Antibody response to BK polyomavirus as a prognostic biomarker and potential therapeutic target in prostate cancer

Infectious agents, including the BK polyomavirus (BKPyV), have been proposed as important inflammatory pathogens in prostate cancer. Here, we evaluated whether the preoperative antibody response to BKPyV large T antigen (LTag) and viral capsid protein 1 (VP1) was associated with the risk of biochemical recurrence in 226 patients undergoing radical prostatectomy for primary prostate cancer. Essentially, the multivariate Cox regression analysis revealed that preoperative seropositivity to BKPyV LTag significantly reduced the risk of biochemical recurrence, independently of established predictors of biochemical recurrence such as tumor stage, Gleason score and surgical margin status. The predictive accuracy of the regression model was denotatively increased by the inclusion of the BKPyV LTag serostatus. In contrast, the VP1 serostatus was of no prognostic value. Finally, the BKPyV LTag serostatus was associated with a peculiar cytokine gene expression profile upon assessment of the cellular immune response elicited by LTag. Taken together, our findings suggest that the BKPyV LTag serology may serve as a prognostic factor in prostate cancer. If validated in additional studies, this biomarker may allow for better treatment decisions after radical prostatectomy. Finally, the favorable outcome of LTag seropositive patients may provide a potential opportunity for novel therapeutic approaches targeting a viral antigen.     

Enhanced cell migration and apoptosis resistance may underlie the association between high SERPINE1 expression and poor outcome in head and neck carcinoma patients

High SERPINE1 expression is a common event in head and neck squamous cell carcinoma (HNSCC); however, whether it plays a role in determining clinical outcome remains still unknown. We studied SERPINE1 as a prognostic marker in two HNSCC patient cohorts. In a retrospective study (n = 80), high expression of SERPINE1 was associated with poor progression-free (p = 0.022) and cancer-specific (p = 0.040) survival. In a prospective study (n = 190), high SERPINE1 expression was associated with poor local recurrence-free (p = 0.022), progression-free (p = 0.002) and cancer-specific (p = 0.006) survival. SERPINE1 expression was identified as an independent risk factor for progression-free survival in patients treated with chemo-radiotherapy or radiotherapy (p = 0.043). In both patient cohorts, high SERPINE1 expression increased the risk of metastasis spread (p = 0.045; p = 0.029). The association between SERPINE1 expression and survival was confirmed using the HNSCC cohort included in The Cancer Genome Atlas project (n = 507). Once again, patients showing high expression had a poorer survival (p < 0.001). SERPINE1 over-expression in HNSCC cells reduced cell proliferation and enhanced migration. It also protected cells from cisplatin-induced apoptosis, which was accompanied by PI3K/AKT pathway activation. Downregulation of SERPINE1 expression had the opposite effect.We propose SERPINE1 expression as a prognostic marker that could be used to stratify HNSCC patients according to their risk of recurrence.     

Treatment of cognitive impairment in multiple sclerosis: position paper

Cognitive impairment in multiple sclerosis (MS) is common, debilitating and burdensome. Key evidence from trials was reviewed to enable recommendations to be made to guide clinical practice and research. Behavioural and pharmacological interventions on cognition reported in published studies were reviewed. Most studies evaluating behavioural treatment for impairment in learning and memory, deficits of attention and executive function have demonstrated some improvement. Controlled studies in relapsing remitting MS indicate interferon (IFN) β-1b and IFN β-1a were associated with modest cognitive improvement. The effects of symptomatic therapies such as modafinil and donepezil are inconsistent. Most studies yielding positive findings have significant methodological difficulties limiting the confidence in making any broad treatment recommendations. There are no published reports of glatiramer acetate, natalizumab and fingolimod being effective in improving cognition in controlled trials. The effects of disease modifying therapies in other forms of MS and clinically isolated syndrome have not yielded positive results. Data linking behavioural therapy, symptomatic treatment or disease modifying treatment, to either reducing cognitive decline or improving impaired cognition are limited and inconsistent. The treatment and prevention of cognitive impairment needs to remain a key research focus, identifying new interventions and improving clinical trial methodology.     

Causes and predictors of nonresponse to treatment of intensive care unit-acquired pneumonia

OBJECTIVE: To prospectively evaluate the predictive factors for the nonresponse to empirical antibiotic treatment and mortality in patients with intensive care unit-acquired pneumonia. DESIGN: A 1-yr prospective cohort of patients with suspicion of intensive care unit-acquired pneumonia. SETTING: Five medical and surgical intensive care units of Hospital Clinic in Barcelona. PATIENTS: A total of 71 patients with intensive care unit-acquired pneumonia were studied. The definition of nonresponse included at least one of the following: failure to improve the Pao2/Fio2 ratio or need of intubation because of pneumonia, persistence of fever or hypothermia and purulent respiratory secretions, worsening of pulmonary infiltrates, or occurrence of septic shock or multiple organ dysfunction not present at onset of pneumonia. INTERVENTIONS: Clinical assessment, including severity scores, blood and quantitative cultures of respiratory secretions, and cytokine measurements in serum and bronchoalveolar lavage at onset of pneumonia and 72 hrs after antimicrobial treatment. MEASUREMENTS AND RESULTS: A total of 44 patients (62%) fulfilled criteria of nonresponse, and at least one cause of nonresponse could be determined in 28 cases (64%): inappropriate treatment in ten (23%), superinfection in six (14%), concomitant foci of infection in 12 (27%), and noninfectious causes in seven cases (16%). The remaining 16 patients with no definite cause of nonresponse presented with septic shock, multiple organ dysfunction, or acute respiratory distress syndrome. Increased levels of interleukin-6 at onset of pneumonia (odds ratio, 9.7; p =.014) was an independent predictor of nonresponse to treatment. Likewise, increased level of interleukin-6 at follow-up (odds ratio, 27; p =.001) was the only independent predictor for hospital mortality. CONCLUSION: Increased systemic inflammatory response was the main predictor of nonresponse to treatment and mortality.     

Methicillin-resistant <Emphasis Type="Italic">Staphylococcus aureus</Emphasis>(MRSA) in rehabilitation and chronic-care-facilities: what is the best strategy?

Background

The risk associated with methicillin-resistant Staphylococcus aureus (MRSA) has been decreasing for several years in intensive care departments, but is now increasing in rehabilitation and chronic-care-facilities (R-CCF). The aim of this study was to use published data and our own experience to discuss the roles of screening for MRSA carriers, the type of isolation to be implemented and the efficiency of chemical decolonization.

Discussion

Screening identifies over 90% of patients colonised with MRSA upon admission to R-CCF versus only 50% for intensive care units. Only totally dependent patients acquire MRSA. Thus, strict geographical isolation, as opposed to "social reinsertion", is clearly of no value. However, this should not lead to the abandoning of isolation, which remains essential during the administration of care. The use of chemicals to decolonize the nose and healthy skin appeared to be of some value and the application of this procedure could make technical isolation unnecessary in a non-negligible proportion of cases.

Summary

Given the increase in morbidity associated with MRSA observed in numerous hospitals, the emergence of a community-acquired disease associated with these strains and the evolution of glycopeptide-resistant strains, the voluntary application of a strategy combining screening, technical isolation and chemical decolonization in R-CCF appears to be an urgent matter of priority.

     

Intranasal Exposure to Rift Valley Fever Virus Live-Attenuated Strains Leads to High Mortality Rate in Immunocompetent Mice

Rift Valley fever virus (RVFV) is a pathogenic arthropod-borne virus that can cause serious illness in both ruminants and humans. The virus can be transmitted by an arthropod bite or contact with contaminated fluids or tissues. Two live-attenuated veterinary vaccines—the Smithburn (SB) and Clone 13 (Cl.13)—are currently used during epizootic events in Africa. However, their residual pathogenicity (i.e., SB) or potential of reversion (i.e., Cl.13) causes important adverse effects, strongly limiting their use in the field. In this study, we infected immunocompetent mice with SB or Cl.13 by a subcutaneous or an intranasal inoculation. Interestingly, we found that, unlike the subcutaneous infection, the intranasal inoculation led to a high mortality rate. In addition, we detected high titers and viral N antigen levels in the brain of both the SB- and Cl.13-infected mice. Overall, we unveil a clear correlation between the pathogenicity and the route of administration of both SB and Cl.13, with the intranasal inoculation leading to a stronger neurovirulence and higher mortality rate than the subcutaneous infection.