A positive feedback regulatory loop involving the lncRNA PVT1 and HIF-1α in pancreatic cancer.

Extreme hypoxia is among the most prominent pathogenic features of pancreatic cancer (PC). Both the long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) and hypoxic inducible factor-1α (HIF-1α) are highly expressed in PC patients and play a crucial role in disease progression. Reciprocal regulation involving PVT1 and HIF-1α in PC, however, is poorly understood. Here, we report that PVT1 binds to the HIF-1α promoter and activates its transcription. In addition, we found that PVT1 could bind to HIF-1α and increases HIF-1α post-translationally. Our findings suggest that the PVT1‒HIF-1α positive feedback loop is a potential therapeutic target in the treatment of PC.

Urinary miRNA-29a-3p levels are associated with metabolic parameters via regulation of IGF1 in patients with metabolic syndrome.

Circulating microRNAs (miRNAs or miRs) have been demonstrated to serve as diagnostic and prognostic biomarkers in metabolic syndrome (MetS). The role of urinary miRNAs in MetS diagnosis remains unknown. Here, elevated miR-29a-3p levels were observed in urine samples of patients with MetS compared with control subjects using a microarray analysis (n=4/group) and validation via reverse transcription-quantitative polymerase chain reaction (n=40/group). Associations between urinary miR-29a-3p levels and parameters associated with metabolism, such as adiposity, insulin resistance, lipid profiles and hepatic enzymes were further assessed. Multiple linear regression analyses revealed that urinary miR-29a-3p levels were independently correlated with fasting insulin (ß=0.561; P<0.001), high density lipoprotein-cholesterol (ß=0.242; P<0.001) and body mass index (ß=-0.141; P<0.05). The area under the receiver operating characteristic curve was 0.776 and miR-29a-3p had a diagnostic value for MetS with 68.2% sensitivity and 77.3% specificity. Furthermore, insulin-like growth factor 1 was identified as a target of miR-29a-3p by searching bioinformatics databases and was validated by dual-luciferase reporter and western blot assays. In conclusion, elevated urinary miR-29a-3p levels were positively associated with MetS and demonstrated to have a potential value as biomarkers in the diagnosis of MetS. The findings provided a better understanding of the role of urinary miRNAs in pathogenesis of MetS.

Circulating miR-143-3p inhibition protects against insulin resistance in Metabolic Syndrome via targeting of the insulin-like growth factor 2 receptor.

Metabolic syndrome (MetS) is characterized by a cluster of metabolic disorders including obesity, dyslipidemia, hyperglycemia, and hypertension. Here, we report that 27 microRNAs were found to be expressed differently in serum and urine samples of MetS patients compared to control subjects on microarray analysis. Further qualitative real time- polymerase chain reaction analyses confirmed that circulating levels of miR-143-3p were significantly elevated in MetS patients compared with controls, both in serum and urine samples. After accounting for confounding factors, high levels of miR-143-3p remained an independent risk factor for insulin resistance. Inhibition of miR-143-3p expression in mice protected against development of obesity-associated insulin resistance. Furthermore, we demonstrated that insulin-like growth factor 2 receptor (IGF2R) was among the target genes of miR-143-3p by searching 3 widely used bioinformatics databases and preliminary validation. Our experiments suggest that knockdown of circulating miR-143-3p may protect against insulin resistance in the setting of MetS via targeting of IGF2R and activation of the insulin signaling pathway. Our results characterize the miR-143-3p-IGF2R pathway as a potential target for the treatment of obesity-associated insulin resistance.

A Small Indel Mutant Mouse Model of Epidermolytic Palmoplantar Keratoderma and Its Application to Mutant-specific shRNA Therapy.

Epidermolytic palmoplantar keratoderma (EPPK) is a relatively common autosomal-dominant skin disorder caused by mutations in the keratin 9 gene (KRT9), with few therapeutic options for the affected so far. Here, we report a knock-in transgenic mouse model that carried a small insertion-deletion (indel) mutant of Krt9, c.434delAinsGGCT (p.Tyr144delinsTrpLeu), corresponding to the human mutation KRT9/c.500delAinsGGCT (p.Tyr167delinsTrpLeu), which resulted in a human EPPK-like phenotype in the weight-stress areas of the fore- and hind-paws of both Krt9(+/mut) and Krt9(mut/mut) mice. The phenotype confirmed that EPPK is a dominant-negative condition, such that mice heterozygotic for the K9-mutant allele (Krt9(+/mut)) showed a clear EPPK-like phenotype. Then, we developed a mutant-specific short hairpin RNA (shRNA) therapy for EPPK mice. Mutant-specific shRNAs were systematically identified in vitro using a luciferase reporter gene assay and delivered into Krt9(+/mut) mice. shRNA-mediated knockdown of mutant protein resulted in almost normal morphology and functions of the skin, whereas the same shRNA had a negligible effect in wild-type K9 mice. Our results suggest that EPPK can be treated by gene therapy, and this has significant implications for future clinical application.

Transcatheter arterial embolization for intercostal arterial bleeding in a patient after chest tube insertion.

Retrograde tube radiography is commonly used in cholangiography and pyelography. We present a case of massive chest tube bleeding 10 days after tube insertion with no noted contrast extravasation on contrast enhanced chest CT with active bleeding detected by retrograde radiography via the chest tube. Subsequent transcatheter arterial embolization (TAE) was successfully performed as a definitive treatment to stop active bleeding. We consider that retrograde tube radiography may be an alternative diagnostic method for patients with active bleeding from a drainage tube, helping to localize bleeding points and presenting TAE an attractive, minimally invasive and effective treatment modality for intercostal artery rupture.

Primary hepatic angiosarcoma: A report of two cases and literature review.

Primary hepatic angiosarcoma (PHA) is a rare malignancy that carries a poor prognosis. Of 1500 patients who underwent hepatectomy for primary hepatic tumors between 1994 and 2013 at our center, two patients were pathologically diagnosed with PHA. Clinical characteristics, treatment modalities, and outcomes of the two patients were collected and analyzed. Both patients underwent hepatectomy and had a postoperative survival time of 8 and 16 mo, respectively. A search of PubMed yielded eight references reporting 35 cases of PHA published between 2004 and 2013. On the basis of the presented cases and review of the literature, we endorse complete surgical resection as the mainstay definitive treatment of PHA, with adjuvant postoperative chemotherapy potentially improving survival. Palliative chemotherapy is an option in advanced hepatic angiosarcoma.

Resection of a cholangiocarcinoma via laparoscopic hepatopancreato- duodenectomy: a case report.

Some laterally advanced cholangiocarcinomas behave as ductal spread or local invasion, and hepatopancreatoduodenectomy (HPD) may be performed for R0 resection. To date, there have been no reports of laparoscopic HPD (LHPD) in the English literature. We report the first case of LHPD for the resection of a Bismuth IIIa cholangiocarcinoma invading the duodenum. The patient underwent laparoscopic pancreaticoduodenectomy and right hemihepatectomy. Child's approach was used for the reconstruction. The patient recovered well with bile leakage from the 2(nd) postoperative day and was discharged on the 16(th) postoperative day with a drainage tube in place which was removed 2 wk after discharge. Postoperative pathology revealed a well-differentiated cholangiocarcinoma and the margin of liver parenchyma, pancreas and stomach was negative for metastases. The results suggest that LHPD is a feasible and safe procedure when performed in highly specialized centers and in suitable patients with cholangiocarcinoma.

Successful interventional radiological management of postoperative complications of laparoscopic distal pancreatectomy.

During the past decade, laparoscopic distal pancreatectomy (LDP) has gained increasing acceptance in the surgical community as a viable treatment option for distal pancreatic lesions. However, the possible complication of post-LDP pancreatic leakage remains a challenge, because it may lead to a series of events resulting in intraperitoneal abscess formation, sepsis, pseudoaneurysm formation, and occasional fatal hemorrhage. Dealing with these complications is extremely difficult and not much experience has been reported to date. We report a case involving the aforementioned post-LDP complications successfully managed by interventional radiological techniques while avoiding reoperation. We conclude that these management options are attractive, safe and minimally invasive alternatives to standard protocols.

EGB1212 post-treatment ameliorates hippocampal CA1 neuronal death and memory impairment induced by transient global cerebral ischemia/reperfusion.

Extracts of Ginkgo biloba have been used in traditional medicines for centuries, and have potential for clinical applications in cerebral ischemia/reperfusion injury. However, standardized extracts have proven protective only as pre-treatments, and the major mechanisms of action remain unclear. We explored the potential of the novel extract EGB1212, which meets the United States Pharmacopeia (USP) 31 standardization criteria for pharmaceutical use, as a post-treatment after global cerebral ischemia/reperfusion (GCI/R) injury in a rat model. The pre-treated group was administered EGB1212 for 7 d prior to common carotid artery occlusion (i.e., ischemia, for 20 min). Post-treated rats received the same but starting 2 h after ischemia and continuing for 7 d. Seven days after GCI/R, brains of each group were processed for H&E staining of hippocampal CA1 neurons. Remaining rats underwent the Morris water maze and Y-maze tests of spatial learning and memory, beginning eight days after reperfusion. To assess hippocampal autophagy, light chain (LC)-3-I/LC3-II and Akt/pAkt were determined via a Western blot of rat hippocampi harvested 12, 24, or 72 h after reperfusion. EGB1212 pre- and post-treatments both improved neuronal survival and spatial learning and memory functions. Pre-treatment effectively reduced LC3-II levels and post-treatment resulted in significantly elevated pAkt levels. We conclude that EGB1212 exerted significant neuroprotection in GCI/R in both preventative and post-treatment settings. This extract shows great potential for clinical applications.

Pancreatic solid cystic desmoid tumor: case report and literature review.

Desmoid tumors (DTs) are nonmetastatic, locally aggressive neoplasms with a high rate of postoperative recurrence. Pancreatic DTs are especially rare; only a few cases have been reported to date. This paper describes a case of a sporadic cystic DT of the pancreas managed successfully with central pancreatectomy, with no signs of recurrence 40 mo after surgery. According to the literature, this is the first reported case in China of a pancreatic DT presenting as a solid cystic lesion, as well as the first pancreatic DT managed with central pancreatectomy and pancreaticogastrostomy. We report the case for its rarity and emphasize disease management by concerted application of clinical, pathological, radiological and immunohistochemical analyses.

Modeling, synthesis and biological evaluation of potential retinoid X receptor (RXR) selective agonists: novel analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene).

This report describes the synthesis of analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), commonly known as bexarotene, and their analysis in acting as retinoid X receptor (RXR)-specific agonists. Compound 1 has FDA approval to treat cutaneous T-cell lymphoma (CTCL); however, its use can cause side effects such as hypothyroidism and increased triglyceride concentrations, presumably by disruption of RXR heterodimerization with other nuclear receptors. The novel analogues in the present study have been evaluated for RXR activation in an RXR mammalian-2-hybrid assay as well as an RXRE-mediated transcriptional assay and for their ability to induce apoptosis as well as for their mutagenicity and cytotoxicity. Analysis of 11 novel compounds revealed the discovery of three analogues that best induce RXR-mediated transcriptional activity, stimulate apoptosis, have comparable K(i) and EC(50) values to 1, and are selective RXR agonists. Our experimental approach suggests that rational drug design can develop new rexinoids with improved biological properties.