bluuebunny/crossref_metadata_2025_split huggingface dataset:
PTEN Loss Compromises Homologous Recombination Repair in Astrocytes: Implications for Glioblastoma Therapy with Temozolomide or Poly(ADP-Ribose) Polymerase Inhibitors
Authors: McEllin Brian , Camacho Cristel V. , Mukherjee Bipasha , Hahm Brandon , Tomimatsu Nozomi , Bachoo Robert M. , Burma Sandeep 
Published: June 2010

Abstract
Glioblastomas (GBM) are lethal brain tumors that are highly resistant to therapy. The only meaningful improvement in therapeutic response came from use of the SN1-type alkylating agent temozolomide in combination with ionizing radiation. However, no genetic markers that might predict a better response to DNA alkylating agents have been identified in GBMs, except for loss of O6-methylguanine-DNA methyltransferase via promoter methylation. In this study, using genetically defined primary murine astrocytes as well as human glioma lines, we show that loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) confers sensitivity to N-methyl-N′-nitro-N-nitrosoguanidine (MNNG), a functional analogue of temozolomide. We find that MNNG induces replication-associated DNA double-strand breaks (DSB), which are inefficiently repaired in PTEN-deficient astrocytes and trigger apoptosis. Mechanistically, this is because PTEN-null astrocytes are compromised in homologous recombination (HR), which is important for the repair of replication-associated DSBs. Our results suggest that reduced levels of Rad51 paralogs in PTEN-null astrocytes might underlie the HR deficiency of these cells. Importantly, the HR deficiency of PTEN-null cells renders them sensitive to the poly(ADP-ribose) polymerase (PARP) inhibitor ABT-888 due to synthetic lethality. In sum, our results tentatively suggest that patients with PTEN-null GBMs (about 36%) may especially benefit from treatment with DNA alkylating agents such as temozolomide. Significantly, our results also provide a rational basis for treating the subgroup of patients who are PTEN deficient with PARP inhibitors in addition to the current treatment regimen of radiation and temozolomide. Cancer Res; 70(13); 5457–64. ©2010 AACR.
Colorectal Cancer Incidence Trends in the United States and United Kingdom: Evidence of Right- to Left-Sided Biological Gradients with Implications for Screening
Authors: Meza Rafael , Jeon Jihyoun , Renehan Andrew G. , Luebeck E. Georg 
Published: June 2010

Abstract
Several lines of evidence support the premise that screening colonoscopy reduces colorectal cancer (CRC) incidence, but there may be differential benefits for right- and left-sided tumors. To better understand the biological basis of this differential effect, we derived biomathematical models of CRC incidence trends in U.S. and U.K. populations, representing relatively high- and low-prevalence screening, respectively. Using the Surveillance Epidemiology and End Results (SEER) and the Office for National Statistics (ONS) registries (both 1973–2006), we derived stochastic multistage clonal expansion (MSCE) models for right-sided (proximal colon) and left-sided (distal colon and rectal) tumors. The MSCE concept is based on the initiation-promotion-progression paradigm of carcinogenesis and provides a quantitative description of natural tumor development from the initiation of an adenoma (via biallelic tumor suppressor gene inactivation) to the clinical detection of CRC. From 1,228,036 (SEER: 340,582; ONS: 887,454) cases, parameter estimates for models adjusted for calendar-year and birth-cohort effects showed that adenoma initiation rates were higher for right-sided tumors, whereas, paradoxically, adenoma growth rates were higher for left-sided tumors. The net effect was a higher cancer risk in the right colon only after age 70 years. Consistent with this finding, simulations of adenoma development predicted that the relative prevalence for right- versus left-sided tumors increases with increasing age, a differential effect most striking in women. Using a realistic biomathematical description of CRC development for two nationally representative registries, we show age- and sex-dependent biological gradients for right- and left-sided colorectal tumors. These findings argue for an age-, sex-, and site-directed approach to CRC screening. Cancer Res; 70(13); 5419–29. ©2010 AACR.
Targeting Notch to Target Cancer Stem Cells
Authors: Pannuti Antonio , Foreman Kimberly , Rizzo Paola , Osipo Clodia , Golde Todd , Osborne Barbara , Miele Lucio 
Published: June 2010

Abstract
The cellular heterogeneity of neoplasms has been at the center of considerable interest since the “cancer stem cell hypothesis”, originally formulated for hematologic malignancies, was extended to solid tumors. The origins of cancer “stem” cells (CSC) or tumor-initiating cells (TIC; henceforth referred to as CSCs) and the methods to identify them are hotly debated topics. Nevertheless, the existence of subpopulations of tumor cells with stem-like characteristics has significant therapeutic implications. The stem-like phenotype includes indefinite self-replication, pluripotency, and, importantly, resistance to chemotherapeutics. Thus, it is plausible that CSCs, regardless of their origin, may escape standard therapies and cause disease recurrences and/or metastasis after apparently complete remissions. Consequently, the idea of selectively targeting CSCs with novel therapeutics is gaining considerable interest. The Notch pathway is one of the most intensively studied putative therapeutic targets in CSC, and several investigational Notch inhibitors are being developed. However, successful targeting of Notch signaling in CSC will require a thorough understanding of Notch regulation and the context-dependent interactions between Notch and other therapeutically relevant pathways. Understanding these interactions will increase our ability to design rational combination regimens that are more likely to prove safe and effective. Additionally, to determine which patients are most likely to benefit from treatment with Notch-targeting therapeutics, reliable biomarkers to measure pathway activity in CSC from specific tumors will have to be identified and validated. This article summarizes the most recent developments in the field of Notch-targeted cancer therapeutics, with emphasis on CSC. Clin Cancer Res; 16(12); 3141–52. ©2010 AACR.
Targeting Hedgehog — a Cancer Stem Cell Pathway
Authors: Merchant Akil A. , Matsui William 
Published: June 2010

Abstract
The Hedgehog (Hh) pathway has been implicated in a wide variety of human tumors, and early clinical trials with pathway antagonists have validated Hh signaling as a bona fide anticancer target. Despite these encouraging results, several issues surrounding the basic biology of the Hh pathway in human cancers remain unclear. These include the influence of specific oncogenic events on Hh signal transduction, the precise mode of Hh signaling (i.e., autocrine or paracrine) that occurs within human tumors, and the best means to inhibit aberrant pathway activity in the clinical setting. The cancer stem cell (CSC) hypothesis may explain a number of clinical phenomena, such as unchecked self-renewal and the development of metastatic disease, and to some extent, the Hh signaling pathway has been implicated in all of these processes. Therefore, Hh pathway inhibitors may also represent some of the first agents to formally examine the CSC hypothesis in the clinical setting. The diverse nature of Hh signaling in human cancers suggests that disease-specific factors must be carefully considered to identify the optimal use of novel pathway inhibitors. Clin Cancer Res; 16(12); 3130–40. ©2010 AACR.
Enhanced Anticancer Effect of the Combination of BIBW2992 and Thymidylate Synthase–Targeted Agents in Non–Small Cell Lung Cancer with the T790M Mutation of Epidermal Growth Factor Receptor
Authors: Takezawa Ken , Okamoto Isamu , Tanizaki Junko , Kuwata Kiyoko , Yamaguchi Haruka , Fukuoka Masahiro , Nishio Kazuto , Nakagawa Kazuhiko 
Published: June 2010

Abstract
Most non–small cell lung cancer (NSCLC) tumors with activating mutations of the epidermal growth factor receptor (EGFR) are initially responsive to first-generation, reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib, but they subsequently develop resistance to these drugs through either acquisition of an additional T790M mutation of EGFR or amplification of the proto-oncogene MET. We have now investigated the effects of combination treatment with thymidylate synthase (TS)–targeting drugs and the second-generation, irreversible EGFR-TKI BIBW2992 on the growth of NSCLC cells with the T790M mutation. The effects of BIBW2992 on EGFR signaling and TS expression in gefitinib-resistant NSCLC cells were examined by immunoblot analysis. The effects of BIBW2992 and the TS-targeting agents S-1 (or 5-fluorouracil) or pemetrexed on the growth of gefitinib-resistant NSCLC cells were examined both in vitro and in vivo. The combination of BIBW2992 with 5-fluorouracil or pemetrexed synergistically inhibited the proliferation of NSCLC cells with the T790M mutation in vitro, whereas an antagonistic interaction was apparent in this regard between gefitinib and either of these TS-targeting agents. BIBW2992 induced downregulation of TS in the gefitinib-resistant NSCLC cells, implicating depletion of TS in the enhanced antitumor effect of the combination therapy. The combination of BIBW2992 and either the oral fluoropyrimidine S-1 or pemetrexed also inhibited the growth of NSCLC xenografts with the T790M mutation to an extent greater than that apparent with either agent alone. The addition of TS-targeting drugs to BIBW2992 is a promising strategy to overcome EGFR-TKI resistance in NSCLC with the T790M mutation of EGFR. Mol Cancer Ther; 9(6); 1647–56. ©2010 AACR.
Abrogation of De novo Lipogenesis by Stearoyl-CoA Desaturase 1 Inhibition Interferes with Oncogenic Signaling and Blocks Prostate Cancer Progression in Mice
Authors: Fritz Vanessa , Benfodda Zohra , Rodier Geneviève , Henriquet Corinne , Iborra François , Avancès Christophe , Allory Yves , de la Taille Alexandre , Culine Stéphane , Blancou Hubert , Cristol Jean Paul , Michel Françoise , Sardet Claude , Fajas Lluis 
Published: June 2010

Abstract
Increased de novo fatty acid (FA) synthesis is one hallmark of tumor cells, including prostate cancer. We present here our most recent results showing that lipid composition in human prostate cancer is characterized by an increased ratio of monounsaturated FA to saturated FA, compared with normal prostate, and evidence the overexpression of the lipogenic enzyme stearoyl-CoA desaturase 1 (SCD1) in human prostate cancer. As a new therapeutic strategy, we show that pharmacologic inhibition of SCD1 activity impairs lipid synthesis and results in decreased proliferation of both androgen-sensitive and androgen-resistant prostate cancer cells, abrogates the growth of prostate tumor xenografts in nude mice, and confers therapeutic benefit on animal survival. We show that these changes in lipid synthesis are translated into the inhibition of the AKT pathway and that the decrease in concentration of phosphatidylinositol-3,4,5-trisphosphate might at least partially mediate this effect. Inhibition of SCD1 also promotes the activation of AMP-activated kinase and glycogen synthase kinase 3α/β, the latter on being consistent with a decrease in β-catenin activity and mRNA levels of various β-catenin growth-promoting transcriptional targets. Furthermore, we show that SCD1 activity is required for cell transformation by Ras oncogene. Together, our data support for the first time the concept of targeting the lipogenic enzyme SCD1 as a new promising therapeutic approach to block oncogenesis and prostate cancer progression. Mol Cancer Ther; 9(6); 1740–54. ©2010 AACR.
Evaluation of Selective γ-Secretase Inhibitor PF-03084014 for Its Antitumor Efficacy and Gastrointestinal Safety to Guide Optimal Clinical Trial Design
Authors: Wei Ping , Walls Marlena , Qiu Ming , Ding Richard , Denlinger Robert H. , Wong Anthony , Tsaparikos Kosta , Jani Jitesh P. , Hosea Natilie , Sands Michelle , Randolph Sophia , Smeal Tod 
Published: June 2010

AbstractAberrant regulation of Notch signaling has been implicated in tumorigenesis. Proteolytic release of the Notch intracellular domain (NICD) by γ-secretase plays a key role in Notch-dependent nuclear signaling. γ-Secretase is an attractive pharmaceutical target for therapeutic intervention in cancer. We describe the potent antitumor effects of PF-03084014, a small molecule that is a reversible, noncompetitive, and selective γ-secretase inhibitor. The ability of PF-03084014 to inhibit γ-secretase activity was shown by the reduction of endogenous NICD levels and by the downregulation of Notch target genes Hes-1 and cMyc in the T-cell acute lymphoblastic leukemia (T-ALL) cell line HPB-ALL. PF-03084014 caused cell growth inhibition of several T-ALL cell lines via cell cycle arrest and induction of apoptosis. PF-03084014 treatment also resulted in robust NICD reduction in HBP-ALL xenograft models. Broad antitumor efficacy at well-tolerated dose levels was observed in six Notch-dependent models. Additional mechanism-of-action studies showed inhibition of tumor cell proliferation and induction of apoptosis in HPB-ALL tumors, suggesting that the antitumor activity of PF-03084014 may be mediated by its direct effects on tumor cell growth or survival. Further studies on PF-03084014–induced gastrointestinal toxicity identified an intermittent dosing schedule that displayed reduced body weight loss and sustained antitumor efficacy. We also showed that glucocorticoids abrogated PF-03084014–induced gastrointestinal toxicity and delayed administration of glucocorticoids did not compromise its protection effect. Collectively, the results show that inhibition of Notch signaling by PF-03084014 while minimizing gastrointestinal toxicity presents a promising approach for development of therapies for Notch receptor–dependent cancers. This compound is being investigated for the treatment of T-ALL and advanced solid tumors in phase I clinical trials. Mol Cancer Ther; 9(6); 1618–28. ©2010 AACR.
Zinc Protoporphyrin IX Stimulates Tumor Immunity by Disrupting the Immunosuppressive Enzyme Indoleamine 2,3-Dioxygenase
Authors: Metz Richard , DuHadaway James B. , Rust Sonja , Munn David H. , Muller Alexander J. , Mautino Mario , Prendergast George C. 
Published: June 2010

Abstract
The tryptophan catabolic enzyme indoleamine 2,3-dioxygenase (IDO) has emerged as an important driver of immune escape in a growing number of cancers and cancer-associated chronic infections. In this study, we define novel immunotherapeutic applications for the heme precursor compound zinc protoporphyrin IX (ZnPP) based on our discovery that it is a potent small-molecule inhibitor of IDO. Inhibitory activity was determined using in vitro and in-cell enzyme assays as well as a novel in vivo pharmacodynamic system. An irreversible mechanism of inhibition was documented, consistent with competition for heme binding in newly synthesized cellular protein. siRNA methodology and an IDO-deficient mouse strain were used to verify the specificity of ZnPP as an IDO inhibitor. In a preclinical model of melanoma, ZnPP displayed antitumor properties that relied on T-cell function and IDO integrity. ZnPP also phenocopied the known antitumor properties of IDO inhibitors in preclinical models of skin and breast carcinoma. Our results suggest clinical evaluation of ZnPP as an adjuvant immunochemotherapy in chronic infections and cancers in which there is emerging recognition of a pathophysiologic role for IDO dysregulation. Mol Cancer Ther; 9(6); 1864–71. ©2010 AACR.
Autophagy Regulates Keratin 8 Homeostasis in Mammary Epithelial Cells and in Breast Tumors
Authors: Kongara Sameera , Kravchuk Olga , Teplova Irina , Lozy Fred , Schulte Jennifer , Moore Dirk , Barnard Nicola , Neumann Carola A. , White Eileen , Karantza Vassiliki 
Published: June 2010

Abstract
Autophagy is activated in response to cellular stressors and mediates lysosomal degradation and recycling of cytoplasmic material and organelles as a temporary cell survival mechanism. Defective autophagy is implicated in human pathology, as disruption of protein and organelle homeostasis enables disease-promoting mechanisms such as toxic protein aggregation, oxidative stress, genomic damage, and inflammation. We previously showed that autophagy-defective immortalized mouse mammary epithelial cells are susceptible to metabolic stress, DNA damage, and genomic instability. We now report that autophagy deficiency is associated with endoplasmic reticulum (ER) and oxidative stress, and with deregulation of p62-mediated keratin homeostasis in mammary cells, allograft tumors, and mammary tissues from genetically engineered mice. In human breast tumors, high phospho(Ser73)-K8 levels are inversely correlated with Beclin 1 expression. Thus, autophagy preserves cellular fitness by limiting ER and oxidative stress, a function potentially important in autophagy-mediated suppression of mammary tumorigenesis. Furthermore, autophagy regulates keratin homeostasis in the mammary gland via a p62-dependent mechanism. High phospho(Ser73)-K8 expression may be a marker of autophagy functional status in breast tumors and, as such, could have therapeutic implications for breast cancer patients. Mol Cancer Res; 8(6); 873–84. ©2010 AACR.
On the Social and Legal Status of Slaves in the North Caucasus
Authors: Inozemtseva Elena 
Published: June 2010

AbstractThe present paper is an attempt to elucidate some aspects of the social and legal status of slaves and, generally, the dependent populace in the North-Eastern Caucasus. The material introduced here allows to reveal some characteristic features of slavery and servitude, as well as several forms of deprivation of rights and social harrasment of the people belonging to lower classes in the mentioned area during the late mediaeval period.
The Rise of the Russian Khalifat: The View from the Jihadist Side
Authors: Shlapentokh Dmitry 
Published: June 2010

AbstractRussia, similar to many other parts of the globe, continues to be affected by terrorism, mostly since the beginning of the conflicts in the Caucasus. While started by the Chechens after the beginning of the First Chechen War (1994-1996), terrorism and resistance to Moscow in general soon moved outside Chechen borders, absorbing representatives from other ethnic groups of the Caucasus and beyond. As a result, what originally had been mostly a Chechen nationalist movement finally transformed itself into a multi-ethnic force where the liberation of Chechnya from Russian rule became just one aspect of the struggle. Moreover, nationalist-minded Chechens seemed to have moved to the margins of the resistance, for increasing numbers of the resistance members could well go to the official Chechen leadership. While nationalistic and, in a way, a moderate model of the Chechen resistance became increasingly unworkable, jihadism provided an increasingly acceptable modus operandi. To start with, jihadism emphasises an ideological, Muslim identity and discards any sense of ethnicity, nationalism in general, that separates Muslims from each other. Secondly, jihadism promulgates the creation of a universal Khalifat as the final goal. Khalifat is seen as the ideal society, in a way similar to that of the “thousand-year rule of Christ” and/or communism, each of which actually transcends history as it is known. All of this has led to the increasing influence of jihadists among the members of the Chechen resistance, and a final split between them and the nationalist-minded members of the resistance. This paper presents a detailed analytic account of the recent developments within the Chechen resistance, as well as the jihadist ideology, and terrorism in the North Caucasus and Russia in general.
Effects of a scapula-oriented shoulder exercise programme on upper limb dysfunction in breast cancer survivors: a randomized controlled pilot trial
Authors: Seung Ah Lee  , Kang Ji-Young , Yong Duck Kim  , Ah Ra An  , Kim Sung-Won , Kim Yeon-Soo , Lim Jae-Young 
Published: June 2010

Objective: To examine the effects of a scapula-oriented exercise on upper limb dysfunction in breast cancer survivors. Study design: A prospective randomized, controlled pilot trial with historical control. Setting: Rehabilitation department at a university hospital. Subjects: Thirty-two women with breast cancer were randomly assigned to scapula-oriented exercise group (n = 16) and general exercise group (n = 16). An historical control group (n = 18) without exercise was enrolled from breast cancer survivors. Interventions: The scapula-oriented exercises were designed focusing on scapulothoracic movement. The general exercise group performed body conditioning exercise. Exercise therapies were performed for one session per week for eight weeks. Main outcome measures: Pain and physical disabilities related to upper limb dysfunction, quality of life and depression were used as subjective outcomes. Objective outcome measures included shoulder range of motion and strength. Outcomes were assessed at baseline and post exercise. Results: At baseline, no significant difference was observed among the three groups. The scapula-oriented exercise group showed improvements in pain, physical function, social function, and global quality of life compared with baseline, whereas the general exercise group showed improved fatigue and range of motion. The change in global quality of life (P = 0.067; effect size, 0.33) and strength of external rotation (P = 0.001; effect size, 0.55) were significantly greater in the scapula-oriented exercise group than in the general exercise and control group. Conclusion: Scapula-oriented exercise had beneficial effects on pain, quality of life and aspects of strength. The sample size required in a larger definitive study is 32 subjects per group.
Interprofessional teamwork in medical rehabilitation: a comparison of multidisciplinary and interdisciplinary team approach
Authors: Körner Mirjam 
Published: June 2010

Objective: To compare multi- and interdisciplinary team approaches concerning team process (teamwork) and team effectiveness (team performance and staff satisfaction) in German medical rehabilitation clinics. Design: A cross-sectional study with a descriptive—explorative design. Setting: Eighteen medical rehabilitation clinics divided into two groups (somatic and psychosomatic indication fields). Subjects: The 18 head physicians or psychotherapists in the clinics and their complete rehabilitation teams (n = 824). Main measures: An interview guide was designed to determine the team approach in a telephone interview. A staff questionnaire for team members measured teamwork and team effectiveness with psychometrically validated questionnaires and self-administered items. Results: All 18 head physicians took part in the telephone interview. The response rate of the employee attitude survey averaged 46% (n = 378). Eight teams were categorized as multidisciplinary and seven teams as interdisciplinary. In three cases the results were ambiguous. These teams were not considered in the further study. As expected, the interdisciplinary team approach showed significantly better results for nearly all aspects of teamwork and team effectiveness in comparison with the multidisciplinary team approach. The differences between multi- and interdisciplinary approach concerning teamwork and team effectiveness were higher in the somatic (8 teams, n = 183) than in the psychosomatic indication fields (7 teams, n = 195). Conclusions: Teamwork and team effectiveness are higher in teams working with the interdisciplinary team approach. Therefore the interdisciplinary approach can be recommended, particularly for clinics in the somatic indication field. Team development can help to move from the multidisciplinary to the interdisciplinary approach.