bluuebunny/crossref_metadata_2025 huggingface dataset:
An integrated analysis of germline and somatic, genetic and epigenetic alterations at 9p21.3 in glioblastoma
Authors: Feng Junjie , Kim Seong‐Tae , Liu Wennuan , Kim Jin Woo , Zhang Zheng , Zhu Yi , Berens Michael , Sun Jielin , Xu Jianfeng
Published: June 2011

BACKGROUND:

Glioblastoma multiforme (GBM) is the most prevalent and deadly brain tumor. A variety of germline and somatic, genetic and epigenetic alterations at 9p21.3, which encode CDKN2A/CDKN2B tumor suppressor genes, have been isolatedly reported to be associated with GBM risk and prognosis.

METHODS:

To obtain a comprehensive view of these events, we leveraged the wide‐spectrum GBM data available from The Cancer Genome Atlas project and performed an integrated analysis by systematically evaluating 9p21.3‐related germline single‐nucleotide polymorphisms, somatic copy number alterations (CNAs), DNA methylation, and microRNAs (miRNAs) with regard to CDKN2A/CDKN2B expression and patient prognosis in GBM.

RESULTS:

Our multivariate analysis indicated that expression of CDKN2A and CDKN2B was both strongly affected by CNAs (P = 1.00 × 10−4 and 2.37 × 10−14). The miRNAs hsa‐mir‐126, hsa‐mir‐517a, and hsa‐mir‐125b exhibited significant negative correlations with CDKN2A expression (P = 0.003, 0.041, and 0.050). Survival analysis showed that complete 9p21.3 loss and low CDKN2B expression were associated with worse prognosis for both tumor progression/recurrence‐free survival (P = .041 and .019) and patient overall survival (P = .043 and .021) after adjustment for age and treatment, and that higher methylation at cg17449661 predicted poorer overall survival (P = .048).

CONCLUSION:

Representing one of the first attempts to systematically integrate various levels of alterations associated with the often complex cancer genomes and phenotypes, our study provided a holistic view and a mechanistic explanation over the functional connections of multiple 9p21.3‐related events in GBM, as well as clinically useful biomarker information for predicting disease outcomes. Cancer 2012;. © 2011 American Cancer Society.
Serum cell‐free DNA in renal cell carcinoma
Authors: de Martino Michela , Klatte Tobias , Haitel Andrea , Marberger Michael
Published: June 2011

BACKGROUND:

Currently, there are no established diagnostic and prognostic serum markers for renal cell carcinoma (RCC). The objective of this study was to evaluate the putative significance of serum cell‐free DNA.

METHODS:

Preoperative serum samples from 200 consecutive patients with sporadic, solid renal tumors were analyzed (157 patients with RCC and 43 patients with benign renal tumors). Quantitative real‐time polymerase chain reaction was used to assess total cell‐free DNA (ring finger protein 185 [RNF185]) and CpG island methylation of Ras association domain family member 1A (RASSF1A) von Hippel‐Lindau (VHL), prostaglandin‐endoperoxidase synthase 2 (PTGS2), and P16 (cyclin‐dependent kinase inhibitor 2A). Associations with RCC, pathologic variables, and disease‐specific survival were evaluated.

RESULTS:

Total cell‐free DNA levels and CpG island methylation of RASSF1A and VHL were highly diagnostic for RCC with an area under the receiver operating characteristic curve of 0.755, 0.705, and 0.694, respectively. VHL methylation was detected more frequently in patients with clear cell RCC than in those with other subtypes (P = .007). Total cell‐free DNA levels were higher in patients with metastatic RCC (P < .001) and necrotic RCC (P = .003) and were associated with poorer disease‐specific survival (P < .001). In multivariate analysis, the tumor stage, size, grade, and necrosis (SSIGN) score (P < .001) and categorized total cell‐free DNA levels (P = .028) were retained as independent prognostic factors.

CONCLUSIONS:

The current results indicated that cell‐free DNA represents a novel serum‐based diagnostic and prognostic biomarker for RCC. Total serum cell‐free DNA levels and CpG island methylation of RASSF1A and VHL may be useful diagnostic biomarkers for RCC. VHL methylation of cell‐free DNA is suggestive of clear cell RCC. Total serum cell‐free DNA may be a useful prognostic biomarker that may assist in tailoring postoperative surveillance and therapy. External prospective validation of these data will be required. Cancer 2012;. © 2011 American Cancer Society.
Identification of potential prognostic biomarkers in patients with untreated, advanced pancreatic cancer from a phase 3 trial (Cancer and Leukemia Group B 80303)
Authors: Roberts Andrew S. , Campa Michael J. , Gottlin Elizabeth B. , Jiang Chen , Owzar Kouros , Kindler Hedy L. , Venook Alan P. , Goldberg Richard M. , O'Reilly Eileen M. , Patz Edward F.
Published: June 2011

BACKGROUND:

Patients with advanced stage adenocarcinoma of the pancreas have a poor prognosis. The identification of prognostic and/or predictive biomarkers may help stratify patients so that therapy can be individualized.

METHODS:

Serum samples from patients enrolled in the Cancer and Leukemia Group B 80303 phase 3 trial, “Randomized Study of Gemcitabine With Versus Without Bevacizumab in Patients With Locally Advanced or Metastatic Adenocarcinoma of the Pancreas” were used to discover novel biomarkers. For the discovery phase, 40 sera were selected based on length of survival and type of therapy, and subjected to liquid chromatography coupled to tandem mass spectrometry analysis (LC‐MS‐MS). The top features (proteins) were then further selected for validation by enzyme‐linked immunosorbent assay (ELISA).

RESULTS:

Quantification by nano–LC‐MS‐MS resulted in 1452 peptides mapping to 156 proteins across all 40 samples, 92 of which had 2 or more peptides. After curation of the data, the authors selected 1 putative prognostic protein, alpha 1‐antichymotrypsin (AACT), and 2 putative predictive proteins, histidine‐rich glycoprotein (HRG) and complement factor H (CFH), for validation by ELISA. AACT was found to be negatively correlated with overall survival (τ = −0.30 [−0.38, −0.22]; P < .00001). There was no evidence for interaction with bevacizumab and HRG, but there was some evidence for a weak positive correlation of HRG with overall survival (τ = 0.11 [0.03, 0.19]; P < .01). CFH was found to be neither a predictive nor a prognostic factor for overall survival.

CONCLUSIONS:

AACT may be a useful prognostic marker in patients with advanced stage pancreatic carcinoma, although additional validation studies are needed. Cancer 2011;. © 2011 American Cancer Society.
A scoring system to predict the risk of death during induction with anthracycline plus cytarabine‐based chemotherapy in patients with de novo acute myeloid leukemia
Authors: Valcárcel David , Montesinos Pau , Sánchez‐Ortega Isabel , Brunet Salut , Esteve Jordi , Martínez‐Cuadrón David , Ribera José M. , Tormo Mar , Bueno Javier , Duarte Rafael , Llorente Andrés , Torres Juan Pio , Guardia Ramón , Sanz Miguel A. , Sierra and Jorge ,   on behalf of the CETLAM Group
Published: June 2011

BACKGROUND:

A prognostic index to predict induction death in adult patients receiving induction chemotherapy for de novo acute myeloid leukemia (AML) was developed.

METHODS:

The authors analyzed 570 patients (aged 16‐70 years) included in 2 multicenter trials of the CETLAM Group to develop a scoring system (study cohort). The scoring system was tested in 209 patients from an external single institution (validation cohort). Induction regimens consisted of anthracycline and cytarabine combination with or without etoposide. Induction death was defined as death in the first 42 days without evidence of leukemic resistance.

RESULTS:

The cumulative incidence of induction death was 11% in the study cohort and 18% in the validation cohort. Median age was 48 years in the study cohort and 56 years in the validation cohort (P < .001). Multivariate analysis in the study cohort showed the following adverse risk factors for induction death: leukocyte count >100 × 109/L, serum creatinine >1.2 mg/dL, and age ≥50 years. According to these factors, the authors developed a predictive score: low risk (no risk factors), intermediate risk (1 factor), and high risk (2 or 3 factors). The cumulative incidence of induction death in the 3 respective groups was 5%, 13%, and 26% (P < .001). The scoring system was applied in the validation cohort, resulting in cumulative incidence rates of induction death of 6%, 19%, and 32%, for the low‐risk, intermediate‐risk, and high‐risk categories, respectively (P < .001).

CONCLUSIONS:

By using this validated and simple scoring system, the risk of induction death in patients with AML can be predicted accurately. The score may be helpful to design risk‐adapted induction strategies. Cancer 2011;. © 2011 American Cancer Society.
Measuring response to BCR‐ABL inhibitors in chronic myeloid leukemia
Authors: Radich Jerald P.
Published: June 2011

In patients with chronic myeloid leukemia (CML), the hallmark Philadelphia chromosome is the marker of disease that can be detected by conventional metaphase cytogenetics, fluorescence in situ hybridization, or polymerase chain reaction. The current “gold standard” of treatment response is cytogenetic response. Cytogenetic response to imatinib is strongly associated with disease progression and survival. Various strategies aimed at improving cytogenetic response have been explored, such as escalation of imatinib and switching to the newer breakpoint cluster region/v‐abl Abelson murine leukemia viral oncogene (BCR‐ABL) inhibitors dasatinib and nilotinib. Data from recent randomized trials of dasatinib and nilotinib as first‐line therapy of newly diagnosed chronic‐phase CML suggest that these agents are more effective than imatinib in achieving 6‐month and 12‐month complete cytogenetic responses. However, it is still too early to know whether or not this early response will translate into a long‐term survival advantage. In addition, more sensitive assays to detect residual disease also may be associated with improved long‐term outcomes. The deepest measure of response—a complete molecular response—may help identify patients who can stop taking imatinib for the short term, although the long‐term consequences of this strategy remain unknown. Cancer 2011;. © 2011 American Cancer Society.
High‐dose cytarabine induction is well tolerated and active in patients with de novo acute myeloid leukemia older than 60 years
Authors: Arellano Martha , Winton Elliott , Pan Lin , Lima Lisa , Tighiouart Mourad , Bhalla Kapil , Heffner Leonard T. , Neely Jessica , Hutcherson Donald , McLemore Morgan , Langston Amelia , Khoury H. Jean
Published: June 2011

BACKGROUND:

High‐dose cytarabine (HiDAC) is safe and very effective in younger patients with acute myeloid leukemia (AML), but it generally is not well tolerated in the elderly.

METHODS:

The authors explored the safety and tolerability of a modified HiDAC induction regimen consisting of 6 daily doses of cytarabine at 2 g/m2 in combination with 3 daily doses of daunorubicin at 45 mg/m2 in 59 consecutive patients aged >60 years who had de novo AML diagnosed between July 1996 and February 2005.

RESULTS:

The median patient age was 68 years (range, 60‐86 years). The regimen was well tolerated. Infections were common and occurred in 39% of patients, but cerebellar toxicities occurred in only 7% of patients and were reversible. The day‐30 induction‐related mortality rate was 10%. Overall, 69% of patients achieved complete remissions (CR), and 80% received up to 3 consolidations with HiDAC. The median follow‐up for surviving patients was 53 months (range, 17‐114 months). The median overall survival was 15.3 months (range, 1‐114 months), and the relapse‐free survival was 13.8 months (range, 1‐113 months). Survival for patients who achieved CR was 27 months (range, 2‐114 months).

CONCLUSIONS:

The modified HiDAC regimen was well tolerated in patients aged >60 years with AML and was associated with low induction mortality and high rates of CR. Nevertheless, these high remissions still were associated with poor overall outcomes. Cancer 2011;. © 2011 American Cancer Society.
Phase 2 randomized study of p53 antisense oligonucleotide (cenersen) plus idarubicin with or without cytarabine in refractory and relapsed acute myeloid leukemia
Authors: Cortes Jorge , Kantarjian Hagop , Ball Edward D. , DiPersio John , Kolitz Jonathan E. , Fernandez Hugo F. , Goodman Mark , Borthakur Gautam , Baer Maria R. , Wetzler Meir
Published: June 2011

BACKGROUND:

The p53 antisense oligonucleotide cenersen has been shown to sensitize acute myeloid leukemia (AML) stem cells to DNA damaging agents.

METHODS:

To determine whether cenersen merits testing in larger efficacy studies, an exploratory study of cenersen in combination with idarubicin either alone or with 1 of 2 doses of cytarabine was performed in first‐salvage AML patients. Patients who either had failed to respond to a single induction course or had responded to induction but relapsed within 12 months were enrolled. Stopping rules based on an expected 14% complete response (CR) rate were applied to each treatment arm.

RESULTS:

Fifty‐three patients were treated, and none of the arms was terminated for lack of activity. Nearly all patients received a single course unless they responded. Ten of the 53 (19%) patients responded (8 CR and 2 CR with incomplete platelet recovery). There was a positive trend for a better response rate with increasing intensity of chemotherapy in the patients refractory to front‐line treatment compared with those who had relapsed previously. One‐third (17/53) of the patients received cenersen inhibitors (acetaminophen and/or high dose antioxidants) during treatment, and none of these responded to treatment. No unique toxicity was attributed to cenersen.

CONCLUSION:

The results of this study suggested that the combination of cenersen with chemotherapy may have clinical efficacy, and additional studies are warranted to explore its full potential. Cancer 2011;. © 2011 American Cancer Society.
Long‐term outcomes of BRCA1/BRCA2 testing: risk reduction and surveillance
Authors: Schwartz Marc D. , Isaacs Claudine , Graves Kristi D. , Poggi Elizabeth , Peshkin Beth N. , Gell Christy , Finch Clinton , Kelly Scott , Taylor Kathryn L. , Perley Lauren
Published: June 2011

BACKGROUND:

For BRCA1/BRCA2 gene testing to benefit public health, mutation carriers must initiate appropriate risk management strategies. There has been little research examining the long‐term use and prospective predictors of the full range of risk management behaviors among women who have undergone BRCA1/2 testing. We evaluated long‐term uptake and predictors of risk‐reducing mastectomy (RRM), risk‐reducing bilateral salpingo‐oophorectomy (RRBSO), chemoprevention, and cancer screening among women at a mean of 5.3 years after testing.

METHODS:

The study participants comprised 465 women who underwent BRCA1/2 testing. Prior to genetic counseling, we measured family/personal cancer history, sociodemographics, perceived risk, cancer‐specific distress, and general distress. We contacted patients at a mean of 5.3 years after testing to measure use of RRM, RRBSO, chemoprevention, and breast and ovarian cancer screening.

RESULTS:

Among participants with intact breasts and/or ovaries at the time of testing, BRCA1/2 carriers were significantly more likely to obtain RRM (37%) and RRBSO (65%) compared with women who received uninformative (RRM, 6.8%; RRBSO, 13.3%) or negative (RRM, 0%; RRBSO, 1.9%) results. Among carriers, precounseling anxiety was associated with subsequent uptake of RRM. RRO was predicted by age. Carriers were also more likely have used breast cancer chemoprevention and have undergone magnetic resonance imaging screening.

CONCLUSION:

This prospective evaluation of the uptake and predictors of long‐term management outcomes provides a clearer picture of decision making in this population. At a mean of 5.3 years after testing, more than 80% of carriers had obtained RRM, RRBSO, or both, suggesting that BRCA1/2 testing is likely to have a favorable effect on breast and ovarian cancer outcomes. Cancer 2011;. © 2011 American Cancer Society.
IDH1 mutations in grade II astrocytomas are associated with unfavorable progression‐free survival and prolonged postrecurrence survival
Authors: Thon Niklas , Eigenbrod Sabina , Kreth Simone , Lutz Juergen , Tonn Joerg‐Christian , Kretzschmar Hans , Peraud Aurelia , Kreth Friedrich‐Wilhelm
Published: June 2011

BACKGROUND:

The favorable prognostic impact of mutations in the IDH1 gene is well documented for malignant gliomas; its influence on World Health Organization (WHO) grade II astrocytomas, however, is still under debate.

METHODS:

A previously published database of 127 predominantly surgically treated patients harboring WHO grade II astrocytomas was revisited. Patients were screened for TP53 mutations (sequencing analysis), IDH1 mutations (pyrosequencing), and MGMT promoter methylation (methylation‐specific polymerase chain reaction and bisulfite sequencing). Endpoints were overall survival, progression‐free survival (PFS), time to malignant transformation, and postrecurrence survival. Radiotherapy was usually withheld until tumor progression/malignant transformation occurred.

RESULTS:

IDH1 mutations, TP53 mutations, and methylated MGMT promoters were seen in 78.1%, 51.2%, and 80.0% of the analyzed tumors, respectively. IDH1 mutations, which were significantly associated with TP53 mutations and/or MGMT promoter methylation (P < .001), resulted in shortened PFS (median, 47 vs 84 months; P = .004); postrecurrence survival, however, was significantly increased in those patients undergoing malignant transformation (median, 49 vs 13.5 months; P = .006). Overall survival was not affected by IDH1. A similar pattern of influence was seen for MGMT promoter methylation. Methylated tumors did significantly worse (better) in terms of PFS (postrecurrence survival); a low number of unmethylated tumors, however, limited the power of this analysis. Conversely, TP53 mutations were stringently associated with a worse prognosis throughout the course of the disease.

CONCLUSIONS:

IDH1 mutations are associated with a Janus headlike phenomenon; unfavorable prognostic influence on PFS turns into favorable impact on postrecurrence survival. A similar pattern of influence might exist for MGMT methylation. Cancer 2011;. © 2011 American Cancer Society.
Prophylactic recombinant erythropoietin therapy and thalidomide are predictors of venous thromboembolism in patients with multiple myeloma: limited effectiveness of thromboprophylaxis
Authors: Anaissie Elias J. , Coleman Elizabeth A. , Goodwin Julia A. , Kennedy Robert L. , Lockhart Kimberly D. , Stewart Carol B. , Coon Sharon K. , Bailey Clyde , Barlogie Bart
Published: June 2011

BACKGROUND:

Venous thromboembolism (VTE) is a significant but poorly understood complication in patients with newly diagnosed multiple myeloma (NDMM). As a result, most patients receive thromboprophylaxis with low molecular weight heparin (LMWH). The purpose of this retrospective study was to identify risk factors for VTE in NDMM and evaluate the effectiveness of LMWH.

METHODS:

A total of 604 patients with newly diagnosed myeloma completed 3 induction cycles with multiagent chemotherapy with up‐front randomization to thalidomide between 1998 and 2004. Prophylactic enoxaparin was given to thalidomide recipients beginning in June 2001, and 122 subjects received prophylactic epoetin alfa (EPO) as part of an exercise trial. The primary study endpoint was grades 3‐4 VTE.

RESULTS:

A total of 72 patients (11.9%) developed VTE (mostly deep venous thrombosis), with a higher incidence among EPO recipients (P = .001), although only significant for upper extremity DVT (P = .0002). The EPO‐treated patients had higher hemoglobin (Hb) levels throughout the study (P < .0005), although no relationship between higher Hb levels and increasing incidence of VTE could be shown. A history of VTE was a strong predictor of VTE on univariate analysis (P < .000005). Enoxaparin did not reduce the rate of VTE (P = .158). Logistic regression analysis identified thalidomide therapy (P = .001; odds ratio [OR], 2.428; 95% confidence interval [CI], 1.418‐4.159) and prophylactic EPO (P = .002; OR, 2.488; 95% CI, 1.432‐4.324) as risk factors for VTE. Myeloma response and survival were not negatively affected by prophylactic EPO or VTE.

CONCLUSIONS:

Prophylactic EPO, thalidomide therapy, and VTE history, but not higher Hb levels, were found to increase the risk of VTE among NDMM patients receiving multiagent chemotherapy. This risk was not found to be reduced in this population by LMWH thromboprophylaxis. Cancer 2011;. © 2011 American Cancer Society.
Distinct clinical features and outcomes in never‐smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement
Authors: Kim Hye Ryun , Shim Hyo Sup , Chung Jin‐Haeng , Lee Young Joo , Hong Yun Kyoung , Rha Sun Young , Kim Se Hoon , Ha Sang‐Jun , Kim Se Kyu , Chung Kyung Young , Soo Ross , Kim Joo Hang , Cho Byoung Chul
Published: June 2011

BACKGROUND:

The objectives of this study were to determine the proportions of major oncogenic alterations and to examine survival in genotype‐specific subsets of never‐smokers with nonsmall cell lung cancer (NSCLC).

METHODS:

The authors concurrently analyzed mutations in the epidermal growth factor receptor (EGFR) and v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genes and investigated anaplastic lymphoma kinase (ALK) gene rearrangements in samples from 229 never‐smokers with NSCLC. ALK rearrangements were identified by fluorescent in situ hybridization and were confirmed by immunohistochemistry. Mutations in EGFR (exons 18 to 21) and KRAS (codons 12 and 13) were determined by direct sequencing.

RESULTS:

Of 229 tumors, the frequency of EGFR mutations, ALK rearrangements, KRAS mutations, and no mutations (wild type [WT]) in any of the 3 genes (WT/WT/WT) was 48%, 8.3%, 3.5%, and 40.2%, respectively. All genetic alterations were mutually exclusive. The median progression‐free survival after treatment with EGFR tyrosine kinase inhibitors (TKIs) was 12.8 months, 6.3 months, 2.1 months, and 1.6 months in patients with EGFR mutations, the WT/WT/WT genotype, KRAS mutations, and ALK rearrangements, respectively. In a Cox regression model, the adjusted hazard ratio for the risk of disease progression after treatment with EGFR TKIs was 0.59 (95% confidence interval [CI], 0.40‐0.87; P = .008) for patients with EGFR mutations, 4.58 (95% CI, 2.07‐10.15; P < .001) for patients with ALK rearrangements, and 4.23 (95% CI, 1.65‐10.8; P = .003) for patients with KRAS mutations. Overall survival also differed significantly among genotypes.

CONCLUSIONS:

To the authors' knowledge, this was the largest comprehensive and concurrent analysis to date of 3 major oncogenic alterations in a cohort of East Asian never‐smokers with NSCLC. Because survival outcomes differed among genotypes, and drugs that target specific alterations currently are available, genetic profiling to identify genotype‐specific subsets can lead to successful treatment with appropriate kinase inhibitors. Cancer 2012;. © 2011 American Cancer Society.
Can radicality of surgery be safely modulated on the basis of MRI and PET/CT imaging in locally advanced cervical cancer patients administered preoperative treatment?
Authors: Ferrandina Gabriella , Petrillo Marco , Restaino Gennaro , Rufini Vittoria , Macchia Gabriella , Carbone Arnaldo , Zannoni Gian Franco , Lucidi Alessandro , D'Angelo Giorgia , Scambia Giovanni
Published: June 2011

BACKGROUND:

The goal of this study was to prospectively analyze the diagnostic performances of magnetic resonance imaging (MRI) and positron emission tomography (PET)/computed tomography (CT) in predicting pathologically assessed residual disease in a large, single‐institution series of locally advanced cervical cancer (LACC) patients triaged to neoadjuvant treatments followed by radical surgery.

METHODS:

Between April 2007 and March 2010, 96 patients with histologically documented cervical cancer (any histology) and FIGO stage IB2‐IVA were enrolled. MRI and PET/CT were recommended to be performed within 4‐6 weeks from the end of treatment, and histology was the reference standard. Sensitivity, specificity, and accuracy were compared using the McNemar test.

RESULTS:

For residual disease in the cervix, sensitivity was higher for MRI than for PET/CT (86.1% vs 63.1%; P = .002), while specificity was significantly higher for PET/CT compared with MRI (P = .002). There was no difference in accuracy values between the 2 imaging modalities. For MRI analysis of lymph node groups, sensitivity, specificity, and accuracy were 35.7%, 95.9%, and 88.0%, respectively. Conversely, sensitivity, specificity, and accuracy for PET/CT were 28.6%, 97.8%, and 88.7%, respectively. Absence of follicular structures replaced by prevalent sclerosis and/or sinus histiocytosis was the most frequently documented morphological pattern in false‐positive cases.

CONCLUSION:

Neither MRI nor PET/CT accurately detected residual disease in LACC patients triaged to radical surgery after neoadjuvant treatment, disallowing the option of avoiding or modulating completion surgery. Cancer 2011;. © 2011 American Cancer Society.
Individualizing antimetabolic treatment strategies for head and neck squamous cell carcinoma based on TP53 mutational status
Authors: Sandulache Vlad C. , Skinner Heath D. , Ow Thomas J. , Zhang Aijun , Xia Xuefeng , Luchak James M. , Wong Lee‐Jun C. , Pickering Curtis R. , Zhou Ge , Myers Jeffrey N.
Published: June 2011

BACKGROUND:

Mutations in the tumor protein 53 (TP53) tumor suppressor gene are common in head and neck squamous cell carcinoma (HNSCC) and correlate with radioresistance. Currently, there are no clinically available therapeutic approaches targeting p53 in HNSCC. In this report, the authors propose a strategy that uses TP53 mutational status to individualize antimetabolic strategies for the potentiation of radiation toxicity in HNSCC cells.

METHODS:

Glycolytic flux and mitochondrial respiration were evaluated in wild‐type (wt) and mutant (mut) TP53 HNSCC cell lines. Sensitivity to external‐beam radiation (XRT) was measured using a clonogenic assay.

RESULTS:

HNSCC cells that expressed mutTP53 demonstrated radioresistance compared with HNSCC cells that expressed wtTP53. Glycolytic inhibition potentiated radiation toxicity in mutTP53‐expressing, but not wtTP53‐expressing, HNSCC cells. The relative sensitivity of mutTP53 HNSCC cells to glycolytic inhibition was caused by a glycolytic dependence associated with decreased mitochondrial complex II and IV activity. The wtTP53‐expressing cells maintained mitochondrial reserves and were relatively insensitive to glycolytic inhibition. Inhibition of respiration using metformin increased glycolytic dependence in wtTP53‐expressing cells and potentiated the effects of glycolyic inhibition on radiation toxicity.

CONCLUSIONS:

TP53 mutation in HNSCC cells was correlated with a metabolic shift away from mitochondrial respiration toward glycolysis, resulting in increased sensitivity to the potentiating effects of glycolytic inhibition on radiation toxicity. In contrast, wtTP53‐expressing cells required inhibition of both mitochondrial respiration and glycolysis to become sensitized to radiation. Therefore, the authors concluded that TP53 mutational status may be used as a marker of altered tumor cell metabolism to individualize HNSCC treatment selection of specific, targeted metabolic agents that can overcome cellular resistance to radiation therapy. Cancer 2012;. © 2011 American Cancer Society.
Molecular organization and timing of Wnt1 expression define cohorts of midbrain dopamine neuron progenitors in vivo
Authors: Brown Ashly , Machan Jason T. , Hayes Lindsay , Zervas Mark
Published: June 2011

Midbrain dopamine (MbDA) neurons are functionally heterogeneous and modulate complex functions through precisely organized anatomical groups. MbDA neurons are generated from Wnt1‐expressing progenitors located in the ventral mesencephalon (vMes) during embryogenesis. However, it is unclear whether the progenitor pool is partitioned into distinct cohorts based on molecular identity and whether the timing of gene expression uniquely identifies subtypes of MbDA neurons. In this study we show that Wnt1‐expressing MbDA progenitors from embryonic day (E)8.5–12.5 have dynamic molecular identities that correlate with specific spatial locations in the vMes. We also tested the hypothesis that the timing of Wnt1 expression in progenitors is related to the distribution of anatomically distinct cohorts of adult MbDA neurons using genetic inducible fate mapping (GIFM). We demonstrate that the Wnt1 lineage contributes to specific cohorts of MbDA neurons during a 7‐day epoch and that the contribution to MbDA neurons predominates over other ventral Mb domains. In addition, we show that calbindin‐, GIRK2‐, and calretinin‐expressing MbDA neuron subtypes are derived from Wnt1‐expressing progenitors marked over a broad temporal window. Through GIFM and quantitative analysis we demonstrate that the Wnt1 lineage does not undergo progressive lineage restriction, which eliminates a restricted competence model of generating MbDA diversity. Interestingly, we uncover that two significant peaks of Wnt1 lineage contribution to MbDA neurons occur at E9.5 and E11.5. Collectively, our findings delineate the temporal window of MbDA neuron generation and show that lineage and timing predicts the terminal distribution pattern of MbDA neurons. J. Comp. Neurol. 519:2978–3000, 2011. © 2011 Wiley‐Liss, Inc.
Cloud computing paradigms for pleasingly parallel biomedical applications
Authors: Gunarathne Thilina , Wu Tak‐Lon , Choi Jong Youl , Bae Seung‐Hee , Qiu Judy
Published: June 2011

Cloud computing offers exciting new approaches for scientific computing that leverage major commercial players’ hardware and software investments in large‐scale data centers. Loosely coupled problems are very important in many scientific fields, and with the ongoing move towards data‐intensive computing, they are on the rise. There exist several different approaches to leveraging clouds and cloud‐oriented data processing frameworks to perform pleasingly parallel (also called embarrassingly parallel) computations. In this paper, we present three pleasingly parallel biomedical applications: (i) assembly of genome fragments; (ii) sequence alignment and similarity search; and (iii) dimension reduction in the analysis of chemical structures, which are implemented utilizing a cloud infrastructure service‐based utility computing models of Amazon Web Services (http://Amazon.com Inc., Seattle, WA, USA) and Microsoft Windows Azure (Microsoft Corp., Redmond, WA, USA) as well as utilizing MapReduce‐based data processing frameworks Apache Hadoop (Apache Software Foundation, Los Angeles, CA, USA) and Microsoft DryadLINQ. We review and compare each of these frameworks, performing a comparative study among them based on performance, cost, and usability. High latency, eventually consistent cloud infrastructure service‐based frameworks that rely on off‐the‐node cloud storage were able to exhibit performance efficiencies and scalability comparable to the MapReduce‐based frameworks with local disk‐based storage for the applications considered. In this paper, we also analyze variations in cost among the different platform choices (e.g., Elastic Compute Cloud instance types), highlighting the importance of selecting an appropriate platform based on the nature of the computation. Copyright © 2011 John Wiley & Sons, Ltd.
Modern Molecular Photochemistry of Organic Molecules. by N. J. Turro, V. Ramamurthy, J. C. Scaiano.
Authors: Nau Werner
Published: June 2011

Science Books, 2010, 1120 pp., hardcover, £159.00, ISBN 978‐1891389252
Hydrogen Electrocatalysis on Single Crystals and on Nanostructured Electrodes
Authors: Santos Elizabeth , Hindelang Peter , Quaino Paola , Schulz Eduardo N. , Soldano Germán , Schmickler Wolfgang
Published: June 2011

We investigate hydrogen evolution on plain and nanostructured electrodes with a theory developed by us. On electrodes involving transition metals the most strongly adsorbed hydrogen is often only a spectator, while the reaction proceeds via a weakly adsorbed species. For Pt(111) the isotherms for both species are calculated. We explain why a nanostructure consisting of a monolayer of Pd on Au(111) is a good catalysts, and predict that Rh/Au(111) should be even better. Our calculations for a fair number of metals are in good agreement with experiment.
Generalized graph entropies
Authors: Dehmer Matthias , Mowshowitz Abbe
Published: June 2011

This article deals with generalized entropies for graphs. These entropies result from applying information measures to a graph using various schemes for defining probability distributions over the elements (e.g., vertices) of the graph. We introduce a new class of generalized measures, develop their properties, compute the measures for selected graphs, and briefly discuss potential applications to classification and clustering problems. © 2011 Wiley Periodicals, Inc. Complexity, 17,45–50, 2011
Formation of oxygen deficient BaPbO3‐x by oxalate decomposition
Authors: Franz A. , Klimm D. , Schmitz W. , Haferkorn I. , Bente K.
Published: June 2011

BaPbO3 is assumed to be oxygen deficient but the exact determination has never been reported. The aim of this study is to investigate the correlation between synthetic conditions and the resulting oxygen deficiency of BaPbO3‐x. The formation of BaPbO3‐x by decomposition of barium‐ and lead oxalate up to 850 °C is significantly faster compared to conventional high temperature solid state reactions of oxide compounds. The discrete reaction steps were studied by simultaneous thermal analysis and X‐ray powder diffraction. The oxygen content was determined by temperature‐programmed reduction analysis. It is shown that the formation process is very sensitive to the chosen starting materials leading to different oxygen deficits caused by partial oxidation from Pb2+ to Pb4+. The resulting perovskites show chemical compositions of BaPbO2.74 and BaPbO2.82. The varying oxygen deficits should have an effect on structural properties. (© 2011 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Morphology control of CuO micro‐particles using Zn2+ ion and ultrasonic treatment
Authors: Si Limin , Yue Linhai , Jin Dalai
Published: June 2011

Novel tomato‐shaped copper oxide crystals has been prepared by a simple hydrothermal method with the presence of Zn2+ ion. The ultrasonic pretreatment has proved to be the key factor during the synthesis process. Scanning electron microscope, energy dispersive X‐ray spectrometry and powder X‐ray diffraction were used to characterize the microstructure and morphology of the as‐prepared products. The obtained tomato‐shaped CuO particles were constructed by nanorods with the diameter of about 20 nm. The possible growth mechanism was proposed based on the experimental results. (© 2011 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Modeling of flame assisted chemical vapor deposition of silicon films
Authors: Masi M. , Cavallotti C. , Raffa E.
Published: June 2011

The simulation of a flame assisted chemical vapor deposition (FACVD) process is here proposed with reference to the growth of silicon thin films through the silane/chlorosilanes/hydrogen/chlorine route. The goal is to design a reactor able to deposit micromorphous or multicrystalline films at the high growth rates necessary for photovoltaic applications. In fact, since FACVD processes can operate in atmospheric conditions and in auto‐thermal mode, they present significant energetic advantages with respect to the plasma assisted technology used today. This work is in particular devoted to illustrate the multi‐hierarchical modeling procedure adopted to determine the process optimal operating conditions and to design the deposition chamber. Different burner geometries (single, porous or multiple nozzles burner) were investigated in order to exploit the advantages of the two classical stagnation flow and Bunsen stretched flames. (© 2011 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Photoluminescence from screen printed ZnO based nanocrystalline films
Authors: Srivastava A. , Shukla R. K. , Misra K. P.
Published: June 2011

Photoluminescence from ZnO based films deposited by screen printing is studied. PL spectra of undoped films show strong broad green emission around 500 nm and a weak (nearly one fourth of visible) UV emission around 398 nm. Further enhancement of 30% in the green emission is observed as 5 at.% Ca is doped in ZnO which for higher dopant concentration falls monotonously. The films are polycrystalline and the particle size lies between 33 to 47 nm as determined by Debye‐Scherrer method. Film with 5 at.% doping is under tensile strain and the others are under compressive strain. SEM shows microclusters, consisting of nanoparticles, scattered throughout the substrate which club together with increase in dopant amount. (© 2011 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
The effect of diluting crystallization droplets on protein crystallization in vapor diffusion method
Authors: Lu Qin‐Qin , Yin Da‐Chuan , Xie Si‐Xiao , Liu Yong‐Ming , Chen Rui‐Qing
Published: June 2011

In this study, effects of diluting either protein or crystallization agents in the droplets on the success rate of protein crystallization was investigated. Diluting the crystallization agent was found to increase the success rate of protein crystallization. Theoretical analysis showed that, concentration ranges of both protein and crystallization agent that can be scanned during the vapor diffusion process are wider with diluting the crystallization agent than that without dilution, resulting in more opportunities for the crystallization solution to be in the nucleation zone. On the other hand, diluting protein could lead to controversial results depending on the location of the initial concentration relative to that of the nucleation zone in the phase diagram. The method of diluting the crystallization agent is therefore proposed as an alternative modification to the conventional vapor diffusion method for obtaining more crystallization conditions in protein crystallization screening. (© 2011 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Channel capacity per user in a power and rate adaptive hybrid DS/FFH‐CDMA cellular system over Rayleigh fading channels
Authors: Varzakas P.
Published: June 2011

The theoretically achievable average channel capacity (in the Shannon sense) per user of a hybrid cellular direct sequence/fast frequency hopping code‐division multiple‐access (DS/FFH‐CDMA) system, operating in a Rayleigh fading environment, was examined. The analysis covers the downlink transmission and leads to the derivation of a novel expression between the average channel capacity available to each system's user under simultaneous optimal power and rate adaptation and the system's parameters, providing an optimistic upper bound, useful for practical modulation and coding schemes. The final derived closed‐form expression can be useful for the design of the DS/FFH‐CDMA system because it provides a theoretical tool for the initial quantitative analysis. Finally, avoiding the application of complex theoretical algorithm or lengthy simulation, we theoretically derived numerical results to illustrate the presented analysis. Copyright © 2011 John Wiley & Sons, Ltd.
Urine cytopathology: Challenges, pitfalls, and mimics
Authors: Thiryayi, S. A. , Rana D. N.
Published: June 2011

Urine cytopathology is a useful and noninvasive tool in the diagnosis and follow‐up of urothelial neoplasia, which remains complementary to emerging molecular tests. These specimens may be challenging and there are numerous mimics and diagnostic pitfalls with which to contend. This review discusses these various entities and includes consideration of ancillary tests that may be useful in the diagnostic procedure. Diagn. Cytopathol. 2012. © 2011 Wiley Periodicals, Inc.
The S. mansoni glycoprotein ω‐1 induces Foxp3 expression in NOD mouse CD4+ T cells
Authors: Zaccone Paola , Burton Oliver T. , Gibbs Sarah E. , Miller Nigel , Jones Frances M. , Schramm Gabriele , Haas Helmut , Doenhoff Michael J. , Dunne David W. , Cooke Anne
Published: June 2011

Immunization with Schistosoma mansoni soluble antigen preparations protects non‐obese diabetic (NOD) mice against the development of type 1 diabetes. These preparations have long been known to induce Th2 responses in vitro and in vivo. Recently, two separate groups have reported that ω‐1, a well‐characterized glycoprotein in S. mansoni soluble egg antigens (SEA), which with IL‐4 inducing principle of S. mansoni eggs (IPSE/α‐1) is one of the two major glycoproteins secreted by live eggs, is a major SEA component responsible for this effect. We found that ω‐1 induces Foxp3 as well as IL‐4 expression when injected in vivo. We confirmed that ω‐1 conditions DCs to drive Th2 responses and further demonstrated that ω‐1 induces Foxp3+ T cells from NOD mouse naïve T cells. In contrast, IPSE/α‐1 did not drive Foxp3 responses. The in vitro development of Foxp3‐expressing T cells by ω‐1 was TGF‐β‐ and retinoic acid‐dependent. Our work, therefore, identifies ω‐1 as an important factor for the induction of Foxp3+ T cells by SEA in NOD mice.
A Tetranuclear Planar Hafnium Complex Containing O–Hf–S Moieties
Authors: Maratini Federica , Pandolfo Luciano , Rizzato Silvia , Albinati Alberto , Venzo Alfonso , Tondello Eugenio , Gross Silvia
Published: June 2011

The HfIV‐oxothiocluster, [Hf4(η2‐μ2‐SAc)4(η2‐μ2‐SAc)2(η2‐μ2‐BuO)4(η2‐BuO)2(μ3‐O)2], was synthesized by reaction of hafnium butoxide with thioacetic acid. The crystal structure shows the presence of a planar tetranuclear Hf4 core, in which the metal atoms are μ3‐O bridged and the thioacetate ligands coordinate the Hf ions both through a bridging and a chelating mode. The structural findings are confirmed by multinuclear NMR spectroscopic data.
Through‐Space J(P,P) and J(P,F) Spin–Spin Coupling in C1‐Symmetric Biaryl Diphosphanes
Authors: Bonnafoux Laurence , Ernst Ludger , Leroux Frédéric R. , Colobert Françoise
Published: June 2011

The first simultaneous 31P,31P and 31P,19F solution‐phase through‐space nuclear spin–spin coupling in biphenyl derivatives is reported. The magnitudes of the coupling constants are in the range 5.3–28.7 and 2.3–5.1 Hz, respectively. Their observation became possible through access to a recently developed class of C1‐symmetric biphenyl diphosphanes. We used this to prepare a series of model compounds for the study of the through‐space couplings. Various 1D and 2D techniques [COSY, NOESY, heteronuclear single quantum coherence (HSQC), HMBC, HSCQ‐TOCSY, selective 1H{31P}‐decoupling and iterative bandshape analysis] were applied to assign the 1H, 13C, 19F and 31P NMR spectra as completely as possible. X‐ray structure determinations confirmed the structural assignments and afforded P···P distances and torsion angles in the solid state. No simple correlation was found between the experimental J(31P,31P) values in solution and the relevant geometric parameters (P···P distance and torsional angle between the phosphorus lone pairs) in the solid state.
Facile Synthesis of Alternating Benzene–Pyrrole Oligomers by Cyclization of Propargylic Dithioacetals and Imines and Their Fluorescent Properties
Authors: Huang Tong‐Hui , Zhu Xiao‐Lei , Zhang Ai‐Dong , Tu Hai‐Yang
Published: June 2011

Alternating benzene–heteroaryl oligomers possess fascinating optoelectronic properties and a wide range of applications. This article presents the facile synthesis of benzene–pyrrole oligomers with diverse functional groups and the elongated alternating heterocycle–benzene–pyrrole oligoaryls. The syntheses are based on a one‐pot, three‐step reaction of propargylic dithioacetals and imines. The subtle influence of functional groups, such as ether, ester, hydroxy, and dithiacetal groups on the peripheral benzene rings, on the reaction, has been explored and the reaction conditions were finely changed accordingly to achieve reasonable yields. The elongation could be accomplished by using a similar procedure. The fluorescent properties of original and elongated alternating benzene–pyrrole oligomers were determined. Theoretical calculations preliminarily reveal that the fluorescent intensity is closely related to the molecular geometry and to the HOMO/LUMO energy difference in the ground state.
Synthesis of Multi‐Functionalized Chromeno[2,3‐c]pyrrol‐9(2H)‐ones: Investigation and Application of Baker–Venkataraman Rearrangement Involved Reactions Catalyzed by 4‐(Dimethylamino)pyridine
Authors: Yu Yanjun , Hu Yun , Shao Weiyan , Huang Jianing , Zuo Yinglin , Huo Yingpeng , An Linkun , Du Jun , Bu Xianzhang
Published: June 2011

An efficient one‐pot synthesis of multi‐functionalized chromeno[2,3‐c]pyrrol‐9(2H)‐ones from 1,3‐diaryl‐1,3‐diketones and amino acids is described. The synthesis is based on the 4‐(dimethylamino)pyridine‐catalyzed Baker–Venkataraman rearrangement and subsequent reactions.
New Potent Fluorescent Analogues of Strigolactones: Synthesis and Biological Activity in Parasitic Weed Germination and Fungal Branching
Authors: Prandi Cristina , Occhiato Ernesto G. , Tabasso Silvia , Bonfante Paola , Novero Mara , Scarpi Dina , Bova Maria Elena , Miletto Ivana
Published: June 2011

In this work we report the synthesis of new fluorescent analogues of strigolactones, their spectroscopic properties and the evaluation of their biological activity both on seeds of Orobanche aegyptiaca and on the AM fungus Gigaspora margarita. The synthesis has been accomplished according to two different synthetic plans and allows the introduction of various substituents on the A and C rings of the framework, thus enabling access to bioactive molecules with different spectroscopic properties.
Proteomic analysis of a spring wheat cultivar in response to prolonged cold stress
Authors: Rinalducci Sara , Egidi Maria Giulia , Karimzadeh Ghasem , Jazii Ferdous Rastgar , Zolla Lello
Published: June 2011

Cold represents one of the major abiotic factors influencing plant growth and development worldwide. We analysed the long‐term responsiveness of an Iranian spring wheat (cv. Kohdasht) to cold from a proteomic point of view, in order to unravel the molecular mechanisms helping a cold‐sensitive cultivar to survive exposure to suboptimal temperatures. Plants were grown at 20 or 4°C until entering the reproductive stage and a cross‐comparison on the leaf proteomes was performed. Quantitative analyses on protein alterations occurring upon low‐temperature exposure showed a reinforcement in ascorbate recycling (dehydroascorbate reductase, ascorbate peroxidase) and protein processing (proteasome subunit, cysteine proteinase), as well as the accumulation of the enzyme devoted to tetrapyrrole resynthesis (glutamate semialdehyde aminomutase). In contrast, among proteins down‐regulated after cold stress, we could identify some key Krebs cycle enzymes (isocitrate dehydrogenase, malate dehydrogenase), together with many photosynthesis‐related proteins (oxygen‐evolving complex proteins, ATP synthase subunits, ferredoxin NADPH oxidoreductase and some Calvin cycle enzymes). Physiological and biochemical parameters (such as shoot apex dissection, chlorophyll, proline and sugar content determination) sustained proteomics findings allowing the present research to contribute to the current knowledge on these long‐term responses, which may be crucial to stress adaptation under field conditions.