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.

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.

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.

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.

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.

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.

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.

A Case of Laparoscopic-Assisted Percutaneous Endoscopic Gastrostomy (LAPEG) for Gastric Volvulus.

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) is the standard modality for long-term enteral nutrition for patients with dysphagia. Compared with open gastrostomy, though PEG is an extremely safe procedure with fewer complications, there are severe cases due to anatomical features. For these cases, laparoscopic-assisted percutaneous endoscopic gastrostomy (LAPEG) is the optimal method. CASE PRESENTATION: A 52-year-old man had a disturbance in swallowing because of cerebral infarction. We attempted PEG under gastrointestinal fiberscope (GIF) and colon fiberscope inspection; however, the procedure was unsuccessful because it was impossible to move the transverse colon downward. We therefore attempted LAPEG to observe the stomach and other organs. Under laparoscopic observation, we diagnosed gastric volvulus, classified as the organo-axial type. For this reason, inserting the tube through the skin was very difficult. We easily corrected the gastric volvulus by using laparoscopic forceps and were finally able to place the PEG tube safely. DISCUSSION: Gastric volvulus is rare in clinical practice. The treatment of gastric volvulus depends on whether mucosal ischemia is present. Endoscopic reduction of gastric volvulus is effective for many patients. Surgical treatment should be considered for patients with gastric volvulus that frequently recurs. In our patient, completely inserting the GIF was impossible; therefore, we could not correctly diagnose gastric volvulus. Laparoscopy-assisted PEG is a useful and safe technique for placing a gastrostomy tube in patients presenting with anatomical difficulties. Moreover, in our patient, gastropexy was performed with PEG. Therefore, LAPEG may be used to prevent the recurrence of gastric volvulus. Gastropexy is a useful option in LAPEG. CONCLUSIONS: Laparoscopy has the advantage of allowing a direct inspection of the stomach while gastrostomy is performed and may reveal complications to PEG insertion. Furthermore, in our patient, gastropexy was performed with PEG.

Pathophysiological Role of Organelle Stress/Crosstalk in AKI-to-CKD Transition.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are interconnected syndromes that represent a global public health challenge. Organelles play essential roles in a vast range of cell functions, and their damage is related to several kidney diseases. Organelles launch the stress signal or trigger the stress response, and organelles interact with each other through a phenomenon termed organelle crosstalk. The endoplasmic reticulum (ER) is a major organelle that controls protein synthesis, folding, and degradation via the unfolded protein response pathway. Renal pathogenic conditions, such as chronic hypoxia, induce a maladaptive unfolded protein response pathway (ER stress) in the kidney, leading to progression of AKI and CKD. Mitochondria have an essential role in producing adenosine triphosphate for maintaining the cellular/organelle functions, including protein homeostasis in the ER. Thus, mitochondrial dysfunction also can induce ER stress (altered protein homeostasis) and subsequent cellular damage. Recent evidence has shown that ER or mitochondrial dysfunction disrupts the organelle crosstalk between mitochondria and ER in the kidney. Such alterations of ER-mitochondria crosstalk might contribute to the progression of AKI to CKD. Mitochondrial injury induces aberrant tubular inflammation, which is one of the major fibrotic processes. We recently found that a novel tubular inflammatory pathway that is activated specifically by the interaction of mitochondrial DNA with the ER membrane molecule triggers the progression of tubular inflammation in AKI. Thus, there is accumulating evidence for the pathophysiologic importance of organelle crosstalk, especially mitochondria-ER crosstalk. Organelle stress and crosstalk can serve as potential therapeutic targets for the prevention of AKI-to-CKD transition.

Detection of gene mutations in gastric cancer tissues using a commercial sequencing panel.

Predicting malignancy is important for adequate adjuvant therapy in patients with cancer. Due to cancer being a genetic disease, the detection of gene mutations could be helpful in predicting the prognosis and efficacy of drugs. Gastric cancer is the fifth most common cancer and is the third leading cause of cancer associated mortality worldwide. Mutations in genes may correlate with clinical information in patients with gastric cancer after surgery and, therefore, may be useful for predicting the prognosis of this disease. In the present study, to assess the usefulness of a commercial sequencing panel, TruSeq® Amplicon-Cancer Panel (Illumina), using a next-generation sequencer (Illumina MiSeq), mutation analysis of fresh as well as formalin-fixed paraffin-embedded (FFPE) gastric cancer tissues was performed retrospectively. The study group comprised of 4 patients who underwent gastrectomy for gastric cancer. Cancer and normal stomach tissues were collected immediately following surgical removal. Thereafter, the specimens were fixed in 10% neutral formalin for 24-72 h. Normal and FFPE cancer tissues were histologically examined and confirmed. A total of 3 mutations were identified in the driver genes (KRAS, TP53 and APC) in cancer tissues from 2 of the 4 patients, using fresh samples. In addition, FFPE samples were analysed for the same tissues and the same results were obtained by setting the threshold for the percentage of the mutation rate to avoid detection of pseudo-positive mutations. In conclusion, the sequencing analysis using FFPE-derived DNA samples was successfully performed.

Mitochondrial Damage Causes Inflammation via cGAS-STING Signaling in Acute Kidney Injury.

Acute kidney injury (AKI) is characterized by mitochondrial dysfunction and activation of the innate immune system. The cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway detects cytosolic DNA and induces innate immunity. Here, we investigate the role of mitochondrial damage and subsequent activation of the cGAS-STING pathway using a genetically engineered animal model of cisplatin-induced AKI and cultured tubular cells. Cisplatin induced mtDNA leakage into the cytosol-probably through BCL-2-like protein 4 (BAX) pores in the mitochondrial outer membrane-in tubules, with subsequent activation of the cGAS-STING pathway, thereby triggering inflammation and AKI progression, which is improved in STING-deficient mice. STING knockdown in cultured tubular cells ameliorates inflammatory responses induced by cisplatin. mtDNA depletion and repletion studies support tubular inflammatory responses via the cGAS-STING signal activation by cytosolic mtDNA. Therefore, we conclude that mitochondrial dysfunction and subsequent activation of the mtDNA-cGAS-STING pathway is a critical regulator of kidney injury.

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.

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.

Aneurysms of Pancreaticoduodenal Artery due to Median Arcuate Ligament Syndrome, Treated by Open Surgery and Laparoscopic Surgery.

INTRODUCTION: There are many possible causes of an abdominal visceral aneurysm, including the obstruction of the celiac artery by the median arcuate ligament (MAL). We report two cases of an aneurysm of the pancreaticoduodenal artery due to MAL syndrome that we treated surgically. CASE PRESENTATION: Case 1: a 66-year-old Japanese woman was diagnosed with a rupture of an aneurysm of the inferior pancreaticoduodenal artery. Because of the difficulty of endovascular therapy, we performed an emergency operation. We chose an abdominal operation, and the postoperative course was uneventful. Case 2: a 75-year-old Japanese man presented at our hospital with acute abdominal pain, nausea, and cold sweat. Our experience of treating MAL syndrome in case 1 enabled us to diagnose the disease accurately. We chose laparoscopic surgery, and the postoperative course was uneventful. DISCUSSION: There are several treatment choices for an aneurysm of the pancreaticoduodenal artery due to MAL syndrome. We have performed only a release of the MAL for treatment, but it is difficult to conclude whether only releasing the MAL is enough to ensure a positive long-term prognosis. Regular follow-up is needed in such cases. CONCLUSION: Laparoscopic surgery can be considered one of the options for MAL syndrome.

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.

Group A Streptococcal Toxic Shock-Like Syndrome in a Male Presenting as Primary Peritonitis: A Case Report and a Review in Japan.

BACKGROUND: Streptococcal toxic shock-like syndrome (TSLS) is a severe infection caused by group A hemolytic streptococcus. It is clinically characterized by rapidly progressive septic shock and multiple organ failure within just a few hours. TSLS presenting as primary peritonitis is rare, especially in a male. Herein, we report a case of TSLS in a male presenting with primary peritonitis, with a review of 25 cases in Japan. CASE PRESENTATION: A 51-year-old male was referred to our hospital with abdominal pain and hypotension. We made a preoperative diagnosis of peritonitis with septic shock and performed an emergency operation. Intraoperative findings indicated no marked origin of the peritonitis. Preoperative blood culture showed the presence of group A hemolytic streptococcus. The patient required intensive care involving artificial respiration, abdominal drainage and cytokine absorption therapy, and was discharged on postoperative day 25. CONCLUSION: TSLS in a male presenting as primary peritonitis is rare. Although this condition is a severe infection, it can be treated by multimodal therapy.

Abdominoperineal Resection for Unexpected Distal Intramural Spreading of Rectal Cancer.

INTRODUCTION: In rectal cancer, distal intramural spread may sometimes occur, but a maximum extent of distal spread of > 6 cm is very rare. CASE PRESENTATION: A 65-year-old Japanese male with an advanced rectal cancer tumor with para-aortic lymph node metastasis was admitted. We performed a low anterior resection with lymphadenectomy, but the intraoperative frozen-section analysis of margins revealed malignant cell positivity; we, therefore, performed an abdominoperineal resection. Pathological findings showed that the maximum extent of distal spread was 6 cm. After 12 courses of FOLFOX4 as adjuvant chemotherapy, abdominal computed tomography revealed whole lymph node metastases, including Virchow's node. Though FOLFIRI + panitumumab was started, he was not eligible for additional chemotherapy after 10 cycles. CONCLUSION: An intraoperative frozen pathology examination was helpful for the additional resection, when unexpected distal spreading had occurred in rectal cancer. The evidence of a distal negative margin should not be underestimated.

Mixed Neuroendocrine Carcinoma and Squamous Cell Carcinoma of the Colon: Case Report and Literature Review.

Neuroendocrine carcinoma (NEC) of the colon is very rare, and squamous cell carcinoma (SCC) of colon cancer is rare. We recently treated a patient with both NEC and SCC that initially presented as multiple unresectable liver and lung metastases. A 68-year-old Japanese man was referred to our hospital because of diarrhea with descending colon cancer obstruction. He underwent a left colectomy. Based on immunohistochemistry results, we diagnosed mixed NEC and SCC, the primary lesion location of which was probably the lung in the final pathologic examination. He began systemic palliative chemotherapy with CDDP and CPT-11. After 3 months of treatment, shown the progressive disease, we started CDDP and VP-16. The patient was not eligible for additional chemotherapy after 2 months.