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Purpose: Many systemic inflammatory markers have been identified to be prognostic factors in various diseases, including colorectal cancer (CRC). The Colon Inflammatory Index (CII), which is based on the lactate dehydrogenase (LDH) level and the neutrophil-to-lymphocyte ratio (NLR), is reportedly a predictor of the outcome of chemotherapy in patients with metastatic CRC. This retrospective review study aimed to determine whether CII can predict the prognosis after surgical resection of CRC. Methods: A total of 1,273 patients who underwent CRC resection were enrolled and divided into a training cohort (n = 799) and a validation cohort (n = 474). The impact of the preoperative CII score on overall survival (OS) and recurrence-free survival (RFS) was assessed. Results: In the training cohort, the CII score was good in 569 patients (71.2%), intermediate in 209 (26.2%), and poor in 21 (2.6%). There were significant between-group differences in body mass index, American Society of Anaesthesiologists physical status, and preoperative tumour markers. The 5-year OS rate was significantly lower in patients with an intermediate or poor CII score (CII risk) than in those with no CII risk (73.8% vs. 84.2%; p < 0.001, log-rank test). In multivariate analysis, CII risk remained a significant independent predictor of poor OS (hazard ratio 1.75; 95% confidence interval 1.18–2.60; p = 0.006). In the validation cohort, the 5-year OS rate was significantly lower in patients with CII risk than in those with no CII risk (82.8% vs. 88.4%; p = 0.046, log-rank test). Conclusion: These findings indicate that the CII can predict OS after resection of CRC. [ABSTRACT FROM AUTHOR]

[21][24] We wish to report herein our synthetic approach toward -hydroxyamino ketones, which involves the radical acylation of nitrone with 2-acylbenzothiazolene under organophotoredox catalysis (route C). Metal- and Additive-Free Synthesis of -Hydroxyamino Ketones Enabled by Organophotocatalyst Hydroxyamino ketone, hydroxylamine, nitrone, benzothiazoline, metal-free, organophotocatalyst Keywords: hydroxyamino ketone; hydroxylamine; nitrone; benzothiazoline; organophotocatalyst; metal-free EN hydroxyamino ketone hydroxylamine nitrone benzothiazoline organophotocatalyst metal-free 1391 1394 4 07/11/23 20230725 NES 230725 Graph Nitrogen-containing compounds are prevalent in organic compounds, and a range of novel catalytic approaches have been extensively explored. [Extracted from the article]

Photoinduced single‐electron reduction is an efficient method for the mono‐selective activation of the C−F bond on a trifluoromethyl group to construct a difluoroalkyl group. We have developed an electron‐donor‐acceptor (EDA) complex mediated single‐electron transfer (EDA‐SET) of α,α,α‐trifluoromethyl arenes in the presence of lithium salt to give α,α‐difluoroalkylarenes. The C−F bond reduction was realized by lithium iodide and triethylamine, two common feedstock reagents. Mechanistic studies revealed the generation of a α,α‐difluoromethyl radical by single‐electron reduction and defluorination, followed by the radical addition to alkenes. Lithium salt interacted with the fluorine atom to promote the photoinduced reduction mediated by the EDA complex. Computational studies indicated that the lithium‐assisted defluorination and the single‐electron reduction occurred concertedly. We call this phenomenon fluoride‐coupled electron transfer (FCET). FCET is a novel approach to C−F bond activation for the synthesis of organofluorine compounds. [ABSTRACT FROM AUTHOR]

Asymmetric catalysis stands at the forefront of modern chemistry, serving as a cornerstone for the efficient creation of enantiopure chiral molecules characterized by their high selectivity. In this review, we delve into the realm of asymmetric catalytic reactions, which spans various methodologies, each contributing to the broader landscape of the enantioselective synthesis of chiral molecules. Transition metals play a central role as catalysts for a wide range of transformations with chiral ligands such as phosphines, N-heterocyclic carbenes (NHCs), etc., facilitating the formation of chiral C-C and C-X bonds, enabling precise control over stereochemistry. Enantioselective photocatalytic reactions leverage the power of light as a driving force for the synthesis of chiral molecules. Asymmetric electrocatalysis has emerged as a sustainable approach, being both atom-efficient and environmentally friendly, while offering a versatile toolkit for enantioselective reductions and oxidations. Biocatalysis relies on nature's most efficient catalysts, i.e., enzymes, to provide exquisite selectivity, as well as a high tolerance for diverse functional groups under mild conditions. Thus, enzymatic optical resolution, kinetic resolution and dynamic kinetic resolution have revolutionized the production of enantiopure compounds. Enantioselective organocatalysis uses metal-free organocatalysts, consisting of modular chiral phosphorus, sulfur and nitrogen components, facilitating remarkably efficient and diverse enantioselective transformations. Additionally, unlocking traditionally unreactive C-H bonds through selective functionalization has expanded the arsenal of catalytic asymmetric synthesis, enabling the efficient and atom-economical construction of enantiopure chiral molecules. Incorporating flow chemistry into asymmetric catalysis has been transformative, as continuous flow systems provide precise control over reaction conditions, enhancing the efficiency and facilitating optimization. Researchers are increasingly adopting hybrid approaches that combine multiple strategies synergistically to tackle complex synthetic challenges. This convergence holds great promise, propelling the field of asymmetric catalysis forward and facilitating the efficient construction of complex molecules in enantiopure form. As these methodologies evolve and complement one another, they push the boundaries of what can be accomplished in catalytic asymmetric synthesis, leading to the discovery of novel, highly selective transformations which may lead to groundbreaking applications across various industries. [ABSTRACT FROM AUTHOR]

Introduction: The present study assessed the utility of a dry box time trial during laparoscopic surgical training to improve laparoscopic surgical skills and surgical outcomes. Methods: In a monthly time trial, surgeon trainees twice completed a set task that involved grasping a suture, aligning a needle with a needle holder, passing the suture, making three knots, and cutting the two tails of the suture. The mean suturing time was then analyzed. To assess the utility of this time trial, we analyzed the short‐term outcomes of patients with stage I to III colon cancer who had undergone laparoscopic colectomy before and after the introduction of the time trial. Results: The monthly time trial was introduced in October 2018, and 52 surgeon trainees participated in the trials examined in this study. Within 6 months of the program's introduction, the mean suturing time had significantly declined to less than 70% of the time trial, while the standard deviations had declined to less than 30%. In comparisons of the short‐term outcomes of laparoscopic colon cancer surgery before (n = 49) and after (n = 46) the introduction of the time trial, the operative time tended to decline (P =.074) after the introduction of the time trial, and blood loss was significantly reduced (P =.018). The rate of postoperative complications was similar before and after the introduction. Conclusion: Regular time trials of laparoscopic surgical suture training using a dry box can be useful for improving laparoscopic surgical skills and surgical outcomes. Moreover, time trials can keep trainees motivated. [ABSTRACT FROM AUTHOR]

Quinoline and indole are important core structures in biologically active compounds and materials. Atropisomeric biaryls consisting of quinoline and indole are a unique class of axially chiral molecules. We report herein enantioselective synthesis of 3-(N-indolyl)quinolines having both C–N axial chirality and carbon central chirality by a photoredox Minisci-type addition reaction catalyzed by a chiral lithium phosphate/Ir-photoredox complex. The catalytic system enabled access to a unique class of 3-(N-indolyl)quinolines with high chemo-, regio-, and stereoselectivities in good yields through the appropriate choice of an acid catalyst and a photocatalyst. This is the first example of the synthesis of 3-(N-indolyl)quinoline atropisomers in a highly enantioselective manner. [ABSTRACT FROM AUTHOR]

The hydrosilylation of alkenes is one of the most important methods for the synthesis of organosilicon compounds. In addition to the platinum‐catalyzed hydrosilylation, silyl radical addition reactions are notable as economic reactions. An efficient and widely applicable silyl radical addition reaction was developed by using 2‐silylated dihydroquinazolinone derivatives under photocatalytic conditions. Electron‐deficient alkenes and styrene derivatives underwent hydrosilylation to give addition products in good to high yields. Mechanistic studies indicated that the photocatalyst functioned not as a photoredox catalyst but as an energy transfer catalyst. DFT calculations clarified that the triplet excited state of 2‐silylated dihydroquinazolinone derivatives released a silyl radical through the homolytic cleavage of a carbon‐silicon bond, and this was followed by the hydrogen atom transfer pathway, not the redox pathway. [ABSTRACT FROM AUTHOR]

Fibroblast activation protein (FAP) generally shows low or undetectable expression in most normal tissues but is highly expressed in fibroblasts in almost all carcinomas. FAP is one of the potential molecules to detect activated fibroblasts and has multiple roles in tumour progression. We generated transgenic mice that specifically expressed tdTomato along with FAP promoter activity. Coculturing a mouse gastric cancer cell line and FAP‐tdTomato transgenic mouse‐derived fibroblasts showed that tdTomato expression was elevated in the cocultured fibroblasts. Moreover, stomach wall transplanted tumours in mice also showed FAP‐tdTomato expression in fibroblasts of the stomach and each metastatic legion. These results indicated that FAP‐tdTomato expression in fibroblasts was elevated by stimulation through the interaction with cancer cells. Functionally, collagen production was increased in FAP/tdTomato‐positive fibroblasts cocultured with mouse cancer cells. These FAP‐tdTomato transgenic mice have the potential to be used to investigate real‐time FAP dynamics and the importance of FAP expression in tumour development. [ABSTRACT FROM AUTHOR]

Background: Remodeling the tumor microenvironment (TME) to benefit cancer cells is crucial for tumor progression. Although diffuse-type gastric cancer (DGC) preferentially interacts with the TME, the precise mechanism of the complicated network remains unknown. This study aimed to investigate the mutual activation mechanism underlying DGC progression. Methods: Mass cytometry analysis of co-cultured macrophages, noncancerous fibroblasts (NFs), and DGC cells was performed. RNA sequencing was applied to examine gene expression in fibroblasts. DGC cells were treated with cytokines to examine their effect on characteristic changes. The TCGA and Kumamoto University cohorts were used to evaluate the clinical relevance of the in vitro findings. Results: Cohort analysis revealed that DGC patients had a poor prognosis. The fibroblasts and macrophages interacted with DGC cells to form a cell cluster in the invasive front of DGC tissue. The original 3D triple co-culture system determined the promotional effects of nonmalignant cells on DGC invasive growth. We notably identified a mixed-polarized macrophage cell type with M1/M2 cell surface markers in a triple co-culture system. IL-1β from mixed-polarized macrophages induced the conversion of NFs to cancer-associated fibroblast-like (CAF-like) cells, promoting the malignant phenotype of DGC cells by inducing the secretion of IL-6, IL-24, and leukemia inhibitory factor (LIF). Moreover, IL-6 and colony stimulating factor 2 (GM-CSF) cooperated to maintain the stable state of mixed-polarized macrophages. Finally, we found that mixed-polarized macrophages were frequently detected in DGC tissues. Conclusion: These findings demonstrated that mixed-polarized macrophages exist as a novel subtype through the reciprocal interaction between DGC cells and nonmalignant cells. [ABSTRACT FROM AUTHOR]

Background: Advanced lung cancer inflammation index (ALI) is reported to be a prognosticator in various cancer patients with chemotherapy. However, the clinical impact of the ALI on treatment strategies in metastatic colorectal cancer (mCRC) patients remains unclear. Methods: A total of 356 patients, who received first-line chemotherapy for mCRC between April 2005 and November 2019 in a single institution, were retrospectively enrolled. The association of pretreatment ALI (calculated as follows: BMI × albumin value/neutrophil-to-lymphocyte ratio) status with clinicopathological factors and patient survival outcome was analyzed, using subgroup analysis. Results: The ALI-low cases were significantly associated with female sex, more synchronous metastasis, multiple metastatic sites, less primary tumor resection, less liver resection after chemotherapy, and poor overall survival (OS). A multivariate Cox proportional hazards analysis clarified that the ALI-low status was independently associated with poor OS (HR: 1.78, 95% CI 1.27–2.48, P = 0.001), in addition to right side tumor, multiple metastatic sites, and the non-performance of liver resection after chemotherapy. A subgroup analysis revealed that primary tumor resection and the resection of liver metastases after chemotherapy could not improve the prognosis of ALI-low cases in comparison with ALI-high cases, and the type of first-line chemotherapy did not significantly affect the association between the prognosis and the ALI status. Conclusion: ALI comprehensively evaluates the prognostic host status and is a reliable prognosticator for the mCRC patients with chemotherapy. Calculating pretreatment ALI may serve as a cost-effective and easily available tool for constructing treatment strategies. [ABSTRACT FROM AUTHOR]

A chiral calcium phosphate-catalyzed enantioselective Friedel–Crafts alkylation reaction of pyrroles and α-trifluoromethyl-β-nitrostyrenes has been developed. Pyrroles bearing an all-carbon quaternary center at 2-position were obtained with high to excellent enantioselectivity. Use of 4,7-dihydroindole as a nucleophile and subsequent oxidation resulted in the formation a 2-substituted indole derivative with excellent enantioselectivity. A 3,4-dihydropyrrolo[1,2- c ]pyrimidine derivative was successfully synthesized by reduction followed by benzoylation of the product without loss of enantioselectivity. Application to a 1 mmol scale reaction was successfully achieved. [ABSTRACT FROM AUTHOR]

Background: Signet ring cell carcinoma (SRCC) is a particular histologic variant of gastric cancer (GC). However, the critical factor related to the aggressive characteristics of SRCC has not been determined. Methods: We collected surgically resected tissues from 360 GC patients in the Kumamoto University cohort and generated survival curves via the Kaplan–Meier method. In vitro, we identified the specific transcript variant of MUC20 in SRCC cells by direct sequencing and investigated the role of MUC20 in GC progression using GC cells with MUC20 silencing and forced expression. In vivo, we examined chemoresistance using MUC20 variant 2 (MUC20v2)-overexpressing non-SRCC cells to construct a xenograft mouse model. Results: We analyzed a comprehensive GC cell line database to identify the specifically expressed genes in gastric SRCC. We focused on MUC20 and investigated its role in GC progression. Survival analysis revealed that GC patients with high MUC20 expression exhibited a poor prognosis and that MUC20 expression was significantly correlated with SRCC histological type. Moreover, we found that gastric SRCC cells specifically expressed MUC20v2, which was dominantly expressed in the cytoplasm. Silencing MUC20v2 caused cell death with characteristic morphological changes in gastric SRCC cells. To further determine the types of cell death, we examined apoptosis, pyroptosis and ferroptosis by detecting cleaved PARP, gasdermin E-N-terminal (GSDME-N), and lipid reactive oxygen species (ROS) levels, respectively. We found that apoptosis and pyroptosis occurred in MUC20-silenced gastric SRCC cells. In addition, MUC20v2-overexpressing GC cells exhibited chemoresistance to cisplatin (CDDP) and paclitaxel (PTX). RNA sequencing revealed that the pathways involved in intracellular calcium regulation were significantly upregulated in MUC20v2-overexpressing GC cells. Notably, forced expression of MUC20v2 in the cytoplasm of GC cells led to the maintenance of mitochondrial calcium homeostasis and mitochondrial membrane potential (MMP), which promoted cell survival and chemoresistance by suppressing apoptosis and pyroptosis. Finally, we investigated the significance of MUC20v2 in a xenograft model treated with CDDP and showed that MUC20v2 overexpression caused chemoresistance by inhibiting cell death. Conclusion: These findings highlight the novel functions of MUC20v2, which may confer cell survival and drug resistance in GC cells. Significance: MUC20v2 protects GC cells from apoptosis and pyroptosis by maintaining mitochondrial calcium levels and mitochondrial membrane potential and subsequently induces drug resistance. [ABSTRACT FROM AUTHOR]

Background: This study aimed to examine whether preoperative serum transferrin, a rapid-turnover protein, correlates with short- and long-term outcomes after esophagectomy. Methods: Preoperative transferrin levels, calculated by summing serum iron and unsaturated iron-binding capacity, were evaluated in 224 patients who underwent esophagectomy for stage I–III esophageal cancer without preoperative treatment. Transferrin levels are directly proportional to total iron-binding capacity (TIBC), and we defined TIBC < 250 μg/dL as low transferrin. We evaluated the relationship between preoperative transferrin levels and short- and long-term outcomes after esophagectomy using univariate and multivariate Cox proportional hazards analyses. Results: Of all patients, 25 (11.2%) had low preoperative transferrin levels. Low preoperative transferrin levels were strongly correlated with worse preoperative performance status, advanced pathological T stage, and more open esophagectomy (p = 0.0078, 0.0001, and 0.013, respectively). Patients with low preoperative transferrin levels experienced significantly more frequent postoperative pneumonia in univariate and multivariate analysis [hazard ratio (HR) 3.30, 95% confidence interval (CI) 1.032–10.033, p = 0.0443]. Additionally, these patients were significantly correlated with worse overall survival (OS) in univariate and multivariate analyses (HR 2.75, 95% CI 1.018–7.426, p = 0.0460). Furthermore, we investigated the relationship between OS and postoperative pneumonia to elucidate why low preoperative transferrin, which is an independent risk factor for postoperative pneumonia, leads to poor prognosis. Patients with postoperative pneumonia were strongly associated with a shorter OS (p = 0.0099). Conclusion: Preoperative serum transferrin levels may be a novel indicator of postoperative pneumonia and OS after esophagectomy. [ABSTRACT FROM AUTHOR]

Cancer cells craftily adapt their energy metabolism to their microenvironment. Nutrient deprivation due to hypovascularity and fibrosis is a major characteristic of pancreatic ductal adenocarcinoma (PDAC); thus, PDAC cells must produce energy intrinsically. However, the enhancement of energy production via activating Kras mutations is insufficient to explain the metabolic rewiring of PDAC cells. Here, we investigated the molecular mechanism underlying the metabolic shift in PDAC cells under serine starvation. Amino acid analysis revealed that the concentrations of all essential amino acids and most nonessential amino acids were decreased in the blood of PDAC patients. In addition, the plasma serine concentration was significantly higher in PDAC patients with PHGDH-high tumors than in those with PHGDH-low tumors. Although the growth and tumorigenesis of PK-59 cells with PHGDH promoter hypermethylation were significantly decreased by serine starvation, these activities were maintained in PDAC cell lines with PHGDH promoter hypomethylation by serine biosynthesis through PHGDH induction. In fact, DNA methylation analysis by pyrosequencing revealed that the methylation status of the PHGDH promoter was inversely correlated with the PHGDH expression level in human PDAC tissues. In addition to PHGDH induction by serine starvation, PDAC cells showed enhanced serine biosynthesis under serine starvation through 3-PG accumulation via PGAM1 knockdown, resulting in enhanced PDAC cell growth and tumor growth. However, PHGDH knockdown efficiently suppressed PDAC cell growth and tumor growth under serine starvation. These findings provide evidence that targeting the serine biosynthesis pathway by inhibiting PHGDH is a potent therapeutic approach to eliminate PDAC cells in nutrient-deprived microenvironments. [ABSTRACT FROM AUTHOR]

Background: Iron deficiency anemia is represented in colorectal cancer (CRC) patients. Iron surplus load to increase non-transferrin bound iron (NTBI), and NTBI promotes cancer progression and influences microbiota. This study investigated whether preoperative serum iron status was associated with prognosis after CRC resection. Methods: We evaluated preoperative iron and transferrin saturation (TSAT), which was calculated as iron divided by total iron-binding capacity, in 327 patients who underwent surgery for Stage II–III CRC. Fe < 60 μg/dl and TSAT > 40% were defined as low and high iron, respectively. The associations between iron status and overall survival (OS) were evaluated in univariate and multivariate Cox proportional hazards analysis. Results: Of the 327 patients, 179 (54.7%), 124 (37.9%) and 24 (7.3%) had low, normal and high iron, respectively. In univariate analysis, low iron was associated with shorter OS (hazard ratio [HR] 2.821, 95% confidence interval [CI] 1.451–5.485, P = 0.002). High iron was also associated with shorter OS (HR 3.396, 95% CI 1.359–8.489, P = 0.009). In multivariate analysis, high age (P = 0.002), depth of invasion pT4 (P = 0.012), lymph-node metastasis presence (P = 0.035), low albumin (P = 0.011), low iron (HR 2.282, 95% CI 1.163–4.478, P = 0.016) and high iron (HR 3.757, 95% CI 1.486–9.494 P = 0.005) were independently associated with shorter OS. High iron was associated with the amount of intratumoral Fusobacterium nucleatum compared with normal iron. Conclusion: Both low and high preoperative iron in Stage II–III CRC patients were associated with unfavorable OS in univariate and multivariate analyses. [ABSTRACT FROM AUTHOR]