Angiopoietin-like protein 8 (ANGPTL8) has been implicated in metabolic syndrome and reported to regulate adipose FA uptake through unknown mechanisms. Here, we studied how complex formation of ANGPTL8 with ANGPTL3 or ANGPTL4 varies with feeding to regulate lipoprotein lipase (LPL). In human serum, ANGPTL3/8 and ANGPTL4/8 complexes both increased postprandially, correlated negatively with HDL, and correlated positively with all other metabolic syndrome markers. ANGPTL3/8 also correlated positively with LDL-cholesterol and blocked LPL-facilitated hepatocyte VLDL-cholesterol uptake. LPL-inhibitory activity of ANGPTL3/8 was >100-fold more potent than that of ANGPTL3, and LPL-inhibitory activity of ANGPTL4/8 was >100-fold less potent than that of ANGPTL4. Quantitative analyses of inhibitory activities and competition experiments among the complexes suggested a model in which localized ANGPTL4/8 blocks the LPL-inhibitory activity of both circulating ANGPTL3/8 and localized ANGPTL4, allowing lipid sequestration into fat rather than muscle during the fed state. https://www.selleckchem.com/products/Ki16425.html Supporting this model, insulin increased ANGPTL3/8 secretion from hepatocytes and ANGPTL4/8 secretion from adipocytes. These results suggest that low ANGPTL8 levels during fasting enable ANGPTL4-mediated LPL inhibition in fat tissue to minimize adipose FA uptake. During feeding, increased ANGPTL8 increases ANGPTL3 inhibition of LPL in muscle via circulating ANGPTL3/8, while decreasing ANGPTL4 inhibition of LPL in adipose tissue through localized ANGPTL4/8, thereby increasing FA uptake into adipose tissue. Excessive caloric intake may shift this system toward the latter conditions, possibly predisposing to metabolic syndrome.Mycobacterium tuberculosis is the causative agent of tuberculosis and remains one of the most widespread and deadliest bacterial pathogens in the world. A distinguishing feature of mycobacteria that sets them apart from other bacteria is the unique architecture of their cell wall, characterized by various species-specific lipids, most notably mycolic acids (MAs). Therefore, targeted inhibition of enzymes involved in MA biosynthesis, transport, and assembly has been extensively explored in drug discovery. Additionally, more recent evidence suggests that many enzymes in the MA biosynthesis pathway are regulated by kinase-mediated phosphorylation, thus opening additional drug development opportunities. However, how phosphorylation regulates MA production remains unclear. Here, we employed genetic strategies combined with lipidomics and phosphoproteomics approaches to investigate the role of protein phosphorylation in Mycobacterium. The results of this analysis revealed that the Ser/Thr protein kinase PknB regulates export of MAs and promotes remodeling of the mycobacterial cell envelope. In particular, we identified the essential mycobacterial membrane protein large 3 (MmpL3) as a substrate negatively regulated by PknB. Taken together, our findings add to the understanding of how PknB activity affects the mycobacterial MA biosynthesis pathway and reveal the essential role of protein phosphorylation/dephosphorylation in governing lipid metabolism, paving the way towards novel antimycobacterial strategies.Background In RECOURSE (, trifluridine/tipiracil significantly improved overall survival and progression-free survival (PFS) versus placebo in patients with pretreated metastatic colorectal cancer (mCRC). PRECONNECT was designed to further characterise safety and clinical use of trifluridine/tipiracil. Methods In this ongoing, international, multicentre, open-label trial, patients with pretreated mCRC received oral trifluridine/tipiracil 35 mg/m2 twice daily on days 1-5 and 8-12 of each 28-day cycle. The primary endpoint was safety; secondary endpoints included PFS and quality of life (QoL). Results 793 patients (median age 62 years) from 13 countries received trifluridine/tipiracil for a median of 2.84 months (IQR 2.64). Adverse events (AEs) were experienced by 96.7%; the most common (≥20% of patients) were neutropaenia, asthenia/fatigue, nausea, anaemia and diarrhoea. Grade ≥3 AEs occurred in 73.9% of patients, with the most common being neutropaenia (39.1% of patients), anaemia (9.8%) and asthenia/fatigue (5.0%). Median PFS was 2.8 months (95% CI 2.7 to 2.9). Median time to Eastern Cooperative Oncology Group performance status deterioration (≥2) was 8.9 months (range 0.03-14.72). There was no clinically relevant change from baseline in QoL. Conclusions PRECONNECT showed consistent results with the previously demonstrated safety and efficacy profile of trifluridine/tipiracil, with no new safety concerns identified. QoL was maintained during treatment. Trial registration number NCT03306394.Purpose Pseudocirrhosis is a radiological term used to describe rapid changes in the contour of liver invaded by metastases and treated with chemotherapy. Our primary objectives were to analyse the clinical and biological characteristics of those patients with breast cancer and to assess the prevalence of complications generally associated with decompensated cirrhosis. We have also assessed associated treatments and response. Methods This retrospective study included all women with metastatic breast cancer to the liver who had imaging protocols describing diffuse liver contour abnormalities during systemic treatment between 2003 and 2018 in our centre. The following were identified neoplastic characteristics, complications presented, treatments administered and response. Results 48 patients were included. There was a trend towards an increased proportion of luminal cancers (88.2%, n=30, p=0052) when compared with our hospital cancer registry. Most patients (97.9%, n=47) had a widespread liver invasion, 58.3% (n=28) had ascites on physical examination; 90% (n=18) of ascites were classified as transudate. Nearly 23% (n=11) of patients had oesophageal varices and 6.5% (n=3) had an episode of variceal rupture. At the time of the appearance of liver contour abnormalities, the most frequently used molecules were 5-fluorouracil (22.9%; n=11) and cisplatin (18.8%; n=9). A partial response was observed in 52.1% (n=25) of patients. Conclusion This is the largest reported series of patients with pseudocirrhosis. Many patients developed complications related to portal hypertension and liver failure, similar to those observed in decompensated cirrhosis. Luminal subtypes could be over-represented. In our series, pseudocirrhosis appears to develop at the expense of extensive liver disease burden and most often under 5-fluorouracil, or its derivatives, with or without cisplatin, possibly following a response to treatment.