Neighbour (kNN) showed high AUC values of 0.801, 0.805 and 0.810 respectively. High AUC values for the three predictive models indicates that the accuracy of the model is approaching that of the BI-RADS method., Discussion: Our machine learning project showed to have capabilities to be potentially used in the clinical settings to help categorise mammograms into extremely dense breasts (BI-RADS Group A) from entirely fatty breasts (BI-RADS Group D)., Conclusion: Findings from the present study suggest that the machine learning method is potentially useful to quantify the amount of MBD in mammograms., (Copyright © 2021. Published by Elsevier Inc.)

Dysregulation of glycosylation pathways has been well documented in several types of cancer, where it often participates in cancer development and progression, especially cancer metastasis. Hence, inhibition of glycosidases such as mannosidases can disrupt the biosynthesis of glycans on cell surface glycoproteins and modify their role in carcinogenesis and metastasis. Several reviews have delineated the role of N-glycosylation in cancer, but the data regarding effective inhibitors remains sparse. Golgi α-mannosidase has been an attractive therapeutic target for preventing the formation of ß1,6-branched complex type N-glycans. However, due to its high structural similarity to the broadly specific lysosomal α-mannosidase, undesired co-inhibition occurs and this leads to serious side effects that complicates its potential role as a therapeutic agent. Even though extensive efforts have been geared towards the discovery of effective inhibitors, no breakthrough has been achieved thus far which could allow for their use in clinical settings. Improving the specificity of current inhibitors towards Golgi α-mannosidase is requisite in progressing this class of compounds in cancer chemotherapy. In this review, we highlight a few potent and selective inhibitors discovered up to the present to guide researchers for rational design of further effective inhibitors to overcome the issue of specificity., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background & Aims: In critically ill patients, direct measurement of skeletal muscle using bedside ultrasound (US) may identify a patient population that might benefit more from optimal nutrition practices. When US is not available, survey measures of nutrition risk and functional status that are associated with muscle status may be used to identify patients with low muscularity. This study aims to determine the association between baseline and changing ultrasound quadriceps muscle status with premorbid functional status and 60-day mortality., Methods: This single-center prospective observational study was conducted in a general ICU. Mechanically ventilated critically ill adult patients (age ≥18 years) without pre-existing systemic neuromuscular diseases and expected to stay for ≥96 h in the ICU were included. US measurements were performed within 48 h of ICU admission (baseline), at day 7, day 14 of ICU stay and at ICU discharge (if stay >14 days). Quadriceps muscle layer thickness (QMLT), rectus femoris cross sectional area (RFCSA), vastus intermedius pennation angle (PA) and fascicle length (FL), and rectus femoris echogenicity (mean and standard deviation [SD]) were measured. Patients' next-of-kin were interviewed by using established questionnaires for their pre-hospitalization nutritional risk (nutrition risk screening-2002) and functional status (SARC-F, clinical frailty scale [CFS], Katz activities of daily living [ADL] and Lawton Instrumental ADL)., Results: Ninety patients were recruited. A total of 86, 53, 24 and 10 US measures were analyzed, which were performed at a median of 1, 7, 14 and 22 days from ICU admission, respectively. QMLT, RFCSA and PA reduced significantly over time. The overall trend of change of FL was not significant. The only independent predictor of 60-day mortality was the change of QMLT from baseline to day 7 (adjusted odds ratio 0.95 for every 1% less QMLT loss, 95% confidence interval 0.91-0.99; p = 0.02). Baseline measures of high nutrition risk (modified nutrition risk in critically ill ≥5), sarcopenia (SARC-F ≥4) and frailty (CFS ≥5) were associated with lower baseline QMLT, RFCSA and PA and higher 60-day mortality., Conclusions: Every 1% loss of QMLT over the first week of critical illness was associated with 5% higher odds of 60-day mortality. SARC-F, CFS and mNUTRIC are associated with quadriceps muscle status and 60-day mortality and may serve as a potential simple and indirect measures of premorbid muscle status at ICU admission., Competing Interests: Conflict of interest None of the authors have any conflict of interest., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background & Aims: The effect of provision of full feeding or permissive underfeeding on mortality in mechanically ventilated critically ill patients in the intensive care unit (ICU) is still controversial. This study investigated the relationship of energy and protein intakes with 60-day mortality, and the extent to which ICU length of stay and nutritional risk status influenced this relationship., Methods: This is a prospective observational study conducted among critically ill patients aged ≥18 years, intubated and mechanically ventilated within 48 h of ICU admission and stayed in the ICU for at least 72 h. Information on baseline characteristics and nutritional risk status (the modified Nutrition Risk in Critically ill [NUTRIC] score) was collected on day 1. Nutritional intake was recorded daily until death, discharge, or until the twelfth evaluable days. Mortality status was assessed on day 60 based on the patient's hospital record. Patients were divided into 3 groups a) received <2/3 of prescribed energy and protein (both <2/3), b) received ≥2/3 of prescribed energy and protein (both ≥2/3) and c) either energy or protein received were ≥2/3 of prescribed (either ≥2/3). The relationship between the three groups with 60-day mortality was examined by using logistic regression with adjustment for potential confounders. Sensitivity analysis was performed to examine the influence of ICU length of stay (≥7 days) and nutritional risk status., Results: Data were collected from 154 mechanically ventilated patients (age, 51.3 ± 15.7 years; body mass index, 26.5 ± 6.7 kg/m 2 ; 54% male). The mean modified NUTRIC score was 5.7 ± 1.9, with 56% of the patients at high nutritional risk. The patients received 64.5 ± 21.6% of the amount of energy and 56.4 ± 20.6% of the amount of protein prescribed. Provision of energy and protein at ≥2/3 compared with <2/3 of the prescribed amounts was associated with a trend towards increased 60-day mortality (Adjusted odds ratio [Adj OR] 2.23; 95% confidence interval [CI], 0.92-5.38; p = 0.074). No difference in mortality status was found between energy and protein provision at either ≥2/3 compared with <2/3 of the prescribed amounts (Adj OR 1.61, 95% CI, 0.58-4.45; p = 0.357). Nutritional risk status, not ICU length of stay, influenced the relationship between nutritional adequacy and 60-day mortality., Conclusions: Energy and protein adequacy of ≥2/3 of the prescribed amounts were associated with a trend towards increased 60-day mortality among mechanically ventilated critically ill patients. However, neither energy nor protein adequacy alone at ≥ or <2/3 adequacy affect 60-day mortality. Increased mortality was associated with provision of energy and protein at ≥2/3 of the prescribed amounts, which only affected patients with low nutritional risk., (Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

For wafer fabrication in the semiconductor industry, maintenance engineers are potentially exposed to hazards during their work of disassembling machine components for cleanup. One special concern is the presence of arsenic or arsenic compounds in the working environment. This study analyzed speciated urinary inorganic arsenic metabolites of the maintenance engineers using high-performance liquid chromatography-hydride generation atomic absorption spectrometry to study the potential arsenic exposure during their maintenance work. In total, from six wafer fabrication facilities, 30 maintenance engineers were recruited as the exposed group and another 12 office-based engineers served as the control group. First morning-voided urine samples of each study subject were collected for 7 consecutive days. The levels of total urinary inorganic arsenic metabolites for the exposed group were 1.7+/-1.4, 1.4+/-1.1, 6.2+/-6.7, 20.2+/-14.1, and 29.5+/-17.2 micro g/L for As3+, As5+, monomethylarsonic acid, dimethylarsinic acid, and total inorganic arsenic, respectively. Both the concentration of monomethylarsonic acid and its percentage in total urinary inorganic arsenic metabolites showed significantly ascending trends for the control group, for the engineers without preventative maintenance work prior to their urine sampling, and for the engineers with such work prior to their urine sampling (P<0.05 and P<0.0005, respectively). The data also suggested that, at low-level occupational arsenic exposure, the concentration of total urinary inorganic arsenic metabolites might be misleading due to the confounding effect resulting from intake of seafood, such as arsenosuger. Nevertheless, monitoring of urinary arsenic species by using the percentage change of monomethylarsonic acid in total urinary inorganic arsenic metabolites as an indicator for the verification of arsenic exposure is helpful and appropriate in such cases.