Pathophysiological Roles of the cGAS-STING Inflammatory Pathway.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) inflammatory pathway is a component of the innate immune system that recognizes cytosolic nucleic acids. The pathway has been implicated in several processes including aging, autoinflammatory conditions, cancer, and metabolic diseases. The cGAS-STING pathway represents a promising therapeutic target in a variety of chronic inflammatory diseases.

Activation of Angiopoietin-Tie2 Signaling Protects the Kidney from Ischemic Injury by Modulation of Endothelial-Specific Pathways.

SIGNIFICANCE STATEMENT: Ischemia-reperfusion AKI (IR-AKI) is common and causes significant morbidity. Effective treatments are lacking. However, preclinical studies suggest that inhibition of angiopoietin-Tie2 vascular signaling promotes injury, whereas activation of Tie2 is protective. We show that kidney ischemia leads to increased levels of the endothelial-specific phosphatase vascular endothelial protein tyrosine phosphatase (VE-PTP; PTPRB), which inactivates Tie2. Activation of Tie2 through VE-PTP deletion, or delivery of a novel angiopoietin mimetic (Hepta-ANG1), abrogated IR-AKI in mice. Single-cell RNAseq analysis showed Tie2 activation promotes increased Entpd1 expression, downregulation of FOXO1 target genes in the kidney vasculature, and emergence of a new subpopulation of glomerular endothelial cells. Our data provide a molecular basis and identify a candidate therapeutic to improve endothelial integrity and kidney function after IR-AKI. BACKGROUND: Ischemia-reperfusion AKI (IR-AKI) is estimated to affect 2%-7% of all hospitalized patients. The significant morbidity and mortality associated with AKI indicates urgent need for effective treatments. Previous studies have shown activation of the vascular angiopoietin-Tie2 tyrosine kinase signaling pathway abrogates ischemia-reperfusion injury (IRI). We extended previous studies to (1) determine the molecular mechanism(s) underlying kidney injury and protection related to decreased or increased activation of Tie2, respectively, and (2) to test the hypothesis that deletion of the Tie2 inhibitory phosphatase vascular endothelial protein tyrosine phosphatase (VE-PTP) or injection of a new angiopoietin mimetic protects the kidney from IRI by common molecular mechanism(s). METHODS: Bilateral IR-AKI was performed in VE-PTP wild-type or knockout mice and in C57BL/6J mice treated with Hepta-ANG1 or vehicle. Histologic, immunostaining, and single-cell RNA sequencing analyses were performed. RESULTS: The phosphatase VE-PTP, which negatively regulates the angiopoietin-Tie2 pathway, was upregulated in kidney endothelial cells after IRI, and genetic deletion of VE-PTP in mice protected the kidney from IR-AKI. Injection of Hepta-ANG1 potently activated Tie2 and protected the mouse kidney from IRI. Single-cell RNAseq analysis of kidneys from Hepta-ANG1-treated and vehicle-treated mice identified endothelial-specific gene signatures and emergence of a new glomerular endothelial subpopulation associated with improved kidney function. Overlap was found between endothelial-specific genes upregulated by Hepta-ANG1 treatment and those downregulated in HUVECs with constitutive FOXO1 activation, including Entpd1 / ENTPD1 that modulates purinergic receptor signaling. CONCLUSIONS: Our data support a key role of the endothelium in the development of IR-AKI, introduce Hepta-ANG1 as a putative new therapeutic biologic, and report a model to explain how IRI reduces Tie2 signaling and how Tie2 activation protects the kidney. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_05_23_JSN_Ang_EP23_052323.mp3.

Activation of α7 nicotinic acetylcholine receptors attenuates monocyte-endothelial adhesion through FUT7 inhibition.

Cholinergic anti-inflammatory pathway (CAP) describes a neuronal-inflammatory reflex centered on systemic cytokine regulation by α7 nicotinic acetylcholine receptor (α7nAChR) activation of spleen-residue macrophage. However, the CAP mechanism attenuating distal tissue inflammation, inducing a low level of systemic inflammation, is lesser known. In this study, we hypothesized that CAP regulates monocyte accessibility by influencing their adhesion to endothelial cells. Using RNA-seq analysis, we identified that α1,3-Fucosyltransferase 7 (FucT-VII), the enzyme required for processing selectin ligands, was significantly downregulated by α7nAChR agonist among other cell-cell adhesion genes. The α7nAChR agonist inhibited monocytic cell line U-937 binding to P-selectin and adhesion to endothelial cells. Furthermore, α7nAChR agonist selectivity was confirmed by α7nAChR knockdown assays, showing that FUT7 inhibition and adhesion attenuation by the agonist was abolished by siRNA targeting α7nAChR encoding gene. Consistently, FUT7 knockdown inhibited the adhesive properties of U-937 and prevented them to adhere to endothelial cells. Overexpression of FUT7 also abrogated the adhesion attenuation induced by GTS-21 indicating that FUT7 inhibition was sufficient for inhibiting adhesion by α7nAChR activation. Our work demonstrated that α7nAChR activation regulates monocyte adhesion to endothelial cells through FUT7 inhibition, providing a novel insight into the CAP mechanism.

Decreased IFT88 expression with primary cilia shortening causes mitochondrial dysfunction in cisplatin-induced tubular injury.

The relevance of primary cilia shortening in kidney disease and its pathomechanism are largely unknown. Tubular damage in acute kidney injury (AKI) is strongly associated with mitochondrial dysfunction. Thus, we investigated the interaction between primary cilia and mitochondria in cisplatin-induced AKI mouse models. We observed that the expression of intraflagellar transport 88 (IFT88), a ciliary maintenance protein, was decreased in the renal cortex following tubular damage due to cisplatin-induced AKI. This result was consistent with the decreased IFT88 expression in cisplatin-treated RPTEC/TERT1 cells (human primary proximal tubular cells) parallel to the shortening of primary cilia, suggesting a causative link between tubular damage and IFT88-mediated cilia regulation. To address the effect of impaired primary cilia with decreased IFT88 expression on tubular function, RPTEC/TERT1 cells treated with cisplatin and knocked down for IFT88 using siRNA (IFT88-KD) were assessed for phenotypic changes and mitochondrial metabolic function. Both cisplatin and IFT88-KD caused primary cilia shortening, downregulated mitochondrial oxidative phosphorylation capacity, and had defective fatty acid oxidation and decreased ATP production. Furthermore, IFT88 overexpression enhanced mitochondrial respiration, which partially counteracted cisplatin-induced defective fatty acid oxidation. These results are indicative of the contribution of IFT88 to mitochondrial homeostasis. Our findings suggest that tubular mitochondrial dysfunction in cisplatin-induced AKI is mediated, at least in part, by a decrease in IFT88 expression with primary cilia shortening. That is, tubular mitochondrial damage followed by tubular injury in AKI may occur through alteration of IFT88 expression and subsequent ciliary shortening in tubular cells.NEW & NOTEWORTHY Here, we demonstrated organelle cross-talk between primary cilia and mitochondria of proximal tubular cells in cisplatin-induced acute kidney injury. The primary cilia-mitochondria interaction may open new avenues for the development of novel therapeutic approaches in the treatment of acute kidney injury.

The updated five-year overall survival and long-term oxaliplatin-related neurotoxicity assessment of the FACOS study.

PURPOSE: We previously reported the first evidence of oncological benefits from a Japanese phase II trial of oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (the FACOS study). We herein report the long-term survival and persistent oxaliplatin-related peripheral sensory neuropathy (PSN) for patients enrolled in this trial. METHODS: Patients were scheduled to receive the mFOLFOX6 or CAPOX regimen in the adjuvant setting. The five-year overall survival (OS) rate and persistent PSN were evaluated. RESULTS: A total of 130 patients (mFOLFOX6, n = 73; CAPOX, n = 57) were eligible. The 5-year OS rate was 91.4%. No significant difference in the OS rate was observed between regimens (mFOLFOX6, 94.4%; CAPOX, 87.4%; P = 0.25). The incidence of PSN during adjuvant treatment was 55.4% in grade 1 (G1), 30.0% in G2, and 4.6% in G3. No patients showed G3 PSN at 12 months, but G1 or G2 residual PSN after 5 years was observed in 21.8% (G1, 20%; G2, 1.8%). CONCLUSIONS: Updated results from the FACOS study support the benefits of oxaliplatin-based adjuvant chemotherapy in terms of the long-term survival among Japanese patients with stage III colon cancer. However, long-term persistent PSN occurs in about 20% of survivors, counterbalancing the favorable OS.

Organelle crosstalk in the kidney.

Organelle damage can cause various kidney diseases. In particular, organelle stress such as decreased proteostatic activity in the endoplasmic reticulum (ER) and altered energy metabolism in mitochondria contribute to glomerular and tubulointerstitial damage, resulting in the progression and development of kidney diseases. The ER regulates protein quality control via the unfolded protein response (UPR) pathway. Pathogenic ER stress leads to dysregulation of this pathway, and a maladaptive UPR is highly deleterious to renal cell function, and thereby has been implicated in the pathophysiology of various kidney diseases. The UPR pathway in the ER also regulates mitochondrial metabolic status, indicating the pathophysiological significance of organelle crosstalk between the ER and mitochondria via the UPR pathway. In recent years, it has become obvious that communication among organelles also is conducted through direct interactions at membrane contact sites (MCSs). Organelles exchange materials including lipids, ions, and proteins at the MCS. Accordingly, alterations to these networks, such as impaired ER-mitochondria MCSs, have been linked to several diseases such as neurodegeneration and diabetes. In this review, we describe the roles of organelles in kidney diseases and the mechanisms underlying organelle communication at the MCS, and especially at the mitochondria-associated ER membrane. Potential treatment options that are focused on organelle crosstalk are discussed, in addition to the relationship between this phenomenon and various diseases, especially kidney diseases.

ATF6α downregulation of PPARα promotes lipotoxicity-induced tubulointerstitial fibrosis.

Tubulointerstitial fibrosis is a strong predictor of progression in patients with chronic kidney disease, and is often accompanied by lipid accumulation in renal tubules. However, the molecular mechanisms modulating the relationship between lipotoxicity and tubulointerstitial fibrosis remain obscure. ATF6α, a transcription factor of the unfolded protein response, is reported to be an upstream regulator of fatty acid metabolism. Owing to their high energy demand, proximal tubular cells (PTCs) use fatty acids as their main energy source. We therefore hypothesized that ATF6α regulates PTC fatty acid metabolism, contributing to lipotoxicity-induced tubulointerstitial fibrosis. Overexpression of activated ATF6α transcriptionally downregulated peroxisome proliferator-activated receptor-α (PPARα), the master regulator of lipid metabolism, leading to reduced activity of fatty acid ß-oxidation and cytosolic accumulation of lipid droplets in a human PTC line (HK-2). ATF6α-induced lipid accumulation caused mitochondrial dysfunction, enhanced apoptosis, and increased expression of connective tissue growth factor (CTGF), as well as reduced cell viability. Atf6α-/- mice had sustained expression of PPARα and less tubular lipid accumulation following unilateral ischemia-reperfusion injury (uIRI), resulting in the amelioration of apoptosis; reduced expression of CTGF, α-smooth muscle actin, and collagen I; and less tubulointerstitial fibrosis. Administration of fenofibrate, a PPARα agonist, reduced lipid accumulation and tubulointerstitial fibrosis in the uIRI model. Taken together, these findings suggest that ATF6α deranges fatty acid metabolism in PTCs, which leads to lipotoxicity-mediated apoptosis and CTGF upregulation, both of which promote tubulointerstitial fibrosis.

A Japanese multicenter phase II study of adjuvant chemotherapy with mFOLFOX6/CAPOX for stage III colon cancer treatment after D2/D3 lymphadenectomy.

PURPOSE: A phase II trial was conducted to investigate the benefit of oxaliplatin-based adjuvant chemotherapy in Japanese stage III colon cancer patients. METHODS: Eligible patients were scheduled to receive 12 cycles of mFOLFOX6 or 8 cycles of CAPOX in adjuvant settings. The primary endpoint was the 3-year disease-free survival (DFS). Cox proportional hazards regression was performed to identify risk factors for a worse DFS. RESULTS: A total of 130 patients, including 73 patients receiving mFOLFOX6 and 57 patients receiving CAPOX, were enrolled from 16 institutions between April 2010 and April 2014. The 3-year DFS was 82.2%, exceeding the expected primary endpoint of 81.7%. The 3-year DFS tended to be higher in patients receiving mFOLOFOX6 than in those receiving CAPOX (mFOLFOX6, 86.3%; CAPOX, 76.9%; P = 0.06). The 3-year DFS rates did not differ markedly based on the risk stratification (T1/T2/T3 N1 vs. T4 or N2) indicated by the IDEA COLLABORATION study (P = 0.22). In the multivariate analysis, stage IIIC (P = 0.046) and early discontinuation (P < 0.01) were identified as independent significant risk factors for a worse DFS. CONCLUSION: Our findings represent the first positive results in a Japanese phase II trial of adjuvant chemotherapy with mFOLFOX6/CAPOX. Early discontinuation within 2 months was an independent risk factor for a shorter DFS.

Palmitate deranges erythropoietin production via transcription factor ATF4 activation of unfolded protein response.

Lipotoxicity plays an important role in the progression of chronic kidney damage via various mechanisms, such as endoplasmic reticulum stress. Several studies proposed renal lipotoxicity in glomerular and tubular cells but the effect of lipid on renal erythropoietin (EPO)-producing (REP) cells in the interstitium has not been elucidated. Since renal anemia is caused by derangement of EPO production in REP cells, we evaluated the effect of palmitate, a representative long-chain saturated fatty acid, on EPO production and the endoplasmic reticulum stress pathway. EPO production was suppressed by palmitate (palmitate-conjugated bovine serum albumin [BSA]) or a high palmitate diet, but not oleic acid-conjugated BSA or a high oleic acid diet, especially under cobalt-induced pseudo-hypoxia both in vitro and in vivo. Importantly, suppression of EPO production was not induced by a decrease in transcription factor HIF activity, while it was significantly associated with endoplasmic reticulum stress, particularly transcription factor ATF4 activation, which suppresses 3'-enhancer activity of the EPO gene. ATF4 knockdown by siRNA significantly attenuated the suppressive effect of palmitate on EPO production. Studies utilizing inherited super-anemic mice (ISAM) mated with EPO-Cre mice (ISAM-REC mice) for lineage-labeling of REP cells showed that ATF4 activation by palmitate suppressed EPO production in REP cells. Laser capture microdissection confirmed ATF4 activation in the interstitial area of ISAM-REC mice treated with palmitate-conjugated BSA. Thus, endoplasmic reticulum stress induced by palmitate suppressed EPO expression by REP cells in a manner independent of HIF activation. The link between endoplasmic reticulum stress, dyslipidemia, and hypoxia may contribute to development and progression of anemia in CKD.

Extended Sessions of Polymyxin-B Immobilized Fiber Column Hemoperfusion Ameliorate Renal Outcome and Mortality in Septic Shock with Acute Kidney Injury.

BACKGROUND/AIMS: Polymyxin-B (PMX) treatment has been reported to decrease mortality in patients with septic shock and acute kidney injury (AKI). In this study, we aimed to evaluate whether extended sessions of PMX (Ext-PMX) immobilized fiber column hemoperfusion ameliorate clinical outcomes in patients complicated with septic shock and AKI without surgical control. METHODS: Twenty-two patients with nonsurgical septic shock and AKI who received PMX were included. They were divided according to the duration of PMX treatment: Ext-PMX and standard PMX (Std-PMX). RESULTS: The mean blood pressure increased and inotrope requirement decreased within 24 h after PMX initiation. The median value of predicted mortality was 52.5%, and the -28-day mortalities in the Ext-PMX and Std-PMX groups were 44.4 and 75% respectively. Renal replacement therapy (RRT) was also initiated in 17 patients, and renal insufficiency was recovered. CONCLUSION: Ext-PMX combined with RRT improved clinical outcomes in patients with nonsurgical septic shock and AKI.

Analysis of the efficacy of direct hemoperfusion with polymyxin B-immobilized fiber (PMX-DHP) according to the prognostic factors in patients with colorectal perforation.

PURPOSE: Direct hemoperfusion with polymyxin B-immobilized fiber (PMX-DHP) has been reported to improve the outcomes in patients with colorectal perforation. We retrospectively identified prognostic factors in patients with colorectal perforation and considered the efficacy of PMX-DHP based on these prognostic factors. METHODS: One hundred and fifty-six patients who underwent surgery for colorectal perforation in our department between November 1995 and March 2011 were enrolled in this study. The clinicopathological factors were compared between the survivor and non-survivor groups. RESULTS: There were 28 patients (17.9 %) who died within 28 days after surgery. According to the multivariate analysis, an Acute Physiology and Chronic Health Evaluation II (APACHE II) score of 17 or more was a significant independent prognostic factor (P = 0.002, odds ratio = 5.39). There was a significant difference in the survival rates between the patients with APACHE II scores of 16 or less and those with scores of 17 or more who had received the PMX-DHP (+) (P < 0.0001). CONCLUSION: The APACHE II score is useful as a prognostic factor in patients with colorectal perforation, and the survival rate was 50 % or lower among the patients with APACHE II scores of 17 or higher. Therefore, PMX-DHP appears to have limited efficacy in serious cases.

Intraoperative blood transfusion contributes to decreased long-term survival of patients with esophageal cancer.

BACKGROUND: Several prognostic factors for patients who have undergone esophagectomy owing to esophageal squamous cell carcinoma have been suggested, including intraoperative blood loss. There are few data, however, suggesting such an association with the prognosis following radical esophagectomy. METHODS: Patients with esophageal squamous cell carcinoma who underwent radical esophagectomy were divided into two groups based on the median value of the intraoperative blood loss (510 g). A multivariate Cox proportional-hazard regression analysis was performed to determine if intraoperative blood loss could be an independent prognostic factor for long-term survival following radical esophagectomy. Kaplan-Meier survival analysis with a log-rank test was performed between the groups. RESULTS: From April 2005 to May 2009, a total of 37 patients underwent radical esophagectomy for the treatment of esophageal squamous cell carcinoma at the Juntendo Shizuoka Hospital and were assigned either to one of two groups: those with ≥510 g blood loss [bleeding group (BG), n = 19] or of those with <510 g blood loss [less bleeding group (LBG), n = 18]. The distribution of the stage of disease, the number of positive lymph nodes, and the presence of lymphatic and vascular invasion was comparable between the groups, but the Kaplan-Meier survival analysis demonstrated that survival was significantly worse in the BG group than in the LBG group (p = 0.00295). This was supported by the multivariate analysis, which indicated that intraoperative blood loss was independently associated with long-term survival after radical esophagectomy. CONCLUSIONS: Intraoperative blood loss could be a useful prognostic factor following radical esophagectomy in patients with esophageal squamous cell carcinoma.

Complete wedge resection for duodenal gastrointestinal stromal tumour: A case series of three patients.

INTRODUCTION: Duodenal gastrointestinal stromal tumours (GIST) are rare. Therefore, difficulties are experienced when selecting the appropriate surgical procedure in patients with duodenal GISTs. This report presents the cases of three patients with duodenal GISTs who underwent wedge resection. This report would help surgeons identify clinical features and surgical procedures in patients with duodenal GISTs. PRESENTATION OF CASE: Three patients were diagnosed with duodenal submucosal tumours. The first patient presented with melena, the second with postoperative anaemia, and the third with an incidental finding of a large abdominal tumour after presenting with ischaemic colitis. All tumours arose in the 2nd portion of the duodenum and measured 3.5, 3, and 9.2 cm, respectively. Wedge resection of the duodenum was performed in all patients. In patients one and two, simple closure of duodenal wall was performed after wedge resection. In patient three, side-to-side anastomosis with the jejunum was performed because a large area of the wall was removed using the wedge resection technique. Pancreatoduodenectomy was avoided in all patients. Recurrence was not noted in any patient. DISCUSSION: Since GISTs are not generally associated with lymph node metastasis, local resection with negative margins is sufficient to surgically manage patients with GISTs. CONCLUSION: Our results indicated the effectiveness of performing wedge resection for duodenal GISTs not in close proximity to the ampulla of Vater. Moreover, less invasive procedures should be adopted in patients with duodenal GISTs.

Signet-ring cell carcinoma co-existing with adenocarcinoma of the ampulla of vater. A case report.

CONTEXT: We report a case of signet-ring cell carcinoma admixed with adenocarcinoma of the ampulla of Vater. Signet-ring cell carcinoma of the ampulla of Vater is rarely encountered in clinical practice. CASE REPORT: A 78-year-old man was admitted to our hospital with jaundice. Computed tomography demonstrated dilatation of the biliary tract and an enhanced mass lesion measuring 1.5 cm in the pancreatic head. Endoscopic examination showed a reddish swollen papilla of Vater, and the pathological findings on a biopsy from the papilla suggested signet-ring cell carcinoma. A pancreaticoduodenectomy was performed with a diagnosis of carcinoma of the ampulla of Vater. Postoperative pathological examination showed that the tumor was composed of signet-ring cell carcinoma and tubular adenocarcinoma. The signet-ring cell carcinoma had infiltrated to the duodenal wall and pancreatic parenchyma. Both the signet-ring cell carcinoma and the adenocarcinoma were positive on immunohistochemical staining with 45M1. CONCLUSION: Several cases of signet-ring cell carcinoma of the ampulla of Vater have previously been reported. In our case, the histological origin of both signet-ring cell and adenocarcinoma was hypothesized to have been pancreaticobiliary epithelial cells.

Direct hemoperfusion with polymyxin B immobilized fiber for abdominal sepsis in Europe.

Since direct hemoperfusion with polymyxin B immobilized fiber (PMX-DHP) received its product certification for use in Europe in 1998, several prospective randomized controlled trials (RCTs) have been conducted in European countries. The first RCT, performed in six European academic medical centers in 2005, concluded that PMX-DHP is associated with improved hemodynamic status and cardiac function. Subsequently, a meta-analysis of PMX-DHP was presented in Italy in 2007. This systematic review found positive effects of PMX-DHP on mean arterial pressure and dopamine/ dobutamine use, PaO2/FiO2 ratio, endotoxin removal, and mortality. However, like most trials on extracorporeal therapies, none of the studies was double-blinded. The EUPHAS study, a multicenter RCT performed in ten Italian intensive care units in 2009, found that PMX-DHP improved 28-day survival, blood pressure, vasopressor requirement, and degree of organ failure. However, investigators in Belgium and Canada pointed out that there was no statistical difference in 28-day survival. Two more RCTs, the ABDO-MIX and EUPHRATES studies, the primary end points of which are 28-day mortality, were started in Europe and the United States at the end of 2010. We are hoping that these RCTs will resolve this issue.

Immunotactoid Glomerulopathy with Nontuberculous Mycobacterial Infection: A Novel Association.

A 70-year-old woman underwent a renal biopsy due to nephrotic syndrome. She had suffered from nontuberculous mycobacterial infection (NTM) for 14 years. The patient was diagnosed as having membranoproliferative glomerulonephritis (MPGN) type 3 and immunoglobulin (Ig)-associated MPGN based upon LM/erythromycin and IF findings, respectively. In high-magnification imaging, electron-dense deposits showed immunotactoid glomerulopathy (ITG). There was no evidence of hematological cancer, and the patient improved after receiving treatments for NTM. To the best of our knowledge, this patient is the first to show an association between ITG and NTM. Although ITG is generally considered as related to lymphoproliferative disease, it is suggested that ITG is driven by bacterial infection and is a potential outcome of Ig-associated MPGN.

Alu-derived cis-element regulates tumorigenesis-dependent gastric expression of GASDERMIN B (GSDMB).

GASDERMIN B (GSDMB) belongs to the novel gene family GASDERMIN (GSDM). All GSDM family members are located in amplicons, genomic regions often amplified during cancer development. Given that GSDMB is highly expressed in cancerous cells and the locus resides in an amplicon, GSDMB may be involved in cancer development and/or progression. However, only limited information is available on GSDMB expression in tissues, normal and cancerous, from cancer patients. Furthermore, the molecular mechanisms that regulate GSDMB expression in gastric tissues are poorly understood. We investigated the spatiotemporal expression patterns of GSDMB in gastric cancer patients and the 5' regulatory sequences upstream of GSDMB. GSDMB was not expressed in the majority of normal gastric-tissue samples, and the expression level was very low in the few normal samples with GSDMB expression. Most pre-cancer samples showed moderate GSDMB expression, and most cancerous samples showed augmented GSDMB expression. Analysis of genome sequences revealed that an Alu element resides in the 5' region upstream of GSDMB. Reporter assays using intact, deleted, and mutated Alu elements clearly showed that this Alu element positively regulates GSDMB expression and that a putative IKZF binding motif in this element is crucial to upregulate GSDMB expression.

Jejunal cancer detected after a resection of bilateral ovarian metastasis: report of a case.

A 50-year-old woman was admitted to our hospital because of abdominal distension and fullness. Computed tomography and magnetic resonance imaging showed bilateral ovarian tumors. Although these ovarian tumors were suspected of being metastatic, the primary tumor site could not be detected before the bilateral salpingo-oophorectomy. At the time of laparotomy, there was no apparent peritoneal dissemination or ascites. The pathological findings suggested that the ovarian tumors were metastases from cancer of the digestive tract. Positron emission tomography using (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and double-balloon enteroscopy detected jejunal cancer. A second laparotomy for the resection of jejunal cancer was performed. The patient received adjuvant chemotherapy, and there has not been any recurrence for 24 months since the resection was performed. In conclusion, FDG-PET was found to play a valuable role in the detection of the primary tumor. Intensive chemotherapy and surgical treatment also contributed to the long-term survival of the patient.

Analysis of the methylation of CpG islands in the CDO1, TAC1 and CHFR genes in pancreatic ductal cancer.

No difference in the gene methylation status of tumor-suppression genes between pancreatic cancer tissues and adjacent non-cancer tissues is observed. The present study investigated whether the promoter CpG islands of the cysteine dioxygenase 1 (CDO1), tachykinin precursor 1 (TAC1) and checkpoint with forkhead and ring finger domains (CHFR) genes were methylated in pancreatic cancer and adjacent non-cancerous pancreatic tissue in order to determine if they could be considered as markers for the detection of pancreatic cancer. A total of 38 Formalin-fixed and paraffin-embedded pancreatic adenocarcinoma tissues and their adjacent non-cancerous specimens from patients with pancreatic cancer, as well as 9 non-cancerous pancreatic samples from patients without pancreatic adenocarcinoma were obtained following surgical resection. The hypermethylation of CpG islands was detected using a methylation-specific quantitative PCR. The methylation values were calculated using the ∆Cq method and were expressed as 2-ΔCq. The 2-ΔCq value of the CDO1 promoter from pancreatic adenocarcinoma specimens was significantly higher compared with that of adjacent non-cancerous and tumor-free pancreatic tissues (P<0.0001 and P=0.0008, respectively). The 2-ΔCq value of the TAC1 promoter of pancreatic adenocarcinoma was also significantly higher compared with that of adjacent non-cancerous tissues and tumor-free pancreatic samples (both P<0.0001). However, there was no significant difference in the 2-ΔCq value of the CHFR promoter among the pancreatic cancer, adjacent non-cancer tissue and tumor-free pancreatic samples. Furthermore, 12 out of the 38 pancreatic adenocarcinoma cases (31.6%) presented some methylation in the CHFR promoter. The results from Kaplan-Meier analysis between CHFR promoter methylation values and the clinicopathological characteristics of patients with pancreatic adenocarcinoma demonstrated that CHFR promoter methylation was significantly associated with lymph node metastasis. The methylation values of CDO1 and TAC1 promoters in cancer tissues were higher compared with adjacent tissues. However, whether hypermethylation of CDO1 and TAC1 promoters may serve as a biomarker in the diagnosis of pancreatic adenocarcinoma remains unclear.

Workforce and Contents of Home Dental Care in Japanese Insurance System.

BACKGROUND: In Japan's super-aging society, it is required to establish a home dental service provision system. It is necessary to analyze the current state of visiting dentistry. METHODS: A cross-sectional survey was conducted using a self-administered postal mail questionnaire distributed to all members of the Iwate Dental Association. We analyzed the implementation status of dental care at home/nursing facilities, the number of dental clinic staff, and the contents of dental home care. Correspondence analysis, item response theory, and zero-inflated model were used for the analysis. RESULTS: Of the 354 dental clinics, 187 (52.8%) performed visiting dental care and 195 (55.1%) implemented dental care in a nursing home. Visit dentistry was mainly performed by part-time workers. Denture treatment and oral care were common treatments for dental home care. CONCLUSION: More than half of the dental clinics did not offer visiting dentistry. In order to fully provide dental visiting services, infrastructure development is necessary. Specifically, human resources are most important, even if they are part-time workers.