bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted Radiosensitization of Cells Expressing Truncated DNA Polymerase β
Authors: Neijenhuis Sari , Verwijs-Janssen Manon , van den Broek Lenie J. , Begg Adrian C. , Vens Conchita 
Published: October 2010

Abstract
Ionizing radiation (IR) is an effective anticancer treatment, although failures still occur. To improve radiotherapy, tumor-targeted strategies are needed to increase radiosensitivity of tumor cells, without influencing normal tissue radiosensitivity. Base excision repair (BER) and single-strand break repair (SSBR) contribute to the determination of sensitivity to IR. A crucial protein in BER/SSBR is DNA polymerase β (polβ). Aberrant polβ expression is commonly found in human tumors and leads to inhibition of BER. Here, we show that truncated polβ variant (polβ-Δ)–expressing cells depend on homologous recombination (HR) for survival after IR, indicating that a considerable fraction of polβ-Δ–induced lesions are subject to repair by HR. Increased sensitization was found not to result from involvement in DNA-dependent protein kinase–dependent nonhomologous end joining, the other major double-strand break repair pathway. Caffeine and the ATM inhibitor Ku55933 cause polβ-Δ–dependent radiosensitization. Consistent with the observed HR dependence and the known HR-modulating activity of ATM, polβ-Δ–expressing cells showed increased radiosensitization after BRCA2 knockdown that is absent under ATM-inhibited conditions. Our data suggest that treatment with HR modulators is a promising therapeutic strategy for exploiting defects in the BER/SSBR pathway in human tumors. Cancer Res; 70(21); 8706–14. ©2010 AACR.
Characterization of a Candidate Tumor Suppressor Gene Uroplakin 1A in Esophageal Squamous Cell Carcinoma
Authors: Kong Kar Lok , Kwong Dora L. , Fu Li , Chan Tim Hon Man , Chen Leilei , Liu Haibo , Li Yan , Zhu Ying-Hui , Bi Jiong , Qin Yan-Ru , Law Simon Ying Kit , Guan Xin-Yuan 
Published: October 2010

AbstractEsophageal squamous cell carcinoma (ESCC) is increasing in incidence, but the knowledge of the genetic underpinnings of this disease remains limited. In this study, we identified the tetraspanin cell surface receptor uroplakin 1A (UPK1A) as a candidate tumor suppressor gene (TSG), and we investigated its function and mechanism in ESCC cells. UPK1A downregulation occurred in 68% of primary ESCCs examined, where it was correlated significantly with promoter hypermethylation (P &lt; 0.05). Ectopic expression of UPK1A in ESCC cells inhibited cell proliferation, clonogenicity, cell motility, and tumor formation in nude mice. Mechanistic investigations suggested that these effects may be mediated by inhibiting nuclear translocation of β-catenin and inactivation of its downstream targets, including cyclin-D1, c-jun, c-myc, and matrix metalloproteinase 7 (MMP7). Cell cycle arrest elicited by UPK1A at the G1-S checkpoint was associated with downregulation of cyclin D1 and cyclin-dependent kinase 4, whereas metastasis suppression was associated with reduction of MMP7. These findings were consistent with evidence derived from clinical samples, where UPK1A downregulation was correlated with lymph node metastasis (P = 0.009), stage (P = 0.015), and overall survival (P &lt; 0.0001). Indeed, multivariate cyclooxygenase regression analysis showed that UPK1A was an independent prognostic factor for overall survival. Taken together, our findings define a function for UPK1A as an important TSG in ESCC development. Cancer Res; 70(21); 8832–41. ©2010 AACR.
A Major Role of p95/611-CTF, a Carboxy-Terminal Fragment of HER2, in the Down-modulation of the Estrogen Receptor in HER2-Positive Breast Cancers
Authors: Parra-Palau Josep Lluís , Pedersen Kim , Peg Vicente , Scaltriti Maurizio , Angelini Pier Davide , Escorihuela Marta , Mancilla Sandra , Sánchez Pla Alexandre , Ramón y Cajal Santiago , Baselga José , Arribas Joaquín 
Published: October 2010

Abstract
Current classification of breast cancers depends in great part on the expression of human epidermal growth factor receptor 2 (HER2), a cell surface tyrosine kinase receptor, and estrogen receptor (ER), the nuclear receptor for estrogen. In addition to reliable biomarkers, these receptors are targets of effective and widely used antitumor drugs. During malignant progression, HER2 and ER can establish an intricate cross-talk. In some cases, HER2 overexpression leads to the downregulation of ER and undermining of anti-ER therapies. A subgroup of HER2-positive breast cancer patients with poor prognosis expresses a heterogeneous collection of HER2 carboxy-terminal fragments (CTF) collectively known as p95HER2. One of these fragments, 611-CTF, is oncogenic in a variety of preclinical models. However, because of the lack of an appropriate tool to specifically analyze its levels in the clinical setting, the value of 611-CTF as a biomarker has not been established yet. Here, we show that 611-CTF induces resistance to antiestrogen therapy and a more pronounced down-modulation of ER than that induced by full-length HER2. To validate this effect in breast cancer samples, we developed specific anti–611-CTF antibodies. With these antibodies, we showed that, whereas the frequency of ER positivity in HER2-positive/611-CTF–negative tumors (72.6%) is similar to that reported for HER2-negative tumors (70–80%), the number of ER-positive tumors in the 611-CTF–positive subgroup is very low (31.2%). These results reveal a mechanism of ER regulation mediated by HER2, which suggests a new strategy to improve responses to endocrine therapy in breast cancer. Cancer Res; 70(21); 8537–46. ©2010 AACR.
A Phase I Study of a Tropism-Modified Conditionally Replicative Adenovirus for Recurrent Malignant Gynecologic Diseases
Authors: Kimball Kristopher J. , Preuss Meredith A. , Barnes Mack N. , Wang Minghui , Siegal Gene P. , Wan Wen , Kuo Huichien , Saddekni Souheil , Stockard Cecil R. , Grizzle William E. , Harris Raymond D. , Aurigemma Rosemarie , Curiel David T. , Alvarez Ronald D. 
Published: October 2010

Abstract
Purpose: To determine the maximum tolerated dose (MTD), toxicity spectrum, clinical activity, and biological effects of the tropism-modified, infectivity-enhanced conditionally replicative adenovirus (CRAd), Ad5–Δ24–Arg-Gly-Asp (RGD), in patients with malignant gynecologic diseases.
Experimental Design: Cohorts of eligible patients were treated daily for 3 days through an i.p. catheter. Vector doses ranged from 1 × 109 to 1 × 1012 viral particles per day. Toxicity was evaluated using CTCv3.0. CA-125 and Response Evaluation Criteria in Solid Tumors (RECIST) criteria were used to determine clinical efficacy. Corollary biological studies included assessment of CRAd replication, wild-type virus generation, viral shedding, and neutralizing antibody response.
Results: Twenty-one patients were treated. Adverse clinical effects were limited to grade 1/2 fever, fatigue, or abdominal pain. No vector-related grade 3/4 toxicities were noted. No clinically significant laboratory abnormalities were noted. The maximum tolerated dose was not reached. Over a 1 month follow-up, 15 (71%) patients had stable disease and six (29%) had progressive disease. No partial or complete responses were noted. Seven patients had a decrease in CA-125; four had a &gt;20% drop. RGD-specific PCR showed the presence of study vector in ascites of 16 patients. Seven revealed an increase in virus after day 3, suggesting replication of Ad5-Δ24-RGD. Minimal wild-type virus generation was detected. Viral shedding studies showed insignificant shedding in the serum, saliva, and urine. Anti-adenoviral neutralizing antibody effects were prevalent.
Conclusions: This study, the first to evaluate an infectivity-enhanced CRAd in human cancer, shows the feasibility, safety, potential antitumor response, and biological activity of this approach in ovarian cancer. Further evaluation of infectivity enhanced virotherapy approaches for malignant gynecologic diseases is warranted. Clin Cancer Res; 16(21); 5277–87. ©2010 AACR.
Lenalidomide in Nonmetastatic Biochemically Relapsed Prostate Cancer: Results of a Phase I/II Double-Blinded, Randomized Study
Authors: Keizman Daniel , Zahurak Marianna , Sinibaldi Victoria , Carducci Michael , Denmeade Samuel , Drake Charles , Pili Roberto , Antonarakis Emmanuel S. , Hudock Susan , Eisenberger Mario 
Published: October 2010

AbstractPurpose: To evaluate the safety and activity of 6 months of treatment with lenalidomide at 5 or 25 mg/d in nonmetastatic biochemically relapsed prostate cancer.Experimental Design: Sixty men with non-castrate, nonmetastatic, biochemically relapsed prostate cancer were stratified by prostate-specific antigen (PSA) doubling time, surgery/radiation therapy, prior androgen deprivation therapy (ADT), and randomized to lenalidomide 5 mg (n = 26) or 25 mg/d (n = 34) for 3 weeks repeated monthly for 6 months or until dose-limiting toxicity or disease progression. Toxicity was evaluated monthly, and PSAs and X-rays/scans every 6 months. Study size was determined to detect a progression rate of 40% at 6 months in either arm with 85% power (compared with a rate of 80% in the population receiving no treatment). Changes in PSA slopes were calculated using the regression of the log PSA for each patient before and during the initial 6 months and compared by t test.Results: Baseline variables were balanced between arms. Grade 3/4 toxicity rates were 12% (n = 3) with 5 mg and 29% (n = 10) with 25 mg (P = 0.1), most commonly neutropenia (five patients, all on 25 mg). Two patients per arm had thromboembolic events. The change in PSA slope was greater with 25 mg versus 5 mg [−0.172 (−0.24 to −0.11) versus −0.033 (−0.11 to 0.04); P = 0.005]. With a mean follow-up of 31.4 months (range 14-44), five patients on 25 mg and one patient on 5 mg remain on the study.Conclusions: Lenalidomide has acceptable toxicity and is associated with long-term disease stabilization and PSA declines. Randomized studies evaluating conventional clinical disease end points in this patient population are planned. Clin Cancer Res; 16(21); 5269–76. ©2010 AACR.
Thiocolchicoside Exhibits Anticancer Effects through Downregulation of NF-κB Pathway and Its Regulated Gene Products Linked to Inflammation and Cancer
Authors: Reuter Simone , Prasad Sahdeo , Phromnoi Kanokkarn , Ravindran Jayaraj , Sung Bokyung , Yadav Vivek R. , Kannappan Ramaswamy , Chaturvedi Madan M. , Aggarwal Bharat B. 
Published: October 2010

AbstractThe discovery of new uses for older, clinically approved drugs is one way to expedite drug development for cancer. Thiocolchicoside, a semisynthetic colchicoside from the plant Gloriosa superba, is a muscle relaxant and used to treat rheumatologic and orthopedic disorders because of its analgesic and anti-inflammatory mechanisms. Given that activation of the transcription factor NF-κB plays a major role in inflammation and tumorigenesis, we postulated that thiocolchicoside would inhibit NF-κB and exhibit anticancer effects through the modulation of NF-κB–regulated proteins. We show that thiocolchicoside inhibited proliferation of leukemia, myeloma, squamous cell carcinoma, breast, colon, and kidney cancer cells. Formation of tumor colonies was also suppressed by thiocolchicoside. The colchicoside induced apoptosis, as indicated by caspase-3 and poly(ADP-ribose) polymerase cleavage, and suppressed the expression of cell survival [e.g., Bcl-2, X-linked inhibitor of apoptosis (XIAP), MCL-1, bcl-xL, cIAP-1, cIAP-2, and cFLIP] proteins. Cell proliferation biomarkers such as c-MYC and phosphorylation of phosphoinositide 3-kinase and glycogen synthase kinase 3β were also blocked by thiocolchicoside. Because most cell survival and proliferation gene products are regulated by NF-κB, we studied the effect of thiocolchicoside on this transcription factor and found that thiocolchicoside inhibited NF-κB activation, degradation of inhibitory κBα (IκBα), IκBα ubiquitination, and phosphorylation, abolished the activation of IκBα kinase, and suppressed p65 nuclear translocation. This effect of thiocolchicoside on the NF-κB pathway led to inhibition of NF-κB reporter activity and cyclooxygenase-2 promoter activity. Our results indicate that thiocolchicoside exhibits anticancer activity through inhibition of NF-κB and NF-κB–regulated gene products, which provides novel insight into a half-century old drug. Cancer Prev Res; 3(11); 1462–72. ©2010 AACR.
Making Sense of Missense in Lynch Syndrome: The Clinical Perspective
Authors: Lynch Henry T. , Jascur Thomas , Lanspa Stephen , Boland C. Richard 
Published: October 2010

Abstract
The DNA mismatch repair (MMR) system provides critical genetic housekeeping, and its failure is associated with tumorigenesis. Through distinct domains on the DNA MMR proteins, the system recognizes and repairs errors occurring during DNA synthesis, but signals apoptosis when the DNA damage cannot be repaired. Certain missense mutations in the MMR genes can selectively alter just one of these functions. This affects the clinical features of tumors associated with defective DNA MMR activity. New work reported by Xie et al. in this issue of the journal (beginning on page 1409) adds to the understanding of DNA MMR. Cancer Prev Res; 3(11); 1371–4. ©2010 AACR.
Breaking the NF-κB and STAT3 Alliance Inhibits Inflammation and Pancreatic Tumorigenesis
Authors: Surh Young-Joon , Bode Ann M. , Dong Zigang 
Published: October 2010

Abstract
This perspective on Liby et al. (beginning on page 1427 in this issue of the journal) discusses the importance of the finding that two synthetic triterpenoids prolonged survival in a pancreatic cancer mouse model. This finding is significant because pancreatic cancer is one of the deadliest human cancers. These compounds inhibited the interaction between NF-κB and signal transducer and activator of transcription 3, and determining the mechanisms underlying this inhibition will help to rapidly move these compounds into phase I clinical trials. Cancer Prev Res; 3(11); 1379–81. ©2010 AACR.
Venous thromboembolism in medical outpatients – a cross-sectional survey of risk assessment and prophylaxis
Authors: Lawall Holger , Matthiessen Andreas , Hohmann Volker , Bramlage Peter , Haas Sylvia , Schellong Sebastian 
Published: October 2010

SummaryThe degree of thromboprophylaxis in medical outpatients is low despite a substantial risk for venous thromboembolism (VTE). This may be attributable to difficulties in assessing risk. Assessment tools like the Haas’ scorecard aid in determining the need for thromboprophylaxis. We aimed at evaluating how the use of this tool may aid physicians in appropriately using anticoagulants. This was an epidemiological, cross-sectional survey of acute medically ill patients with limited mobility treated by general practitioners and internists. Risk assessment for VTE by the treating physician was compared to calculated risk. Of 8,123 patients evaluated between August 2006 and April 2008, 7,271 fulfilled the in- and exclusion criteria. Mean age was 69.4 ± 13.6 years, and 45.2% were male. Of these 82.8% were high risk based on their acute medical condition, 37.9% based on their underlying chronic condition. Immobilisation, heart failure, pneumonia, age, obesity, and major varicosis were the most frequently encountered risk factors. The agreement between the Haas’ scorecard and physician indicated risk was high. At least 94.1% of patients with high risk received adequate anticoagulation mostly as low molecular weight heparins for a mean duration of 15.1 ± 30.5 days. There is a substantial risk for VTE in medical out-patients. Using a simple structured scorecard resulted in an overall appropriate risk assessment and high degree of anticoagulation. The scorecard may provide a tool to improve the overall awareness for VTE risk in medical outpatients, substantially improving the degree of prophylaxis in a patient population with largely underestimated risk.
Effects of Aggrenox and aspirin on plasma endothelial nitric oxide synthase and oxidised low-density lipoproteins in patients after ischaemic stroke
Authors: Sani Yanti , Eisert Christian , Schevchuck Alex , Fong Alan , Hanley Dan , Serebruany Victor 
Published: October 2010

SummaryPlasma endothelial nitric oxide synthase (eNOS), and oxidised low-density lipoproteins (oxLDL) are established biomarkers of atherosclerosis. We defined the time course and magnitude of changes of plasma eNOS and oxLDL after Aggrenox or aspirin in post-stroke patients. Baseline pretreatment eNOS levels were significantly diminished (110 ± 66pg /ml vs. 374 ± 88 pg/ml, p=0.0001), while oxLDL was twice higher (58 ± 9 mg/l vs. 23 ± 7 mg/l, p=0.004) in post-stroke survivors when compared to controls. Both Aggrenox and aspirin similarly increased plasma eNOS activity. However, oxLDL levels were static after aspirin, but inhibited late after Aggrenox. In the small randomised study, both aspirin and Aggrenox produced fast and sustained recovery of plasma eNOS levels, while only therapy with Aggrenox was associated with oxLDL inhibition late in the trial.
Human endothelial and platelet septin SEPT11: Cloning of novel variants and characterisation of interaction partners
Authors: Bartsch Ingrid , Bläser Susanne , Röseler Sabrina , Sandrock Kirstin , Busse Anja , Huber Michael , Rempp Hansjörg , Lieber Mareike , Horn Julia , Brendle Cornelia , Zieger Barbara 
Published: October 2010

SummarySeptins are cytoskeletal GTPases forming heteropolymeric complexes involved in processes characterised by active membrane movement such as cytokinesis, vesicle trafficking, and exocytosis. Septins are expressed in non-mitotic cells such as neurons and platelets. SEPT11 belongs to the SEPT6 group and was identified as interaction partner of SEPT5. We cloned and characterised novel SEPT11 variants and investigated interaction partners of SEPT11 in platelets and human umbilical vein endothelial cells. An endothelial cell library was used for cloning novel SEPT11 variants. Using Northern analysis the different SEPT11 transcripts were illustrated. Interaction studies were performed using yeast two-hybrid system, precipitation, FRET, and immunofluorescence microscopy. We demonstrate that SEPT11 partners with SEPT2, SEPT4 and SEPT7 using yeast two-hybrid system and precipitation. The interaction of SEPT11 with SEPT7 is also demonstrated by FRET. In addition to the known SEPT11 transcript (SEPT11_v1) we identified a novel SEPT11 variant (SEPT11_v2) as interaction partner of SEPT4 and SEPT7. Library screening of an endothelial cell library also revealed the presence of this novel SEPT11_v2 transcript. In addition, a third SEPT11 variant (SEPT11_v3) was identified. Expression of SEPT11_v1 and of SEPT11_v2 and SEPT11_v3 in human brain regions was investigated by Northern analysis. Further interaction partners of SEPT11 are characterised using immunofluorescence. Co-localisation of SEPT2, SEPT4, SEPT7 and SEPT11 with tubulin and transferrin receptor (endocytotic marker) is demonstrated. In addition, co-localisation of SEPT4 and SEPT11 with the vesicle-associated protein synaptobrevin 1 (VAMP1), but not clearly with actin, was shown. Only SEPT2 and SEPT7 definitely co-localised with actin, but not clearly with VAMP1.
Analyses of heat recovery devices in the HVAC system in an operating theatre in the tropics
Authors: Yau YH 
Published: October 2010

The air-conditioning system is the major electricity consumption for the non-domestic buildings. A significant part of energy savings can be achieved if heat recovery technologies such as run-around coils, plate-to-plate heat exchangers, heat recovery wheels and heat pipe heat exchangers are incorporated into the ACMV system of these buildings. Non-domestic buildings, such as hospitals, expense even more energy as the supply of fresh air into the space is deemed necessary. For example, air must be changed at least 25 times hourly and recirculation of RA is prohibited for the operating theatres. Therefore, an operating theatre of a hospital in a tropical climate country was chosen for this research. The performance of the existing air-conditioning system has been thoroughly studied to investigate the potential in energy savings in the building. The transient system simulation program (TRNSYS) was used to analyse the air-conditioning system incorporated with heat recovery devices. Generally, there are eight heat recovery systems analysed using TRNSYS, which divided into two groups: the heat recovery ventilating system and heat recovery dehumidification system. The energy savings, payback period, dehumidification enhancement, stability of indoor air conditions and preventing the cross contamination, for each of the systems, were analysed in comparison to each other. Based on this study, it is recommended that the heat recovery systems should be installed to enhance moisture removal and reduce energy usage of HVAC system operating in hospitals. Practical application: The good amount of technical information of real application conducted on heat recovery devices installed in HVAC systems in operating theatres in the tropics could be used as a comprehensive guide for building services engineers and researchers who are intending to apply heat recovery devices as ‘coolness’ recovery and dehumidification devices in HVAC systems operating in tropical countries.
First use of thymus transplantation therapy for FOXN1 deficiency (nude/SCID): a report of 2 cases
Authors: Markert M. Louise , Marques José G. , Neven Bénédicte , Devlin Blythe H. , McCarthy Elizabeth A. , Chinn Ivan K. , Albuquerque Adriana S. , Silva Susana L. , Pignata Claudio , de Saint Basile Geneviève , Victorino Rui M. , Picard Capucine , Debre Marianne , Mahlaoui Nizar , Fischer Alain , Sousa Ana E. 
Published: October 2010

AbstractFOXN1 deficiency is a primary immunodeficiency characterized by athymia, alopecia totalis, and nail dystrophy. Two infants with FOXN1 deficiency were transplanted with cultured postnatal thymus tissue. Subject 1 presented with disseminated Bacillus Calmette-Guérin infection and oligoclonal T cells with no naive markers. Subject 2 had respiratory failure, human herpes virus 6 infection, cytopenias, and no circulating T cells. The subjects were given thymus transplants at 14 and 9 months of life, respectively. Subject 1 received immunosuppression before and for 10 months after transplantation. With follow up of 4.9 and 2.9 years, subjects 1 and 2 are well without infectious complications. The pretransplantation mycobacterial disease in subject 1 and cytopenias in subject 2 resolved. Subject 2 developed autoimmune thyroid disease 1.6 years after transplantation. Both subjects developed functional immunity. Subjects 1 and 2 have 1053/mm3 and 1232/mm3 CD3+ cells, 647/mm3 and 868/mm3 CD4+ T cells, 213/mm3 and 425/mm3 naive CD4+ T cells, and 10 200 and 5700 T-cell receptor rearrangement excision circles per 100 000 CD3+ cells, respectively. They have normal CD4 T-cell receptor β variable repertoires. Both subjects developed antigen-specific proliferative responses and have discon-tinued immunoglobulin replacement. In summary, thymus transplantation led to T-cell reconstitution and function in these FOXN1 deficient infants.