Potential of Modulating Aldosterone Signaling and Mineralocorticoid Receptor with microRNAs to Attenuate Diabetic Kidney Disease.

Diabetic Kidney Disease (DKD) is a significant complication of diabetes and primary cause of end-stage renal disease globally. The exact mechanisms underlying DKD remain poorly understood, but multiple factors, including the renin-angiotensin-aldosterone system (RAAS), play a key role in its progression. Aldosterone, a mineralocorticoid steroid hormone, is one of the key components of RAAS and a potential mediator of renal damage and inflammation in DKD. miRNAs, small noncoding RNA molecules, have attracted interest due to their regulatory roles in numerous biological processes. These processes include aldosterone signaling and mineralocorticoid receptor (MR) expression. Numerous miRNAs have been recognized as crucial regulators of aldosterone signaling and MR expression. These miRNAs affect different aspects of the RAAS pathway and subsequent molecular processes, which impact sodium balance, ion transport, and fibrosis regulation. This review investigates the regulatory roles of particular miRNAs in modulating aldosterone signaling and MR activation, focusing on their impact on kidney injury, inflammation, and fibrosis. Understanding the complex interaction between miRNAs and the RAAS could lead to a new strategy to target aldosterone signaling and MR activation using miRNAs. This highlights the potential of miRNA-based interventions for DKD, with the aim of enhancing kidney outcomes in individuals with diabetes.

Appropriate treatment within 13 hours after onset may improve outcome in patients with high-grade aneurysmal subarachnoid hemorrhage.

OBJECTIVE: This retrospective study evaluated whether earlier timing of appropriate treatment of high-grade aneurysmal subarachnoid hemorrhage (aSAH), defined as management of ruptured intracranial aneurysm (RIA) combined with required additional surgical measures for control of increased intracranial pressure (ICP), is associated with more favorable outcomes. METHODS: The study cohort comprised 253 patients with high-grade aSAH. Modified Rankin Scale score of 0-3 at 3-month follow-up after the ictus was considered as favorable outcome. RESULTS: Appropriate treatment of aSAH was completed in 205 patients (81 %), and included clipping or coiling of RIA without (64 cases) and with (141 cases) additional surgical measures for control of increased ICP (evacuation of intracranial hematoma, decompressive craniotomy, and/or cerebrospinal fluid drainage). Favorable outcome was noted significantly more often if appropriate treatment was completed within 13 h after aSAH than between 13 and 72 h (37 % vs. 17 %; adjusted P = 0.0475), which was confirmed by evaluation in the multivariate model along with other prognostic factors. Subgroup analysis revealed that completion of the appropriate treatment within 13 h was associated with more favorable outcome in those patients, who underwent management of RIA in combination with additional surgical measures for control of increased ICP (P = 0.0023), and in those, who felt into poor outcome predicting group (P = 0.0046). CONCLUSIONS: Appropriate treatment of high-grade aSAH with management of RIA in combination with required additional surgical measures for control of increased ICP, may be associated with more favorable outcomes if completed within 13 h after the ictus.

Nonconvulsive status epilepticus as sign of tumor recurrence.

Status epilepticus (SE) can be a sign of brain tumor progression or recurrence, but there are few reports of nonconvulsive status epilepticus (NCSE) being a sign of tumor progression or recurrence. Moreover, much remains to be elucidated about its clinical course, and outcome. This is the first report of NCSE associated with the progression of a metastatic brain tumor treated by surgical excision of the tumor. The patient was 74-year-old woman. She had a history of craniotomy for tumor resection and gamma knife treatment for multiple metastatic brain tumors originating from breast cancer. She suddenly developed dysarthria and right hemiparesis, followed by convulsive seizures in the right side of her body. Magnetic resonance imaging showed tumor recurrence in the left parietal lobe and worsening edematous changes around the tumor. Antiseizure medication was initiated, however her seizures did not improve; therefore, tumor resection was performed. Postoperatively, her consciousness, seizures, and electroencephalogram findings improved. NCSE caused by brain tumors may be refractory to treatment with antiseizure medications, and early surgical treatment may be useful for seizure control.

Acute subdural hematoma associated with disruption of tumor vessels due to rapid growth of falx meningioma: A case report and literature review.

Background: Meningiomas associated with acute subdural hematoma (ASDH) are rare. The rapid growth of meningiomas has been shown to be one of the mechanisms underlying bleeding. We report the first case of ASDH during an imaging follow-up for the rapid growth of a falx meningioma. Case Description: A 77-year-old woman was diagnosed with an incidental tumor along the right falx cerebri 3 years before bleeding. The follow-up magnetic resonance imaging (MRI) after 3 years showed that the tumor volume had rapidly increased from 4.31 cm3 to 22.27 cm3. The blood vessels around the tumor were stretched. The patient was scheduled to undergo tumor removal surgery. However, the patient experienced a sudden onset of disturbance of consciousness and was transferred to our hospital. On arrival, her Glasgow Coma Scale (GCS) score was 6 (E1V1M4) and right hemiplegia was observed. The patient had no history of traumatic events. Computed tomography (CT) showed left hemispheric and interhemispheric ASDH. Digital subtraction angiography revealed neither tumor staining nor abnormal vessels. Gross total tumor removal and hematoma evacuation were performed. There were no obvious active intraoperative bleeding points. The pathologic diagnosis was meningioma, the World Health Organization Grade I. Postoperative course revealed a GCS score of 10 (E4V1M5) and she was transferred to a rehabilitation hospital. Conclusion: The disruption of tumor vessels due to the rapid growth of meningiomas may be a cause of bleeding. Incidental falx meningiomas with stretched tumor vessels due to rapid growth could indicate the need for early surgery.

Preoperative plasma D-dimer level may be predictive for success of cerebral reperfusion and outcome after emergency mechanical thrombectomy for intracranial large vessel occlusion.

Presented retrospective analysis evaluated whether preoperative plasma D-dimer level may predict the success of cerebral reperfusion and outcome after emergency mechanical thrombectomy (MT) for intracranial large vessel occlusion (ILVO). Study cohort comprised 121 patients (mean age, 76 ± 12 years) from two participating centers. ILVO mostly affected the M1 segment (48 cases) and internal carotid artery (ICA; 37 cases). Mean preoperative National Institutes of Health Stroke Scale (NIHSS) score was 18 ± 8. Mean preoperative plasma D-dimer level was 4.4 ± 6.6 µg/ml. In 88 patients (73%) MT resulted in successful cerebral reperfusion. Multivariate analysis revealed independent associations of non-successful cerebral reperfusion with preoperative plasma D-dimer level > 6.7 µg/ml (P = 0.0021), location of ILVO other than ICA (P = 0.0056), and prolonged antiplatelet or anticoagulant therapy before stroke onset (P = 0.0172). Plasma D-dimer level ≤ 6.7 µg/ml predicted successful cerebral reperfusion with 0.91 sensitivity and 0.36 specificity. In 39 patients (32%) treatment resulted in favorable outcome. Multivariate analysis revealed independent associations of the unfavorable outcome with non-successful cerebral reperfusion after MT (P = 0.0005), preoperative plasma D-dimer level > 1.9 µg/ml (P = 0.0131), higher preoperative NIHSS score (P = 0.0171), and chronic arterial hypertension before stroke onset (P = 0.0254). Plasma D-dimer level ≤ 1.9 µg/ml predicted favorable outcome with 0.64 sensitivity and 0.62 specificity. In conclusion, preoperative plasma D-dimer level may be predictive for success of cerebral reperfusion and outcome after emergency MT for ILVO, which may be potentially helpful for prediction of prognosis in selected treatment candidates.

Alantolactone is a natural product that potently inhibits YAP1/TAZ through promotion of reactive oxygen species accumulation.

Yes-associated protein 1 (YAP1) and its paralogue PDZ-binding motif (TAZ) play pivotal roles in cell proliferation, migration, and invasion, and abnormal activation of these TEAD transcriptional coactivators is found in diverse cancers in humans and mice. Targeting YAP1/TAZ signaling is thus a promising therapeutic avenue but, to date, few selective YAP1/TAZ inhibitors have been effective against cancer cells either in vitro or in vivo. We screened chemical libraries for potent YAP1/TAZ inhibitors using a highly sensitive luciferase reporter system to monitor YAP1/TAZ-TEAD transcriptional activity in cells. Among 29 049 low-molecular-weight compounds screened, we obtained nine hits, and the four of these that were the most effective shared a core structure with the natural product alantolactone (ALT). We also tested 16 other structural derivatives of ALT and found that natural ALT was the most efficient at increasing ROS-induced LATS kinase activities and thus YAP1/TAZ phosphorylation. Phosphorylated YAP1/TAZ proteins were subject to nuclear exclusion and proteosomic degradation such that the growth of ALT-treated tumor cells was inhibited both in vitro and in vivo. Our data show for the first time that ALT can be used to target the ROS-YAP pathway driving tumor cell growth and so could be a potent anticancer drug.

A Liposomal Gemcitabine, FF-10832, Improves Plasma Stability, Tumor Targeting, and Antitumor Efficacy of Gemcitabine in Pancreatic Cancer Xenograft Models.

PURPOSE: The clinical application of gemcitabine (GEM) is limited by its pharmacokinetic properties. The aim of this study was to characterize the stability in circulating plasma, tumor targeting, and payload release of liposome-encapsulated GEM, FF-10832. METHODS: Antitumor activity was assessed in xenograft mouse models of human pancreatic cancer. The pharmacokinetics of GEM and its active metabolite dFdCTP were also evaluated. RESULTS: In mice with Capan-1 tumors, the dose-normalized areas under the curve (AUCs) after FF-10832 administration in plasma and tumor were 672 and 1047 times higher, respectively, than after using unencapsulated GEM. The tumor-to-bone marrow AUC ratio of dFdCTP was approximately eight times higher after FF-10832 administration than after GEM administration. These results indicated that liposomal encapsulation produced long-term stability in circulating plasma and tumor-selective targeting of GEM. In mice with Capan-1, SUIT-2, and BxPC-3 tumors, FF-10832 had better antitumor activity and tolerability than GEM. Internalization of FF-10832 in tumor-associated macrophages (TAMs) was revealed by flow cytometry and confocal laser scanning microscopy, and GEM was efficiently released from isolated macrophages of mice treated with FF-10832. These results suggest that TAMs are one of the potential reservoirs of GEM in tumors. CONCLUSION: This study found that FF-10832 had favorable pharmacokinetic properties. The liposomal formulation was more effective and tolerable than unencapsulated GEM in mouse xenograft tumor models. Hence, FF-10832 is a promising candidate for the treatment of pancreatic cancer.

Resolution of the large middle fossa arachnoid cyst without any identifiable cause: Case report.

Although the possibility of spontaneous regression of intracranial arachnoid cysts (AC) during observational follow-up is widely recognized, the number of reports documenting such clinical course, often associated with the mild head trauma, is rather limited. We present a case of nearly complete resolution of the large middle fossa AC in a 5-year-old boy without any identifiable cause in 2.3 years after the initial diagnosis. It once again justifies observational strategy for AC not accompanying by mass effect and manifesting with minimal symptoms or diagnosed incidentally.

Optimal timing and safety of the external ventricular drainage in patients with high-grade aneurysmal subarachnoid hemorrhage treated with endovascular coiling.

The presented retrospective analysis has evaluated the optimal timing and safety of external ventricular drainage (EVD) for acute hydrocephalus after aneurysmal subarachnoid hemorrhage (aSAH). The study cohort comprised 102 patients, 49 of whom underwent EVD at 3-120 h (mean, 16 h) after the clinical onset of aSAH, either before (N = 27) or after (N = 22) ruptured aneurysm coiling. Among those treated with EVD, favorable and fair outcomes at discharge (modified Rankin Scale [mRS] scores 0-3) were noted in 14 (29%) and unfavorable (mRS scores 4-6) in 35 (71%). The former was more common among women (P = 0.019) and patients without chronic arterial hypertension (P = 0.028). The cut-off value for optimal timing of EVD was defined at 13 h after the onset of aSAH. Favorable and fair outcomes were more frequent after early (≤13 h; N = 30) than late (>13 h; N = 19) EVD (40% vs. 11%; P = 0.026), whereas did not differ significantly between those in whom such procedure was done before or after ruptured aneurysm coiling (19% vs. 41%; P = 0.083). In the entire study cohort, 2 patients had re-rupture of the aneurysm, and while both of them were treated with EVD, neither case of complication was directly associated with the procedure and, in fact, preceded it. In conclusion, EVD for management of acute hydrocephalus in patients with high-grade aSAH should be preferably applied within 13 h after the clinical onset of stroke, which may be considered sufficiently safe regardless whether it is performed before or after ruptured aneurysm coiling.

Differential organ-specific inflammatory response to progranulin in high-fat diet-fed mice.

Progranulin (PGRN) has been reported to bind tumor necrosis factor (TNF) receptor and to inhibit TNFα signaling. We evaluated the effect of augmentation of TNFα signaling by PGRN deficiency on the progression of kidney injury. Eight-week-old PGRN knockout (KO) and wild-type (WT) mice were fed a standard diet or high-fat diet (HFD) for 12 weeks. Albuminuria, markers of tubular damage, and renal mRNA levels of inflammatory cytokines were higher in HFD-fed KO (KO-HFD) mice than in HFD-fed WT (WT-HFD) mice. Body weight, vacuolization in proximal tubules, and systemic and adipose tissue inflammatory markers were lower in the KO-HFD mice than in the WT-HFD mice. The renal megalin expression was lower in the KO mice than in the WT mice regardless of the diet type. The megalin expression was also reduced in mouse proximal tubule epithelial cells stimulated with TNFα and in those with PGRN knockdown by small interfering RNA in vitro. PGRN deficiency was associated with both exacerbated renal inflammation and decreased systemic inflammation, including that in the adipose tissue of mice with HFD-induced obesity. Improved tubular vacuolization in the KO-HFD mice might partially be explained by the decreased expression of megalin in proximal tubules.

Fractional excretion of tumor necrosis factor receptor 1 and 2 in patients with type 2 diabetes and normal renal function.

AIMS/INTRODUCTION: Increased concentrations of serum tumor necrosis factor (TNF) receptors (TNFRs; TNFR1 and TNFR2) are positively associated with the urinary albumin-to-creatinine ratio (ACR), and negatively associated with the estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes. However, the mechanism underlying this increase and the relationship between TNFRs in serum, and urine and kidney measures (ACR and eGFR) are unclear. MATERIALS AND METHODS: This was a cross-sectional study that included 499 patients with type 2 diabetes and eGFR ≥60 mL/min/1.73 m2 . The concentrations of TNFRs in serum and urine, and their respective fractional excretion, were measured. RESULTS: Serum and urinary TNFR levels were positively associated with the ACR, and negatively associated with the eGFR. The fractional excretion of TNFRs did not differ between patients with an eGFR ≥90 and those with an eGFR 60-89 mL/min/1.73 m2 , and also did not correlate with eGFR. After adjustment for relevant covariates, the serum TNFRs were associated with a lower eGFR (60-89 mL/min/1.73 m2 ) and an increased ACR (≥30 mg/gCr), but urinary TNFRs were associated with an increased ACR (≥30 mg/gCr) alone, in the multivariate logistic model. CONCLUSIONS: The pattern of fractional excretion TNFRs showed that an increase in serum TNFRs might result from their increased systemic production, including in the kidney, rather than being a simple reflection of GFR decline. Kidney measures appear to be strongly associated with serum TNFRs rather than urinary TNFRs in patients with type 2 diabetes and normal renal function.

Potential Targeting of Renal Fibrosis in Diabetic Kidney Disease Using MicroRNAs.

Diabetic kidney disease (DKD) is a major health problem and one of the leading causes of end-stage renal disease worldwide. Despite recent advances, there exists an urgent need for the development of new treatments for DKD. DKD is characterized by the excessive synthesis and deposition of extracellular matrix proteins in glomeruli and the tubulointerstitium, ultimately leading to glomerulosclerosis as well as interstitial fibrosis. Renal fibrosis is the final common pathway at the histological level leading to an end-stage renal failure. In fact, activation of the nuclear factor erythroid 2-related factor 2 pathway by bardoxolone methyl and inhibition of transforming growth factor beta signaling by pirfenidone have been assumed to be effective therapeutic targets for DKD, and various basic and clinical studies are currently ongoing. MicroRNAs (miRNAs) are endogenously produced small RNA molecules of 18-22 nucleotides in length, which act as posttranscriptional repressors of gene expression. Studies have demonstrated that several miRNAs contribute to renal fibrosis. In this review, we outline the potential of using miRNAs as an antifibrosis treatment strategy and discuss their clinical application in DKD.

Risk of Intracranial Hemorrhage and Short-Term Outcome in Patients with Minor Head Injury.

OBJECTIVE: To examine the occurrence of traumatic intracranial hemorrhage (tICH) and outcome in patients with minor head injury and assess the probable risk factors. METHODS: Patients with minor head injury who visited our hospital from January 2015 to July 2017 were registered consecutively, and enrolled patients were aged ≥18 years, visited within 24 hours of the injury, and had a Glasgow Coma Scale score of 15 at outpatient clinic or before the injury. RESULTS: Of the 1122 enrolled patients, 55 (4.9%) had tICH. An antiplatelet agent was administered in 114 patients, an anticoagulant agent was administered in 49 patients, and none of them were administered in 948 patients. A multivariate analysis of tICH identified it as a risk factor, showing significant difference between antiplatelet medication (P = 0.0312), fall from stairs (P = 0.0057), traffic accident (P = 0.0117), neurologic symptoms (P = 0.0091), and modified Rankin Scale (mRS) score before trauma (P < 0.0001). We also analyzed association of enlargement of tICH with different parameters and only anticoagulant medication indicated an increased risk (P = 0.0005). Thirty patients (2.6%) were dependent or died at discharge (mRS 3-6). The mRS score before trauma (P < 0.0001), tICH (P < 0.0001), spinal injury (P < 0.0001), and enlargement of intracranial hemorrhage (P = 0.0008) indicated an increased probability of morbidity (mRS 3-6) in multivariate analysis. CONCLUSIONS: Antiplatelet and anticoagulant medications were risk factor for tICH and enlargement of tICH in patients with minor head injury, respectively. A pretrauma condition of disability/dependence is an important risk factor for tICH and outcome.

Twelve-year single critical care center experience of nicardipine prolonged-release implants in patients with subarachnoid hemorrhage: a propensity score matching analysis.

OBJECTIVE: To develop a nicardipine prolonged-release implant (NPRI) to prevent cerebral vasospasm in patients with subarachnoid hemorrhage in 1999, which may be used during craniotomy, and report the results of our recent 12-year single critical care center experience. METHODS: Of 432 patients with aneurysmal subarachnoid hemorrhage treated between 2007 and 2019, 291 were enrolled. 97 Patients were aged >70 years (33%), 194 were female (67%), 138 were World Federation of Neurological Societies grades 1, 2, and 3 (47%), 218 were Fisher group 3 (75%), and 243 had an anterior circulation aneurysm (84%). Using a propensity score matching method for these five factors, the severity of cerebral vasospasm, occurrence of delayed cerebral infarction, and modified Rankin Scale (mRS) score at discharge were analyzed. RESULTS: One hundred patients each with or without NPRI were selected, and the ratios of coil/clip were 0/100 and 88/12, respectively. Cerebral vasospasm and delayed cerebral infarction were both significantly less common in the NPRI group (p=0.004, OR=0.412 (95% CI 0.223 to 0.760) and p=0.005, OR=0.272 (95% CI 0.103 to 0.714, respectively); a significant difference was seen in the mRS score at discharge by Fisher's exact test (p=0.0025). A mRS score of 6 (dead) was less common in the group with NPRI, and mRS scores of 0 and 1 were also less common. No side effects were seen. CONCLUSIONS: NPRIs significantly reduced the occurrence of cerebral vasospasm and delayed cerebral infraction without any side effects. The NPRI and non-NPRI groups showed different patterns of short-term outcomes in the single critical care center, which might have been due to selection bias and patient characteristics. Differences in outcomes may become clear in comparisons with patients treated by craniotomy.

Discovery of a new pyrimidine synthesis inhibitor eradicating glioblastoma-initiating cells.

BACKGROUND: Glioblastoma-initiating cells (GICs) comprise a tumorigenic subpopulation of cells that are resistant to radio- and chemotherapies and are responsible for cancer recurrence. The aim of this study was to identify novel compounds that specifically eradicate GICs using a high throughput drug screening approach. METHODS: We performed a cell proliferation/death-based drug screening using 10 560 independent compounds. We identified dihydroorotate dehydrogenase (DHODH) as a target protein of hit compound 10580 using ligand-fishing and mass spectrometry analysis. The medical efficacy of 10580 was investigated by in vitro cell proliferation/death and differentiation and in vivo tumorigenic assays. RESULTS: Among the effective compounds, we identified 10580, which induced cell cycle arrest, decreased the expression of stem cell factors in GICs, and prevented tumorigenesis upon oral administration without any visible side effects. Mechanistic studies revealed that 10580 decreased pyrimidine nucleotide levels and enhanced sex determining region Y-box 2 nuclear export by antagonizing the enzyme activity of DHODH, an essential enzyme for the de novo pyrimidine synthesis. CONCLUSION: In this study, we identified 10580 as a promising new drug against GICs. Given that normal tissue cells, in particular brain cells, tend to use the alternative salvage pathway for pyrimidine synthesis, our findings suggest that 10580 can be used for glioblastoma therapy without side effects.Key Points1. Chemical screening identified 10580 as a novel GIC-eliminating drug that targets DHODH, an essential enzyme for the de novo pyrimidine synthesis pathway. 2. Compound 10580 induced cell cycle arrest, apoptosis, and differentiation in GICs.

FF-10832 enables long survival via effective gemcitabine accumulation in a lethal murine peritoneal dissemination model.

Chemotherapy has been the treatment of choice for unresectable peritoneal dissemination; however, it is difficult to eradicate such tumors because of poor drug delivery. To solve this issue, we developed FF-10832 as liposome-encapsulated gemcitabine to maintain a high concentration of gemcitabine in peritoneal tumors from the circulation and ascites. A syngeneic mouse model of peritoneal dissemination using murine Colon26 cell line was selected to compare the drug efficacy and pharmacokinetics of FF-10832 with those of gemcitabine. Despite the single intravenous administration, FF-10832 treatment enabled long-term survival of the lethal model mice as compared with those treated with gemcitabine. Pharmacokinetic analysis clarified that FF-10832 could achieve a more effective gemcitabine delivery to peritoneal tumors owing to better stability in the circulation and ascites. The novel liposome-encapsulated gemcitabine FF-10832 may be a curative therapeutic tool for cancer patients with unresectable peritoneal dissemination via the effective delivery of gemcitabine to target tumors.

[A Case of Segmental Arterial Mediolysis:Subarachnoid Hemorrhage Followed by Abdominal Bleeding].

We describe a case involving subarachnoid and intraperitoneal hemorrhage due to segmental arterial mediolysis(SAM). A 77-year-old female patient with sudden subarachnoid hemorrhage was immediately transferred to our institution. The hemorrhage was classified as grade 2 according to the World Federation of Neurosurgical Societies system. The patient was a non-smoker and did not drink alcohol regularly. A right internal carotid aneurysm was detected using CT angiography and was clipped during frontotemporal craniotomy. Bleeding was observed from the anterior wall of the internal carotid artery, and the tear was clipped. The patient had an uneventful postoperative course until sudden cardiopulmonary arrest eight days after craniotomy. She died of massive intraperitoneal hemorrhage. Autopsy revealed that the hemorrhage was due to dissection of the celiac artery. Tunica media denaturation was observed not only in the celiac artery, but also in the splenic and internal carotid arteries, which exhibited ruptured aneurysms, and the patient was diagnosed with segmental arterial mediolysis(SAM). SAM is an arterial degenerative disease affecting the medial layer of the arterial and dissecting walls. Multiple lesions are sometimes found. Radiographic imaging findings of SAM are similar to those of dissecting aneurysms, which are characterized by a single continuous dissection of the medial layer. As observed in this case, abdominal bleeding caused by SAM can occur after intracranial bleeding. When surgeons encounter unusual intracranial dissecting aneurysms, SAM should be considered as a differential diagnosis.

Investigation into metastatic processes and the therapeutic effects of gemcitabine on human pancreatic cancer using an orthotopic SUIT-2 pancreatic cancer mouse model.

Prognosis of pancreatic cancer is poor, thus the development of novel therapeutic drugs is necessary. During preclinical studies, appropriate models are essential for evaluating drug efficacy. The present study sought to determine the ideal pancreatic cancer mouse model for reliable preclinical testing. Such a model could accurately reflect human pancreatic cancer phenotypes and predict future clinical trial results. Systemic pathology analysis was performed in an orthotopic transplantation model to prepare model mice for use in preclinical studies, mimicking the progress of human pancreatic cancer. The location and the timing of inoculated cancer cell metastases, pathogenesis and cause of fatality were analyzed. Furthermore, the efficacy of gemcitabine, a key pancreatic cancer drug, was evaluated in this model where liver metastasis and peritoneal dissemination occur. Results indicated that the SUIT-2 orthotopic pancreatic cancer model was similar to the phenotypic sequential progression of human pancreatic cancer, with extra-pancreatic invasion, intra-peritoneal dissemination and other hematogenous organ metastases. Notably, survival was prolonged by administering gemcitabine to mice with metastasized pancreatic cancer. Furthermore, the detailed effects of gemcitabine on the primary tumor and metastatic tumor lesions were pathologically evaluated in mice. The present study indicated the model accurately depicted pancreatic cancer development and metastasis. Furthermore, the detailed effects of pancreatic cancer drugs on the primary tumor and on metastatic tumor lesions. We present this model as a potential new standard for new drug development in pancreatic cancer.

RAGE Deletion Confers Renoprotection by Reducing Responsiveness to Transforming Growth Factor-ß and Increasing Resistance to Apoptosis.

Signaling via the receptor of advanced glycation end products (RAGE)-though complex and not fully elucidated in the setting of diabetes-is considered a key injurious pathway in the development of diabetic nephropathy (DN). We report here that RAGE deletion resulted in increased expression of fibrotic markers (collagen I and IV, fibronectin) and the inflammatory marker MCP-1 in primary mouse mesangial cells (MCs) and in kidney cortex. RNA sequencing analysis in MCs from RAGE-/- and wild-type mice confirmed these observations. Nevertheless, despite these gene expression changes, decreased responsiveness to transforming growth factor-ß was identified in RAGE-/- mice. Furthermore, RAGE deletion conferred a more proliferative phenotype in MCs and reduced susceptibility to staurosporine-induced apoptosis. RAGE restoration experiments in RAGE-/- MCs largely reversed these gene expression changes, resulting in reduced expression of fibrotic and inflammatory markers. This study highlights that protection against DN in RAGE knockout mice is likely to be due in part to the decreased responsiveness to growth factor stimulation and an antiapoptotic phenotype in MCs. Furthermore, it extends our understanding of the role of RAGE in the progression of DN, as RAGE seems to play a key role in modulating the sensitivity of the kidney to injurious stimuli such as prosclerotic cytokines.