The presence of PIM3 increases hepatoblastoma tumorigenesis and tumor initiating cell phenotype and is associated with decreased patient survival

PurposeHepatoblastoma is the most common primary liver cancer of childhood and has few prognostic indicators. We have previously shown that Proviral Integration site for Moloney murine leukemia virus (PIM3) kinase decreased hepatoblastoma tumorigenicity. We sought to determine the effect of PIM3 overexpression on hepatoblastoma cells and whether expression of PIM3 correlated with patient/tumor characteristics or survival.MethodsThe hepatoblastoma cell line, HuH6, and patient-derived xenograft, COA67, were utilized. Viability, proliferation, migration, sphere formation, and tumor growth in mice were assessed in PIM3-overexpressing cells. Immunohistochemistry was performed for PIM3 on patient samples. Correlation between stain score and clinical/pathologic characteristics was assessed.ResultsPIM3 overexpression rescued the anti-proliferative effect observed with PIM3 knockdown. Sphere formation was increased in PIM3 overexpressing cells. Cells with PIM3 overexpression yielded larger tumors than those with empty vector. Seventy-four percent of samples expressed PIM3. There was no statistical difference in patient characteristics between subjects with strong versus weak PIM3 staining, but patients with strong PIM3 staining had decreased survival.ConclusionsPIM3 expression plays a role in hepatoblastoma tumorigenesis. PIM3 was present in the majority of hepatoblastomas and higher PIM3 expression correlated with decreased survival. PIM3 warrants investigation as a therapeutic target and prognostic marker for hepatoblastoma.     

Spinal and supraspinal midazolam potentiates antinociceptive effects of isoflurane

The effects of lumbar intrathecal (i.t.) and intracerebroventricular(i.c.v.) midazolam on nociception during isoflurane anaesthesiawere studied in rats using the tail-flick test. Rats receivedi.t. midazolam 2 and 4 µg or i.c.v. midazolam 4 and 8µg during 1.1, 1.2 and 1.3% isoflurane or without isoflurane.Neither i.t. nor i.c.v. midazolam alone at doses studied influencednociceptive responses. 1.1% isoflurane showed a minimum antinociceptiveeffect which was not influenced by i.t. or i.c.v. midazolam.1.2 and 1.3% isoflurane produced moderate antinociception whichwas markedly potentiated by both i.t. and i.c.v. midazolam.The effects of midazolam shown in the present study are differentfrom the reported effects of midazolam on opioid-induced antinociception;where spinally administered midazolam potentiates and supraspinalmidazolam inhibits the antinociceptive effects of morphine.The present results suggest that midazolam potentiates isoflurane-inducedantinociception at doses where no effect is seen alone. Br J Anaesth 2000; 85: 881–6     

Propofol potentiates the neuromuscular blocking effects of vecuronium in man

The possible interaction between vecuronium and propofol has been investigated in 40 healthy (ASA I-II) patients. They were randomly allocated to two groups according to the method of anesthesia; continuous propofol infusion group (propofol) and droperidol and fentanyl group (control). The electromyographic response of abductor digiti minimi was monitored at 20-s interval after train-of-four stimulations of the ulnar nerve. The ED50 and ED95 (dose required to produce a 50% and 95% depression of twitch tension, respectively,) of vecuronium in the propofol group (n = 20) were 29.4 +/- 0.5 and 56.6 +/- 2.1 micrograms.kg-1 (mean +/- SEM), and in the control group (n = 20), 36.7 +/- 1.8 and 73.6 +/- 5.2 micrograms.kg-1, respectively. Under propofol anesthesia, the cumulative dose-response curves of vecuronium were shifted to the left when compared with control ED50 and the slope showed that propofol had potentiated the action of vecuronium.     

成人肝母细胞瘤的诊治:近20年国内文献分析

自1969年Carter[1]首次报道肝母细胞瘤(hepatoblastoma)以来,截止2006年11月英文文献共报道肝母细胞瘤约1000余例.因肝母细胞瘤多发生于儿童,故在文献中亦被称为婴儿型肝癌、肝混合瘤或肝畸胎瘤,而成人肝母细胞瘤则非常罕见.为提高成人肝母细胞瘤诊疗水平,作者复习近20年国内文献报道,对成人肝母细胞瘤的诊断与治疗进行分析.     

VIP potentiates cholinergic effects on the mucociliary system in the maxillary sinus

The neuropeptide vasoactive intestinal polypeptide (VIP), which is found in a population of cholinergic parasympathetic neurons in the airways, has no effects per se on mucociliary activity. In order to test the hypothesis that VIP may modulate cholinergic regulation of the mucociliary system, VIP was infused intraarterially (8.4 pmol/kg/min), and the response to challenges with methacholine in the maxillary sinus of rabbits were recorded with a photoelectric technique. Occurrence of VIP-like immunoreactivity in the rabbit maxillary sinus, maxillary nerve, and sphenopalatine ganglion was investigated. Immunoreactivity against VIP was found in nerve fibers in the subepithelial layer of the maxillary sinus and in numerous nerve cell bodies in the sphenopalatine ganglion. Infusion of VIP potentiated the mucociliary increase induced by methacholine. The mucociliary wave frequency change increased from 6.1% +/- 1.7% to 13.3% +/- 3.9% (0.01 micrograms/kg methacholine), from 11.6% +/- 3.6% to 18.8% +/- 2.2% (0.05 micrograms/kg) and from 17.0% +/- 3.0% to 27.4% +/- 3.6% (0.1 micrograms/kg). Both peak responses and response durations increased during infusions. In contrast, the vasodilating agent papaverine sulphate did not influence the mucociliary response to methacholine. The modulating effect of VIP on the mucociliary system, taken together with the morphologic observations, suggest that VIP may have a physiologic role in the regulation of the mucociliary system in the maxillary sinus.     

Clinical and biological significance of PIM1 kinase in osteosarcoma

Osteosarcoma is the most prevalent histological form of primary malignant bone tumor. The majority of osteosarcoma patients have limited alternative therapeutic options and metastatic patients generally have a poor prognosis. Proto‐oncogene serine/threonine‐protein kinase PIM1 is associated with growth and survival of many kinds of tumor cells. However, the role of PIM1 in osteosarcoma remains largely unknown. In this study, we investigated the functional and therapeutic relevance of PIM1 as a putative target in osteosarcoma. We found PIM1 was highly expressed in various osteosarcoma cell lines and in tumor tissues from osteosarcoma patients. Tissue microarray and immunohistochemistry analysis showed that the overall and disease‐free survival rate of patients with high levels of PIM1 protein expression were significantly shorter than patients with low levels. High levels of PIM1 were also associated with present metastasis and can be considered as an independent prognostic factor in osteosarcoma patients. Knockdown of PIM1 expression by synthetic siRNA or shRNA greatly inhibited cell growth, migration, and invasion. Moreover, these changes accompanied with down‐regulation of anti‐apoptotic protein Bcl‐2. The similar results were obtained in osteosarcoma cells treated with PIM1 specific inhibitor (SMI‐4a). These results suggest that PIM1 kinase is critical for the growth and metastasis of osteosarcoma cells and can be a potential therapeutic target for osteosarcoma treatment. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1185–1194, 2016.     

小儿肝母细胞瘤的诊断和外科治疗

目的总结小儿肝母细胞瘤诊治经验，探讨影响预后因素。方法回顾性分析1992年1月至2005年1月经手术、病理证实的29例肝母细胞瘤的临床资料。结果29例中TNMⅠ期8例、Ⅱ期14例、Ⅲ期6例、Ⅳ期1例；病理学类型有胎儿型18例，胚胎型5例，未分化型3例，混合型3例；行根治性切除25例（86％），姑息性切除4例（14％），并发症发生率13．7％（4／29），术后肝功能10d恢复正常。22例获随访，1、3、4年累积存活率分别为86．4％（n=19）、68．2％（n=15）、36．4％（n=8）。结论手术切除是小儿肝母细胞瘤首选的治疗方法，影响其预后的主要因素是临床分期和肿瘤组织分化程度、病理学类型。     

Endothelin blockade potentiates endothelial protective effects of ACE inhibitors in saphenous veins

BACKGROUND: Angiotensin II and endothelin-1 are potent endothelium-derived contracting factors. The effects of acute endothelin antagonism on endothelial function in saphenous vein from patients treated with and without angiotensin-converting enzyme inhibitors were compared. METHODS: Vascular segments of saphenous vein were obtained perioperatively from 14 patients on angiotensin-converting enzyme inhibitors and 29 controls. In vitro endothelium-dependent and -independent responses to acetylcholine and sodium nitroprusside were assessed by constructing isometric dose-response curves in precontracted rings in the presence and absence of bosentan (endothelinA/B receptor antagonist) and BQ-123 (endothelinA antagonist) using isolated organ baths. Percent maximum relaxation and sensitivity were compared between interventions. RESULTS: Endothelium-dependent relaxation to acetylcholine was augmented in the angiotensin-converting enzyme inhibitor-treated group (p < 0.005). Both specific and mixed endothelin receptor blockade improved acetylcholine-mediated relaxation in the angiotensin-converting enzyme inhibitor-treated and untreated groups (p < 0.02). The effects of these antagonists were endothelium specific as endothelium-independent responses to sodium nitroprusside remain unaltered. CONCLUSIONS: These data demonstrate that (1) chronic angiotensin-converting enzyme inhibition improves endothelial function in saphenous veins, and (2) this effect can be further augmented by acute endothelin blockade. These data suggest that antagonism of both angiotensin II and endothelin may be important in attenuating saphenous vein arteriosclerosis.     

Fructose-1,6-diphosphate alone and in combination with cyclosporine potentiates rat cardiac allograft survival and inhibits lymphocyte proliferation and interleukin-2 expression

BACKGROUND: Fructose-1,6-diphosphate (FDP) reduces postischemic reperfusion injury and is used alone and in combination with cyclosporine A (CsA) as an immunosuppressant. METHODS: Wistar-Furth rat hearts were grafted to Lewis rats. Activated T-cell proliferation, viability, and interleukin-2 expression were determined. RESULTS: Mean survival in days were: saline 7.12+/-0.64, FDP 350 mg/kg perioperatively 13.5+/-1.4, FDP 350 mg/kg twice daily 11.4+/-0.75, CsA 2.5 mg/kg daily 12+/-0.81, CsA 5.0 mg/kg daily 12.4+/-0.81, CsA 2.5 mg/kg + FDP 350 mg/kg twice daily 17.6+/-0.4, and CsA 5 mg/kg + FDP 350 mg/kg twice daily 28.2+/-0.97. FDP maximally inhibits T-cell proliferation and concomitantly increases cell viability at 5,000 to 500 microg/mL, whereas CsA inhibits at 500 ng/mL. FDP completely inhibited interleukin-2 expression at 5,000 to 500 microg/mL, whereas CsA partially inhibited at 50 to 500 ng/mL. CONCLUSION: FDP + CsA prolongs cardiac survival and FDP inhibits T-cell proliferation.     

Survivin mRNA和蛋白在肝母细胞瘤组织中的表达

目的 观察肝母细胞瘤组织中Survivin mRNA与蛋白表达.方法 采用逆转录-聚合酶链反应(RT-PCR)方法检测16例肝母细胞瘤及相应癌旁组织中Survivin mRNA的表达,免疫组织化学SP法及Western blot法检测Survivin蛋白在肝母细胞瘤中的表达.结果 在肝母细胞瘤及其相应的癌旁组织中Survivin mRNA表达的阳性率分别为62.5％和11.1％,Survivin蛋白表达的阳性率分别为81.3％和22.2％,肝母细胞瘤组均远高于癌旁组,差异有统计学意义(P＜0.01);Survivin蛋白在肝母细胞瘤组织中的表达随肿瘤分期增高而增加;Ⅲ、Ⅳ期肝母细胞瘤组织Survivin mRNA 的表达量分别为2.390±0.071和4.506±0.309,明显高于早期肝母细胞瘤组织(P＜0.05).结论 Survivin 基因的高表达可能在肝母细胞瘤的发生及发展中起重要作用.     

细胞凋亡对肝母细胞瘤化学药物治疗效果和预后的影响

目的 研究肝母细胞瘤（ＨＢ）在化学药物治疗（下称化疗）前后细胞凋亡发生情况,评价其对化疗效果和预后的影响。方法 应用ＴＵＮＥＬ方法对１３例ＨＢ化疗前后标本中检测并计算出凋亡指数（ＡＩ）。结果 全组ＨＢ化疗前后１３例标本中均有凋亡细胞检出。化疗前ＨＢ细胞自发性凋亡ＡＩ高者,化疗后瘤体明显减少,与化疗后瘤体直径减少值呈正相关（ｒ＝０．６９）。化疗后ＡＩ与化疗前ＡＩ呈正相关（ｒ＝０．９０７）。化疗前ＡＩ     

Association between surgical margins and long-term outcome in advanced hepatoblastoma

Background

Many patients with hepatoblastoma present with unresectable disease. Neoadjuvant therapy has improved resectability rates to as high as 70% to 90%. Despite this improvement, many patients will be left with tumors that are of borderline resectability. The authors hypothesize that favorable outcomes may be achieved even with resection margins less than 1 cm thus sparing the need for liver transplantation.

Methods

Between January 1981 and March 2003, 23 patients age less than 16 years with a diagnosis of hepatoblastoma undergoing surgical resection were identified. The clinical characteristics, pathologic resection margins, and survival status were reviewed.

Results

Eighteen (78%) of the patients were alive with no evidence of recurrence at last follow-up. Thirteen (56.5%) had ≥1 cm resection margins, whereas 10 (43.5%) had resection margins less than 1 cm. Eleven (47.8%) presented with PRETEXT III tumors. There was no significant difference in survival rate between resection margins less than 1 cm and ≥1 cm (P = .13; 95% CI 0.91 to 2.61). Thirteen patients (56.5%) presented with synchronous pulmonary metastatic disease, where survival was significantly worse (P = .04; 95% CI 1.10 to 2.50). Subgroup analysis confirmed that margins less than 1 cm did not significantly affect survival after controlling for pulmonary metastatic disease (P = .56; 95% CI 0.71 to 3.61).

Conclusions

Surgical resection with margins less than 1 cm are associated with survival that is equivalent to resection with margins ≥1 cm. Our findings suggest it is preferable to preserve key structures with a small resection margin and therefore spare the need for liver transplantation in patients with advanced hepatoblastoma.     

Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of angiotensin receptor blockers

Dietary sodium restriction has been shown to enhance the short-term response of blood pressure and albuminuria to angiotensin receptor blockers (ARBs). Whether this also enhances the long-term renal and cardiovascular protective effects of ARBs is unknown. Here we conducted a post-hoc analysis of the RENAAL and IDNT trials to test this in patients with type 2 diabetic nephropathy randomized to ARB or non-renin-angiotensin-aldosterone system (non-RAASi)-based antihypertensive therapy. Treatment effects on renal and cardiovascular outcomes were compared in subgroups based on dietary sodium intake during treatment, measured as the 24-h urinary sodium/creatinine ratio of 1177 patients with available 24-h urinary sodium measurements. ARB compared to non-RAASi-based therapy produced the greatest long-term effects on renal and cardiovascular events in the lowest tertile of sodium intake. Compared to non-RAASi, the trend in risk for renal events was significantly reduced by 43%, not changed, or increased by 37% for each tertile of increased sodium intake, respectively. The trend for cardiovascular events was significantly reduced by 37%, increased by 2% and 25%, respectively. Thus, treatment effects of ARB compared with non-RAASi-based therapy on renal and cardiovascular outcomes were greater in patients with type 2 diabetic nephropathy with lower than higher dietary sodium intake. This underscores the avoidance of excessive sodium intake, particularly in type 2 diabetic patients receiving ARB therapy.     

Role of Ets transcription factors in mammary gland development and oncogenesis

PEA3 is the founding member of a subfamily of closely related ets genes that includes ER81 and ERM. PEA3 is expressed in the epithelial cells of mammary buds at the time that these first appear during mouse embryogenesis, and it is differentially expressed during postnatal mammary gland development. PEA3 expression is highest at the onset of puberty and during early pregnancy, times of extensive epithelial outgrowth and branching. PEA3 is expressed in undifferentiated epithelial cap cells of terminal end buds, and in differentiated myoepithelial cells of ducts and alveoli. Loss-of-function mutations in the PEA3 gene compromise mammary ductal branching at the onset of puberty and early during pregnancy. PEA3 is overexpressed in the vast majority of human breast tumors and in nearly all of the HER2-positive subclass of such tumors. PEA3 is similarly overexpressed in transgenic mouse models of this malignancy. Expression of dominant-negative PEA3 in the mouse mammary gland of MMTV-HER2 transgenic mice dramatically delays the onset and reduces the incidence of mammary tumors. Hence PEA3 and/or its close relatives play key regulatory roles in both mammary gland development and oncogenesis.