Copy number gain and oncogenic activity of YWHAZ/14‐3‐3ζ in head and neck squamous cell carcinoma

Gene amplification, a common mechanism for oncogene activation in cancers, has been used in the discovery of novel oncogenes. Low‐level copy number gains are frequently observed in head and neck squamous cell carcinomas (HNSCCs) where numerous amplification events and potential oncogenes have already been reported. Recently, we applied restriction landmark genome scanning to study gene amplifications in HNSCC and located novel and uncharacterized regions in primary tumor samples. Gain on chromosome 8q22.3, the location of YWHAZ (14‐3‐3ζ), is found in 30–40% HNSCC cases. Data obtained from fluorescence in situ hybridization and immunohistochemistry on HNSCC tissue microarrays confirmed frequent low‐level YWHAZ copy number gain and protein overexpression. YWHAZ mRNA was frequently upregulated in patients' tumor tissues. Furthermore, YWHAZ RNAi significantly suppressed the growth rate of HNSCC cell lines, and overexpression of YWHAZ in HaCaT immortalized human skin keratinocytes promotes overgrowth, as well as morphological changes. Reduced YWHAZ levels increased the G1/G0‐phase proportion, decreased the S‐phase proportion and the rate of DNA synthesis. Based on this evidence, we suggest that YWHAZ is a candidate proto‐oncogene and deserves further investigation into its role in HNSCC carcinogenesis. © 2009 UICC     

Outcomes of Hepatosplenic T-Cell Lymphoma: The Mayo Clinic Experience

BackgroundHepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of peripheral T-cell lymphoma accounting for less than 1% of non-Hodgkin lymphomas. It is generally associated with poor prognosis.Patients and MethodsWe performed a cohort study of patients with HSTCL treated at the Mayo Clinic between 1996 and 2020 exploring the clinical characteristics and therapeutic outcomes.ResultsTwenty-two cases of HSTCL were identified with a median (range) age at diagnosis of 45.5 (15.5-80.6) years and a male predominance (15/22, 68.2%). Clinical characteristics include massive splenomegaly in 16 patients (73%), hepatic involvement in 13 (59%), and chronic immunosuppressed state in 8 (36%). Phenotypically, lymphoma cells had gamma/delta T-cell receptor expression in 18 (82%) and alpha/beta in 4 patients. Cytogenetic abnormalities included isochromosome 7q (i7q) in 8 (62%) of 13 and trisomy 8 in 4 (44%) of 9. The median (range) follow-up of surviving patients was 33 (2.5-137) months. The median progression-free and overall survival were 9.5 months (95% CI, 1.8, 16.3) and 12.4 months (95% CI, 4.9, 18.5), respectively. Long-term survival was seen in 4 (18%) of 22 patients, with survival of 55, 74, 95, and 137 months. Moreover, 3 of 4 long-term survivors had splenectomy as part of initial treatment, and 2 of 4 long-term survivors received an allogeneic hematopoietic cell transplant (allo-HCT).ConclusionLiver involvement and chronic immunosuppression were associated with shorter survival. Although splenectomy and allo-HCT have anecdotal benefit in the literature, our data do not show a statistically significant benefit of splenectomy and/or allo-HCT, likely as a result of our small sample size.     

The Association of Pre-diagnostic Inflammatory Markers and Adipokines and the Risk of Non-Hodgkin Lymphoma Development in Egypt

Non-Hodgkin lymphoma (NHL) is an etiologically, clinically, and histologically heterogeneous group of lymphoproliferative disorders. Immune dysfunction is a well-known risk factor and dysregulation of cytokines may mediate disease progression. Obesity is one of the important relations connecting immune system abnormalities and lymphomagenesis. We conducted a study to find out the association between obesity as measured by body mass index (BMI), and risk of non-Hodgkin lymphoma (NHL) development by assessment the of inflammatory cytokines levels, (IL-6, IL-10, IFN-gamma and CRP) and adipokines levels (leptin and adiponectin). Also, to predict the effect of higher BMI on the incidence of NHL. The study included 180 NHL patients and 172 healthy controls. The inflammatory markers (IL-6, IL-10, IFN-γ & CRP) together with adiponectin were assessed by ELISA technique. IL-6, IL-10, CRP, IFN-γ and Adiponectin were statistically higher in cases than control. A positive significant difference of Leptin (p-value 0.001) was found with higher levels in patients with BMI (≥ 25 kg/m²) than in patients with < 25 kg/m². IL-6, IL-10, CRP, IFN-γ and Adiponectin could be implicated in lymphomagenesis in Egyptian NHL. The study results support the hypothesis that obesity has a major role in the development of NHL. An association between Leptin and NHL risk with higher levels in patients with BMI (≥ 25 kg/m²) was proved.     

Evaluation of the diagnostic efficacy of Fasciola adult worm vomit for serodiagnosis of human fasciolosis

The diagnostic efficacy of Fasciola gigantica adult worm vomit (AWV) preparation in diagnosis of human fasciolosis was evaluated using conventional enzyme-linked immunosorbent assay (ELISA) and Falcon assay screening test (FAST)-ELISA in comparison with F. gigantica adult total soluble extract (TSE). Sera of fasciolosis patients, patients with other parasitic diseases (hydatid disease, schistosomiasis, toxoplasmosis, and amebiasis), and sera of healthy individuals were enrolled in this study. The results showed that the sensitivity of both conventional ELISA and FAST-ELISA was improved from 95 % using TSE to 100 % when using AWV. The specificity of conventional ELISA was 93.3 % using TSE and increased to 96.7 % using AWV. The specificity of FAST-ELISA using TSE was 96.7 % and became 100 % AWV antigen. The diagnostic accuracy of conventional ELISA was 94 % using TSE and increased to 98 % using AWV. The diagnostic accuracy of FAST-ELISA was 96 % using TSE and increased to 100 % using AWV. It is concluded that both TSE and AWV antigenic preparations are efficient for use in the serodiagnosis of human fasciolosis.     

Ventilator-associated pneumonia in adults in developing countries: a systematic review.

BACKGROUND: Ventilator-associated pneumonia (VAP) is a leading cause of death in hospitalized patients, but there has been no systematic analysis of the incidence, microbiology, and outcome of VAP in developing countries or of the interventions most applicable in that setting. METHODS: We reviewed MEDLINE (January 1966-April 2007) and bibliographies of the retrieved articles for all observational or interventional studies that examined the incidence, microbiology, outcome, and prevention of VAP in ventilated adults in developing countries. We evaluated the rates of VAP using the National Healthcare Safety Network (NHSN) definitions and the impact of VAP on the intensive care unit (ICU) length of stay (LOS) and mortality, and the impact of interventions used to reduce VAP rates. RESULTS: The rates of VAP varied from 10 to 41.7 per 1000 ventilator-days and were generally higher than NHSN benchmark rates. Gram-negative bacilli were the most common pathogens (41-92%), followed by Gram-positive cocci (6-58%). VAP was associated with a crude mortality that ranged from 16% to 94% and with increased ICU LOS. Only a small number of VAP intervention studies were performed; these found that staff education programs, implementation of hand hygiene, and VAP prevention practice guidelines, and/or implementation of sedation protocol were associated with a significant reduction in VAP rates. Only one interventional study was a randomized controlled trial comparing two technologies, the rest were sequential observational. This study compared a heat and moisture exchanger (HME) to a heated humidifying system (HHS) and found no difference in VAP rates. CONCLUSIONS: Based on the existing literature, the rate of VAP in developing countries is higher than NHSN benchmark rates and is associated with a significant impact on patient outcome. Only a few studies reported successful interventions to reduce VAP. There is a clear need for additional epidemiologic studies to better understand the scope of the problem. Additionally, more work needs to be done on strategies to prevent VAP, probably with emphasis on practical, low-cost, low technology, easily implemented measures.     

Determinants of right ventricular failure in patients admitted with acute left heart failure

Pulmonary hypertension, which may lead to right ventricular (RV) failure, increases with left ventricular (LV) diastolic dysfunction severity. The prevalence and determinants of RV failure were analyzed in 120 patients admitted with acute left heart (LH) failure. Patients were divided into RV failure (n=50) and non-RV failure (n=70) groups. The prevalence of RV failure was found to be 42%. In both groups, two thirds of the patients had isolated LV diastolic dysfunction and the rest had combined LV systolic and diastolic dysfunction. Patients in the RV failure group were characterized by higher LV diastolic grade (2.2 ± 0.6 vs 1.84 ± 0.7; P=.0070), pulmonary artery systolic pressure (PASP; 57.8 ± 15.3 vs 50.14 ± 12.1 mm Hg; P=.0028), right atrial enlargement (92% vs 25.7%; P=.000001), and more-than-moderate tricuspid regurgitation (58% vs 27.1%; P=.0006). RV failure is a frequent finding in patients with advanced LH failure. It is strongly associated with the severity of LV diastolic dysfunction and the severity of PASP.     

Cloning and expression of human membrane-bound and soluble engineered T cell receptors for immunotherapy

We report here the design and construction of several gene vectors for expression in mammalian cells of membrane-bound and soluble human T cell receptors (TR). We designed a vector (TR-ALPHA-IRES-TR-BETA pEF4) that encodes high-level expression of the full-length TR on the surface of T cells. Furthermore, we engineered TR that does not require the presence of endogenous CD3 molecules for surface expression and thus expression is not limited to T cells. We also constructed a vector encoding a single-chain TR (scTR) as a fusion protein of V-ALPHA-V-BETA-C-BETA with CD3Z. Since it is encoded and expressed as a single molecule, this scTR is well suited for gene therapy. Lastly, we successfully used a mammalian expression vector for generation of soluble human TR. The approaches we used here for manipulation of a human tumor-specific TR can be useful for other investigators interested in TR-based immunotherapy.     

Bench-to-bedside review: Early tracheostomy in critically ill trauma patients

A significant proportion of trauma patients require tracheostomy during intensive care unit stay. The timing of this procedure remains a subject of debate. The decision for tracheostomy should take into consideration the risks and benefits of prolonged endotracheal intubation versus tracheostomy. Timing of tracheostomy is also influenced by the indications for the procedure, which include relief of upper airway obstruction, airway access in patients with cervical spine injury, management of retained airway secretions, maintenance of patent airway and airway access for prolonged mechanical ventilation. This review summarizes the potential advantages of tracheostomy versus endotracheal intubation, the different indications for tracheostomy in trauma patients and studies examining early versus late tracheostomy. It also reviews the predictors of prolonged mechanical ventilation, which may guide the decision regarding the timing of tracheostomy.     

A Randomized Controlled Trial of Oral Administration of Tetanus Toxoid (TT) Versus Tetanus and Reduced Diphtheria (Td) in Pregnant Women

Introduction  The present study was designed as a randomized clinical trial to compare the immunogenicity, reactogenicity, and efficacy of tetanus toxoid (TT) and the combined tetanus and reduced diphtheria (Td) in pregnant women in four rural communities in Egypt. The pregnant women in each four villages received either TT or Td randomly. Both TT and Td vaccines are manufactured by the Egyptian Company for Biological Products & Vaccines (VACSERA) in Egypt. A total of 131 pregnant women were enrolled during the time of antenatal care visit (at 20 weeks gestational age of pregnancy) in one of four health units in Abu Homos district, Beheira Governorate, Egypt. Discussion  Unimmunized women received two random doses of either TT or Td 8 weeks apart during their pregnancy. Outpatient follow-up for adverse reactions occurred at the third day after each vaccine dose as either local effects such as pain, redness, and swelling or systematic effects such as fever, malaise, and headache or body aches which was served as primary safety endpoint. Blood was collected three times from each woman for determination of antibody titer against tetanus and diphtheria by using enzyme-linked immunosorbent assay technique. The first sample was collected immediately before the first dose, the second before the second dose, and the third sample 1 week after delivery. Active surveillance home visits to all study participants were done twice: the first home visit during the first week after delivery and the second 1 month after labor to report the health status of the mother and the baby. A total of 122 pregnant women received two ordinary doses with interdose intervals within the allowable range and three blood samples were collected in each protocol analysis (62 in the TT group and 60 in the Td group). There was no statistically significant difference between groups in the percentage of reporting a primary safety endpoint (fever, malaise, body ache, headache) or local reactions at the site of injection as redness and swelling, at third day after each dose. While in the Td group, after doses I and II, there was significant reporting pain at injection site as compared with TT group, home visits clinical examination revealed that the mothers and children were normal on in both groups. However, in the TT group, some children suffered from physiological jaundice. In all women in the two groups, protective immunity for tetanus was acquired, which reflected in neutralization of antibodies at titer (>0.10 IU/ml) after complete vaccination; however, the tetanus geometric mean titers postdoses I and II were significantly higher in TT vaccines group (P < 0.001). The postvaccination seroprotection titer (>0.10 IU/ml) in diphtheria was significantly higher in Td group than the TT group; diphtheria geometric mean titers of postdose II were significantly higher in Td vaccines as compared to the other group (P < 0.0001). From this results, we can conclude that the use of Td vaccine improves immunogenicity for both tetanus and diphtheria more than the use of TT vaccine alone and we can recommend to replace TT in immunization of pregnant women.