bluuebunny/crossref_metadata_2025 huggingface dataset:
Cutaneous Nociception Evoked by 15-delta PGJ2 via Activation of Ion Channel TRPA1
Authors: Cruz-Orengo Lillian , Dhaka Ajay , Heuermann Robert J , Young Timothy J , Montana Michael C , Cavanaugh Eric J , Kim Donghee , Story Gina M
Published: July 2008

Background:

A number of prostaglandins (PGs) sensitize dorsal root ganglion (DRG) neurons and contribute to inflammatory hyperalgesia by signaling through specific G protein-coupled receptors (GPCRs). One mechanism whereby PGs sensitize these neurons is through modulation of “thermoTRPs,” a subset of ion channels activated by temperature belonging to the Transient Receptor Potential ion channel superfamily. Acrid, electrophilic chemicals including cinnamaldehyde (CA) and allyl isothiocyanate (AITC), derivatives of cinnamon and mustard oil respectively, activate thermoTRP member TRPA1 via direct modification of channel cysteine residues.

Results:

Our search for endogenous chemical activators utilizing a bioactive lipid library screen identified a cyclopentane PGD2 metabolite, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), as a TRPA1 agonist. Similar to CA and AITC, this electrophilic molecule is known to modify cysteines of cellular target proteins. Electophysiological recordings verified that 15d-PGJ2 specifically activates TRPA1 and not TRPV1 or TRPM8 (thermoTRPs also enriched in DRG). Accordingly, we identified a population of mouse DRG neurons responsive to 15d-PGJ2 and AITC that is absent in cultures derived from TRPA1 knockout mice. The irritant molecules that activate TRPA1 evoke nociceptive responses. However, 15d-PGJ2 has not been correlated with painful sensations; rather, it is considered to mediate anti-inflammatory processes via binding to the nuclear peroxisome proliferator-activated receptor gamma (PPARγ). Our in vivo studies revealed that 15d-PGJ2 induced acute nociceptive responses when administered cutaneously. Moreover, mice deficient in the TRPA1 channel failed to exhibit such behaviors.

Conclusion:

In conclusion, we show that 15d-PGJ2 induces acute nociception when administered cutaneously and does so via a TRPA1-specific mechanism.
Predicting suicide attempts in young adults with histories of childhood abuse
Authors: Brezo Jelena , Paris Joel , Vitaro Frank , Hébert Martine , Tremblay Richard E. , Turecki Gustavo
Published: July 2008

Background

Although childhood abuse is an important correlate of suicidality, not all individuals who were abused as children attempt suicide.

Aims

To identify correlates and moderators of suicide attempts in adults reporting childhood physical abuse, contact sexual abuse, or both.

Method

A French-Canadian, school-based cohort (n=1684) was prospectively followed.

Results

The identity of the abuser moderated the relationship of abuse frequency and suicide attempts, with individuals abused by their immediate family being at highest risk. Although paternal education exhibited negative associations (OR=0.71, 95% CI 0.58–0.88), several externalising phenotypes had positive associations with suicide attempts: disruptive disorders (OR=3.10, 95% CI 1.05–9.15), conduct problems (OR=1.09, 95% CI 1.01–1.19) and childhood aggression (OR=1.41, 95% CI 1.08–1.83).

Conclusions

Characteristics of the abuser and abusive acts may be important additional indicators of risk for suicide attempts. Future research needs to employ developmental approaches to examine the extent and mechanisms by which childhood abuse contributes to the shared variance of suicidality, maladaptive traits and psychopathology.
Abnormal anterior cingulum integrity in bipolar disorder determined through diffusion tensor imaging
Authors: Wang Fei , Jackowski Marcel , Kalmar Jessica H. , Chepenik Lara G. , Tie Karen , Qiu Maolin , Gong Gaolang , Pittman Brian P. , Jones Monique M. , Shah Maulik P. , Spencer Linda , Papademetris Xenophon , Constable R. Todd , Blumberg Hilary P.
Published: July 2008

Background

Convergent evidence implicates white matter abnormalities in bipolar disorder. The cingulum is an important candidate structure for study in bipolar disorder as it provides substantial white matter connections within the corticolimbic neural system that subserves emotional regulation involved in the disorder.

Aims

To test the hypothesis that bipolar disorder is associated with abnormal white matter integrity in the cingulum.

Method

Fractional anisotropy in the anterior and posterior cingulum was compared between 42 participants with bipolar disorder and 42 healthy participants using diffusion tensor imaging.

Results

Fractional anisotropy was significantly decreased in the anterior cingulum in the bipolar disorder group compared with the healthy group (P=0.003); however, fractional anisotropy in the posterior cingulum did not differ significantly between groups.

Conclusions

Our findings demonstrate abnormalities in the structural integrity of the anterior cingulum in bipolar disorder. They extend evidence that supports involvement of the neural system comprising the anterior cingulate cortex and its corticolimbic gray matter connection sites in bipolar disorder to implicate abnormalities in the white matter connections within the system provided by the cingulum.
Lithium and eGFR: A new routinely available tool for the prevention of chronic kidney disease
Authors: Morriss Richard , Benjamin Benson
Published: July 2008

The National Strategic Framework for Renal Services introduced the routine reporting of estimated glomerular filtration rates (eGFR) on serum urea and electrolyte tests. Estimated glomerular filtration rates might reduce renal failure induced by lithium and cardiovascular mortality but there are many false positives. We propose how eGFR might be used in lithium monitoring.
Differences in psychological effects in hospital doctors with and without post-traumatic stress disorder
Authors: Einav Sharon , Shalev Arieh Y. , Ofek Hadas , Freedman Sara , Matot Idit , Weiniger Carolyn F.
Published: July 2008

Post-traumatic stress disorder (PTSD) can reduce performance. The association between PTSD and other psychopathologies among hospital doctors was examined using self-report questionnaires during a wave of suicide bombing in Jerusalem. Thirty-three doctors with PTSD symptoms and 155 without were compared on coping, burnout and acceptance of treatment. Doctors with PTSD symptoms demonstrated significantly more anxiety, depression, negative coping strategies and burnout. Hospital doctors who develop PTSD symptoms suffer greater burnout and manifest negative coping strategies but are reluctant to receive treatment.
Relationships between residents in secure psychiatric units: are safety and sensitivity really incompatible?
Authors: Dein Kalpana , Williams Paul Simon
Published: July 2008

Since the 1960s, Western society has adopted a more liberal attitude to sexuality. Choice of sexual partners, sexual preferences, attitudes and practices are increasingly a matter of individual choice and freedom. These changes, however, have had little impact on the lives of psychiatric in-patients (Eiguer et al, 1974; Akhtar et al, 1977; Taylor & Swan, 1999). ‘Mental illness,’ it has been suggested, ‘is one of the few disabilities where people run the risk of losing their freedom in order to receive in-patient treatment’ (Cook, 2000). This loss of liberty and rights becomes more pronounced in secure settings where mentally disordered offenders can spend a substantial part of their adult (sexual/reproductive) lives. Prisoners in some US state prisons (of medium and low security) are afforded conjugal visits from their married partners, in view of the rights of the latter. Paradoxically, detention in secure units, which we consider a therapeutic and not a punitive measure, places constraints on the formation of new relationships and the maintenance of previously existing ones. New relationships are, in our experience, viewed with more concern than previously existing ones.
Providing a liaison psychiatry service in the absence of a consultant liaison psychiatrist
Authors: Flahavan Claire , Flahavan Claire
Published: July 2008

Aims and Method

Liaison psychiatry services in Ireland are currently unequally distributed. In the absence of a specialist liaison psychiatry team, general adult psychiatrists may provide a consultation service to their local hospital. Demographic and clinical characteristics pertaining to all psychiatric consultations at the Louth County Hospital were collected over 12 months to examine one such local service and to highlight the challenges of this mode of service delivery.

Results

A total of 232 consults were audited. the most frequent reasons for referral were assessment following deliberate self-harm (38%), affective symptoms (28%) and alcohol or substance misuse (25%). This differs from documented referral patterns to specialist liaison teams. Referring physicians had a low diagnostic ‘hit-rate’ with respect to affective disorders. Difficulties in service provision included poor communication by referring teams and time constraints due to other sectoral commitments.

Clinical Implications

Refinements to service delivery may be beneficial in managing the workload more effectively. Priority should be placed on fostering communication with non-psychiatric colleagues.
Nurse-led liaison psychiatry service for older adults: service evaluation
Authors: Anderson Daniel , Cattell Howard , Bentley Elaine
Published: July 2008

Aims and Method

To comprehensively describe a nurse-led consultation liaison service for older adults by retrospectively reviewing all referrals received in 2006 and comparing them against other services and benchmark reports.

Results

Of the 298 individuals referred to psychiatric services from other hospital wards, 120 were aged 85–94 years old (40%), 193 were male (65%) and 152 were referred from geriatrics (51%). A majority of 204 have not had previous contact with psychiatric services (69%). the most common diagnosis was dementia (33%, n=88), with 27% individuals (n=65) being referred onwards to secondary care.

Clinical Implications

This nurse-led service, using a novel approach of a support worker providing further community support, functions well compared with traditional consultation models. It helps identify many individuals with dementia and engages them into community psychiatric services.
Oxford serious incident review: 7 years on
Authors: Rose Nick
Published: July 2008

In 2000, an article published in this journal described a method of reviewing serious incidents based on peer group discussion, a model then in its sixth year (Rose, 2000). This paper describes how the model has changed in response to the National Health Service (NHS) developments since then.
Quality of Life in Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib or Interferon Alfa: Results From a Phase III Randomized Trial
Authors: Cella David , Li Jim Z. , Cappelleri Joseph C. , Bushmakin Andrew , Charbonneau Claudie , Kim Sindy T. , Chen Isan , Motzer Robert J.
Published: July 2008

Purpose

In an international, randomized phase III trial, sunitinib demonstrated statistically significant efficacy over interferon alfa (IFN-α) as first-line therapy in patients with metastatic renal cell carcinoma (mRCC) (progression-free survival time, 11 v 5 months, respectively; P < .001; objective response rate, 31% v 6%, respectively; P < .001). We report health-related quality-of-life (QOL) results from this trial.

Patients and Methods

Seven hundred fifty mRCC patients were randomly assigned to sunitinib (6-week cycles: 50 mg orally once daily for 4 weeks, followed by 2 weeks off) or IFN-α (9 million units subcutaneous injections, three times weekly). QOL measures included the Functional Assessment of Cancer Therapy–General (FACT-G), the FACT-Kidney Symptom Index–15 item (FKSI-15), and the EuroQoL-5D's utility score (EQ-5D Index) and its visual analog scale (EQ-VAS). The primary QOL end point was the FKSI Disease-Related Symptoms (FKSI-DRS) subscale. Higher scores indicated better outcomes (better QOL or fewer symptoms). Data were analyzed for the intent-to-treat population using mixed-effects models, supplemented with pattern-mixture models.

Results

Patients receiving sunitinib reported higher FKSI-15 and FKSI-DRS scores at each cycle than those receiving IFN-α, with a significant difference in the overall least squares means (3.27 and 1.98, respectively; P < .0001). Similarly, differences in least squares means for FACT-G (and all subscales), EQ-5D Index, and EQ-VAS were all significantly favorable for sunitinib (P < .01). Per pre-established thresholds, between-treatment differences in the mean scores were clinically meaningful after cycle 4 for FKSI-DRS and at all assessments for FKSI-15, FACT-G, and the FACT-G functional well-being subscale.

Conclusion

Sunitinib provides superior QOL compared with IFN-α in mRCC patients.
Phase II Stopping Rules That Employ Response Rates and Early Progression
Authors: Goffin John R. , Tu Dongsheng
Published: July 2008

Purpose

Phase II oncology trials traditionally have used response rate (RR) as the primary end point, but newer targeted agents require the consideration of alternative end points. High rates of early progressive disease (EPD) suggest inadequate drug activity and may be useful in the early stopping of trials. This study used a simulation to define a set of rules to assess a combined end point of RR and EPD.

Methods

The simulation assumed a two-stage trial with a specified α error and power. It randomly generated the true response rate, r, of the agent under study and its true rate of early progressive disease, epd, for each run of the simulation. Two pairs of parameters were specified: (rnul, epdnul) and (ralt, epdalt). A drug was considered uninteresting for further development if r was less than or equal to rnul and epd was greater than or equal to epdnul (ie, the null hypothesis) and interesting for further development if r was greater than or equal to ralt or epd was less than or equal to epdalt (ie, the alternate hypotheses). Thresholds for the required number of patients with responses, nr and EPD, np, were generated for each set of parameters.

Results

Thresholds for nr and np that satisfied the specified error rates were generated. There was at least an 89% likelihood that a study would be stopped at the first stage of accrual if r and epd were uninteresting.

Conclusion

The simulation was able to establish stopping rules by combining the RR and the EPD that achieved the desired error rates. High rates of early stopping suggest that this design could shorten phase II trials of inactive agents.
Survival End Point Reporting in Randomized Cancer Clinical Trials: A Review of Major Journals
Authors: Mathoulin-Pelissier Simone , Gourgou-Bourgade Sophie , Bonnetain Franck , Kramar Andrew
Published: July 2008

Purpose

Several publications showed that the standards for reporting randomized clinical trials (RCTs) might not be entirely suitable. Our aim was to evaluate the reporting of survival end points in cancer RCTs.

Methods

A search in MEDLINE databases identified 274 cancer RCTs published in 2004 in four general medical journals and four clinical oncology journals. Eligible articles were those that reported primary analyses of RCT with survival end points. Methodologists reviewed and scored the articles according to seven key points: prevalence of complete definition of survival end points (time of origin, survival events, censoring events) and relevant information about their analyses (estimation or effect size, precision, number of events, patients at risk). Concordance of key points was evaluated from a random subsample.

Results

After screening, 125 articles were selected; 104 trials were phase III (83%) and 98 publications (78%) were obtained from oncology journals. Among these RCTs, a total of 267 survival end points were recorded, and overall survival (OS) was the most frequent outcome (118 terms, 44%). Survival terms were totally defined for 113 end points (42%) in 65 articles (52%). Accurate information about analysis was retrieved for 73 end points (27%) in 40 articles (32%). The less well-defined information was the number of patients at risk (55%). The reliability was good (κ = 0.72). Finally, according to the key points, optimal reporting was found in 33 end points (12%) or 10 publications.

Conclusion

A majority of articles failed to provide a complete reporting of survival end points, thus adding another source of uncontrolled variability.
Clinical Importance of Estrogen Receptor-β Evaluation in Breast Cancer Patients Treated With Adjuvant Tamoxifen Therapy
Authors: Honma Naoko , Horii Rie , Iwase Takuji , Saji Shigehira , Younes Mamoun , Takubo Kaiyo , Matsuura Masaaki , Ito Yoshinori , Akiyama Futoshi , Sakamoto Goi
Published: July 2008

Purpose

The clinicopathologic importance of a second estrogen receptor (ER), ER-β, in breast cancers has been intensely studied; however, there is still no real consensus regarding the clinical utility of an ER-β assay, probably because of the lack of standardized methodology, the presence of several ER-β isotypes (ER-β1-5, and so on), and, more importantly, the lack of convincing data on whether the ER-β status provides clinically useful information over what is already provided by the traditional ER-α/progesterone receptor (PR) assay. A large and systematic study is needed to address these important issues.

Patients and Methods

Archival materials of 442 invasive breast cancers from women treated with adjuvant tamoxifen monotherapy and with a long follow-up period (median, 11.1 years) were subjected to immunohistochemical study using three commercially available anti–ER-β antibodies that detect ER-β1-3 (ER-βN), ER-β1, and ER-βcx (ER-β2).

Results

Positive staining for ER-βN or ER-β1 was associated with significantly better survival. By contrast, ER-βcx status did not influence survival. In multivariate analysis, ER-β1 status emerged as an independent predictor of recurrence and mortality. ER-β1 status was significantly associated with survival in postmenopausal, but not premenopausal, women. Importantly, ER-β1 positivity was associated with significantly better survival in patients with ER-α–negative/PR-negative or ER-α–negative/PR–negative/human epidermal growth factor receptor 2–negative (triple-negative) tumors, which are widely believed to be hormone unresponsive, have poor prognosis, and require chemotherapy.

Conclusion

Immunohistochemical examination of ER-β1 in addition to ER-α and PR is clinically important in patients with breast cancer treated with tamoxifen monotherapy. Further studies are needed to confirm our findings.
Impact of Late Treatment-Related Toxicity on Quality of Life Among Patients With Head and Neck Cancer Treated With Radiotherapy
Authors: Langendijk Johannes A. , Doornaert Patricia , Verdonck-de Leeuw Irma M. , Leemans Charles R. , Aaronson Neil K. , Slotman Ben J.
Published: July 2008

Purpose

To investigate the impact of treatment-related toxicity on health-related quality of life (HRQoL) among patients with head and neck squamous cell carcinoma treated with radiotherapy either alone or in combination with chemotherapy or surgery.

Patients and Methods

The study sample was composed of 425 disease-free patients. Toxicity was scored according to the European Organisation for Research and Treatment of Cancer (EORTC)/Radiation Therapy Oncology Group (RTOG) late radiation-induced morbidity scoring system. HRQoL was assessed using the EORTC Quality of Life Questionnaire C30. These assessments took place at 6, 12, 18, and 24 months after completion of radiotherapy. The analysis was performed using a multivariate analysis of variance.

Results

Of the six RTOG scales investigated, two significantly affected self-reported HRQoL, salivary gland (RTOGxerostomia) and esophagus/pharynx (RTOGswallowing). Although RTOGxerostomia was reported most frequently, HRQoL was most affected by RTOGswallowing, particularly in the first 18 months after completion of radiotherapy.

Conclusion

Late radiation-induced toxicity, particularly RTOGswallowing and RTOGxerostomia, has a significant impact on the more general dimensions of HRQoL. These findings suggest that the development of new radiation-induced delivery techniques should not only focus on reduction of the dose to the salivary glands, but also on anatomic structures that are involved in swallowing.
Anthracycline Cardiotoxicity: From Bench to Bedside
Authors: Gianni Luca , Herman Eugene H. , Lipshultz Steven E. , Minotti Giorgio , Sarvazyan Narine , Sawyer Douglas B.
Published: July 2008

Anthracyclines remain among the most widely prescribed and effective anticancer agents. Unfortunately, life-threatening cardiotoxicity continues to compromise their usefulness. Despite more than four decades of investigation, the pathogenic mechanisms responsible for anthracycline cardiotoxicity have not been completely elucidated. In addition, new drugs and combination therapies often exacerbate the toxicity. The First International Workshop on Anthracycline Cardiotoxicity, held in fall 2006, in Como, Italy, focused on the state-of-the-art knowledge and discussed the research needed to address the cardiotoxicity of these drugs. Here, we incorporate these discussions into the framework of a broader review of preclinical and clinical issues.
Usefulness of the Serum Carcinoembryonic Antigen Kinetic for Chemotherapy Monitoring in Patients With Unresectable Metastasis of Colorectal Cancer
Authors: Iwanicki-Caron Isabelle , Di Fiore Frédéric , Roque Isabelle , Astruc Emilie , Stetiu Monica , Duclos Aude , Tougeron David , Saillard Sandrine , Thureau Sébastien , Benichou Jacques , Paillot Bernard , Basuyau Jean Pierre , Michel Pierre
Published: July 2008

Purpose

The aim of the study was to evaluate the relationship between serum carcinoembryonic antigen (CEA) kinetic and response to chemotherapy in patients with unresectable metastasis of colorectal cancer.

Patients and Methods

The kinetic was calculated using the slope of an exponential-regressive curve connecting the semi-logarithmic values of CEA. Receiver operating characteristic (ROC) curves were drawn to select the CEA slope thresholds to define patients with progressive or responsive disease with the highest sensitivity, specificity, and diagnosis accuracy odds ratio (DOR). The correlation between the CEA slopes and progression-free survival (PFS) was evaluated by the Cox model and Kaplan-Meier methods.

Results

A total of 122 patients were included. Progression defined by CEA slope greater than +0.05 resulted in sensitivity of 85.7%, specificity of 85.1%, and DOR of 34. The area under the ROC (AUROC) curve was 0.885 (95% CI, 0.815 to 0.936; P = .0001). Response defined by CEA slope less than −0.2 resulted in sensitivity of 74.7%, specificity of 82.5%, and DOR of 16. The AUROC curve was 0.847 (95% CI, 0.770 to 0.906; P = .0001). The difference between AUROC curves calculated with six or four CEA values was not significant. PFS was correlated with CEA slopes (hazard ratio, 4.6; 95% CI, 2.48 to 8.57). The median PFS was 10 months for patients with CEA slope values less than −0.2 months versus 6 months for patients with CEA slope values greater than −0.2 (P < .0001).

Conclusion

These results suggest that the CEA kinetic is an accurate, simple, and noninvasive method to identify the disease progression in patients with unresectable metastasis of colorectal cancer.
Chemoimmunotherapy Reinduction With Epratuzumab in Children With Acute Lymphoblastic Leukemia in Marrow Relapse: A Children's Oncology Group Pilot Study
Authors: Raetz Elizabeth A. , Cairo Mitchell S. , Borowitz Michael J. , Blaney Susan M. , Krailo Mark D. , Leil Tarek A. , Reid Joel M. , Goldenberg David M. , Wegener William A. , Carroll William L. , Adamson Peter C.
Published: July 2008

Purpose

To determine the tolerability and serum concentration of epratuzumab, a humanized monoclonal antibody targeting CD22, administered alone and in combination with reinduction chemotherapy in children with relapsed acute lymphoblastic leukemia (ALL), and to preliminarily assess tumor targeting and efficacy.

Patients and Methods

Therapy consisted of a single-agent phase (epratuzumab 360 mg/m2/dose intravenously twice weekly × four doses), followed by four weekly doses of epratuzumab in combination with standard reinduction chemotherapy. Morphologic and minimal residual disease (MRD) responses were determined at the end of this 6-week period. Serum concentrations of epratuzumab were determined before and 30 minutes after infusions, and CD22 targeting efficiency was determined by quantifying changes in CD22 expression after epratuzumab administration.

Results

Fifteen patients (12 fully assessable for toxicity) with first or later CD22-positive ALL marrow relapse enrolled on the feasibility portion of this study from December 2005 to June 2006. Two dose-limiting toxicities occurred: one grade 4 seizure of unclear etiology and one asymptomatic grade 3 ALT elevation. In all but one patient, surface CD22 was not detected by flow cytometry on peripheral blood leukemic blasts within 24 hours of drug administration, indicating effective targeting of leukemic cells by epratuzumab. Nine patients achieved a complete remission after chemoimmunotherapy, seven of whom were MRD negative.

Conclusion

Treatment with epratuzumab plus standard reinduction chemotherapy is feasible and acceptably tolerated in children with relapsed CD22-positive ALL. CD22 targeting was efficient, and the majority of patients achieved favorable early responses.
Antitumor Activity and Biomarker Analysis of Sunitinib in Patients With Bevacizumab-Refractory Metastatic Renal Cell Carcinoma
Authors: Rini Brian I. , Michaelson M. Dror , Rosenberg Jonathan E. , Bukowski Ronald M. , Sosman Jeffrey A. , Stadler Walter M. , Hutson Thomas E. , Margolin Kim , Harmon Charles S. , DePrimo Samuel E. , Kim Sindy T. , Chen Isan , George Daniel J.
Published: July 2008

Purpose

To assess the safety and efficacy of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma (mRCC) and explore biomarkers for sunitinib response.

Patients and Methods

Patients with mRCC and disease progression after bevacizumab-based therapy received oral sunitinib 50 mg once daily in 6-week cycles on a 4/2 schedule (4 weeks with treatment followed by 2 weeks without treatment) in a phase II multicenter study. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), duration of response (DR), overall survival (OS), and safety. Plasma soluble proteins (vascular endothelial growth factor [VEGF]-A, VEGF-C, soluble VEGF receptor [sVEGFR]-3, and placental growth factor [PlGF]) levels were measured.

Results

Sixty-one patients were enrolled. The ORR was 23.0% (95% CI, 13.2% to 35.5%), median PFS was 30.4 weeks (95% CI, 18.3 to 36.7 weeks), median DR was 44.1 weeks (95% CI, 25.0 to 102.7 weeks), and median OS was 47.1 weeks (95% CI, 36.9 to 79.4 weeks). Mean plasma VEGF-A and PlGF levels significantly increased whereas VEGF-C and sVEGFR-3 levels decreased with sunitinib treatment. Lower baseline levels of sVEGFR-3 and VEGF-C were associated with longer PFS and ORR. Most treatment-related adverse events were of mild-to-moderate intensity and included fatigue, hypertension, and hand-foot syndrome.

Conclusion

Sunitinib has substantial antitumor activity in patients with bevacizumab-refractory mRCC and modulates circulating VEGF pathway biomarkers. These data support the hypothesis that sunitinib inhibits signaling pathways involved in bevacizumab resistance. Baseline levels of sVEGFR-3 and VEGF-C may have potential utility as biomarkers of clinical efficacy in this setting.
Clinical Benefit and Quality of Life in Patients With Advanced Pancreatic Cancer Receiving Gemcitabine Plus Capecitabine Versus Gemcitabine Alone: A Randomized Multicenter Phase III Clinical Trial—SAKK 44/00–CECOG/PAN.1.3.001
Authors: Bernhard Jürg , Dietrich Daniel , Scheithauer Werner , Gerber Daniela , Bodoky György , Ruhstaller Thomas , Glimelius Bengt , Bajetta Emilio , Schüller Johannes , Saletti Piercarlo , Bauer Jean , Figer Arie , Pestalozzi Bernhard C. , Köhne Claus-Henning , Mingrone Walter , Stemmer Salomon M. , Tàmas Karin , Kornek Gabriela V. , Koeberle Dieter , Herrmann Richard
Published: July 2008

Purpose

To compare clinical benefit response (CBR) and quality of life (QOL) in patients receiving gemcitabine (Gem) plus capecitabine (Cap) versus single-agent Gem for advanced/metastatic pancreatic cancer.

Patients and Methods

Patients were randomly assigned to receive GemCap (oral Cap 650 mg/m2 twice daily on days 1 through 14 plus Gem 1,000 mg/m2 in a 30-minute infusion on days 1 and 8 every 3 weeks) or Gem (1,000 mg/m2 in a 30-minute infusion weekly for 7 weeks, followed by a 1-week break, and then weekly for 3 weeks every 4 weeks) for 24 weeks or until progression. CBR criteria and QOL indicators were assessed over this period. CBR was defined as improvement from baseline for ≥ 4 consecutive weeks in pain (pain intensity or analgesic consumption) and Karnofsky performance status, stability in one but improvement in the other, or stability in pain and performance status but improvement in weight.

Results

Of 319 patients, 19% treated with GemCap and 20% treated with Gem experienced a CBR, with a median duration of 9.5 and 6.5 weeks, respectively (P < .02); 54% of patients treated with GemCap and 60% treated with Gem had no CBR (remaining patients were not assessable). There was no treatment difference in QOL (n = 311). QOL indicators were improving under chemotherapy (P < .05). These changes differed by the time to failure, with a worsening 1 to 2 months before treatment failure (all P < .05).

Conclusion

There is no indication of a difference in CBR or QOL between GemCap and Gem. Regardless of their initial condition, some patients experience an improvement in QOL on chemotherapy, followed by a worsening before treatment failure.
Patient-Reported Outcomes of Patients With Advanced Biliary Tract Cancers Receiving Gemcitabine Plus Capecitabine: A Multicenter, Phase II Trial of the Swiss Group for Clinical Cancer Research
Authors: Koeberle Dieter , Saletti Piercarlo , Borner Markus , Gerber Daniela , Dietrich Daniel , Caspar Clemens B. , Mingrone Walter , Beretta Kurt , Strasser Florian , Ruhstaller Thomas , Mora Oreste , Herrmann Richard
Published: July 2008

Purpose

To evaluate the effects of palliative chemotherapy with gemcitabine plus capecitabine (GemCap) on patient-reported outcomes measured using clinical benefit response (CBR) and quality-of-life (QOL) measures in patients with advanced biliary tract cancer.

Patients and Methods

Patients had to manifest symptoms of advanced biliary tract cancer and have at least one of the following: impaired Karnofsky performance score (60 to 80), average analgesic consumption ≥ 10 mg of morphine equivalents per day, and average pain intensity score of ≥ 20 mm out of 100 mm. Treatment consisted of oral capecitabine 650 mg/m2 twice daily on days 1 through 14 plus gemcitabine 1,000 mg/m2 as a 30-minute infusion on days 1 and 8 every 3 weeks until progression. The primary end point was the number of patients categorized as having a CBR or stable CBR (SCBR) during the first three treatment cycles.

Results

Forty-four patients were enrolled (bile duct cancer, n = 36; gallbladder cancers, n = 8). The main grade 3 or 4 adverse events included hematologic toxicity and fatigue. After three cycles, 36% of patients achieved a CBR, and 34% achieved an SCBR. Over the full course of treatment, 57% of patients achieved a CBR, and 18% achieved an SCBR. Improved QOL was observed in patients with a CBR or SCBR. The objective response rate was 25%. Median time to progression and overall survival times were 7.2 months and 13.2 months, respectively.

Conclusion

Chemotherapy with GemCap is well tolerated and effective and leads to a high CBR rate. Patient-reported outcomes are useful for evaluating the effects of palliative chemotherapy in patients with biliary tract cancer.
Defining early lineage specification of human embryonic stem cells by the orchestrated balance of canonical Wnt/β-catenin, Activin/Nodal and BMP signaling
Authors: Sumi Tomoyuki , Tsuneyoshi Norihiro , Nakatsuji Norio , Suemori Hirofumi
Published: July 2008

The canonical Wnt/β-catenin signaling has remarkably diverse roles in embryonic development, stem cell self-renewal and cancer progression. Here, we show that stabilized expression of β-catenin perturbed human embryonic stem (hES)-cell self-renewal, such that up to 80% of the hES cells developed into the primitive streak (PS)/mesoderm progenitors, reminiscent of early mammalian embryogenesis. The formation of the PS/mesoderm progenitors essentially depended on the cooperative action of β-catenin together with Activin/Nodal and BMP signaling pathways. Intriguingly, blockade of BMP signaling completely abolished mesoderm generation, and induced a cell fate change towards the anterior PS progenitors. The PI3-kinase/Akt, but not MAPK,signaling pathway had a crucial role in the anterior PS specification, at least in part, by enhancing β-catenin stability. In addition,Activin/Nodal and Wnt/β-catenin signaling synergistically induced the generation and specification of the anterior PS/endoderm. Taken together, our findings clearly demonstrate that the orchestrated balance of Activin/Nodal and BMP signaling defines the cell fate of the nascent PS induced by canonical Wnt/β-catenin signaling in hES cells.
Thermoelastic stress analysis by means of an infrared scanner and a two-dimensional fast Fourier transform-based lock-in technique
Authors: Pitarresi G , D'Acquisto L , Siddiolo A M
Published: July 2008

An infrared thermographic experimental set-up has been proposed and evaluated towards the capability to measure thermoelastic-effect-induced temperature changes. A standard infrared thermocamera with a nominal noise-equivalent temperature difference (NETD) resolution of 0.12 K has been employed to measure the temperature from unidirectional glass-reinforced plastic tensile coupons under cyclic sinusoidal loads. The raster scanning mode of the camera single detector produces a time delay in acquiring the signal from two succeeding pixels on the same row, and from consecutive scanned rows. By exploiting the acquired dwell times, it was possible to produce a periodic pattern on the thermal maps, caused by and correlated with the thermoelastic-effect-induced temperature changes. The acquired raw data have then been post-processed with a lock-in algorithm implemented in MATLAB® and based on a two-dimensional fast Fourier transform analysis. The filtered thermoelastic component from the lock-in analysis showed good linearity with the load applied, up to values of the temperature change one order of magnitude lower than the NETD resolution limits of the thermocamera. In the light of this the present experimental set-up and processing methodology can be proposed as a potential low-cost tool for thermoelastic stress analysis investigations.
T-stress determination using thermoelastic stress analysis
Authors: Zanganeh M , Tomlinson R A , Yates J R
Published: July 2008

T-stress and mixed-mode stress intensity factors have been determined experimentally using thermoelastic stress analysis and using a finite element method. Pure mode I, strong mixed-mode I and II, and interacting cracks have been used as the case studies. A new technique has been proposed to identify the crack tip from thermoelastic images. It has also been shown that using three terms of Williams's stress field formulation to determine the T-stress, yields a more accurate solution than using only the first two terms of the expansion.
Determining individual stresses thermoelastically
Authors: Patterson E A , Rowlands R E
Published: July 2008

Thermoelastic stress analysis (TSA, thermoelasticity) uses an infrared radiometer to measure local temperature fluctuations and relates these changes to variations in the stresses or strains in a material by thermodynamic principles. The recorded TSA signal is associated with a combination of the individual stress components. However, engineering analyses typically necessitate knowing the values of the individual stress components, and so it is necessary to ‘separate the stresses’. The various approaches that have been used to evaluate the individual components of stress from the TSA-measured information are reviewed and compared, and some areas potentially worthy of further research are indicated.
A new full-field motion compensation technique for infrared stress measurement using digital image correlation
Authors: Sakagami T , Yamaguchi N , Kubo S , Nishimura T
Published: July 2008

A new full-field motion compensation technique based on digital image correlation was developed for infrared thermoelastic stress measurements. Speckle patterns with variable infrared emissivity were applied to a test sample for motion analysis. Infrared images of the speckle pattern were acquired under the same loading conditions as for thermoelastic stress measurement. Displacements and deformations on the test sample were analysed using digital image correlation based on information on movement of the speckle patterns. Full-field motion compensation was performed in subsequent thermoelastic stress measurements based on the results of displacement measurements. The feasibility of the proposed motion compensation technique is demonstrated experimentally for thermoelastic stress measurement and identification of local plasticity at the stress-concentrated area in a plate specimen with a circular hole.
On the concept of a fully bonded coupon gauge for stress separation from thermoelastic data
Authors: Stanley P , Dulieu-Barton J M , Emery T R
Published: July 2008

Several forms of gauge can be used for the determination of individual stresses from thermoelastic data alone. A particularly useful form of gauge is the ‘coupon gauge’, consisting of a thin coupon of material which is bonded to the stressed specimen (or substrate). A novel formulation of the thermoelastic response of the fully bonded thermoelastic coupon gauge is used as the basis for the appraisal of the four possible gauge—specimen material combinations. The validity of the principal assumptions underlying the performance of these gauges is demonstrated and it is shown experimentally that the behaviour of samples of the orthotropic gauge—isotropic specimen material combination conforms to theory.
Local energy analysis of high-cycle fatigue using digital image correlation and infrared thermography
Authors: Chrysochoos A , Berthel B , Latourte F , Galtier A , Pagano S , Wattrisse B
Published: July 2008

This paper presents the first results provided by an experimental set-up developed to estimate locally the terms of the energy balance associated with the high-cycle fatigue (HCF) of DP 600 steel. The experimental approach involves two quantitative imaging techniques: digital image correlation and infrared thermography. First, a variational method is used to derive stress fields from the displacement fields. Patterns of deformation energy per cycle can then be determined on the basis of stress and strain data. Second, a local form of the heat equation is used to derive separately the thermoelastic and dissipative sources accompanying HCF. Energy balances show that around 50 per cent of the deformation energy associated with the mechanical hysteresis loop is dissipated while the rest corresponds to stored energy variations.
Thermoelastic assessment of plastic deformation
Authors: Quinn S , Dulieu-Barton J M , Eaton-Evans J , Fruehmann R K , Tatum P J
Published: July 2008

Thermoelastic stress analysis (TSA) is used to assess the effect of plastic deformation in small-diameter stainless steel pipework that has been subjected to multiple deformation cycles. In theory the residual stress resulting from the plastic deformation cannot be detected as the thermoelastic response is only a function of the stress change. However, it has been shown that plastic deformation may modify the thermoelastic constant in steel and aluminium. This change can be used to estimate the level of plastic strain that a component has experienced and has potential for TSA to be used as the basis for non-contact non-destructive full-field residual stress assessment. In this paper it is shown that strain hardening during the deformation process plays an important role in modifying the thermoelastic constant. X-ray computed tomography is used on the pipework to verify the estimates of geometry change that are used in determining the applied stress and estimating the residual stress levels. It is shown that TSA is not sensitive to residual stress; however, some interesting anomalies appear in the experimental results that provide a basis for discussion and open avenues of further work. Finally the non-adiabatic thermoelastic response is used to assess whether any damage has occurred in the pipework.
On the thermoelastic response of woven composite materials
Authors: Fruehmann R K , Dulieu-Barton J M , Quinn S
Published: July 2008

The thermoelastic response from a woven composite component is complicated because of the variation in material properties across its surface. In this paper the response is interpreted by treating the woven structure as a ‘patchwork’ of unidirectional cells and considering each in isolation. To make matters as simple as possible, single-ply specimens loaded in uniaxial tension are studied. The experiments show that, even for this simple tensile case, the strain field is non-uniform and the approach fails to produce any correlation with predictions based on treating each cell in isolation. In deriving the predicted response a detailed knowledge of the material properties required for thermoelastic stress analysis (TSA) is necessary. It is demonstrated that the response is sensitive to small variations in certain quantities and this is discussed in detail in the paper. The TSA is carried out using a new system and a description of this together with the motion compensation techniques used in the analysis of the high-resolution data is provided.
Characterization of local effects at core junctions in sandwich structures using thermoelastic stress anaylsis
Authors: Johannes M , Dulieu-Barton J M , Bozhevolnaya E , Thomsen O T
Published: July 2008

Local effects at core junctions in sandwich structures are studied using thermoelastic stress analysis (TSA). At the core junctions, large stress gradients occur owing to local bending of the face sheets and tension and compression of the adjacent cores. In the neighbourhood of large stress gradients it is known that non-adiabatic behaviour occurs which causes significant departures from the isentropic assumption that underpins TSA. Analytical estimates of the boundaries of adiabatic behaviour are made which show that TSA cannot capture the local effects using practical loading frequencies with thin aluminium face sheets, and this is confirmed experimentally. An experimental model of the sandwich beam is designed that shows that the local effects can be captured using TSA. It is also demonstrated that TSA can be used to assess local effects in sandwich constructions with glass-fibre-reinforced plastic face sheets. Reference data obtained from independently validated finite element analyses were used for comparison with the TSA results. A discussion on the effect of surface pattern and the introduction of noise due to motion is included in the paper. The data are presented in terms of stress and calibration tests on the constituent materials are carried out and reported in the paper.
Sequence-specific binding of a chloroplast pentatricopeptide repeat protein to its native group II intron ligand
Authors: Williams-Carrier Rosalind , Kroeger Tiffany , Barkan Alice
Published: July 2008

Pentatricopeptide repeat (PPR) proteins are defined by degenerate 35-amino acid repeats that are related to the tetratricopeptide repeat (TPR). Most characterized PPR proteins mediate specific post-transcriptional steps in gene expression in mitochondria or chloroplasts. However, little is known about the structure of PPR proteins or the biochemical mechanisms through which they act. Here we establish features of PPR protein structure and nucleic acid binding activity through in vitro experiments with PPR5, which binds and stabilizes a chloroplast tRNA precursor harboring a group II intron. Recombinant PPR5 was shown to be monomeric by analytical ultracentrifugation and gel filtration. Circular dichroism spectroscopy showed that PPR5 has a high content of α helices, as predicted from the similarity between PPR and TPR motifs. PPR5 and another PPR protein, CRP1, bind with high affinity to single-stranded RNA, but bind poorly to single-stranded DNA or to double-stranded RNA or DNA. A specific PPR5 binding site was identified within its group II intron ligand. The minimal site spans ∼45 nucleotides, encompasses two group II intron functional motifs, and overlaps the terminus of an in vivo RNA decay product. These results suggest mechanisms by which PPR5 influences both RNA stability and splicing.
The management of bone loss in revision total knee replacement
Authors: Whittaker J. P. , Dharmarajan R. , Toms A. D.
Published: July 2008

The management of bone loss in revision replacement of the knee remains a challenge despite an array of options available to the surgeon. Bone loss may occur as a result of the original disease, the design of the prosthesis, the mechanism of failure or technical error at initial surgery. The aim of revision surgery is to relieve pain and improve function while addressing the mechanism of failure in order to reconstruct a stable platform with transfer of load to the host bone. Methods of reconstruction include the use of cement, modular metal augmentation of prostheses, custom-made, tumour-type or hinged implants and bone grafting.

The published results of the surgical techniques are summarised and a guide for the management of bone defects in revision surgery of the knee is presented.
Double-bundle arthroscopic reconstruction of the anterior cruciate ligament
Authors: Longo U. G. , King J. B. , Denaro V. , Maffulli N.
Published: July 2008

There is a trend towards the use of double-bundle techniques for the reconstruction of the anterior cruciate ligament. This has not been substantiated scientifically. The functional outcome of these techniques is equivalent to that of single-bundle methods. The main advantage of a double-bundle rather than a single-bundle reconstruction should be a better rotational stability, but the validity and accuracy of systems for the measurement of rotational stability have not been confirmed.

Despite the enthusiasm of surgeons for the double-bundle technique, reconstruction with a single-bundle should remain the standard method for managing deficiency of the anterior cruciate ligament until strong evidence in favour of the use of the double-bundle method is available.