Hypoxia promotes vasculogenic mimicry formation by inducing epithelial–mesenchymal transition in ovarian carcinoma

Objectives

The functions of hypoxia and subsequent hypoxia-inducible factor-1α (HIF-1α) activation in vasculogenic mimicry (VM) are currently unclear. This study aimed to investigate the effects of hypoxia on VM formation in ovarian cancer, and explore the possible mechanism involved.

Methods

The expression levels of HIF-1α, E-cadherin, vimentin, Twist1, Slug, and VE-cadherin proteins were analyzed by immunohistochemistry in 71 specimens of epithelial ovarian cancer. The results were correlated with VM and survival analysis. We used a well-established in vitro model of a three-dimensional culture to compare VM formation under hypoxia and normoxia in ovarian cancer cell lines SKOV3 and OVCAR3. To explore the potential mechanism, we examined the effects of hypoxia on the mRNA and protein expression levels of both E-cadherin and vimentin.

Results

HIF-1α expression was correlated with loss of E-cadherin expression and up-regulated vimentin expression in 11 of the 18 VM-positive patients. Ovarian cancer with evidence of VM was significantly more likely to have high Twist1, Slug, and VE-cadherin expression levels. VM was observed in vitro under hypoxia. The ovarian cancer cells presented morphological epithelial–mesenchymal transition (EMT)-like changes (more fibroblastoid morphology and loss of cellular cohesiveness) under hypoxic conditions. The mRNA and protein levels demonstrated the induction of EMT after hypoxia. Clinicopathological analysis revealed that both VM and HIF-1α expression levels presented shorter survival durations.

Conclusions

Hypoxia contributed to VM formation by inducing EMT. These results may offer new insights for consideration in ovarian cancer treatment strategies.     

Vitamin D in the General Population of Young Adults with Autism in the Faroe Islands

Vitamin D deficiency has been proposed as a possible risk factor for developing autism spectrum disorder (ASD). 25-Hydroxyvitamin D₃ (25(OH)D₃) levels were examined in a cross-sectional population-based study in the Faroe Islands. The case group consisting of a total population cohort of 40 individuals with ASD (aged 15–24 years) had significantly lower 25(OH)D₃ than their 62 typically-developing siblings and their 77 parents, and also significantly lower than 40 healthy age and gender matched comparisons. There was a trend for males having lower 25(OH)D₃ than females. Effects of age, month/season of birth, IQ, various subcategories of ASD and Autism Diagnostic Observation Schedule score were also investigated, however, no association was found. The very low 25(OH)D₃ in the ASD group suggests some underlying pathogenic mechanism.     

JAK2T875N is a novel activating mutation that results in myeloproliferative disease with features of megakaryoblastic leukemia in a murine bone marrow transplantation model

Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia associated with a poor prognosis. However, there are relatively few insights into the genetic etiology of AMKL. We developed a screening assay for mutations that cause AMKL, based on the hypothesis that constitutive activation of STAT5 would be a biochemical indicator of mutation in an upstream effector tyrosine kinase. We screened human AMKL cell lines for constitutive STAT5 activation, and then used an approach combining mass spectrometry identification of tyrosine phosphorylated proteins and growth inhibition in the presence of selective small molecule tyrosine kinase inhibitors that would inform DNA sequence analysis of candidate tyrosine kinases. Using this strategy, we identified a new JAK2T875N mutation in the AMKL cell line CHRF-288-11. JAK2T875N is a constitutively activated tyrosine kinase that activates downstream effectors including STAT5 in hematopoietic cells in vitro. In a murine transplant model, JAK2T875N induced a myeloproliferative disease characterized by features of AMKL, including megakaryocytic hyperplasia in the spleen; impaired megakaryocyte polyploidization; and increased reticulin fibrosis of the bone marrow and spleen. These findings provide new insights into pathways and therapeutic targets that contribute to the pathogenesis of AMKL.     

Aetiology,pattern and treatment of mandibular condylar fractures in 549 patients: A 22-year retrospective study

PurposeThe purpose of this study was to retrospectively investigate the aetiology, pattern, and treatment of mandibular condylar fractures in our department over the past 22 years.Patients and methodsData of patients who sustained mandibular condylar fractures from 1988 to 2009 were recorded, including fracture aetiology, pattern of condylar fracture, time, age, sex, associated injury, patient transferred by other clinics, lag time and treatment method. Data analysis included X² test, Fisher exact test, t-test, Ridit analysis and Logistic regression analysis.ResultsThe sample was composed of 549 patients (749 condylar fractures), 404 male and 145 female (male:female = 2.79:1), with a mean age of 30.12 ± 14.44 years. Road traffic accidents were the most common cause (248, 45.2%). Condylar head fractures were significantly related to a fall at ground level (p = .001). A fall from a height had a 3.19-fold risk of bilateral condylar fractures (odds ratio, 3.19; 95% confidence interval, 1.33 to 7.65; p = .010). A majority of the condylar fractures (693, 92.5%) were treated by a surgical procedure. Condylar head were mostly removed (95.0%, p < .001), condylar neck and condylar base fractures were most frequently treated by open reduction and internal fixation with miniplates (74.4%, p < .001). Most of the dislocated condylar fractures were treated by open surgery (96.5%, p = .026).ConclusionsThe anatomic position and uni/bilateral pattern of mandibular condylar fractures were positively related to situations when considerable force is involved. Open condylar surgery was based on the level of fracture and degree of displacement or dislocation.     

In vitro activity and beta-lactamase stability of the new oral cephalosporin Bay v 3522

The activity of the new oral cephalosporin Bay v 3522 was compared to that of six other beta-lactam agents. Bay v 3522 inhibited methicillin-susceptibleStaphylococcus aureus andStaphylococcus epidermidis at 2 µg/ml, compared to MICs of 8 µg/ml for the other cephalosporins tested. It was more active againstStreptococcus pyogenes (MIC 0.06 µg/ml) than cefuroxime, cefixime, cephalexin and cefaclor. Groups B, C and G streptococci were inhibited at 0.12 µg/ml, while the MIC90 forStreptococcus bovis and viridans streptococci was 0.5 and 2 µg/ml, respectively. The MIC90 for enterococci andListeria monocytogenes was 8 µg/ml.Clostridium perfringens was inhibited by 0.12 µg/ml, but mostBacteroides spp. were resistant. The MIC90 for beta-lactamase positiveEscherichia coli (producing primarily TEM-1) was >64 µg/ml and for beta-lactamase negative strains 16 µg/ml. The MIC90 for high-level beta-lactamase producingKlebsiella pneumoniae was >64 µg/ml versus 4 µg/ml for other isolates. The MIC90 forMoraxella catarrhalis was 2 µg/ml, forHaemophilus influenzae 1 µg/ml, and forNeisseria gonorrhoeae 4 µg/ml.Enterobacter cloacae, Citrobacter freundii, Proteus mirabilis, Providencia spp. andPseudomonas aeruginosa were resistant. Bay v 3522 was destroyed by TEM-1, SHV-1, TEM-3 and P99 beta-lactamases.     

喹硫平与利培酮治疗儿童青少年精神分裂症的对照研究

目的比较喹硫平与利培酮对儿童青少年早发性精神分裂症的临床疗效、安全性和耐受性。方法对61例发病年龄为10～18岁符合中国精神障碍分类与诊断标准第3版精神分裂症诊断标准的患者,采用喹硫平或利培酮治疗,其中喹硫平治疗者31例,利培酮治疗者30例。以临床疗效总评量表(CGI)、简明精神病评定量表(BPRS)评估有效性,采用副反应量表(TESS)和一些重要生理指标包括血压、体重等评估安全性和耐受性,观察期限为4周。结果喹硫平每日平均治疗剂量为(835±281)mg,平均加药时间为(8.35±5.89)d。利培酮每日平均治疗剂量为(5.83±1.13)mg,平均加药时间为(10.9±3.82)d。治疗4周后同组BPRS评分均明显低于治疗前,组间BPRS减分率差异无统计学意义(t=-0.157,P=0.876);但喹硫平的锥体外系不良反应明显少于利培酮(χ2=4.510,P=0.034)。结论本研究提示两种药物对治疗儿童青少年精神分裂症均有确切疗效,其中喹硫平的锥体外系不良反应更少。     

Neuroprotective effect of diazoxide on brain injury induced by cerebral ischemia/reperfusion during deep hypothermia

OBJECT: The purpose of this study was to determine the effects of diazoxide on apoptosis and the relative mechanisms in a model of brain injury induced by cerebral ischemia/reperfusion (I/R) during deep hypothermia. METHODS: Three-week-old Sprague-Dawley male rats were randomly and equitably divided into sham-operated group, placebo-treated group and diazoxide-treated group respectively. Specific examination of the regional cerebral blood flow (rCBF) was measured in the three groups continuously during the operation by laser Doppler flowmetry. Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) was showed DNA fragmentation. The mRNA expressions of cytochrome c and full-length caspase-3 were determined by RT-PCR, while the protein expressions of cytochrome c and cleaved caspase-3 were determined by immunohistochemistry at 1 h, 6 h, 24 h, 72 h and 7 days after I/R, respectively. Cytosolic release of cytochrome c at 24 h after I/R was also confirmed by Western blot. RESULTS: rCBF was significantly decreased in both of placebo-treated and diazoxide-treated group just after ischemia in the time interval 0-5 min, and had no obvious changes in all the time intervals during the operation. Diazoxide preconditioning significantly decreased the percentage of TUNEL-positive staining cells. The mRNA expressions of cytochrome c and full-length caspase-3 in diazoxide-treated group were significantly decreased. In addition, diazoxide provided a significant reduction in the protein expressions of cytochrome c and cleaved caspase-3. CONCLUSION: These results suggested that the neuroprotective effects of diazoxide against cerebral I/R injury during deep hypothermia correlated with the reduction of DNA fragmentation, prevention of mitochondrial cytochrome c release and inhibition of caspase-3 activation.     

Constrictive pericarditis and Whipple's disease]

The authors report the case of a 61 year-old patient treated by tetracycline for very probable Whipple's disease who developed constrictive pericarditis requiring pericardectomy. Although intestinal biopsy was negative, histological examination of the resected pericardium was very suggestive of a cardiac localisation of Whipple's disease, showing a fibrous pericarditis with a mononuclear infiltration including PAS-positive histiocytes. In addition, the same histological changes were found in a small fragment of myocardial biopsy. This case illustrates the prevalence and consequences of cardiac involvement in Whipple's disease.     

Photoacoustic treatment mitigates cognitive dysfunction in a model of sleep-wake rhythm disturbance

Sleep-wake rhythm disturbances,which are characterized by abnormal sleep timing or duration,are associated with cognitive dysfunction.Photoacoustic treatments including light and sound stimulation have been found to be effective in modulating sleep patterns and improving cognitive behavior in abnormal sleep-wake pattern experiments.In this study,we examined whether light and sound interventions could reduce sleep-wake pattern disturbances and memory deficits in a sleep rhythm disturbance model.We established a model of sleep rhythm disturbance in C57 BL/6 J mice via a sleep deprivation method involving manual cage tapping,cage jostling,and nest disturbance.We used a Mini Mitter radio transmitter device to monitor motor activity in the mice and fear conditioning tests to assess cognitive function.Our results indicated that an intervention in which the mice were exposed to blue light(40-Hz flickering frequency)for 1 hour during their subjective daytime significantly improved the 24-hour-acrophase shift and reduced the degree of memory deficit induced by sleep deprivation.However,interventions in which the mice were exposed to a 40-Hz blue light at offset time or subjective night time points,as well as 2 Hz-blue light at 3 intervention time points(subjective day time,subjective night time,and offset time points),had no positive effects on circadian rhythm shift or memory deficits.Additionally,a 2000-Hz sound intervention during subjective day time attenuated the24-hour-acrophase shift and memory decline,while 440-Hz and 4000-Hz sounds had no effect on circadian rhythms.Overall,these results demonstrate that photoacoustic treatment effectively corrected abnormal sleep-wake patterns and cognitive dysfunction associated with sleep-deprivation-induced disturbances in sleep-wake rhythm.All animal experiments were approved by the Experimental Animal Ethics Committee of Drum Tower Hospital Affiliated to the Medical College of Nanjing University,China(approval No.20171102)on November20,2017.