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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.
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Neoplasias , Transdução de Sinais , Humanos , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Imunidade InataRESUMO
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.
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Injúria Renal Aguda , Células Endoteliais , Camundongos , Animais , Células Endoteliais/metabolismo , Angiopoietinas/metabolismo , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/metabolismo , Camundongos Endogâmicos C57BL , Endotélio/metabolismo , Rim/metabolismo , Transdução de Sinais , Receptor TIE-2/genética , Angiopoietina-1/uso terapêutico , Camundongos Knockout , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/metabolismo , Isquemia/complicações , Isquemia/metabolismoRESUMO
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.
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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.
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Injúria Renal Aguda/metabolismo , Cílios/metabolismo , Cisplatino/farmacologia , Proteínas Supressoras de Tumor/metabolismo , Injúria Renal Aguda/induzido quimicamente , Animais , Apoptose/genética , Apoptose/fisiologia , Cílios/genética , Cisplatino/metabolismo , Células Epiteliais/metabolismo , Túbulos Renais/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Supressoras de Tumor/genéticaRESUMO
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.
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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.
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Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/mortalidade , Síndromes Neurotóxicas/epidemiologia , Síndromes Neurotóxicas/etiologia , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Doenças do Sistema Nervoso Periférico/etiologia , Células Receptoras Sensoriais , Adulto , Idoso , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Colo/patologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Doenças do Sistema Nervoso Periférico/epidemiologia , Taxa de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
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.
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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.
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Injúria Renal Aguda/complicações , Estresse do Retículo Endoplasmático/fisiologia , Retículo Endoplasmático/metabolismo , Insuficiência Renal Crônica/etiologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/fisiopatologia , Animais , Progressão da Doença , Humanos , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologiaRESUMO
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.
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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.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/cirurgia , Excisão de Linfonodo , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Capecitabina/administração & dosagem , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Japão , Leucovorina/administração & dosagem , Excisão de Linfonodo/métodos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina/administração & dosagem , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores de Tempo , Suspensão de Tratamento/estatística & dados numéricosRESUMO
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.
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OBJECTIVES: To investigate the effect of left colonic artery (LCA) preservation on laparoscopic sigmoidectomy outcomes METHODS: We identified 447 consecutive patients who underwent laparoscopic sigmoidectomy at our hospital group between January 2010 and December 2016. We divided the patients into groups with and without LCA preservation and with and without anastomotic leakage (AL). We compared the patient age and gender, tumor location, stage, D2/D3 lymph node dissection, comorbidities, operating time, and blood loss between these groups. Univariate and multivariate analyses were performed to determine the risk factors for AL. RESULTS: There were significant differences in age, sex, tumor location, D2/D3 lymph node dissection, hypertension, operating time, blood loss, and AL for groups with and without LCA preservation. There were significant differences in sex, tumor location, and LCA preservation for groups with and without AL. Multivariate analysis showed male sex (hazard ratio (HR) = 6.37, 95% confidence interval (CI) 2.39-20.6; p < 0.0001), non-LCA preservation (HR = 5.01, 95% CI 1.41-31.8.0; p = 0.01), and rectosigmoidal tumor location (HR = 2.51, 95% CI 1.15-5.61; p = 0.01) as significant independent risk factors for AL. CONCLUSIONS: Based on the results obtained by performing laparoscopic operation for sigmoid colon cancer and rectosigmoid cancer, the LCA preservative procedure is warranted for prevention of AL.
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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.
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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.
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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.
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Fator 4 Ativador da Transcrição/metabolismo , Anemia/patologia , Eritropoetina/metabolismo , Rim/metabolismo , Palmitatos/metabolismo , Fator 4 Ativador da Transcrição/genética , Anemia/sangue , Anemia/etiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Eritropoetina/sangue , Eritropoetina/genética , Técnicas de Silenciamento de Genes , Células Hep G2 , Humanos , Microdissecção e Captura a Laser , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno/metabolismo , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/patologia , Resposta a Proteínas não DobradasRESUMO
The prevalence of chronic kidney disease (CKD), characterized by progressive renal dysfunction with tubulointerstitial fibrosis, is increasing because of societal aging. Uremic toxins, accumulated during renal dysfunction, cause kidney damage, leading to renal deterioration. A recent metabolomic analysis revealed that plasma D-serine accumulation is associated with faster progression of renal dysfunction in CKD patients. However, the causal relationship and the underlying mechanisms remain unclear. Herein, we demonstrated that D-serine markedly induced cellular senescence and apoptosis in a human proximal tubular cell line, HK-2, and primary culture of human renal tubular cells. The former was accompanied by G2/M cell cycle arrest and senescence-associated secretory phenotype, including pro-fibrotic and pro-inflammatory factors, contributing to tubulointerstitial fibrosis. Integrated stress response mediated by the general control nonderepressible 2 played an important role in D-serine-induced tubular cell toxicity and pro-fibrotic phenotypes, accelerating CKD progression and kidney aging. D-serine upregulated the L-serine synthesis pathway. Furthermore, D-serine-induced suppression of tubular cell proliferation was ameliorated by L-serine administration, indicating that D-serine exposure induced an L-serine-deprived state in tubular cells, compensated by L-serine synthesis. Thus, this study unveils molecular mechanisms underlying D-serine-induced tubular damage and pro-fibrotic phenotypes, suggesting that D-serine is a uremic toxin involved in CKD pathogenesis.
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Envelhecimento/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Nefropatias/fisiopatologia , Túbulos Renais Proximais/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Serina/metabolismo , Apoptose , Pontos de Checagem do Ciclo Celular , Células Cultivadas , Células Epiteliais/patologia , Humanos , Túbulos Renais Proximais/patologiaRESUMO
BACKGROUND: Although segmental arterial mediolysis (SAM) has been increasingly recognized as arteriopathy and there are some case reports about SAM, it is still very rare. It is characterized clinically by aneurysm, dissection, stenosis, and occlusion within splanchnic arterial branches, causing intra-abdominal hemorrhage or bowel ischemia. Mortality is as high as 50% in acute events. CASE PRESENTATION: A 51-year-old man was referred to our hospital with hematemesis. Gastroscopy revealed a submucosal-like tumor on the posterior wall of gastric angle with ulceration. Computed tomography indicated a tumor measuring 65 × 50 mm in the stomach, which was suspected to have invaded into the pancreas. Significant hematemesis recurred; the patient developed shock and underwent emergency distal gastrectomy, distal pancreatectomy, and splenectomy. The pathology and the clinical course were compatible with SAM splenic artery rupture causing retroperitoneal hemorrhage that penetrated into the stomach. After that surgery, aneurysm of common hepatic artery ruptured and coil embolization was performed. CONCLUSION: SAM is an important cause of intra-abdominal or retroperitoneal hemorrhage in patients without underlying disease. SAM typically presents as intra-abdominal hemorrhage, but, in this case, the retroperitoneal hemorrhage penetrated into the stomach and it looked like a submucosal tumor.
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INTRODUCTION: The laparoscopic resection of colorectal cancer and laparoscopic liver surgery are widely considered to be safe. Recently, it has been reported that the simultaneous laparoscopic resection of primary colorectal cancer and liver metastasis is technically feasible and safe when it is performed at experienced centers. However, the feasibility of simultaneous laparoscopic procedures for colorectal cancer and synchronous colorectal liver metastases in elderly patients has not been studied sufficiently. In this study, two cases in which elderly patients with colorectal cancer and synchronous liver metastases were treated with simultaneous laparoscopic resection are reported. PRESENTATION OF CASES: An 83-year-old female was diagnosed with ascending colon cancer and synchronous hepatic metastases. Simultaneous laparoscopic resection of the primary colon cancer and the liver metastasis was performed. Another tiny hepatic metastasis was subsequently detected in the right hepatic lobe. It was treated with hand-assisted radiofrequency ablation (RFA). The total operative time was 470min, and 340g of intraoperative blood loss occurred. The other case involved a 78-year-old male who was diagnosed with ascending colon cancer and synchronous hepatic metastasis in the right hepatic lobe. Simultaneous laparoscopic resection of the primary colon tumor and liver metastasis was performed. The total operative time was 471min, and 240g of intraoperative blood loss occurred. The postoperative courses of both patients were uneventful. DISCUSSION AND CONCLUSION: Our results indicate that simultaneous laparoscopic resection of colorectal cancer and synchronous liver metastases is feasible and safe in elderly patients.
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BACKGROUND/OBJECTIVE: Patients on hemodialysis (HD) who undergo abdominal surgery for gastrointestinal disease are at increased risk of postoperative complications. In this study, we retrospectively investigated the predictors of postoperative complications among such patients. METHODS: The study group comprised 36 HD patients who underwent abdominal surgery for gastrointestinal disease between 2003 and 2012. The clinicopathological factors of the patients who did and did not suffer postoperative complications were compared. RESULTS: The overall morbidity and mortality rates were 39% (14/36) and 14% (5/36), respectively. Physical status according to the American Society of Anesthesiologists (ASA) classification (p = 0.0203) and intraoperative blood loss (p = 0.0013) were found to differ significantly between the groups. CONCLUSION: The morbidity and mortality rates of HD patients who underwent abdominal surgery for gastrointestinal disease were high. Physical status according to the ASA classification and intraoperative blood loss were found to be associated with postoperative complications. Therefore, patients with comorbidities, such as heart disease and diabetes mellitus, have to be treated appropriately before surgery. In addition, it is important that surgeons perform operations carefully and avoid excessive blood loss.
Assuntos
Abdome/cirurgia , Gastroenteropatias/cirurgia , Complicações Pós-Operatórias/etiologia , Diálise Renal , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
Background. Despite complete resection of gastrointestinal stromal tumors (GIST), recurrent and/or metastatic disease occurs, often depending on the grade of malignancy. As such, markers are needed that accurately predict patients at high risk for recurrence. Previously our group reported Pfetin as a prognostic biomarker for GIST. In order to create an approach for predicting risk of recurrence, we incorporated Pfetin expression with clinicopathological data to produce a predictive model. Object. Forty-five patients with localized primary GIST were treated with complete gross surgical resection surgically at our institution between 1995 and 2010 were included. The majority of tumors originated in the stomach (38 cases), as well as small intestine (6 cases) and rectum (1 case). Method. (1) We performed retrospective analysis of the connection between Pfetin expression, clinicopathological data, and incidences of recurrence, using bivariate and multivariate analyses. (2) The reactivity of the monoclonal antibody against Pfetin was examined by immunohistochemistry. Pfetin. We have reported Pfetin, identified microarray technology, and compared between statistically different GISTs for good and poor prognoses and for prognostic marker. Results. There were 7 cases of recurrences. (1) By univariate analysis, tumor size, mitoses, exposure to abdominal cavity, and complete tumor removal predicted risk of recurrence. (2) Pfetin-negative cases were significantly related to recurrence (P = 0.002). Conclusions. This analysis demonstrates that lack of Pfetin expression is an additional predictor of recurrence in resected GIST. Further study may determine the role of this variable added to the current predictive model for selection of adjuvant therapy.