Integrin α5β1 simultaneously controls EGFR-dependent proliferation and Akt-dependent pro-survival signaling in epidermoid carcinoma cells

To delineate distinctive role of the components of α5β1 integrin-EGFR axis in control of epidermoid carcinoma cell proliferation, we performed individual inhibition of α5β1 and EGFR via genetic and phamacological methods, respectively. We demonstrated that pharmacological inhibition of epidermal growth factor receptor (EGFR) significantly affected proliferation of A431 human cells by inducing the G0/G1 cell cycle arrest, whereas shRNA-mediated depletion of α5 subunit of α5β1 integrin led to a similar type of cell cycle arrest followed by significant apoptosis. Both treatments resulted in suppression of activated (phosphorylated) forms of focal adhesion kinase (FAK) and Erk. However, unlike EGFR inhibition, depletion of α5 led to substantial suppression of AKT activity. Accordingly, pharmacological inhibition of EGFR and AKT recapitulated detrimental effects caused by shRNA-mediated depletion of α5. Moreover, depletion of α5 led to a severe drop in the amounts of active EGFR. Thus, for the first time, we demonstrated that α5β1 integrin simultaneously maintains pro-survival signaling via continuous activation of AKT and up-regulates proliferation via activation of EGFR.     

Idiopathic intracranial hypertension from the perspective of headache center

Idiopathic intracranial hypertension (IIH) is a pathological state defined as an increase of intracranial pressure in the absence of a causative pathological process. The aim of this study was to evaluate the clinical features of the patients with IIH diagnosed in our Headache Center according to the current knowledge of this disorder. In the retrospective and cross-sectional analysis of 3395 patients we present 12 newly diagnosed IIH patients, ten women and two men, aged from 19 to 51, with obtained values of cerebrospinal fluid pressure between 250 and 680 mm of water. The symptoms of IIH clinical presentation have been headache, reported by 92 % of patients; papilledema, noted in 67 %; and cranial nerve impairment (25 %). The results obtained from presented patients confirmed the presence of headache features that are included in criteria for headache attributed with IIH in majority of them: progressive, daily, diffuse, non-pulsatile headache with aggravation by coughing or straining. Decrease of pain intensity after lumbar puncture was noted in all patients. We notice the relatively small proportion of patients with headache attributed to IIH among the patients treated in our Headache Center. The prevalence of IIH is not low and headache is the most frequent presenting symptom; therefore, we could only conclude that some chronic headache patients refractory for treatment are patients with IIH.     

Allogeneic stem cell transplantation for mantle cell lymphoma—final report from the prospective trials of the East German Study Group Haematology/Oncology (OSHO)

This study was conducted in order to evaluate allogeneic stem cell transplantation (alloSCT) as consolidation for patients with mantle cell lymphoma (MCL). Patients with MCL were included into two prospective trials OSHO #060 (refractory/relapsed) and #074 (de novo). Induction was rituximab and chemotherapy. Responding patients proceeded to alloSCT. Minimal residual disease was monitored by quantitative RT-PCR detecting either t(11;14) or clonospecific CDR-III regions. In case of circulating lymphoma cells, immunomodulation (cyclosporine A withdrawal, rituximab, donor lymphocyte infusion) was initiated. Thirty-three of 39 patients underwent alloSCT after myeloablative (n?=?7) or toxicity-reduced (n?=?26) conditioning. Leukocytes engrafted at day +16 (median, range 0–101) and platelets at day +14 (0–142). Acute graft-versus-host disease stages I–II occurred in 42 % and stages III–IV in 15 %. Five patients have relapsed after SCT. The overall mortality after SCT was 24 % (n?=?8). Median follow-up after SCT was 2.8 years (range 0.0–10.9). Five-year progression-free survival was 67 %, and overall survival 73 % after SCT. The results were comparable for primary MCL and refractory/relapsed disease as well as for related vs. unrelated SCT. Younger patients had a significantly better outcome than the elderly. AlloSCT is a feasible and promising consolidation therapy for relapsed and refractory disease and an attractive option for young patients with de novo MCL of high risk.     

Acute kidney injury due to rhabdomyolysis and renal replacement therapy: a critical review

Rhabdomyolysis, a clinical syndrome caused by damage to skeletal muscle and release of its breakdown products into the circulation, can be followed by acute kidney injury (AKI) as a severe complication. The belief that the AKI is triggered by myoglobin as the toxin responsible appears to be oversimplified. Better knowledge of the pathophysiology of rhabdomyolysis and following AKI could widen treatment options, leading to preservation of the kidney: the decision to initiate renal replacement therapy in clinical practice should not be made on the basis of the myoglobin or creatine phosphokinase serum concentrations.     

Cryopreserved buffy-coat-derived platelets reconstituted in platelet additive solution: A safe and available product with sufficient haemostatic effectiveness

BackgroundPlatelets (PLTs) stored at 20–24 °C have a short shelf life of only 5 days, which can result in their restricted availability. PLT cryopreservation extends the shelf life to 2 years.MethodsWe implemented a method of PLT freezing at ?80 °C in 5–6% dimethyl sulfoxide. Buffy-coat-derived leucodepleted fresh PLTs blood group O (FP) were used for cryopreservation. Cryopreserved pooled leucodepleted PLTs (CPP) were thawed at 37 °C, reconstituted in PLT additive solution SSP + and compared to FP regarding PLT content, PLT concentration, pH, volume, PLT loss, anti-A/B antibody titre, total protein, plasma content, and PLT swirling. Clot properties were evaluated via rotational thromboelastometry. PLT microparticle number and surface receptor phenotype were assessed via flow cytometry.ResultsCPP met the required quality parameters. The mean freeze-thaw PLT loss was 22.24 %. Anti-A/B antibody titre and plasma content were significantly lower in CPP. CPP were characterised by faster clot initiation and form stable PLT clots. The number of PLT microparticles increased 25 times in CPP and there were more particles positive for the activation marker CD62 P compared to FP.ConclusionThawing and reconstitution are easy and fast processes if platelet additive solution is used. Low anti-A/B antibody titre and plasma content make possible the use of CPP of blood group O reconstituted in SSP + as universal ABO products, including clinical situations where washed PLTs are required. Clot properties evaluated via rotational thromboelastometry demonstrated that CPP retain a significant part of their activity compare to FP and are haemostatically effective.     

Calcitonin gene-related peptide levels in saliva of patients with burning mouth syndrome

Burning mouth syndrome (BMS) is an intraoral burning sensation for which no medical or dental cause can be found. Recent studies suggest that primary neuropathic dysfunction might be involved in the pathogenesis of BMS. Calcitonin gene-related peptide (CGRP) plays an important role in the development of pain and serves as a biological marker of trigeminovascular activation. The aim of this study was to determine the levels of CGRP in the saliva of BMS patients and estimate the trigeminovascular activation in BMS. CGRP levels were measured, by RIA method in 78 BMS patients and 16 healthy subjects. The levels of CGRP were non-significantly decreased in BMS patients in comparison to healthy subjects. These results suggest that trigeminal nerve degeneration may be the underlying cause of BMS.     

Hybrid Ultra-Low-Radioactive Material for Protecting Dark Matter Detector from Background Neutrons

A laboratory technology for a new ultra-low background hybrid material (HM) which meets the requirements for neutron absorption with simultaneous neutron detection has been developed. The technology and hybrid material can be useful for future low background underground detectors designed to directly search for dark matter with liquid noble gases. The HM is based on a polymethylmethacrylate (PMMA) polymer matrix in which gadolinium nuclei are homogeneously distributed up to 1.5 wt% concentration in polymer slabs of 5 cm thickness. To determine the 65 impurity elements by the inductively coupled plasma mass-spectrometry (ICP-MS) technique in the Gd-based preparations in 100–0.01 ppb range, the corresponding method has been developed. Limits of determination (LD) of 0.011 ppb for uranium, and 0.016 ppb for thorium were achieved. An analysis of Gd raw materials showed that the lowest contents of U and Th (1.2–0.2 ppb) were detected in commercial Gd-based preparations. They were manufactured either from secondary raw materials (extraction phosphoric acid) or from mineral raw materials formed in sedimentary rocks (phosphogypsum). To produce the Gd-doped HM the commercial GdCl₃ was purified and used for synthesis of low-background coordination compound, namely, acetylacetonate gadolinium (Gd(acac)₃) with U/Th contents less than LD. When dissolving Gd(acac)₃ in methylmethacrylate, the true solution was obtained and its further thermal polymerization allowed fabrication of the Gd-doped PMMA with ultra-low background.     

Discontinuation of anti-tumor necrosis factor therapy in inflammatory bowel disease patients: a prospective observation

Background: Discontinuation of anti-TNF therapy in patients with inflammatory bowel diseases (IBD) in remission remains a controversial issue. The aims of our study were to assess the proportion of patients who relapse after cessation of biological treatment, and to identify potential risk factors of disease relapse. Methods: Consecutive IBD patients who discontinued anti-TNF therapy in steroid-free clinical and endoscopic remission were prospectively followed. Multiple logistic regression and Cox proportional-hazards models were used to assess the predictors of disease relapse. Results: Seventy-eight IBD patients (Crohn's disease, CD 61; ulcerative colitis, UC 17) were included and followed for a median of 30 months (range 7–47). A total of 32 (53%) CD patients and nine (53%) UC patients relapsed by the end of the follow-up with a median time to relapse of 8 months (range 1–25) in CD patients and 14 months (range 4–37) in UC patients, respectively. The cumulative probabilities of maintaining remission at 6, 12, and 24 months were 82%, 59%, and 51% in CD patients, and 77%, 77%, and 64% in UC patients, respectively. Survival of CD patients who were in deep remission (clinical and endoscopic healing; faecal calprotectin <150?mg/kg; CRP ≤5?mg/l) was not better compared with those who did not fulfill these criteria. In multivariate models, only colonic CD protected patients from disease relapse. Conclusions: Approximately half of the IBD patients relapsed within 2 years after anti-TNF discontinuation. In CD patients, no difference between those who were or were not in deep remission was found. Colonic localization protected patients from relapse.