EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors

Epstein-Barr virus (EBV) persistently infects more than 90% of the human population and is etiologically linked to several B cell malignancies, including Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and diffuse large B cell lymphoma (DLBCL). Despite its growth transforming properties, most immune-competent individuals control EBV infection throughout their lives. EBV encodes various oncogenes, and of the 6 latency-associated EBV-encoded nuclear antigens, only EBNA3B is completely dispensable for B cell transformation in vitro. Here, we report that infection with EBV lacking EBNA3B leads to aggressive, immune-evading monomorphic DLBCL-like tumors in NOD/SCID/γc-/- mice with reconstituted human immune system components. Infection with EBNA3B-knockout EBV (EBNA3BKO) induced expansion of EBV-specific T cells that failed to infiltrate the tumors. EBNA3BKO-infected B cells expanded more rapidly and secreted less T cell-chemoattractant CXCL10, reducing T cell recruitment in vitro and T cell-mediated killing in vivo. B cell lines from 2 EBV-positive human lymphomas encoding truncated EBNA3B exhibited gene expression profiles and phenotypic characteristics similar to those of tumor-derived lines from the humanized mice, including reduced CXCL10 secretion. Screening EBV-positive DLBCL, HL, and BL human samples identified additional EBNA3B mutations. Thus, EBNA3B is a virus-encoded tumor suppressor whose inactivation promotes immune evasion and virus-driven lymphomagenesis.     

A prospective study of contrast preservation using ultra-low contrast delivery technique versus standard automated contrast injector system in coronary procedures

BackgroundWe aimed to assess the decrease in contrast media volume (CMV) with ultra-low contrast delivery technique (ULCD) developed at our institution versus the usual automated contrast injector system (ACIS) contrast delivery in coronary procedures.MethodsWe analyzed the amount of contrast given in the consecutive 204 patients of the operators who use ULCD technique versus consecutive 200 patients of the other operators who use ACIS without ULCD technique for coronary angiograms and/or percutaneous coronary interventions (PCIs) from May 2017 to July 2018 at our center. We calculated the mean CMV between these groups.ResultsWe observed a significant reduction in mean CMV with ULCD technique versus standard ACIS, respectively: angiogram 24.8 ± 15.8 mL (n = 194) vs 42.3 ± 25.1 mL (n = 200) (p < 0.0001); PCI 23.5 ± 19.7 mL (n = 52) vs 48.2 ± 30.8 mL (n = 16) (p < 0.0070); angiogram with ad hoc PCI 53.4 ± 32.1 mL (n = 23) vs 89.7 ± 35.6 mL (n = 16) (p < 0.0024); and overall angiogram and PCI 27.4 ± 20.5 mL (n = 204) vs 44.9 ± 28.0 mL (n = 181) (p < 0.0001).ConclusionOur study showed a highly significant reduction in CMV using ULCD technique compared to standard ACIS contrast delivery in coronary invasive procedures. Even in the standard ACIS arm, CMV was significantly lower than values reported in literature, possibly due to operators' bias toward contrast preservation.     

Management of Vancouver B2 and B3 Periprosthetic Proximal Femoral Fractures by Distal Locking Femoral Stem (Cannulok) in Patients 75 Years and Older

Background

Periprosthetic fracture following total hip arthroplasty is a significant problem faced by hip surgeons, and its management in elderly patients remains a considerable challenge.

Reduced Tim-3 expression on human T-lymphotropic virus type I (HTLV-I) Tax-specific cytotoxic T lymphocytes in HTLV-I infection

T cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3) and programmed cell death-1 (PD-1) are T cell exhaustion molecules. We investigated the expression of Tim-3 and PD-1 in human T-lymphotropic virus type I (HTLV-I) infection. Tim-3 expression, but not PD-1 expression, was reduced on CD4(+) and CD8(+) T cells of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients and HTLV-I carriers as compared with healthy controls. Tim-3 expression was also reduced in HTLV-I Tax-specific cytotoxic T lymphocytes (CTLs) as compared with cytomegalovirus-specific CTLs. Tim-3(+), but not PD-1(+), Tax-specific CTLs produced less interferon-γ and exhibited low cytolytic activity. However, we observed no difference in the expression of Tim-3 or cytolytic activity between Tax-specific CTLs of HAM/TSP patients or carriers. Moreover, HTLV-I-infected CD4(+) T cells showed decreased Tim-3 expression. These data suggest that Tim-3 expression is reduced in HTLV-I infection and that a high number of Tim-3(-) HTLV-I-specific CTLs preserves their cytolytic activity, thereby controlling viral replication.     

Associations of symptomatic or asymptomatic peripheral arterial disease with all-cause mortality and cardiovascular mortality

BackgroundTo investigate the rate of all cause and cardiovascular mortality in patients with symptomatic or asymptomatic peripheral arterial disease (PAD) compared to those without PAD.Methods and resultsAll the subjects were inpatients at high risk of atherosclerosis and enrolled from February to November, 2006. A total of 320 were followed up until an end-point (death) was reached or until February 2010. The mean follow-up time was 37.7 ± 1.5 months. Compared with non-PAD, PAD patients had significantly higher rates of hypertension, diabetes mellitus, and smoking (P < 0.01). Those with symptomatic and asymptomatic PAD had a much higher all cause (37.5% and 23.0% vs. 12.1%) and cardiovascular mortality (18.8% and 13.8% vs. 6.7%) compared to those without PAD (P < 0.001). The symptomatic PAD patients were 1.831 times (95% CI: 1.222–2.741) as likely to die as those without PAD, and 1.646 times (95% CI: 1.301–2.083) in asymptomatic PAD patients after adjusting for other factors. Those with symptomatic or asymptomatic PAD were more than twice as likely to die of CVD as those without PAD (RR: 2.248, 95% CI: 1.366–3.698 and RR: 2.105, 95% CI: 1.566–2.831, respectively).ConclusionsPAD was associated with a higher all cause and cardiovascular mortality whether or not PAD is symptomatic.     

Squamous cell carcinoma arising in Verneuil's disease

BACKGROUND: Verneuil's disease or hidradenitis suppurativa is a chronic suppurative, and cicatricial inflammatory disease, mainly affecting apocrine-bearing area of the skin. Squamous cell carcinoma is an uncommon but a frightening complication of hidradenitis suppurativa. AIM: To report a new case of squamous cell carcinoma arising in Verneuil's disease. CASE REPORT: We reported a case of 60 year old man with a 30 years history of hidradenitis suppurativa in which squamous cell carcinoma arise. A wide surgical excision removing the tumour and leaving a large defect was performed. The patient had a well recovery, wounds healed well by primary intention. No recurrence observed at 18 months of follow up. CONCLUSION: Squamous cell carcinoma is an uncommon complication of hidradenitis suppurativa. Surgical excision represents also the treatment of choice.     

Doxorubicin downregulates cell surface B7-H1 expression and upregulates its nuclear expression in breast cancer cells: role of B7-H1 as an anti-apoptotic molecule

Introduction

B7-H1 (PD-L1, CD274) is a T cell inhibitory molecule expressed in many types of cancer, leading to immune escape of tumor cells. Indeed, in previous reports we have shown an association of B7-H1 expression with high-risk breast cancer patients.

Methods

In the current study, we used immunohistochemistry, immunofluorescence and Western blot techniques to investigate the effect of neoadjuvant chemotherapy on the expression of B7-H1 in breast cancer cells.

Results

Among tested chemotherapeutic agents, doxorubicin was the most effective in downregulating cell surface expression of B7-H1 in vitro. These results were validated in vivo in a xenograft mouse model, as well as in murine heart tissue known to constitutively express B7-H1. The doxorubicin-dependent cell surface downregulation of B7-H1 was accompanied by an upregulation of B7-H1 in the nucleus. This re-distribution of B7-H1 was concurrent with a similar translocation of phosphorylated AKT to the nucleus. Inhibition of the PI3K/AKT pathway abrogated the doxorubicin-mediated nuclear up-regulation of B7-H1, suggesting an involvement of PI3K/AKT pathway in the nuclear up-regulation of B7-H1. Interestingly, siRNA knock down of B7-H1 lead to an increase in spontaneous apoptosis, as well as doxorubicin-induced apoptosis, which indicates an anti-apoptotic role for B7-H1 in breast cancer cells. The novel discovery of B7-H1 expression in the nuclei of breast cancer cells suggests that B7-H1 has functions other than inhibition of T cells.

Conclusions

Our findings explain the previously reported immunomodulatory effect of anthracyclines on cancer cells, and provide a link between immunoresistance and chemoresistance. Finally these results suggest the use of dual combinatorial agents to inhibit B7-H1 beside chemotherapy, in breast cancer patients.