bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deletion of the HAMP domains from the histidine kinase CaNik1p of Candida albicans or treatment with fungicides activates the MAP kinase Hog1p in S. cerevisiae transformants
Authors: El-Mowafy Mohammed , Bahgat Mahmoud M , Bilitewski Ursula 
Published: September 2013

Abstract

Background
Microorganisms use two-component signal transduction (TCST) systems to regulate the response of the organism to changes of environmental conditions. Such systems are absent from mammalian cells and are thus of interest as drug targets. Fungal TCST systems are usually composed of a hybrid histidine kinase, comprising the histidine kinase (HisKA) domain and a receiver domain, a histidine phosphotransfer protein and a response regulator. Among the 11 groups of fungal histidine kinases, group III histidine kinases are of particular relevance as they are essential for the activity of different groups of fungicides. A characteristic feature is the N-terminal amino acid repeat domain comprising multiple HAMP domains, of which the function is still largely unknown. In Candida albicans, a fungal human pathogen, three histidine kinases were identified, of which CaNik1p is a group III histidine kinase. Heterologous expression of this protein in Sacchromyces cerevisiae conferred susceptibility to different fungicides. Fungicide activity was associated with phosphorylation of the mitogen activated protein kinase Hog1p.

Results
We have constructed mutated versions of CaNik1p, from which either all HAMP domains were deleted (CaNik1pΔHAMP) or in which the histidine kinase or the receiver domains were not-functional. Expression of CaNIK1ΔHAMP in S. cerevisiae led to severe growth inhibition. Normal growth could be restored by either replacing the phosphate-accepting histidine residue in CaNik1pΔHAMP or by expressing CaNIK1ΔHAMP in S. cerevisiae mutants, in which single genes encoding several components of the HOG pathway were deleted. Expression of proteins with non-functional histidine kinase or receiver domains resulted in complete loss of susceptibility to antifungals, such as fludioxonil. Conditions leading to growth inhibition of transformants also led to phosphorylation of the MAP kinase Hog1p.

Conclusion
Our results show that functional histidine kinase and receiver domains of CaNik1p were essential for antifungal susceptibility and for activation of the Hog1p. Moreover, for the first time we show that deletion of all HAMP domains from CaNik1p led to activation of Hog1p without an external stimulus. This phenotype was similar to the effects obtained upon treatment with fungicides, as in both cases growth inhibition correlated with Hog1p activation and was dependent on the functionality of the conserved phosphate-accepting histidine residue.
Prognostic impact of tumor infiltrating CD8+ T cells in association with cell proliferation in ovarian cancer patients - a study of the OVCAD consortium
Authors: Bachmayr-Heyda Anna , Aust Stefanie , Heinze Georg , Polterauer Stephan , Grimm Christoph , Braicu Elena Ioana , Sehouli Jalid , Lambrechts Sandrina , Vergote Ignace , Mahner Sven , Pils Dietmar , Schuster Eva , Thalhammer Theresia , Horvat Reinhard , Denkert Carsten , Zeillinger Robert , Castillo-Tong Dan Cacsire 
Published: September 2013

AbstractBackgroundEpithelial ovarian cancer is one of the most lethal gynecologic malignancies. Clinicopathological factors do not permit precise prognosis and cannot provide guidance to specific treatments. In this study we assessed tumor infiltrating CD8+ T cells in association with Ki67 proliferation index and evaluated their prognostic impact in EOC samples.MethodsCD8+ cells and Ki67 proliferation index were immunohistochemically determined on tissue microarrays including 203 primary epithelial ovarian tumors. Additionally, CD8 gene expression was assessed with RT-qPCR. Correlations were analyzed using Pearson’s correlation coefficients, ANOVA or T-test, or Fischer’s exact tests. Prognostic impact was evaluated using the Kaplan-Meier method and Cox regression model.ResultsThe density of CD8+ infiltrating lymphocytes did not correlate with tumor cell proliferation. Epithelial ovarian cancer patients with no Ki67+ cells in the tumor had a more than three times higher risk to die compared to the population with Ki67+ cells in the tumor (Hazard ratio (HR) = 3.34, 95%CI 1.59-7.04). High CD8+ cell infiltration was associated with improved overall survival (HR = 0.82, 95%CI 0.73-0.92).ConclusionsThe density of tumor infiltrating lymphocytes is independent of tumor cell proliferation. Ovarian cancer patients with Ki67- tumors showed a significantly reduced overall survival, presumably due to no or poor response to platinum-based chemotherapy. Moreover, the association of high densities of tumor infiltrating cytotoxic T lymphocytes with a better overall survival was confirmed.
Metabolic markers and microecological characteristics of tongue coating in patients with chronic gastritis
Authors: Sun Zhu-Mei , Zhao Jie , Qian Peng , Wang Yi-Qin , Zhang Wei-Fei , Guo Chun-Rong , Pang Xiao-Yan , Wang Shun-Chun , Li Fu-Feng , Li Qi 
Published: September 2013

Abstract

Background
In Traditional Chinese Medicine (TCM), tongue diagnosis has been an important diagnostic method for the last 3000 years. Tongue diagnosis is a non-invasive, simple and valuable diagnostic tool. TCM treats the tongue coating on a very sensitive scale that reflects physiological and pathological changes in the organs, especially the spleen and stomach. Tongue coating can diagnose disease severity and determine the TCM syndrome (“Zheng” in Chinese). The biological bases of different tongue coating appearances are still poorly understood and lack systematic investigation at the molecular level.

Methods
Tongue coating samples were collected from 70 chronic gastritis patients and 20 normal controls. 16S rRNA denatured gradient gel electrophoresis (16S rRNA–DGGE) and liquid chromatography and mass spectrometry (LC–MS) were designed to profile tongue coatings. The statistical techniques used were principal component analysis and partial least squares–discriminate analysis.

Results
Ten potential metabolites or markers were found in chronic gastritis patients, including UDP-D-galactose, 3-ketolactose, and vitamin D2, based on LC–MS. Eight significantly different strips were observed in samples from chronic gastritis patients based on 16S rRNA–DGGE. Two strips, Strips 8 and 10, were selected for gene sequencing. Strip 10 sequencing showed a 100% similarity to Rothia mucilaginosa. Strip 8 sequencing showed a 96.2% similarity to Moraxella catarrhalis.

Conclusions
Changes in glucose metabolism could possibly form the basis of tongue coating conformation in chronic gastritis patients. The study revealed important connections between metabolic components, microecological components and tongue coating in chronic gastritis patients. Compared with other diagnostic regimens, such as blood tests or tissue biopsies, tongue coating is more amenable to, and more convenient for, both patients and doctors.
HIV infection and drugs of abuse: role of acute phase proteins
Authors: Samikkannu Thangavel , Rao Kurapati VK , Arias Adriana Y , Kalaichezian Aarthi , Sagar Vidya , Yoo Changwon , Nair Madhavan PN 
Published: September 2013

AbstractBackgroundHIV infection and drugs of abuse such as methamphetamine (METH), cocaine, and alcohol use have been identified as risk factors for triggering inflammation. Acute phase proteins such as C-reactive protein (CRP) and serum amyloid A (SAA) are the biomarkers of inflammation. Hence, the interactive effect of drugs of abuse with acute phase proteins in HIV-positive subjects was investigated.MethodsPlasma samples were utilized from 75 subjects with METH use, cocaine use, alcohol use, and HIV-positive alone and HIV-positive METH, cocaine, and alcohol users, and age-matched control subjects. The plasma CRP and SAA levels were measured by ELISA and western blot respectively and the CD4 counts were also measured.ResultsObserved results indicated that the CRP and SAA levels in HIV-positive subjects who are METH, cocaine and alcohol users were significantly higher when compared with either drugs of abuse or HIV-positive alone. The CD4 counts were also dramatically reduced in HIV-positive with drugs of abuse subjects compared with only HIV-positive subjects.ConclusionsThese results suggest that, in HIV-positive subjects, drugs of abuse increase the levels of CRP and SAA, which may impact on the HIV infection and disease progression.
A simple approach of three-isocenter IMRT planning for craniospinal irradiation
Authors: Wang Zheng , Jiang Wei , Feng Yuanming , Guo Yang , Cong Zheng , Song Bin , Guo Yu 
Published: September 2013

Abstract

Purpose
To develop a new IMRT technique to simplify the process and improve efficiency in radiotherapy treatment planning for craniospinal irradiation (CSI) treatment.

Methods
Image data of 9 patients who received CSI treatment in 2012 were used, the prescription was 36Gy in 20 fractions. Two treatment plans were created for each patient, one was with the new technique called three-isocenter overlap-junction (TIOJ) IMRT and the other was with the three-isocenter jagged-junction (TIJJ) IMRT technique. The comparative study was conducted using the parameters of heterogeneity index (HI), conformity index (CI), and doses to the organs at risk (OARs).

Results
Comparing the TIOJ IMRT plans with the TIJJ IMRT plans, the average homogeneity index is 0.071 ± 0.003 and 0.077 ± 0.002, respectively, and the averaged conformity number is 0.80 ± 0.012 and 0.80 ± 0.009, respectively. There are no significant differences (p > 0.05). Both plans provide satisfactory sparing for the OARs.

Conclusions
The TIOJ IMRT technique for CSI treatment planning can create similar plans as with the TIJJ IMRT technique, but the new technique greatly simplifies the steps required to manually set field widths and boundaries and improved efficiency.
Investigation of the biomechanical effect of variable stiffness shoe on external knee adduction moment in various dynamic exercises
Authors: Teoh Jee Chin , Low Jin Huat , Lim Ying Bena , Shim Victor Phyau‐Wui , Park Jaeyoung , Park Seung‐Bum , Park Sang Jun , Lee Taeyong 
Published: September 2013

AbstractBackgroundThe growing ageing population and high prevalence of knee osteoarthritis (OA) in athletes across nations have created a strong demand for improved non‐invasive therapeutic alternatives for knee OA. The aim of this study is to investigate the effect of the variable stiffness shoe (VSS), a new non‐invasive therapeutic approach, on external knee adduction moment (EKAM) in various dynamic exercises. EKAM is believed to have positive correlation with the progression and development of knee OA.MethodsThirty young participants (16 male and 14 female; age 22.6 ± 1.9 years) from National University of Singapore were enrolled in this study. The tested activities were walking, running, drop‐landing, and lateral hopping. All the dynamic exercises were recorded simultaneously by the 8‐camera VICON Motion Systems (Oxford Metric, UK) with a sampling rate of 100 Hz.ResultsThe results showed that the EKAM was reduced in all the dynamic exercises with the use of VSS. The VSS produced significant reductions in the peak EKAM during walking (4.97%, p = 0.039), running (11.15%, p = 0.011), drop‐landing (11.18%, p = 0.038) and lateral hopping (17.34%, p = 0.023) as compared to the control shoe.ConclusionsThe reduction of EKAM with the use of VSS in various dynamic exercises demonstrates its potential in delaying the onset and the progression of knee OA in early stage of knee OA patients.
Opportunities and challenges for gut microbiome studies in the Indian population
Authors: Shetty Sudarshan Anand , Marathe Nachiket Prakash , Shouche Yogesh S 
Published: September 2013

AbstractThe gut microbiome is a complex ecosystem that affects the development, immunological responses and nutritional status of the host. Efforts are being made to unravel the complex interaction between the gut microbiome and host to have a greater understanding about its role in human health. Colonization of the gut by microbes begins at birth, but the succession and composition of the microbial community depends on a number of factors including, but not limited to, the age, diet, genetic composition, gender, geographic location, and health status of an individual. Therefore, inclusion of diverse human subjects in the study of the gut microbiome is indispensable. However, conducting such studies in India presents unique opportunities and challenges. The vast diversity in human genetic composition, dietary habits, and geographic distribution that exists in the Indian population adds to the complexity in understanding the gut microbiome. Gut microbiome-related studies from other parts of the world have reported a possible association of diseases such as obesity and diabetes with the human gut microbiome. In contrast, an in-depth assessment of risk factors associated with altered gut microbiome in such diseases in the Indian population is lacking. Studies including the Indian population may give insights into the association of the gut microbiome with various factors and diseases that may not be possible from studies on western populations. This review briefly discusses the significance of the gut microbiome on human health and the present status of gut microbiome studies in the Indian population. In addition, this review will highlight the unique opportunities and challenges for gut microbiome studies in the Indian population.
Use of Early Tumor Shrinkage to Predict Long-Term Outcome in Metastatic Colorectal Cancer Treated With Cetuximab
Authors: Piessevaux Hubert , Buyse Marc , Schlichting Michael , Van Cutsem Eric , Bokemeyer Carsten , Heeger Steffen , Tejpar Sabine 
Published: September 2013

Purpose Early tumor shrinkage (ETS) is associated with long-term outcome in patients with chemorefractory metastatic colorectal cancer (mCRC) receiving cetuximab. This association was investigated in the first-line setting in the randomized CRYSTAL and OPUS mCRC trials, after controlling for KRAS tumor mutation status. Methods Radiologic assessments at week 8 were used to calculate the relative change in the sum of the longest diameters of the target lesions. Time-dependent receiver operating characteristics provided Cτ-indices (time-dependent c-index). Cox regression models and subpopulation treatment effect pattern plot analysis investigated associations between ETS (radiologic tumor size decrease at week 8) and survival and progression-free survival (PFS). Results In both trials, in patients with KRAS wild-type mCRC, Cτ values for PFS and survival were higher (P < .001) in those receiving chemotherapy plus cetuximab versus chemotherapy alone, indicating a stronger predictive value of ETS for long-term outcome in these patients. In the CRYSTAL and OPUS trials, respectively, the cutoff value of ETS ≥ 20% (v < 20%) identified patients with KRAS wild-type mCRC receiving chemotherapy plus cetuximab with longer PFS (medians 14.1 v 7.3 months, hazard ratio [HR] = 0.32; P < .001, and medians 11.9 v 5.7 months, HR = 0.22; P < .001) and survival (medians 30.0 v 18.6 months, HR = 0.53; P < .001 and medians 26.0 v 15.7 months, HR = 0.43; P = .006). Conclusion ETS was significantly associated with long-term outcome in patients with KRAS wild-type mCRC treated first-line with chemotherapy plus cetuximab. Validation in prospective trials is required to assess the value of this on-treatment marker in the clinical decision-making process.
Denosumab and Bone Metastasis–Free Survival in Men With Nonmetastatic Castration-Resistant Prostate Cancer: Exploratory Analyses by Baseline Prostate-Specific Antigen Doubling Time
Authors: Smith Matthew R. , Saad Fred , Oudard Stephane , Shore Neal , Fizazi Karim , Sieber Paul , Tombal Bertrand , Damiao Ronaldo , Marx Gavin , Miller Kurt , Van Veldhuizen Peter , Morote Juan , Ye Zhishen , Dansey Roger , Goessl Carsten 
Published: September 2013

PurposeDenosumab, an anti–RANK ligand monoclonal antibody, significantly increases bone metastasis–free survival (BMFS; hazard ratio [HR], 0.85; P = .028) and delays time to first bone metastasis in men with nonmetastatic castration-resistant prostate cancer (CRPC) and baseline prostate-specific antigen (PSA) ≥ 8.0 ng/mL and/or PSA doubling time (PSADT) ≤ 10.0 months. To identify men at greatest risk for bone metastasis or death, we evaluated relationships between PSA and PSADT with BMFS in the placebo group and the efficacy and safety of denosumab in men with PSADT ≤ 10, ≤ 6, and ≤ 4 months.Patients and MethodsA total of 1,432 men with nonmetastatic CRPC were randomly assigned 1:1 to monthly subcutaneous denosumab 120 mg or placebo. Enrollment began February 2006; primary analysis cutoff was July 2010, when approximately 660 men were anticipated to have developed bone metastases or died.ResultsIn the placebo group, shorter BMFS was observed as PSADT decreased below 8 months. In analyses by shorter baseline PSADT, denosumab consistently increased BMFS by a median of 6.0, 7.2, and 7.5 months among men with PSADT ≤ 10 (HR, 0.84; P = .042), ≤ 6 (HR, 0.77; P = .006), and ≤ 4 months (HR, 0.71; P = .004), respectively. Denosumab also consistently increased time to bone metastasis by PSADT subset. No difference in survival was observed between treatment groups for the overall study population or PSADT subsets.ConclusionPatients with shorter PSADT are at greater risk for bone metastasis or death. Denosumab consistently improves BMFS in men with shorter PSADT and seems to have the greatest treatment effects in men at high risk for progression.
Barriers Against Psychosocial Communication: Oncologists' Perceptions
Authors: Fagerlind Hanna , Kettis Åsa , Glimelius Bengt , Ring Lena 
Published: September 2013

Purpose To explore oncologists' psychosocial attitudes and beliefs and their perceptions regarding barriers against psychosocial communication. Methods A questionnaire was distributed to oncologists in Sweden (n = 537). Questions covered demography, the Physician Psychosocial Beliefs Scale (PPBS), and barriers against psychosocial communication. Stepwise multiple regression was used to determine what factors contribute the most to the PPBS score and the total number of barriers and barriers affecting clinical practice, respectively. Spearman rank-order correlation was used to determine correlation between PPBS score and number of barriers. Results Questionnaire response rate was 64%. Mean PPBS value was 85.5 (range, 49 to 123; SD, 13.0). Most oncologists (93%) perceived one or more barriers in communicating psychosocial aspects with patients. On average, five different communication barriers were perceived, of which most were perceived to affect clinical practice. These barriers included insufficient consultation time, lack of resources for taking care of problems discovered, and lack of methods to evaluate patients' psychosocial health in clinical practice. There was a positive correlation (rs = 0.490; P < .001) between the PPBS score and the number of perceived barriers (ie, less psychosocially oriented oncologists perceived more barriers). Oncologists with supplementary education with a psychosocial focus perceived fewer barriers/barriers affecting clinical practice (P < .001 and P = .001, respectively) and were more psychosocially oriented (P = .001). Conclusion Oncologists perceive many different barriers affecting psychosocial communication in clinical practice. Interventions aiming to improve psychosocial communication must therefore be multifaceted and individualized to clinics and individual oncologists. It is important to minimize barriers to facilitate optimal care and treatment of patients with cancer.
Phase II Study of Alisertib, a Selective Aurora A Kinase Inhibitor, in Relapsed and Refractory Aggressive B- and T-Cell Non-Hodgkin Lymphomas
Authors: Friedberg Jonathan W. , Mahadevan Daruka , Cebula Erin , Persky Daniel , Lossos Izidore , Agarwal Amit B. , Jung JungAh , Burack Richard , Zhou Xiaofei , Leonard E. Jane , Fingert Howard , Danaee Hadi , Bernstein Steven H. 
Published: September 2013

PurposeAurora A kinase (AAK) is overexpressed in aggressive lymphomas and can correlate with more histologically aggressive forms of disease. We therefore designed a phase II study of alisertib, a selective AAK inhibitor, in patients with relapsed and refractory aggressive non-Hodgkin lymphomas.Patients and MethodsPatients age ≥ 18 years were eligible if they had relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma (MCL), transformed follicular lymphoma, Burkitt's lymphoma, or noncutaneous T-cell lymphoma. Alisertib was administered orally at 50 mg twice daily for 7 days in 21-day cycles.ResultsWe enrolled 48 patients. Histologies included DLBCL (n = 21), MCL (n = 13), peripheral T-cell lymphoma (n = 8), transformed follicular lymphoma (n = 5), and Burkitt's (n = 1). Most common grade 3 to 4 adverse events were neutropenia (63%), leukopenia (54%), anemia (35%), thrombocytopenia (33%), stomatitis (15%), febrile neutropenia (13%), and fatigue (6%). Four deaths during the study were attributed to progressive non-Hodgkin lymphoma (n = 2), treatment-related sepsis (n = 1), and unknown cause (n = 1). The overall response rate was 27%, including responses in three of 21 patients with DLBCL, three of 13 with MCL, one of one with Burkitt's lymphoma, two of five with transformed follicular lymphoma, and four of eight with noncutaneous T-cell lymphoma. The alisertib steady-state trough concentration (n = 25) revealed the expected pharmacokinetic variability, with a trend for higher incidence of adverse event–related dose reductions at higher trough concentrations. Analysis for AAK gene amplification and total AAK protein revealed no differences between histologies or correlation with clinical response.ConclusionThe novel AAK inhibitor alisertib seems clinically active in both B- and T-cell aggressive lymphomas. On the basis of these results, confirmatory single-agent and combination studies have been initiated.
Breast-Conserving Treatment With or Without Radiotherapy in Ductal Carcinoma In Situ: 15-Year Recurrence Rates and Outcome After a Recurrence, From the EORTC 10853 Randomized Phase III Trial
Authors: Donker Mila , Litière Saskia , Werutsky Gustavo , Julien Jean-Pierre , Fentiman Ian S. , Agresti Roberto , Rouanet Philippe , de Lara Christine Tunon , Bartelink Harry , Duez Nicole , Rutgers Emiel J.T. , Bijker Nina 
Published: September 2013

Purpose Adjuvant radiotherapy (RT) after a local excision (LE) for ductal carcinoma in situ (DCIS) aims at reduction of the incidence of a local recurrence (LR). We analyzed the long-term risk on developing LR and its impact on survival after local treatment for DCIS. Patients and Methods Between 1986 and 1996, 1,010 women with complete LE of DCIS less than 5 cm were randomly assigned to no further treatment (LE group, n = 503) or RT (LE+RT group, n = 507). The median follow-up time was 15.8 years. Results Radiotherapy reduced the risk of any LR by 48% (hazard ratio [HR], 0.52; 95% CI, 0.40 to 0.68; P < .001). The 15-year LR-free rate was 69% in the LE group, which was increased to 82% in the LE+RT group. The 15-year invasive LR-free rate was 84% in the LE group and 90% in the LE+RT group (HR, 0.61; 95% CI, 0.42 to 0.87). The differences in LR in both arms did not lead to differences in breast cancer–specific survival (BCSS; HR, 1.07; 95% CI, 0.60 to 1.91) or overall survival (OS; HR, 1.02; 95% CI, 0.71 to 1.44). Patients with invasive LR had a significantly worse BCSS (HR, 17.66; 95% CI, 8.86 to 35.18) and OS (HR, 5.17; 95% CI, 3.09 to 8.66) compared with those who did not experience recurrence. A lower overall salvage mastectomy rate after LR was observed in the LE+RT group than in the LE group (13% v 19%, respectively). Conclusion At 15 years, almost one in three nonirradiated women developed an LR after LE for DCIS. RT reduced this risk by a factor of 2. Although women who developed an invasive recurrence had worse survival, the long-term prognosis was good and independent of the given treatment.