In the 6th edition of the Japanese Gastric Cancer Treatment Guidelines, laparoscopic surgery is recommended as one of the standard treatments for cStage I. On the other hand, the recommendation of ...robot-assisted surgery for gastric cancer was also added, albeit not conclusively, to perform it for cStage I gastric cancer. Conversely, laparoscopic surgery for cStage II/III is not recommended, and several randomized controlled trials (RCTs) are being conducted in East Asia to expand the indication for advanced gastric cancer. Although laparoscopic surgery and robot-assisted surgery are now recommended in the Guidelines for Early-Stage Gastric Cancer, each institution should set its own criteria for indications according to its level of proficiency and try to provide high-quality treatment. For advanced gastric cancer, although there is no solid evidence for laparoscopic or robot-assisted surgery, the reality is that it is already being performed in facilities with ample experience. New evidence is expected to be reported in the future, based on which the recommendations may change.
Here, heptacoordinate and hexacoordinate triorganotin compounds o‐{(Ph2)(O)P}C6H43SnX (X=F (2 a), Cl (2 b), Me (2 f)) featuring three O→Sn interactions were synthesized. Chloro (2 b) and methyl (2 f) ...compounds were obtained from the oxygenation of the heptacoordinate triorganotin compounds {o‐(Ph2P)C6H4}3SnX (X=Cl (1 b), Me (1 f)) bearing three P donors. The fluorination of 2 b using tetrabutylammonium fluoride (TBAF) yielded the fluoro analogue 2 a. Structural studies were performed on a series of hypercoordinate triorganotin compounds, 2. The chloro analogue (2 b) exhibited a hexacoordinate geometry attributed to the Sn−Cl bond cleavage, where the highly electrophilic stannyl cation was stabilized by three O donors. In contrast, both the fluoro (2 a) and methyl (2 f) analogues exhibited heptacoordinate structures. Although 2 f adopted a tricapped tetrahedral geometry, 2 b is classified to adopt a distinctly rare bicapped trigonal pyramidal geometry featuring one strong LP(O)→σ*(Sn−F) interaction and two weak LP(O)→σ*(Sn−C) interactions (LP: lone pair electrons). The origin of the structural alternations depending on the substituent is discussed using density functional theory (DFT) calculations.
Hypercoordinate organotin compounds featuring three O→Sn interactions were synthesized via the oxygenation of phosphine groups. Halogen substituents at the Sn center significantly influenced their geometries; the fluoro compound adopts a rare bicapped trigonal pyramidal geometry, while its chloro analogue adopts a capped trigonal pyramidal geometry with the cationic Sn attributed to the Sn−Cl bond cleavage.
Accumulating evidence suggests that cancer cells with stem cell-like features have higher resistance to chemotherapeutic agents. Herein, we identified T-lymphoma invasion and metastasis-inducing ...protein-1 (TIAM1) as one of the Wnt-signaling associated genes which drives self-renewal and its expression is upregulated by cancer associated fibroblasts (CAFs). TIAM1 expression was assessed in resected colorectal cancer (CRC) tissues from 300 patients who did or did not respond to chemotherapy. siRNA and CRISPR/Cas9 was used to examine whether the inhibition of TIAM1 affects chemosensitivity of CRC. We demonstrate that stemness through Wnt signaling regulates chemosensitivity and this phenomenon occurs exclusively in cancer stem cells. Subsequently, we established patient-derived CAFs and tested whether the drug sensitivity of CRC cell lines is altered with CAF-derived conditioned medium. High-TIAM1 expression correlated significantly with poor prognosis of CRC patients, and was overexpressed in patients who did not respond to chemotherapy. We demonstrated that the inhibition of TIAM1 enhanced sensitivity to chemotherapeutic drugs and reduced tumor invasiveness in a series of experiments in vitro. Moreover, CAF-derived conditioned media increased stemness and chemoresistance in CRC cell lines through TIAM1 overexpression. In addition, we validated TIAM1 associated drug sensitivity using a xenograft model. We have demonstrated that TIAM1 is overexpressed in CRC tumors from patients who did not respond to chemotherapeutic drugs and levels of TIAM1 expression served as an independent prognostic factor. Mechanistically, CAFs enhanced CRC chemoresistance through TIAM1 overexpression. Collectively, these results suggest that TIAM1 regulates chemosensitivity in tumors and stroma and thus may be an attractive therapeutic target.
Background
Several studies have examined controlling nutritional status (CONUT), which is one of the useful biomarkers for predicting patients’ prognosis following cancer treatment. The aim of this ...study was to evaluate the value of CONUT as a postoperative prognostic marker in patients with intrahepatic cholangiocarcinoma (ICC) following curative hepatectomy.
Methods
We retrospectively analyzed 71 patients who underwent curative hepatectomy for ICC between May 2002 and November 2016. Patients were divided into two groups according to their preoperative CONUT score (i.e., CONUT ≧ 2 or CONUT < 2).
Results
The number of patients assigned to the normal, mild, moderate, or severe malnutrition groups was 40, 28, two, and one, respectively. The high CONUT group (CONUT ≧ 2) consisted of 31 patients (43.7%) and had a poor prognosis with regard to overall survival (OS) (
p
= 0.0149). A high CONUT score is also identified as one of the independent predictors of poor prognosis in OS (hazard ratio 3.02; 95% confidence interval 1.4–6.8;
p
= 0.007). However, in the current study, a high CONUT score was not associated with postoperative complications (Clavien–Dindo classification ≧ III or more).
Conclusions
CONUT may be useful for the preoperative assessment of prognosis in patients with ICC who have undergone curative hepatectomy.
Tertiary lymphoid structures (TLSs) provide an immunological antineoplastic effect. Recent evidences link a unique 12‐chemokine (CCL2, ‐3, ‐4, ‐5, ‐8, ‐18, ‐19, ‐21, CXCL9, ‐10, ‐11, ‐13) signature ...status from tumor tissue and the TLS expression. However, the potential significance of 12‐chemokine signature status for clinical use is unknown. We aimed to evaluate the association of 12‐chemokine signature status with patient outcomes in colorectal cancer (CRC). We used integrated data of resected 975 CRC cases within three independent cohorts from France, Japan and the United States (GSE39582, KUMAMOTO from Kumamoto university hospital and TCGA). The association of 12‐chemokine signature status with clinicopathological features, patient outcome, TLS expression status and key tumor molecular features was analyzed. Patients with low 12‐chemokine signature status had a significant shorter relapse‐free survival in discovery cohort (HR: 1.61, 95% CI: 1.11–2.39, p = 0.0123), which was confirmed in validation cohort (HR: 3.31, 95% CI: 1.33–10.08, p = 0.0087). High 12‐chemokine signature status had significant associations with right‐sided tumor, high tumor‐localized TLS expression, BRAF mutant, CIMP‐high status and MSI‐high status. Furthermore, RNA‐seq based analysis showed that high 12‐chemokine signature status was strongly associated with inflammation‐related, immune cells‐related and apoptosis pathways (using gene set enrichment analysis), and more tumor‐infiltrating immune cells, such as cytotoxic T lymphocytes and myeloid dendritic cells (using MCP‐counter analysis). We investigated a promising effect of 12‐chemokine signature status in CRC patients who underwent resection. Our data may be helpful in developing novel immunological treatment strategies for CRC.
What's new?
Chronic inflammation at tumor sites is linked to the emergence of ectopic formations known as tertiary lymphoid structures (TLSs), which combat tumor progression. Here, analyses of human colorectal cancer (CRC) tissue show that high expression of a previously identified 12‐chemokine signature predicts high TLS expression at tumor sites and is associated with increased presence of tumor infiltrating immune cells and reduced CRC recurrence rate. High 12‐chemokine signature status was further linked to key clinicopathological and molecular features of CRC. The findings indicate that the 12‐chemokine signature is informative for host immune status and may have a prognostic role in CRC.
Background
Celiac disease is a chronic autoimmune enteropathy caused by gluten ingestion. While its prevalence in Western countries is reported to be as high as 1%, the prevalence has not been ...evaluated in a large-scale study of a Japanese population. The aim of our study was to clarify the possible presence of celiac disease in a Japanese non-clinical population as well as in patients showing symptoms suggestive of the disease.
Methods
Serum samples were collected from 2008 non-clinical adults and 47 patients with chronic unexplained abdominal symptoms between April 2014 and June 2016. The anti-tissue transglutaminase (TTG) immunoglobulin A antibody titer was determined as a screening test for celiac disease in all subjects, and individuals with a value of >2 U/mL subsequently underwent testing for the presence of serum endomysial IgA antibody (EMA) as confirmation. Those testing positive for EMA or with a high concentration (>10 U/mL) of TTG were further investigated by histopathological examinations of duodenal mucosal biopsy specimens and HLA typing tests.
Results
Of the 2008 non-clinical adults from whom serum samples were collected, 161 tested positive for TTG, and all tested negative for EMA. Four subjects who had a high TTG titer were invited to undergo confirmatory testing, and the histopathological results confirmed the presence of celiac disease in only a single case (0.05%). Of the 47 symptomatic patients, one (2.1%) was found to have a high TTG titer and was diagnosed with celiac disease based on duodenal histopathological findings.
Conclusion
The presence of celiac disease in a non-clinical Japanese population was low at 0.05% and was rarely found in patients with unexplained chronic abdominal symptoms.
In the tumor microenvironment, senescent non-malignant cells, including cancer-associated fibroblasts (CAFs), exhibit a secretory profile under stress conditions; this senescence-associated secretory ...phenotype (SASP) leads to cancer progression and chemoresistance. However, the role of senescent CAFs in metastatic lesions and the molecular mechanism of inflammation-related SASP induction are not well understood. We show that pro-inflammatory cytokine-driven EZH2 downregulation maintains the SASP by demethylating H3K27me3 marks in CAFs and enhances peritoneal tumor formation of gastric cancer (GC) through JAK/STAT3 signaling in a mouse model. A JAK/STAT3 inhibitor blocks the increase in GC cell viability induced by senescent CAFs and peritoneal tumor formation. Single-cell mass cytometry revealed that fibroblasts exist in the ascites of GC patients with peritoneal dissemination, and the fibroblast population shows p16 expression and SASP factors at high levels. These findings provide insights into the inflammation-related SASP maintenance by histone modification and the role of senescent CAFs in GC peritoneal dissemination.
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•EZH2 downregulation leads to SASP maintenance through depletion of H3K27me3 marks•Senescent CAFs in ascites of GC patients with peritoneal dissemination exhibit SASP•Senescent CAFs enhance the peritoneal tumor formation through JAK/STAT3 signaling•A JAK inhibitor blocks peritoneal tumor formation driven by systemic inflammation
Yasuda et al. show the fundamental mechanism by which inflammation-driven senescent CAFs enhance the peritoneal dissemination and the significance of targeting senescent CAFs as well as JAK/STAT3 signaling in GC cells. These findings provide a promising therapeutic approach for GC peritoneal dissemination driven by systemic inflammation.
Cancer‐associated fibroblasts (CAFs) are reportedly involved in invasion and metastasis in several types of cancer, including gastric cancer (GC), through the stimulation of CXCL12/CXCR4 signaling. ...However, the mechanisms underlying these tumor‐promoting effects are not well understood, which limits the potential to develop therapeutic targets against CAF‐mediated CXCL12/CXCR4 signaling. CXCL12 expression was analyzed in resected GC tissues from 110 patients by immunohistochemistry (IHC). We established primary cultures of normal fibroblasts (NFs) and CAFs from the GC tissues and examined the functional differences between these primary fibroblasts using co‐culture assays with GC cell lines. We evaluated the efficacy of a CXCR4 antagonist (AMD3100) and a FAK inhibitor (PF‐573,228) on the invasive ability of GC cells. High CXCL12 expression levels were significantly associated with larger tumor size, increased tumor depth, lymphatic invasion and poor prognosis in GC. CXCL12/CXCR4 activation by CAFs mediated integrin β1 clustering at the cell surface and promoted the invasive ability of GC cells. Notably, AMD3100 was more efficient than PF‐573,228 at inhibiting GC cell invasion through the suppression of integrin β1/FAK signaling. These results suggest that CXCL12 derived from CAFs promotes GC cell invasion by enhancing the clustering of integrin β1 in GC cells, resulting in GC progression. Taken together, the inhibition of CXCL12/CXCR4 signaling in GC cells may be a promising therapeutic strategy against GC cell invasion.
What's new?
The presence in the tumor stroma of cancer‐associated fibroblasts (CAFs) may be an indication of imminent tumor invasion and metastasis. CAFs appear to function through the stimulation of CXCL12/CXCR4 signaling, though precisely how these chemokines contribute to cancer progression is uncertain. Here, in gastric cancer cells, CXCL12/CXCR4 activation by CAF2 was found to enhance the clustering of integrin β1 at the cell surface and thereby promote gastric cancer cell invasiveness and motility. Increased invasiveness was suppressed by treatment with the CXCR4 antagonist, AMD3100, which blocked interactions between integrin β1 and the extracellular matrix.
Prognosis of severe heart failure remains poor. Urgent new therapies are required. Some heart failure patients do not respond to established multidisciplinary treatment and are classified as ..."non-responders". The outcome is especially poor for non-responders, and underlying mechanisms are largely unknown. Mitofusin-1 (Mfn1), a mitochondrial fusion protein, is significantly reduced in non-responding patients. This study aimed to elucidate the role of Mfn1 in the failing heart. Twenty-two idiopathic dilated cardiomyopathy (IDCM) patients who underwent endomyocardial biopsy of intraventricular septum were included. Of the 22 patients, 8 were non-responders (left ventricular (LV) ejection fraction (LVEF) of < 10% improvement at late phase follow-up). Electron microscopy (EM), quantitative PCR, and immunofluorescence studies were performed to explore the biological processes and molecules involved in failure to respond. Studies in cardiac specific Mfn1 knockout mice (c-Mfn1 KO), and in vitro studies with neonatal rat ventricular myocytes (NRVMs) were also conducted. A significant reduction in mitochondrial size in cardiomyocytes, and Mfn1, was observed in non-responders. A LV pressure overload with thoracic aortic constriction (TAC) c-Mfn1 KO mouse model was generated. Systolic function was reduced in c-Mfn1 KO mice, while mitochondria alteration in TAC c-Mfn1 KO mice increased. In vitro studies in NRVMs indicated negative regulation of Mfn1 by the β-AR/cAMP/PKA/miR-140-5p pathway resulting in significant reduction in mitochondrial respiration of NRVMs. The level of miR140-5p was increased in cardiac tissues of non-responders. Mfn1 is a biomarker of heart failure in non-responders. Therapies targeting mitochondrial dynamics and homeostasis are next generation therapy for non-responding heart failure patients.
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