Tobacco-induced hyperglycemia promotes lung cancer progression via cancer cell-macrophage interaction through paracrine IGF2/IR/NPM1-driven PD-L1 expression.

Tobacco smoking (TS) is implicated in lung cancer (LC) progression through the development of metabolic syndrome. However, direct evidence linking metabolic syndrome to TS-mediated LC progression remains to be established. Our findings demonstrate that 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene (NNK and BaP; NB), components of tobacco smoke, induce metabolic syndrome characteristics, particularly hyperglycemia, promoting lung cancer progression in male C57BL/6 J mice. NB enhances glucose uptake in tumor-associated macrophages by increasing the expression and surface localization of glucose transporter (GLUT) 1 and 3, thereby leading to transcriptional upregulation of insulin-like growth factor 2 (IGF2), which subsequently activates insulin receptor (IR) in LC cells in a paracrine manner, promoting its nuclear import. Nuclear IR binds to nucleophosmin (NPM1), resulting in IR/NPM1-mediated activation of the CD274 promoter and expression of programmed death ligand-1 (PD-L1). Restricting glycolysis, depleting macrophages, or blocking PD-L1 inhibits NB-mediated LC progression. Analysis of patient tissues and public databases reveals elevated levels of IGF2 and GLUT1 in tumor-associated macrophages, as well as tumoral PD-L1 and phosphorylated insulin-like growth factor 1 receptor/insulin receptor (pIGF-1R/IR) expression, suggesting potential poor prognostic biomarkers for LC patients. Our data indicate that paracrine IGF2/IR/NPM1/PD-L1 signaling, facilitated by NB-induced dysregulation of glucose levels and metabolic reprogramming of macrophages, contributes to TS-mediated LC progression.

The epidemiology of concurrent infection in patients with pyogenic spine infection and its association with early mortality: A nationwide cohort study based on 10,695 patients.

BACKGROUND: Generally, a sufficient duration of relevant antibiotics based on an appropriate culture combined with proper surgical treatment guarantees a favorable clinical outcome in patients with pyogenic spine infections. However, a patient's condition often deteriorates as concurrent infections occur in other organs, leading to mortality. Therefore, this study aimed to investigate the epidemiology of concurrent infections in patients with a pyogenic spine infection and estimate the rates and risks of early mortality. METHODS: Patients with a pyogenic spine infection were identified using a national claims database that includes the entire population. The epidemiology of the six types of concurrent infections was investigated, and the corresponding early mortality rates and risks were estimated. The results were validated internally by bootstrapping and externally by defining two additional cohorts for sensitivity analysis. RESULTS: Among 10,695 patients with a pyogenic spine infection, the prevalence of the six types of concurrent infections was 11.3 % for urinary tract infections, 9.4 % for intra-abdominal infections, 8.5 % for pneumonia, 4.6 % for septic arthritis or osteomyelitis of the extremities, 0.7 % for central nervous system infections, and 0.5 % for cardiac infections. Patients with a concurrent infection had approximately 4-fold greater mortality than those without (3.3 % vs. 0.8 %). The early mortality rates were particularly higher in patients with multiple or specific types of concurrent infections, including central nervous system infections, cardiac infections, and pneumonia. In addition, the mortality trends differed significantly according to the number and type of concurrent infections. CONCLUSIONS: These data on six types of concurrent infection among patients with pyogenic spinal infection can be used as a source of reference by clinicians.

Antimetastatic Activity of Apoptolidin A by Upregulation of N-Myc Downstream-Regulated Gene 1 Expression in Human Colorectal Cancer Cells.

Colorectal cancer (CRC) is one of the most prevalent tumors with high metastatic potential; consequently, finding new drug candidates that suppress tumor metastasis is essential. Apoptolidin A is a macrocyclic lactone produced by Amycolatopsis sp. DW02G. It exhibits significant cytotoxicity against several cancer cell lines, but its effects on CRC cells remain unknown. Therefore, the present study investigated the antiproliferative and antimetastatic activities of apoptolidin A and its underlying molecular mechanisms in CRC cells. Apoptolidin A effectively inhibited CRC cell growth and colony formation. The induction of G0/G1 phase cell cycle arrest was associated with the downregulation of cyclin D1 and CDK4/6 expression. Long-term exposure to apoptolidin A also induced apoptosis as confirmed by the downregulation and upregulation of Bcl-2 and Bax expression, respectively. Moreover, apoptolidin A effectively upregulated the suppressed expression of N-Myc downstream-regulated gene 1 (NDRG1), a tumor suppressor gene, in a concentration-dependent manner in CRC cells. The antimetastatic potential of apoptolidin A was also correlated with the expression of epithelial-mesenchymal transition (EMT) biomarkers, including the upregulation of E-cadherin and downregulation of N-cadherin, vimentin, snail, and MMP9 in CRC cells. These findings suggest that apoptolidin A exerts antiproliferative and antimetastatic activities by regulating the NDRG1-activated EMT pathway in CRC cells.

Threonine requirement of healthy adults, derived with a 24-h indicator amino acid balance technique.

BACKGROUND: Because we question the validity of the 1985 FAO/ WHO/UNU upper requirement for threonine of 7 mg x kg(-1) x d(-1), we proposed a tentative mean requirement of 15 mg x kg(-1) x d(-1). OBJECTIVE: Our goal was to assess threonine adequacy at 3 test intakes and the consequences of a 6-d compared with a 13-d dietary adaptation phase. DESIGN: We used a 24-h indicator amino acid balance technique ([1-(13)C]leucine as indicator) to assess the threonine requirement. Fifteen healthy adults were randomly assigned to receive 7, 15, or 46 mg threonine x kg(-1) x d(-1) and were studied after 6 and 13 d of adaptation to the experimental diets. Diets were based on an L-amino acid mixture in which the threonine content was varied. At 1700 on days 6 and 13, a 24-h intravenous [(13)C]leucine tracer infusion protocol was begun to assess leucine oxidation and daily leucine balances. RESULTS: There was no detectable effect of duration of dietary adaptation in leucine oxidation or balance, but the 24-h leucine oxidation and balances differed significantly between the 7-mg intake and each of the 2 higher intakes (P < 0.05). The latter were not significantly different. The 24-h leucine oxidation rate decreased across threonine intakes (P < 0.01 for main effect of diet, independent of infusion day). Leucine oxidation was highly correlated (r = 0.80) between the 2 dietary adaptation phases across all test intakes. CONCLUSION: The 1985 FAO/WHO/UNU threonine recommendation is inadequate, and 15 mg x kg(-1) x d(-1) is sufficient to achieve mean indicator (leucine) amino acid balance.