Computational analysis of pediatric ventricular assist device implantation to decrease cerebral particulate embolization

Stroke is the most devastating complication after ventricular assist device (VAD) implantation with a 19% incidence and 65% mortality in the pediatric population. Current pediatric VAD technology and anticoagulation strategies alone are suboptimal. VAD implantation assisted by computational methods (CFD) may contribute reducing the risk of cerebral embolization. Representative three-dimensional aortic arch models of an infant and a child were generated. An 8 mm VAD outflow-graft (VAD-OG) anastomosed to the aorta was rendered and CFD was applied to study blood flow patterns. Particle tracks, originating in the VAD, were computed with a Lagrangian phase model and the percentage of particles entering the cerebral vessels was calculated. Eight implantation configurations (infant = 5 and child = 3) and 5 particle sizes (0.5, 1, 2, 3, and 4 mm) were considered. For the infant model, percentage of particles entering the cerebral vessels ranged from 15% for a VAD-OG anastomosed at 90° to the aorta, to 31% for 30° VAD-OG anastomosis (overall percentages: X² = 10,852, p < 0.0001). For the child model, cerebral embolization ranged from 9% for the 30° VAD-OG anastomosis to 15% for the 60° anastomosis (overall percentages: χ² = 10,323, p < 0.0001). Using detailed CFD calculations, we demonstrate that the risk of stroke depends significantly on the VAD implantation geometry. In turn, the risk probably depends on patient-specific anatomy. CFD can be used to optimize VAD implantation geometry to minimize stroke risk.     

Interferon γ and antisense transforming growth factor β transgenes synergize to enhance the immunogenicity of a murine mammary carcinoma

Transforming growth factor β (TGFβ) is an immunosuppressive cytokine that contributes to the immunological escape of tumor cells. In a previous study we demonstrated that inhibition of TGFβ production by EMT6 murine mammary tumor cells expressing an antisense TGF-β transgene reduces their tumorigenicity. On the basis of this observation we hypothesized that down-regulation of TGFβ production coupled with interferon γ (IFNγ) stimulation would induce an immune response superior to that generated by either strategy alone. In this study, EMT6 tumor cells expressing antisense TGFβ were transduced with the murine IFNγ gene. Tumor cells expressing either or both transgenes grew more slowly than mock-transduced tumors. Dual-transgene-expressing tumor cells were more immunogenic than tumor cells expressing either transgene alone. Studies in mice depleted of T cell subsets indicated that CD8⁺ T cells are the primary effectors of the antitumor activity observed. These results suggest that down-regulation of immunosuppression combined with cytokine-mediated immune augmentation is a useful strategy to improve antitumor immunity. Received: 6 October 1998 / Accepted: 15 January 1999     

Diagnostic accuracy of fine-needle aspiration cytology in histological grade 1 breast carcinomas: are we good enough?

Background: Fine-needle aspiration cytology (FNAC) of both palpable and non-palpable breast carcinomas has a high accuracy and sensitivity in dedicated centres. It is generally thought that low-grade carcinomas have a distinctly lower sensitivity due to discrete cellular atypia that may be difficult to appreciate. Grade 1 carcinomas make up about 45% of screening-detected breast carcinomas and about 20% of symptomatic breast cancers. The aim of this study was to evaluate the diagnostic sensitivity of grade 1 carcinomas and identify the critical features in the cytological diagnostic work-up of these tumours. Methods: There were FNAC smears from 494 histologically confirmed grade 1 carcinomas diagnosed during 1996–2004. The cytological diagnoses were compared with the histology. Results: A definitive malignant diagnosis (absolute sensitivity) was given in 382 cases (77.3%). Equivocal or suspicious diagnoses were given in 75 (15.2%), benign or probably benign (false negative) in 24 (4.8%). Thirteen cases (2.6%) were unsatisfactory. Complete sensitivity was 92.7%. Invasive ductal carcinomas comprised 81.3% of all cases; absolute sensitivity for these was 80.9%. Invasive lobular and tubular carcinomas comprised 7.3% and 5.9% of cases, respectively; absolute sensitivity for these diagnosis was 50.0% and 57.1%, respectively, significantly lower than for other subtypes (P ≤ 0.0001) whereas the difference for complete sensitivity was less but still significant (P = 0.017). Absolute and complete sensitivities were lower for tumours less than 1 cm size compared with more than 1 cm (P ≤ 0.00001). Conclusion: Preoperative FNAC diagnosis of grade 1 breast carcinoma has a high sensitivity, especially in ductal carcinomas. Invasive lobular and tubular carcinomas were less likely to receive a definite preoperative diagnosis. The main reason for not reaching a definitive malignant diagnosis was sampling error due to small tumours less than 1 cm in diameter, irrespective of tumour subtype.     

Epigenetic silencing of Na,K-ATPase β1 subunit gene ATP1B1 by methylation in clear cell renal cell carcinoma

The Na,K-ATPase or sodium pump carries out the coupled extrusion of Na⁺ and uptake of K⁺ across the plasma membranes of cells of most higher eukaryotes. We have shown earlier that Na,K-ATPase-β₁ (NaK-β) protein levels are highly reduced in poorly differentiated kidney carcinoma cells in culture and in patients' tumor samples. The mechanism(s) regulating the expression of NaK-β in tumor tissues has yet to be explored. We hypothesized that DNA methylation plays a role in silencing the NaK-β gene (ATP1B1) expression in kidney cancers. In this study, to the best of our knowledge we provide the first evidence that ATP1B1 is epigenetically silenced by promoter methylation in both renal cell carcinoma (RCC) patients’ tissues and cell lines. We also show that knockdown of the von Hippel-Lindau (VHL) tumor suppressor gene in RCC cell lines results in enhanced ATP1B1 promoter AT hypermethylation, which is accompanied by reduced expression of NaK-β. Furthermore, treatment with 5-Aza-2′-deoxycytidine rescued the expression of ATP1B1 mRNA as well as NaK-β protein in these cells. These data demonstrate that promoter hypermethylation is associated with reduced NaK-β expression, which might contribute to RCC initiation and/or disease progression.     

The aetiology of myocardial injury after non-cardiac surgery

Recognition of myocardial injury after non-cardiac surgery is difficult, since strong analgesics (e.g. opioids) can mask anginal symptoms, and ECG abnormalities are subtle or transient. Thorough knowledge of the pathophysiological mechanisms is therefore essential. These mechanisms can be subdivided into four groups: type I myocardial infraction (MI), type II MI, non-ischaemic cardiac pathology, and non-cardiac pathology. The incidence of type I MI in patients with a clinical suspicion of perioperative acute coronary syndrome (ACS) is 45–57 %. This percentage is higher in patients with a high likelihood of MI such as patients with ST-elevation ACS. Of note, the generalisability of this statement is limited due to significant study limitations. Non-ischaemic cardiac pathology and non-cardiac pathology should not be overlooked as a cause of perioperative myocardial injury (PMI). Especially pulmonary embolism and dysrhythmias are a common phenomenon, and may convey important prognostic value. Implementation of routine postoperative troponin assessment and accessible use of minimally invasive imaging should be considered to provide adequate individualised therapy. Also, addition of preoperative imaging may improve the stratification of high-risk patients who may benefit from preoperative or perioperative interventions.     

Papillary neoplasms of the breast: clues in fine needle aspiration cytology

Papillary neoplasms of the breast include a wide spectrum of mammary lesions. The differential diagnosis of benign and malignant lesions can be problematic not only cytologically, but also histopathologically. Aspiration smears can demonstrate that cytological differentiation is feasible. A retrospective study of 30 cases of papillary tumour of the breast, 15 papillary carcinomas and 15 papillomas, was performed to find the cytological differences between the pathologies. Cytological samples of papillary carcinomas were characterized by an abundance of cellular material, three-dimensional papillary clusters without fibrovascular connective tissue cores, small papillae arranged in cell balls, tall columnar cells and isolated naked nuclei. Numerous haemosiderin-laden macrophages were seen. There were no eosinophilic bipolar cytoplasmic granules, bipolar naked nuclei or apocrine metaplasia. In the papillomas there was less material; the papillae had cohesive stalks surrounded by columnar cells in a honeycomb pattern. We also found fewer small papillae and isolated columnar cells. In addition, the presence of apocrine metaplasia and bipolar naked nuclei was noted. We suggest that papillary carcinoma of the breast can be diagnosed by cytology and differentiated from papilloma.     

Exosomal transfer of miR-106a-5p contributes to cisplatin resistance and tumorigenesis in nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC), a subclass of cancers of the neck and head, is a predominant cause of cancer-associated death worldwide. Hence, there is a critical need for research into NPC-related treatment strategies. Cisplatin is a promising therapy option for NPCs and other cancers that is frequently utilized. Some patients acquire resistance to cisplatin therapy, which complicates the successful use of cisplatin treatment in NPCs. Although exosomal transfer of oncogenic miRNAs has been shown to improve recipient cell proliferation, metastasis and chemoresistance, the molecular mechanism behind this effect on NPC has yet to be fully understood. Exosomal microRNAs (miRNAs) from cisplatin-resistant cells were identified as significant mediators of chemoresistance in NPC cells in this investigation. Initially, we found that exosomal miR-106a-5p levels in the serum of chemoresistant and last-cycle patients were greater than in that of non-resistant and first-cycle patients. Also, exosomal miR-106a-5p enhanced the proliferative ability of NPC cells. Mechanistically, exosomal miR-106a-5p targets ARNT2, which further activates AKT phosphorylation, and thus promotes NPC cell proliferation, decreases apoptosis and in turn regulates tumorigenesis. We found similar results using in vivo NPC models, where exosomal miR-106a-5p through regulation of ARNT2 (aryl hydrocarbon receptor nuclear translocator 2) promoted tumorigenesis. Taken together, these findings indicate that exosomal miR-106a-5p could be a promising diagnostic biomarker and drug target for patients with NPC.