Application of Saliva Inhibition to Detect Underlying Alloantibodies in Bombay Blood Group

IntroductionThe Bombay phenotype is a rare blood group determined by the absence of H antigens. Bombay individuals produce anti-H, a clinically significant antibody that react against all ABO blood group. Anti-H can mask underlying alloantibody during antibody investigation, a challenge in current transfusion practice. The aim of this article is to explore saliva inhibition, a novel method to detect underlying alloantibody in Bombay individuals.Case PresentationThe case is a 93-year-old female transfused with pre-donated autologous blood for a surgery. We determined anti-H subclass and thermal amplitude, secretor status, and optimal ratio of saliva and Bombay plasma. Plasma samples containing anti-H were spiked with anti-Fy(a) to determine the effectiveness of saliva inhibition in uncovering underlying alloantibodies.ResultsAnti-H was confirmed to be predominately IgM with broad thermal amplitude. Tube immediate spin (IS) showed stronger anti-H reactivity compared to column agglutination technology (CAT). Spiked anti-Fy(a) was successfully detected using saliva inhibition method.ConclusionTube IS appears more sensitive to anti-H. Saliva inhibition appears to be a promising method to detect underlying alloantibody in the plasma of Bombay phenotype individuals.     

Analysis of accelerated failure time data with dependent censoring using auxiliary variables via nonparametric multiple imputation

We consider the situation of estimating the marginal survival distribution from censored data subject to dependent censoring using auxiliary variables. We had previously developed a nonparametric multiple imputation approach. The method used two working proportional hazards (PH) models, one for the event times and the other for the censoring times, to define a nearest neighbor imputing risk set. This risk set was then used to impute failure times for censored observations. Here, we adapt the method to the situation where the event and censoring times follow accelerated failure time models and propose to use the Buckley–James estimator as the two working models. Besides studying the performances of the proposed method, we also compare the proposed method with two popular methods for handling dependent censoring through the use of auxiliary variables, inverse probability of censoring weighted and parametric multiple imputation methods, to shed light on the use of them. In a simulation study with time‐independent auxiliary variables, we show that all approaches can reduce bias due to dependent censoring. The proposed method is robust to misspecification of either one of the two working models and their link function. This indicates that a working proportional hazards model is preferred because it is more cumbersome to fit an accelerated failure time model. In contrast, the inverse probability of censoring weighted method is not robust to misspecification of the link function of the censoring time model. The parametric imputation methods rely on the specification of the event time model. The approaches are applied to a prostate cancer dataset. Copyright © 2015 John Wiley & Sons, Ltd.     

Association of Albumin and Globulin with Mortality Risk in Incident Peritoneal Dialysis Patients

Background: Nutrition and inflammation have been implicated in predicting mortality in patients on peritoneal dialysis (PD). Serum albumin and globulin can be regarded for the nutritional and inflammatory status. However, there is lack of data to evaluate the synergistic effect of albumin and globulin on mortality prediction. Methods: In 554 patients initiating PD from January 2001 to July 2016, we divided them into four groups by the combination of two categories of low vs. high albumin and low vs. high globulin. The median values for albumin and globulin were chosen to classify them into low or high groups. Their associations with all-cause and cardiovascular (CV) mortality were examined in Cox regression models adjusted for confounding clinical and laboratory data. Results: Patients, 52.91 ± 15.2 years old and 47.8% men, had a median (interquartile range) value of 3.3 (2.9–3.8) g/dL for albumin and 2.8 (2.5–3.2) g/dL for globulin, respectively. Patients with low albumin and high globulin had the highest all-cause mortality and CV mortality, with adjusted hazard ratios of 3.87 (95% CI 1.83–8.20, p < 0.001) and 5.65 (95% CI 2.23–14.34, p < 0.001), respectively, compared with those with a high albumin and low globulin having the lowest mortality rate. Sensitivity analyses further confirmed this relationship. Conclusions: A patient profile of either low albumin or high globulin is linked to a higher risk for mortality, particularly for a profile of both low albumin and high globulin compared with one without either of them. Further studies are needed to explore the mechanisms underlying this phenomenon and how to improve clinical outcomes in those high-risk patients.     

The effects of atriopeptin II on calcium fluxes in rabbit aorta

Effects of atriopeptin II (AP II) at 10(-7) M on the 45Ca flux and contractile responses to vasoconstrictors including norepinephrine (NE), angiotensin II (angio II) and high K were studied in isolated rabbit aortic strips. Augmentation of 45Ca efflux from aorta in normal physiological saline (PSS) due to NE and angio II each at 3 X 10(-7) M was greatly inhibited by AP II, suggesting that stimulated increase in cytosolic Ca2+ was suppressed. In contrast, the 45Ca efflux responses to KCl (20 and 40 mM) were not affected by AP II. Furthermore, the marked inhibition of contractile responses to NE (-58%) and angio II (-57%) by AP II was accompanied by significant decreases in 45Ca influx, whereas AP II exhibited only a modest inhibition on KCl (40 mM)-induced contraction (-28%) without affecting the accompanying increase in 45Ca influx. The 45Ca efflux from aortae in Ca2+-free PSS due to NE was markedly diminished by AP II, suggesting impairment of intracellular Ca2+ release. With tissues in either a basal or post-stimulation state (tissue Ca2+ previously increased with KCl stimulation), AP II did not stimulate 45Ca efflux in Ca2+-free PSS, suggesting its lack of effect on Ca extrusion. It is concluded that AP II is preferentially antagonistic against vascular responses to NE and angio II vs. high K and that inhibition of Ca entry and release forms the primary basis of its potent vasorelaxant action against vasoconstrictors.     

Vaginal construction using sigmoid colon in children and young adults

OBJECTIVE: To compare two newly designed flexible ureteroscopes with their respective predecessors, to determine whether design advances have overcome the limitation of tip deflection, which may interfere with diagnosis and treatment of lower pole renal pathology. MATERIALS AND METHODS: Two new-generation flexible ureteroscopes, the DUR-8 Elite (ACMI, Southborough, MA, USA) and 11278AU (Karl Storz Endoscopy, Culver City, CA, USA) were compared with their previous models, the ACMI DUR-8 and the Storz 11274AAU. Active tip deflection and irrigation flow rates with and without various endoscopic tools were assessed. Specifications, purchase prices and repair costs were obtained from each manufacturer. The field of view and screen image size of each ureteroscope were also compared. RESULTS: The ACMI DUR-8 Elite and the Storz 11278AU had improvements of 79 degrees and 144 degrees, respectively, from their respective older models. Although the tip deflection of all ureteroscopes was compromised by inserting different endoscopic tools, these new instruments were less affected. With a 3 F basket inside the working channel, the ACMI DUR-8 Elite and the Storz 11278AU had only 0.7% and 2.8% loss of upward tip deflection, compared with their older models, at 9.6% and 5.0%, respectively. However, the flow rates of these new instruments were decreased. CONCLUSION: The new flexible ureteroscopes have significantly better active tip deflection than previous models, both with and without endoscopic instrumentation inserted. However, improved flexibility is at the expense of decreased flow rates and higher purchase costs.     

The impact of spleen volume on the survival of metastatic pancreatic adenocarcinoma patients receiving nanoliposomal irinotecan

Nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (NalFL) comprises the current standard for gemcitabine-failed metastatic pancreatic ductal adenocarcinoma (PDAC). As liposomes generally accumulate in the spleen, we evaluated the impact of spleen volume on prognosis. We enrolled patients with metastatic PDAC who failed gemcitabine-based therapy and were initiated on NalFL between August 2018 and November 2020. The spleen volume before NalFL administration was evaluated. They were stratified into dose subgroups (i.e. low, < 48 mg/m²; intermediate, 48 - < 64 mg/m²; high, ≥ 64 mg/m²) by the average nal-IRI dose during the entire treatment, and multivariate analysis of overall survival (OS) was performed. We included 547 patients with a median age of 63 years (range, 27-89 years) and a median of 1 (range, 0-7) palliative chemotherapy regimen. The median spleen volume was 245 mL (range, 82-817 mL). Among patients with splenomegaly (≥ 245 mL), the low-dose subgroup had the worst median time to treatment failure (TTF, 1.8 months vs. 2.5 months vs. 2.5 months, P = 0.020) and OS (3.3 months vs. 5.9 months vs. 6.6 months, P = 0.018) as against no prognostic impact in patients without splenomegaly. In the multivariate analysis of patients with splenomegaly, performance status (PS) ≥ 2, body surface area (BSA) < 1.6 m², prior fluoropyrimidine use, liver metastasis, and low-dose subgroup were independent poor prognostic factors. A low average nal-IRI dose was significantly associated with poor prognosis, especially among patients with splenomegaly. Further pharmacological studies should validate the relevance of spleen volume on the treatment outcomes of nal-IRI.     

Neuroprotective action of lithium in disorders of the central nervous system

Substantial in vitro and in vivo evidence of neurotrophic and neuroprotective effects of lithium suggests that it may also have considerable potential for the treatment of neurodegenerative conditions.Lithium's main mechanisms of action appear to stem from its ability to inhibit glycogen synthase kinase-3 activity and also to induce signaling mediated by brain-derived neurotrophic factor.This in turn alters a wide variety of downstream effectors,with the ultimate effect of enhancing pathways to cell surviva...     

Recombinant viral protein VP1 suppresses HER-2 expression and migration/metastasis of breast cancer

Breast cancer is one of the most common cancers in women worldwide and metastasis is the major cause of breast cancer death. Development of new therapeutic agents for inhibiting breast cancer metastasis is therefore an urgent need. We previously demonstrated that recombinant DNA-derived viral capsid protein VP1 (rVP1) of foot-and-mouth disease virus-induced apoptosis of MCF-7 breast cancer cells in vitro. Here, we investigated whether rVP1 exhibits any inhibitory effects on migration/metastasis and human epidermal growth factor receptor 2 (HER-2), a well-known biomarker for poor prognosis of breast cancer. The effects of rVP1 on cancer cell migration/invasion and metastasis were evaluated using Transwell migration assay and animal cancer models of metastasis. Western blotting, RT-PCR, flow cytometry, immunohistochemistry, and immunofluorescence staining techniques were used to investigate the effects of rVP1 on HER-2 and signal transduction mediators. Non-cytotoxic concentrations of rVP1-induced mesenchymal-epithelial transition and significantly suppressed AP-2?? and HER-2 expression as well as the migration and invasion of a variety of breast cancer cell lines in a ??1-integrin-dependent manner in vitro. Gross and histopathologic examinations showed that rVP1 also suppressed metastasis of several breast cancer cell lines, including HER-2-overexpressing SK-BR-3 and BT-474 cells to lung, liver, or peripheral lymph node in orthotopic allograft/xenograft murine models. In addition, rVP1 significantly prolonged survival in breast cancer-bearing mice. Notably, no apparent side effects of rVP1 were detected, as shown by normal complete blood count levels and serum biochemistry profiles, including AST, ALT, BUN, and creatine. This study demonstrates that rVP1 suppresses the migration, invasion, and metastasis of breast cancer cells via binding to ??1 integrin receptor and down-regulation of AP-2?? and HER-2 expression. The effectiveness of rVP1 on inhibiting migration/metastasis of breast cancer and HER-2 expression suggests that it may be suitable for serving as potential therapeutics for metastatic breast cancer particularly HER-2-overexpressing cancer.     

Over-expressions of AMPK subunits in ovarian carcinomas with significant clinical implications

ABSTRACT: BACKGROUND: AMP-activated protein kinase (AMPK) has recently been considered as a potential target for cancer therapy. However, the expression status of various subunits of the heterotrimeric AMPK in human cancers is rarely reported. We decided to determine their expressions in ovarian carcinomas and their relationships with the disease. METHODS: Expressions and locations of the AMPK-alpha1, -alpha2, -beta1, -beta2, -gamma1 and -gamma2 were detected by quantitative PCR (Q-PCR) and immunohistochemical staining (IHC). Their expression levels in ovarian tumors were compared with normal controls and also correlated with clinicopathological parameters. RESULTS: Except AMPK-alpha1, expressions of the other five AMPK subunits are significantly higher in ovarian carcinomas as determined by Q-PCR. Although IHC detection of AMPK-gamma1 and -gamma2 were not successful, over-expressions of AMPK-alpha2, -beta1, and -beta2 were further confirmed by IHC. Over-expressions of various AMPK subunits occurred independently and were mainly detected in the cytoplasm. Interestingly, AMPK-alpha2 and -beta1 were also detected in the nucleus and cell membrane, respectively. Clinical correlation analyses indicate that expressions of different AMPK subunits are associated with different subtypes of carcinoma. High expression of AMPK-alpha2 is significantly associated with endometrioid carcinomas. On the other hand, high expressions of AMPK-beta and -gamma subunits are associated with mucinous and serous carcinomas, respectively. Furthermore, high expressions of AMPK-beta1 and -gamma2 are also associated with early and late stages of disease, respectively. Finally, patients with high expression of AMPK-alpha2 had better prognosis. CONCLUSIONS: Aberrant expressions of AMPK subunits may play important roles in ovarian carcinogenesis. Each AMPK subunit may have its own function other than just a component of the AMPK molecule. Correlations with clinical parameters suggest that expressions of AMPK subunits have different clinical implications in ovarian cancer development.