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Aim According to the revised Bethesda Guidelines, colorectal cancer (CRC) occurring under age 50 years should be screened to exclude Lynch syndrome. However, in current practice in East Anglia, tumour screening is initiated only after genetics referral, reserved for those with a strong pedigree. This study aimed to determine how many patients with young-onset CRC undergo tumour screening in hospitals in East Anglia. Method A retrospective case notes review over 5 years in four hospitals was undertaken to determine what proportion of those with young-onset CRC underwent referral for tumour screening and to assess local practices in terms of patient counselling and management. Results One hundred and twenty-two patients were included. There was an average yearly caseload of 6-9 patients per hospital. Documented family history was rare, as was counselling concerning metachronous and extra-colonic tumour risk and CRC risk in relatives. The rate of referral for genetic testing varied from 44% to 65%. Postoperative colonoscopic surveillance was inconsistent. Conclusion Many patients with young-onset CRC are managed as sporadic cancers, without Lynch syndrome having been excluded. This may have implications for survival of patients and any affected relatives. A streamlined management algorithm for tumour screening and genetics referral is recommended. [ABSTRACT FROM AUTHOR]

Oral Diseases (2012) 18, 132-139 Objectives: Autoantibodies from the sera of Sjögren's syndrome patients (SS IgG) have been suggested to inhibit muscarinic receptor function. However, the acute nature of such an inhibitory effect remains controversial. In this study, we investigated the acute effects of SS IgG on muscarinic receptor function in human submandibular gland (HSG) cells. Methods: The effects of autoantibodies on muscarinic receptor function were studied using microspectrofluorimetry, whole-cell patch clamp, immunofluorescence confocal microscopy, and a co-immunoprecipitation assay. Results: Carbachol (CCh) was found to consistently increase intracellular calcium concentration ([Ca2+]i) and activate K+ current in HSG cells. However, pretreatment of the cells with SS IgG for 5 or 30 min significantly attenuated these responses, with a substantially more prominent effect after 30 min of treatment. Like CCh, adenosine 5′-triphosphate (ATP) also increased [Ca2+]i and activated K+ currents in HSG cells, although pretreatment with SS IgG did not affect the cellular response to ATP. CCh was found to reorganize α-fodrin in HSG cells in a Ca2+-dependent manner. However, pretreatment with SS IgG prevented the cytoskeletal reorganization of α-fodrin induced by CCh. Conclusions: SS IgG acutely and reversibly inhibited muscarinic receptor function, thereby inhibiting the Ca2+ mobilization necessary for the activation of K+ currents and α-fodrin reorganization in HSG cells. [ABSTRACT FROM AUTHOR]

Oral Diseases (2012) 18, 132-139 Objectives: Autoantibodies from the sera of Sjögren's syndrome patients (SS IgG) have been suggested to inhibit muscarinic receptor function. However, the acute nature of such an inhibitory effect remains controversial. In this study, we investigated the acute effects of SS IgG on muscarinic receptor function in human submandibular gland (HSG) cells. Methods: The effects of autoantibodies on muscarinic receptor function were studied using microspectrofluorimetry, whole-cell patch clamp, immunofluorescence confocal microscopy, and a co-immunoprecipitation assay. Results: Carbachol (CCh) was found to consistently increase intracellular calcium concentration ([Ca2+]i) and activate K+ current in HSG cells. However, pretreatment of the cells with SS IgG for 5 or 30 min significantly attenuated these responses, with a substantially more prominent effect after 30 min of treatment. Like CCh, adenosine 5′-triphosphate (ATP) also increased [Ca2+]i and activated K+ currents in HSG cells, although pretreatment with SS IgG did not affect the cellular response to ATP. CCh was found to reorganize α-fodrin in HSG cells in a Ca2+-dependent manner. However, pretreatment with SS IgG prevented the cytoskeletal reorganization of α-fodrin induced by CCh. Conclusions: SS IgG acutely and reversibly inhibited muscarinic receptor function, thereby inhibiting the Ca2+ mobilization necessary for the activation of K+ currents and α-fodrin reorganization in HSG cells. [ABSTRACT FROM AUTHOR]

Abstract: In the past decade nanoimprint has been developed to a serious alternative for next generation lithography (NGL). In this work, the most recent developments of UV-nanoimprint Lithography (UV-NIL) with special emphasis to the work accomplished at AMO and the IHT-RWTH Aachen are reviewed and functional applications demonstrated. Further the potentials of various UV-NIL concepts are evaluated and possible interests in certain application areas are discussed. [Copyright &y& Elsevier]

Background and purpose:M2-type pyruvate kinase (M2PK) was found to interact directly with the ‘ITAM’ region of the γ chain of the high-affinity IgE receptor (FcɛRI). Our hypothesis was that mast cell degranulation might require the FcɛRI-mediated inhibition of M2PK activity.Experimental approach:In rat basophilic leukaemia (RBL-2H3) cells, the effects of directly inhibiting M2PK or preventing the FcɛRI-mediated inhibition of M2PK (disinhibition) on degranulation was measured by hexosaminidase release. Effects of blocking the FcɛRI-mediated inhibition of M2PK was also assessed in vivo in a mouse model of allergen-induced airway hyper-responsiveness.Key results:Activation of FcɛRI in RBL-2H3 cells caused the rapid phosphorylation of tyrosine residues in M2PK, associated with a decrease in M2PK enzymatic activity. There was an inverse correlation between M2PK activity and mast cell degranulation. FcɛRI-mediated inhibition of M2PK involved Src kinase, phosphatidylinositol 3-kinase, PKC and calcium. Direct inhibition of M2PK potentiated FcɛRI-mediated degranulation and prevention of the FcɛRI-mediated inhibition of M2PK attenuated mast cell degranulation. Transfection of RBL-2H3 cells with M1PK which prevents FcɛRI-induced inhibition of M2PK, markedly reduced their degranulation and exogenous M1PK (i.p.) inhibited ovalbumin-induced airway hyper-responsiveness in vivo.Conclusions and implications:We have identified a new control point and a novel biochemical pathway in the process of mast cell degranulation. Our study suggests that the FcɛRI-mediated inhibition of M2PK is a crucial step in responses to allergens. Moreover, the manipulation of glycolytic processes and intermediates could provide novel strategies for the treatment of allergic diseases.British Journal of Pharmacology (2008) 154, 1035–1046; doi:10.1038/bjp.2008.148; published online 21 April 2008 [ABSTRACT FROM AUTHOR]

Abstract: The joined research activities on nanoimprint lithography (JRA-NIL) within a European Network of Excellence (ePIXnet) are described. The achievements are presented in three different exemplary applications. [Copyright &y& Elsevier]

OBJECTIVES To determine, in preclinical in vivo animal and in clinical studies, whether raloxifene (a selective oestrogen-receptor (ER) modulator that targets ER-β and induces apoptosis in vitro in androgen-independent prostate cancer, AIPC cells) affects prostate cell differentiation, proliferation and carcinogenesis, and in the pilot phase II clinical trial, the response rate and duration of patients with AIPC treated with a daily oral dose of raloxifene. PATIENTS, MATERIALS AND METHODS Tumour proliferation rate in response to raloxifene treatment, and molecular markers of cell cycle and apoptosis, were evaluated in established ER-β-positive androgen-dependent (AD) CWR22 and AI CWRSA9 human xenograft prostate cancer models. Twenty-one patients with AIPC and evidence of disease progression were enrolled into the clinical trial and given daily oral raloxifene. RESULTS There was significant growth inhibition by raloxifene in the ADPC and AIPC xenograft models (CWR22 68%, P < 0.010; CWRSA9 64%, P < 0.001), with no tumour regression. There was evidence of G1 arrest by increased p27kip1 expression in the raloxifene-treated group. Eighteen patients comprised the efficacy analysis, as three withdrew before the first evaluation. At the first evaluation, five men had stable disease and continued on the study for a median of five cycles. The longest response was 17 cycles. Drug related toxicity was minimal. CONCLUSION Raloxifene has activity in xenograft models, slowing disease progression. This translated to possible disease stabilization in patients with AIPC. Further studies are warranted. [ABSTRACT FROM AUTHOR]

Abstract: We present a new “templated self-organization” method for the preparation of Ge nanocrystals in that combines a bottom-up with a top-down approach for nanostructuring. Ge nanocrystals are formed by self-organization induced by thermal annealing of thin Ge films embedded in whose areas are predefined by nanoimprint patterning. Thus much smaller structure sizes can be achieved than by pure nanostructuring and much more regular structures can be prepared than by pure self-organization. In particular, the method enables the generation of Ge nanocrystals of equal size at predefined vertical and lateral positions thus facilitating the fabrication of nanoscaled devices due to the suppression of structural fluctuations. [Copyright &y& Elsevier]