bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomised clinical trials: linaclotide phase 3 studies in IBS‐C – a prespecified further analysis based on European Medicines Agency‐specified endpoints
Authors: Quigley E. M. M. , Tack J. , Chey W. D. , Rao S. S. , Fortea J. , Falques M. , Diaz C. , Shiff S. J. , Currie M. G. , Johnston J. M. 
Published: November 2012

SummaryBackgroundTreatment options that improve overall symptoms of irritable bowel syndrome with constipation (IBS‐C) are lacking.AimA prespecified further analysis to evaluate the efficacy and safety of linaclotide, a guanylate cyclase C agonist, in patients with IBS‐C, based on efficacy parameters prespecified for European Medicines Agency (EMA) submission.MethodsTwo randomised, double‐blind, multicentre Phase 3 trials investigated once‐daily linaclotide (290 μg) for 12 weeks (Trial 31) or 26 weeks (Trial 302) in patients with IBS‐C. Prespecified primary endpoints were the EMA‐recommended co‐primary endpoints: (i) 12‐week abdominal pain/discomfort responders [≥30% reduction in mean abdominal pain and/or discomfort score (11‐point scales), with neither worsening from baseline, for ≥6 weeks] and (ii) 12‐week IBS degree‐of‐relief responders (symptoms ‘considerably’ or ‘completely’ relieved for ≥6 weeks).ResultsOverall, 803 (Trial 31) and 805 patients (Trial 302) were randomised. A significantly greater proportion of linaclotide‐treated vs. placebo‐treated patients were 12‐week abdominal pain/discomfort responders (Trial 31: 54.8% vs. 41.8%; Trial 302: 54.1% vs. 38.5%; P < 0.001) and IBS degree‐of‐relief responders (Trial 31: 37.0% vs. 18.5%; Trial 302: 39.4% vs. 16.6%; P < 0.0001). Similarly, significantly more linaclotide‐ vs. placebo‐treated patients were responders for ≥13 weeks in Trial 302 (abdominal pain/discomfort: 53.6% vs. 36.0%; IBS degree‐of‐relief: 37.2% vs. 16.9%; P < 0.0001). The proportion of sustained responders (co‐primary endpoint responders plus responders for ≥2 of the last 4 weeks of treatment) was also significantly greater with linaclotide vs. placebo in both trials (P < 0.001).ConclusionLinaclotide treatment significantly improved abdominal pain/discomfort and degree‐of‐relief of IBS‐C symptoms compared with placebo over 12 and 26 weeks. Trial registration: ClinicalTrials.gov (identifiers: NCT00948818 and NCT00938717).
Diagnostic value of JAK2 V617F somatic mutation for myeloproliferative cancer in 49 488 individuals from the general population
Authors: Nielsen Camilla , Birgens Henrik S. , Nordestgaard Børge G. , Bojesen Stig E. 
Published: November 2012

SummaryThe JAK2 V617F somatic mutation is present in the majority of patients with myeloproliferative cancer (polycythaemia vera, essential thrombocytosis, and primary myelofibrosis). However, the diagnostic value of the JAK2 V617F somatic mutation for myeloproliferative cancer in the general population is unknown. We examined this question in 49 488 individuals from the Copenhagen General Population Study. We also examined the association between JAK2 V617F somatic mutation, rs10974944 germline genotype, haematological phenotype, any cancer, haematological cancer, myeloproliferative cancer, ischaemic heart disease, and venous thromboembolism. The JAK2 V617F somatic mutation was present in 0·1% (n = 68), increasing across rs10974944 germline genotypes (P‐trend = 0·001). JAK2 V617F somatic mutation positives versus negatives had higher erythrocyte (P = 2 × 10−5), thrombocyte (P = 2 × 10−16), and leucocyte (P = 4 × 10−9) counts, and had 2·7‐/2·5‐fold risk of cancer (prevalent/incident), 44‐/28‐fold risk of haematological cancer, 221‐/97‐fold risk of myeloproliferative cancer, 2·2‐/1·2‐fold risk of ischaemic heart disease, and 3·1‐/1·0‐fold risk of venous thromboembolism. By combining conventional haematological parameters with a test for the JAK2 V617F somatic mutation, myelo;?>proliferative cancer could be identified or ruled out with a sensitivity of 47–100% and a specificity of 98–100%. In conclusion, in the general population the JAK2 V617F somatic mutation has a high diagnostic value for myeloproliferative cancer when combined with conventional haematological parameters.
The sphingosine kinase inhibitor 2‐(p‐hyroxyanilino)‐4‐(p‐chlorophenyl)thiazole reduces androgen receptor expression via an oxidative stress‐dependent mechanism
Authors: Tonelli Francesca , Alossaimi Manal , Williamson Leon , Tate Rothwelle J , Watson David G , Chan Edmond , Bittman Robert , Pyne Nigel J , Pyne Susan 
Published: November 2012

Background and PurposeSphingosine kinase catalyses the formation of sphingosine 1‐phosphate and is linked with androgen receptor signalling in prostate cancer cells. Therefore, we investigated the effect of sphingosine kinase inhibitors on androgen receptor expression.Experimental ApproachAndrogen‐sensitive LNCaP cells were treated with SKi (2‐(p‐hydroxyanilino)‐4‐(p‐chlorophenyl)thiazole), which inhibits sphingosine kinases 1 and 2 activity, and the effect on androgen receptor expression was measured.Key ResultsTreatment of cells with SK1 inhibitors reduced the expression of the androgen receptor and prostate‐specific antigen, while (R)‐FTY720 methyl ether (a sphingosine‐kinase‐2‐selective inhibitor), at a concentration that eliminates sphingosine kinase 2 from cells, had no significant effect on androgen receptor expression. The effect of SKi on androgen receptor expression was independent of the SKi‐induced proteasomal degradation of SK1 and was post translational, although androgen receptor mRNA transcript was reduced. Fumonisin B1 (a ceramide synthase inhibitor) also failed to reverse the effect of SKi on androgen receptor expression, thereby excluding a role for ceramide derived from the salvage pathway. The effect of SKi on androgen receptor expression was reversed by N‐acetylcysteine, which was used to scavenge reactive oxygen species.Conclusion and ImplicationsInhibition of sphingosine kinase 1 activity abrogates androgen receptor signalling via an oxidative stress‐induced, p53‐independent mechanism in prostate cancer cells. Therefore, SK1 inhibitors may offer therapeutic potential in promoting the removal of AR receptors from prostate cancer cells, resulting in an increased efficacy, which is likely to be superior to inhibitors that simply reversibly inhibit AR signalling.
Glutathione S‐transferase P1‐1 as a target for mesothelioma treatment
Authors: De Luca Anastasia , Pellizzari Tregno Francesca , Sau Andrea , Pastore Anna , Palumbo Camilla , Alama Angela , Cicconi Rosella , Federici Giorgio , Caccuri Anna M. 
Published: November 2012

Malignant pleural mesothelioma is a poorly responsive tumor known to overexpress the phase II detoxification enzyme glutathione‐S‐transferase, which catalyzes the conjugation between glutathione and platinum(II)‐containing drugs. Therefore, we evaluated the effect of the strong glutathione S‐transferase inhibitor NBDHEX on human mesothelioma cell lines (MSTO‐211H, MPP89, MM‐B1 and Mero 48a) featuring the most common mesothelioma phenotypes: epithelioid and biphasic. Even though a different response to NBDHEX was observed, the molecule was very effective on all cell lines tested, triggering a sustained activation of both JNK and p38, followed by caspase activation and apoptosis. NBDHEX also caused severe oxidative stress in the MPP89 cells and, to a lesser extent, in the MMB1 cells, while it did not cause a significant redox imbalance in the other cell lines. The efficacy of the drug was found to be comparable or even higher than that of cisplatin. Moreover, it showed synergistic or additive effects when used in combination with cisplatin. In conclusion, NBDHEX was effective on mesothelioma cell lines, with IC50 values in the low micromolar range (IC50 between 1 and 4 μM). These findings indicate that NBDHEX, alone or in combination with cisplatin, is a promising new strategy for treating this rare and aggressive malignancy.
Characteristics ofin-vitrophenotypes of glutamic acid decarboxylase 65 autoantibodies in high-titre individuals
Authors: Chéramy M , Hampe C S , Ludvigsson J , Casas R 
Published: November 2012

SummaryPrevious studies have indicated phenotypical differences in glutamic acid decarboxylase 65 autoantibodies (GADA) found in type 1 diabetes (T1D) patients, individuals at risk of developing T1D and stiff-person syndrome (SPS) patients. In a Phase II trial using aluminium-formulated GAD65 (GAD-alum) as an immunomodulator in T1D, several patients responded with high GADA titres after treatment, raising concerns as to whether GAD-alum could induce GADA with SPS-associated phenotypes. This study aimed to analyse GADA levels, immunoglobulin (Ig)G1–4 subclass frequencies, b78- and b96·11-defined epitope distribution and GAD65 enzyme activity in sera from four cohorts with very high GADA titres: T1D patients (n = 7), GAD-alum-treated T1D patients (n = 9), T1D high-risk individuals (n = 6) and SPS patients (n = 12). SPS patients showed significantly higher GADA levels and inhibited the in-vitro GAD65 enzyme activity more strongly compared to the other groups. A higher binding frequency to the b78-defined epitope was found in the SPS group compared to T1D and GAD-alum individuals, whereas no differences were detected for the b96·11-defined epitope. GADA IgG1–4 subclass levels did not differ between the groups, but SPS patients had higher IgG2 and lower IgG4 distribution more frequently. In conclusion, the in-vitro GADA phenotypes from SPS patients differed from the T1D- and high-risk groups, and GAD-alum treatment did not induce SPS-associated phenotypes. However, occasional overlap between the groups exists, and caution is indicated when drawing conclusions to health or disease status.
Treatment of soft tissue recessions at titanium implants using a resorbable collagen matrix: a pilot study
Authors: Schwarz Frank , Mihatovic Ilja , Shirakata Yoshinori , Becker Jürgen , Bosshardt Dieter , Sculean Anton 
Published: November 2012

AbstractObjectivesTo histologically assess the effectiveness of a porcine‐derived collagen matrix (CM) and a subepithelial connective tissue graft (CTG) for the coverage of single mucosal recessions at osseointegrated dental implants.Materials and methodsChronic‐type mucosal Miller Class I‐like recessions (mean clinical defect height: 0.67 ± 0.33–1.16 ± 0.19 mm) were established at the buccal aspect of titanium implants with platform switch in six beagle dogs. The defects were randomly allocated to either (1) coronally advanced flap surgery (CAF) + CM, (2) CAF + CTG or (3) CAF alone. At 12 weeks, histomorphometrical measurements were made (e.g.) between the implant shoulder (IS) and the mucosal margin (PM) and IS and the outer contour of the adjacent soft tissue (mucosal thickness [MT]).ResultsAll treatment procedures investigated were associated with an almost complete soft tissue coverage of the defect area (i.e. coronal positioning of PM relative to IS). Mean IS‐PM and MT values tended to be increased in both CAF + CM (1.04 ± 0.74 mm/0.71 ± 0.55 mm) and CAF + CTG (0.88 ± 1.23 mm/0.62 ± 0.66 mm) groups when compared with CAF (0.16 ± 0.28 mm/0.34 ± 0.23 mm) alone. These differences, however, did not reach statistical significance.ConclusionsWithin the limits of this pilot study, it was concluded that all treatment procedures investigated were effective in covering soft tissue recessions at titanium implants.
Diagnostic utility of direct immunofluorescence findings around hair follicles and sweat glands in immunobullous disease
Authors: Lehman Julia S. , Camilleri Michael J. 
Published: November 2012

BackgroundInherent to some immunobullous disorders is potential for intraepidermal or dermal–epidermal junction fragility, a phenomenon that may compromise biopsy specimen integrity and direct immunofluorescence (DIF) interpretation. In these situations, cutaneous adnexal structures (e.g. hair follicles, sweat apparatus) usually remain intact. Whether periadnexal DIF findings are reliable in diagnosing immunobullous conditions is unknown.MethodsWe evaluated 56 cutaneous specimens with diagnostic immunoglobulin (Ig) deposition patterns that contained adnexal structures. In a corollary study, we examined 145 hematoxylin‐eosin‐stained frozen specimens to determine biopsy factors associated with the presence of adnexal structures.ResultsPeriadnexal DIF findings offered diagnostic sensitivity in conditions with linear or cell‐surface Ig deposition or lupus band. Periadnexal DIF findings were unreliable in dermatitis herpetiformis. Biopsy specimens from scalp and genitalia were most likely to contain folliculosebaceous units and sweat duct apparatus, respectively. Relative depth of biopsy correlated directly with the likelihood of identifying sweat duct apparatus but not folliculosebaceous units.ConclusionsPeriadnexal DIF findings may add diagnostic sensitivity in DIF evaluation of pemphigoid, pemphigus and lupus erythematosus. Pathologists can guide clinicians to biopsy certain anatomic sites and to obtain sufficient biopsy depth to increase the probability of capturing adnexal structures and, therefore, diagnostic yield from DIF specimens.
Increased hepatitis C virus vaccine clinical trial literacy following a brief intervention among people who inject drugs
Authors: White Bethany , Madden Annie , Hellard Margaret , Kerr Thomas , Prins Maria , Page Kimberly , Dore Gregory J. , Maher Lisa 
Published: November 2012

AbstractIntroduction and AimsWhile people who inject drugs are at high risk of hepatitis C virus (HCV) infection and will be the target population for future HCV vaccine trials, little is known about clinical trial literacy (CTL) in this group. We assessed the impact of a brief intervention (BI) designed to improve HCV vaccine CTL among people who inject drugs in Sydney, Australia.Design and MethodsPeople who inject drugs enrolled in a community‐based prospective observational study between November 2008 and September 2010 (n = 102) completed a CTL assessment followed immediately by the BI. Post‐test assessment was conducted at 24 weeks.ResultsThe median age of the sample was 27 years, 73% were male and 60% had 10 or less years of schooling. The median time since first injection was 5 years and 20% reported daily or more frequent injecting. The mean number of correct responses increased from 5.3 to 6.3/10 (t = −4.2; 101df, P < 0.001) 24 weeks post‐intervention. Statistically significant differences were observed for three knowledge items with higher proportions of participants correctly answering questions related to randomisation (P = 0.002), blinding (P = 0.005) and vaccine‐induced seropositivity (P = 0.003) post‐intervention.Discussion and ConclusionsA significant increase in HCV vaccine CTL was observed, suggesting that new and relatively novel concepts can be learned and recalled in this group. These findings support the feasibility of future trials among this population. [Correction added on 21 November 2012, after first online publication: T‐score for mean number of correct responses was corrected to ‘−4.2’ in the Results section.] [White B, Madden A, Hellard H, Kerr T, Prins M, Page K, Dore GJ, Maher L. Increased hepatitis C virus vaccine clinical trial literacy following a brief intervention among people who inject drugs. Drug Alcohol Rev 2013;32:419–425]
Energy loss via urine and faeces – a combustive analysis in diabetic rats and the impact of antidiabetic treatment on body weight
Authors: Elvert R. , Wille A. , Wandschneider J. , Werner U. , Glombik H. , Herling A. W. 
Published: November 2012

AimsIntensive glycaemic control in type 2 diabetes achieved by insulin is generally accompanied by body weight gain. This study was performed to emphasize the meaning of caloric analysis of urine and faeces for energy balance.MethodsWe measured energetic loss via urine and faeces during antihyperglycaemic treatment in male obese Zucker diabetic fatty (ZDF) rats. Rats were treated for 10 days with the sodium–glucose‐linked transporter‐2 (SGLT2) inhibitor AVE2268, with insulin glargine, with the GLP‐1 receptor agonist lixisenatide and with the combination of insulin glargine and lixisenatide. Each study was accompanied by one lean (Fa/?) and one obese (fa/fa) untreated non‐diabetic and diabetic control group, respectively. Blood glucose, body weight alterations and food assimilation efficiency were monitored.ResultsIn control ZDF rats, more than 12 g/day of pure glucose was urinarily excreted. In total, the energetic loss via urine exceeded 30% from total energy uptake. Insulin glargine treatment decreased urinary energetic loss, leading to a body weight gain of approximately 3 g/day. An almost body weight‐neutral antihyperglycaemic treatment could be achieved with AVE2268 and lixisenatide. While lixisenatide reduced body weight gain via reduction of energy uptake, the SGLT2 inhibitor even increased urinary glucose and thus energy excretion. Combining insulin glargine with lixisenatide attenuated the anabolic effect of insulin resulting in weight neutrality.ConclusionsOur data clearly show renal contribution to the body's energy control by urinary glucose excretion (UGE) during antidiabetic treatment. The undesired retained energy could be reduced via additional UGE or via simultaneous reduction of energy uptake and/or energy retention.
Response to pretransplant hypomethylating agents influences the outcome of allogeneic hematopoietic stem cell transplantation in adults with myelodysplastic syndromes
Authors: Yahng Seung‐Ah , Yoon Jae‐Ho , Shin Seung‐Hwan , Lee Sung‐Eun , Cho Byung‐Sik , Lee Dong‐Gun , Eom Ki‐Seong , Lee Seok , Min Chang‐Ki , Kim Hee‐Je , Cho Seok‐Goo , Kim Dong‐Wook , Lee Jong‐Wook , Min Woo‐Sung , Kim Tai‐Gyu , Park Chong‐Won , Kim Yoo‐Jin 
Published: November 2012

AbstractThis study describes a retrospective analysis on the transplant outcome of 56 consecutive patients with myelodysplastic syndrome (MDS) according to their response to hypomethylating agents (HMA). While 2‐yr disease‐free survival (DFS) of patients who transformed to acute myeloid leukemia (n = 12) was 25%, that of the remaining patients with MDS according to response to HMA was 73.1%, 68.1%, 50.0%, and 20.8% in G‐COR (group of continuous response, n = 19), G‐NoC (group of no change, n = 15), G‐LOR (group of loss of response, n = 6), and G‐DP (group of disease progression, n = 4), respectively. When dichotomized as G‐COR/G‐NoC versus G‐LOR/G‐DP, significantly different 2‐yr DFS (71.0% vs. 33.3%; P = 0.004) and relapse (14.1% vs. 46.7%; P = 0.016) were demonstrated. On multivariate analysis, G‐LOR/G‐DP [hazard ratio (HR), 3.91; P = 0.008] and poor karyotype at transplantation (HR, 2.69; P = 0.017) were the significant predictors for poor DFS, as G‐LOR/G‐DP was for relapse (HR, 6.28; P = 0.011). DFS was significantly poor in patients with any of the two predictors in all MDS (81.5% vs. 34.9%; P = 0.001) or higher‐risk MDS (HrMDS) at the time of HMA (80.7% vs. 29.2%; P = 0.005). G‐COR showed a trend of better DFS compared with G‐NoC among HrMDS (74.6% vs. 36.5%; P = 0.090). These results implicate the significance of response to HMA on hematopoietic stem cell transplantation (HSCT) outcomes and support the need for future study to verify the suggested strategy of proceeding to transplantation before LOR or DP, especially for HrMDS.
The effect of auditory cortex deactivation on stimulus‐specific adaptation in the inferior colliculus of the rat
Authors: Anderson L. A. , Malmierca M. S. 
Published: November 2012

AbstractMany neurons in the central auditory pathway, from the inferior colliculus (IC) to the auditory cortex (AC), respond less strongly to a commonly occurring stimulus than one that rarely occurs. The origin of this phenomenon, called stimulus‐specific adaptation (SSA), remains uncertain. The AC sends descending projections to the IC that terminate most densely upon the dorsal, lateral and rostral IC cortices – areas where strong SSA has been reported. To investigate whether SSA in the IC is dependent upon the AC for its generation, we recorded the response from single IC neurons to stimuli presented in an oddball paradigm before, during and after reversibly deactivating the ipsilateral AC with a cryoloop. While changes in the basic response properties of the IC neurons were widespread (89%), changes in SSA sensitivity were less common; approximately half of the neurons recorded showed a significant change in SSA, while the other half remained unchanged. Changes in SSA could be in either direction: 18% enhanced their SSA sensitivity, while 34% showed reduced SSA sensitivity. For the majority of this latter group, cortical deactivation reduced, but did not eliminate, significant SSA levels. Only eight neurons seemed to inherit SSA from the AC, as their pre‐existing significant level of SSA became non‐significant during cortical deactivation. Thus, the presence of SSA in the IC is generally not dependent upon the corticocollicular projection, suggesting the AC is not essential for the generation of subcortical SSA; however, the AC may play a role in the modulation of subcortical SSA.
The effects of Sophora angustifolia and other natural plant extracts on melanogenesis and melanin transfer in human skin cells
Authors: Singh Suman K. , Baker Richard , Wibawa Judata I. D. , Bell Mike , Tobin Desmond J. 
Published: November 2012

AbstractSkin pigmentation is a multistep process of melanin synthesis by melanocytes, its transfer to recipient keratinocytes and its degradation. As dyspigmentation is a prominent marker of skin ageing, novel effective agents that modulate pigmentation safely are being sought for both clinical and cosmetic use. Here, a number of plant extracts were examined for their effect on melanogenesis (by melanin assay and Western blotting) and melanin transfer (by confocal immunomicroscopy of gp100‐positive melanin granules in cocultures and by SEM analysis of filopodia), in human melanocytes and in cocultures with phototype‐matched normal adult epidermal keratinocytes. Mulberry, Kiwi and Sophora extracts were assessed against isobutylmethylxanthine, hydroquinone, vitamin C and niacinamide. Compared with unstimulated control, all extracts significantly reduced melanogenesis in human melanoma cells and normal adult epidermal melanocytes. These extracts also reduced melanin transfer and reduced filopodia expression on melanocytes, similar to hydroquinone and niacinamide, indicating their effectiveness as multimode pigmentation actives.
Therapeutic drug monitoring of imatinib in chronic myeloid leukemia: experience from 1216 patients at a centralized laboratory
Authors: Bouchet Stéphane , Titier Karine , Moore Nicholas , Lassalle Régis , Ambrosino Basmah , Poulette Sylvie , Schuld Peter , Belanger Coralie , Mahon François‐Xavier , Molimard Mathieu 
Published: November 2012

AbstractThis study set out to examine in a large real‐life cohort of patients with chronic myeloid leukemia (CML) the impact of imatinib threshold of 1000 ng/mL on molecular response, as suggested in a small subset of patients. Patient plasma samples were submitted from around France to a central facility, free of charge under the auspices of the European Treatment and Outcome Study (EUTOS) for CML. Submitting physicians were required to complete an ‘imatinib monitoring request form’, including details of why therapeutic drug monitoring (TDM) was requested, dose and duration of imatinib treatment, cytogenetic and molecular response, adverse events, and concurrent medications. Imatinib trough plasma concentration (Cmin) was measured at the central facility. Among 1985 eligible plasma samples analyzed, from 1216 CML patients, imatinib Cmin correlated positively with reported imatinib dose, but interpatient variability in Cmin was high (60%). A logistic regression analysis revealed that treatment duration and imatinib Cmin > 1000 ng/mL were significantly associated with major and complete molecular responses with odds ratios of 1.69 and 2.08, respectively. These data support in real‐life setting that imatinib Cmin threshold of 1000 ng/mL is associated with major and complete molecular response and that TDM could play an important role in dose optimization.