bluuebunny/crossref_metadata_2025 huggingface dataset:
Arthroscopic Quadriceps Tendon Repair: Two Case Reports
Authors: Saito Hidetomo , Shimada Yoichi , Yamamura Toshiaki , Yamada Shin , Sato Takahiro , Nozaka Koji , Kijima Hiroaki , Saito Kimio
Published: February 2015

Recently, although some studies of open repair of the tendon of the quadriceps femoris have been published, there have been no reports in the literature on primary arthroscopic repair. In our present study, we present two cases of quadriceps tendon injury arthroscopically repaired with excellent results. Case 1 involved a 68-year-old man who was injured while shifting his weight to prevent a fall. MRI showed complete rupture at the insertion of the patella of the quadriceps tendon. The rupture was arthroscopically repaired using both suture anchor and pull-out suture fixation methods via bone tunnels (hereafter, pull-out fixation). Two years after surgery, retearing was not observed on MRI and both Japan Orthopedic Association (JOA) Knee and Lysholm scores had recovered to 100. Case 2 involved a 50-year-old man who was also injured when shifting his weight to prevent a fall. MRI showed incomplete superficial rupture at the insertion of the patella of the quadriceps tendon. The rupture was arthroscopically repaired using pull-out fixation of six strand sutures. One year after surgery, MRI revealed a healed tendon and his JOA and Lysholm scores were 95 and 100, respectively. Thus, arthroscopic repair may be a useful surgical method for repairing quadriceps tendon injury.
Cholesterol-Induced Hepatic Inflammation Does Not Underlie the Predisposition to Insulin Resistance in Dyslipidemic Female LDL Receptor Knockout Mice
Authors: Gruben Nanda , Funke Anouk , Kloosterhuis Niels J. , Schreurs Marijke , Sheedfar Fareeba , Havinga Rick , Houten Sander M. , Shiri-Sverdlov Ronit , van de Sluis Bart , Kuivenhoven Jan Albert , Koonen Debby P. Y. , Hofker Marten H.
Published: February 2015

Chronic inflammation is considered a causal risk factor predisposing to insulin resistance. However, evidence is accumulating that inflammation confined to the liver may not be causal to metabolic dysfunction. To investigate this, we assessed if hepatic inflammation explains the predisposition towards insulin resistance in low-density lipoprotein receptor knock-out (Ldlr−/−) mice. For this, wild type (WT) andLdlr−/−mice were fed a chow diet, a high fat (HF) diet, or a high fat, high cholesterol (HFC) diet for 2 weeks. Plasma lipid levels were elevated in chow-fedLdlr−/−mice compared to WT mice. Although short-term HF or HFC feeding did not result in body weight gain and adipose tissue inflammation, dyslipidemia was worsened inLdlr−/−mice compared to WT mice. In addition, dyslipidemic HF-fedLdlr−/−mice had a higher hepatic glucose production rate than HF-fed WT mice, while peripheral insulin resistance was unaffected. This suggests that HF-fedLdlr−/−mice suffered from hepatic insulin resistance. While HFC-fedLdlr−/−mice displayed the anticipated increased hepatic inflammation, this did neither exacerbate systemic nor hepatic insulin resistance. Therefore, our results show that hepatic insulin resistance is unrelated to cholesterol-induced hepatic inflammation inLdlr−/−mice, indicating that hepatic inflammation may not contribute to metabolic dysfunction per se.
Heat Shock Factor 1 in Protein Homeostasis and Oncogenic Signal Integration
Authors: Home Trisha , Jensen Roy A. , Rao Rekha
Published: February 2015

Heat shock factor 1 (HSF1) is a stress-inducible transcription factor and has been described as a multi-faceted modulator of tumorigenesis. Heat shock, accumulation of misfolded proteins, or malignant transformation promotes the activation and nuclear translocation of HSF1, where it binds to the promoters of heat shock proteins and an array of nonheat shock–regulated proteins to upregulate their transcription. These stress-responsive and tumor-promoting genes in turn alter the ability of tumor cells to respond to a variety of stresses and enable them to thrive in less than favorable growth conditions. Although a direct role for HSF1 in promoting mRNA transcription of tumor-promoting genes has been suggested, it appears that this property is context- and cell-type dependent. Furthermore, recent studies have demonstrated a direct involvement of mTOR signaling in regulating HSF1-mediated transcription, thus establishing a direct link between protein translation and HSF1 activity. Interestingly, there is a growing understanding of the signaling pathways that are modulated by HSF1 in a variety of tumor types and the co-option of these survival pathways by HSF1 to promote tumorigenesis. This review will focus on the role of HSF1 in protein homeostasis and HSF1-mediated oncogenic signaling pathways that together promote tumorigenesis. Cancer Res; 75(6); 907–12. ©2015 AACR.
miR-137 and miR-197 Induce Apoptosis and Suppress Tumorigenicity by Targeting MCL-1 in Multiple Myeloma
Authors: Yang Yijun , Li Fei , Saha Manujendra N. , Abdi Jahangir , Qiu Lugui , Chang Hong
Published: February 2015

Purpose: Deregulation of miRNA has been implicated in the pathogenesis of multiple myeloma. We identified miR-137 and miR-197, mapped to the chromosome 1p (12)–(21) deletion region, and examined their antimyeloma activity as tumor suppressors.

Experimental Design: The expression of miR-137/197 was examined in multiple myeloma and normal plasma cells by qRT-PCR. Functional effect of miR-137/197 was analyzed by cell viability, apoptosis, clonogenic, and migration assays. Antimyeloma activity of miR-137/197 was further evaluated in vivo by lentiviral-based or lipid-based delivery in a mouse xenograft model of multiple myeloma.

Results: miR-137/197 expression was significantly lower in multiple myeloma cell lines and multiple myeloma patient samples compared with normal plasma cells. Transfection of miR-137/197 resulted in reduction of MCL-1 protein expression, as well as alteration of apoptosis-related genes, and induction of apoptosis, inhibition of viability, colony formation, and migration in multiple myeloma cells. MCL-1 was further validated as a direct target of miR-137/197. Conversely, overexpression of MCL-1 partially reverted the effect of miR-137/197. Importantly, in vivo lentiviral-mediated or intratumor delivery of miR-137/197 induced regression of tumors in murine xenograft models of multiple myeloma.

Conclusions: Our study reveals a novel role of miR-137/197 as tumor suppressors in mediating apoptosis in multiple myeloma cells by targeting MCL-1. Our findings provide a proof-of-principle that lentivirus-based or formulated synthetic miR-137/197 exerts therapeutic activity in preclinical models, and support a framework for development of miR-137/197-based treatment strategies in patients with multiple myeloma. Clin Cancer Res; 21(10); 2399–411. ©2015 AACR.
Angiotensin System Inhibitors and Survival Outcomes in Patients with Metastatic Renal Cell Carcinoma
Authors: McKay Rana R. , Rodriguez Gustavo E. , Lin Xun , Kaymakcalan Marina D. , Hamnvik Ole-Petter R. , Sabbisetti Venkata S. , Bhatt Rupal S. , Simantov Ronit , Choueiri Toni K.
Published: February 2015

Purpose: The renin-angiotensin system may play a role in carcinogenesis. The purpose of this study was to evaluate the impact of angiotensin system inhibitors (ASI) on outcomes in metastatic renal cell carcinoma (mRCC) patients treated in the targeted therapy era.

Experimental Design: We conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan–Meier method.

Results: A total of 4,736 patients were included, of whom 1,487 received ASIs and 783 received other antihypertensive agents. Overall, ASI users demonstrated improved overall survival (OS) compared with users of other antihypertensive agents (adjusted HR, 0.838, P = 0.0105, 26.68 vs. 18.07 months) and individuals receiving no antihypertensive therapy (adjusted HR, 0.810, P = 0.0026, 26.68 vs. 16.72 months). When stratified by therapy type, a benefit in OS was demonstrated in ASI users compared with nonusers in individuals receiving VEGF therapy (adjusted HR, 0.737, P < 0.0001, 31.12 vs. 21.94 months) but not temsirolimus or IFNα. An in vitro cell viability assay demonstrated that sunitinib in combination with an ASI significantly decreased RCC cell viability compared with control at physiologically relevant doses. This effect was not observed with either agent alone or with other non-ASI antihypertensives or temsirolimus.

Conclusions: In the largest analysis to date, we demonstrate that ASI use improved survival in mRCC patients treated in the targeted therapy era. Further studies are warranted to investigate the mechanism underlying this interaction and verify our observations to inform clinical practice. Clin Cancer Res; 21(11); 2471–9. ©2015 AACR.
Contribution of Beta-HPV Infection and UV Damage to Rapid-Onset Cutaneous Squamous Cell Carcinoma during BRAF-Inhibition Therapy
Authors: Cohen Daniel N. , Lawson Steven K. , Shaver Aaron C. , Du Liping , Nguyen Harrison P. , He Qin , Johnson Douglas B. , Lumbang Wilfred A. , Moody Brent R. , Prescott James L. , Chandra Pranil K. , Boyd Alan S. , Zwerner Jeffrey P. , Robbins Jason B. , Tyring Stephen K. , Rady Peter L. , Chappell James D. , Shyr Yu , Infante Jeffrey R. , Sosman Jeffrey A.
Published: February 2015

Purpose: BRAF-inhibition (BRAFi) therapy for advanced melanoma carries a high rate of secondary cutaneous squamous cell carcinoma (cSCC) and risk of other cancers. UV radiation and α-genus human papillomavirus (HPV) are highly associated with SCC, but a novel role for β-genus HPV is suspected in BRAFi-cSCC. Cutaneous β-HPV may act in concert with host and environmental factors in BRAFi-cSCC.

Experimental Design: Primary BRAFi-cSCC tissue DNA isolated from patients receiving vemurafenib or dabrafenib from two cancer centers was analyzed for the presence of cutaneous oncogenic viruses and host genetic mutations. Diagnostic specimens underwent consensus dermatopathology review. Clinical parameters for UV exposure and disease course were statistically analyzed in conjunction with histopathology.

Results: Twenty-nine patients contributed 69 BRAFi-cSCC lesions. BRAFi-cSCC had wart-like features (BRAFi-cSCC-WF) in 22% of specimens. During vemurafenib therapy, BRAFi-cSCC-WF arose 11.6 weeks more rapidly than conventional cSCC when controlled for gender and UV exposure (P value = 0.03). Among all BRAFi-cSCC, β-genus HPV-17, HPV-38, HPV-111 were most frequently isolated, and novel β-HPV genotypes were discovered (CTR, CRT-11, CRT-22). Sequencing revealed 63% of evaluated BRAFi-cSCCs harbored RAS mutations with PIK3CA, CKIT, ALK, and EGFR mutations also detected.

Conclusions: We examined clinical, histopathologic, viral, and genetic parameters in BRAFi-cSCC demonstrating rapid onset; wart-like histomorphology; β-HPV-17, HPV-38, and HPV-111 infection; UV damage; and novel ALK and CKIT mutations. Discovered β-HPV genotypes expand the spectrum of tumor-associated viruses. These findings enhance our understanding of factors cooperating with BRAF inhibition that accelerate keratinocyte oncogenesis as well as broaden the knowledge base of multifactorial mediators of cancer in general. Clin Cancer Res; 21(11); 2624–34. ©2015 AACR.
Treatment Planning and Fracture Prediction in Patients with Skeletal Metastasis with CT-Based Rigidity Analysis
Authors: Nazarian Ara , Entezari Vahid , Zurakowski David , Calderon Nathan , Hipp John A. , Villa-Camacho Juan C. , Lin Patrick P. , Cheung Felix H. , Aboulafia Albert J. , Turcotte Robert , Anderson Megan E. , Gebhardt Mark C. , Cheng Edward Y. , Terek Richard M. , Yaszemski Michael , Damron Timothy A. , Snyder Brian D.
Published: February 2015

Purpose: Pathologic fractures could be prevented if reliable methods of fracture risk assessment were available. A multicenter prospective study was conducted to identify significant predictors of physicians' treatment plan for skeletal metastasis based on clinical fracture risk assessments and the proposed CT-based Rigidity Analysis (CTRA).

Experimental Design: Orthopedic oncologists selected a treatment plan for 124 patients with 149 metastatic lesions based on the Mirels method. Then, CTRA was performed, and the results were provided to the physicians, who were asked to reassess their treatment plan. The pre- and post-CTRA treatment plans were compared to identify cases in which the treatment plan was changed based on the CTRA report. Patients were followed for a 4-month period to establish the incidence of pathologic fractures.

Results: Pain, lesion type, and lesion size were significant predictors of the pre-CTRA plan. After providing the CTRA results, physicians changed their plan for 36 patients. CTRA results, pain, and primary source of metastasis were significant predictors of the post-CTRA plan. Follow-up of patients who did not undergo fixation resulted in 7 fractures; CTRA predicted these fractures with 100% sensitivity and 90% specificity, whereas the Mirels method was 71% sensitive and 50% specific.

Conclusions: Lesion type and size and pain level influenced the physicians' plans for the management of metastatic lesions. Physicians' treatment plans and fracture risk predictions were significantly influenced by the availability of CTRA results. Due to its high sensitivity and specificity, CTRA could potentially be used as a screening method for pathologic fractures. Clin Cancer Res; 21(11); 2514–9. ©2015 AACR.
Methionine Deprivation Induces a Targetable Vulnerability in Triple-Negative Breast Cancer Cells by Enhancing TRAIL Receptor-2 Expression
Authors: Strekalova Elena , Malin Dmitry , Good David M. , Cryns Vincent L.
Published: February 2015

Purpose: Many neoplasms are vulnerable to methionine deficiency by mechanisms that are poorly understood. Because gene profiling studies have revealed that methionine depletion increases TNF-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) mRNA, we postulated that methionine stress sensitizes breast cancer cells to proapoptotic TRAIL-R2 agonists.

Experimental Design: Human triple (ER/PR/HER2)-negative breast carcinoma cell lines were cultured in control or methionine-free media. The effects of methionine depletion on TRAIL receptor expression and sensitivity to chemotherapy or a humanized agonistic TRAIL-R2 monoclonal antibody (lexatumumab) were determined. The melanoma-associated antigen MAGED2 was silenced to delineate its functional role in sensitizing TNBC cells to methionine stress. An orthotopic TNBC model was utilized to evaluate the effects of dietary methionine deficiency, lexatumumab, or the combination.

Results: Methionine depletion sensitized TNBC cells to lexatumumab-induced caspase activation and apoptosis by increasing TRAIL-R2 mRNA and cell surface expression. MCF-10A cells transformed by oncogenic H-Ras, but not untransformed cells, and matrix-detached TNBC cells were highly sensitive to the combination of lexatumumab and methionine depletion. Proteomics analyses revealed that MAGED2, which has been reported to reduce TRAIL-R2 expression, was suppressed by methionine stress. Silencing MAGED2 recapitulated features of methionine deprivation, including enhanced mRNA and cell surface expression of TRAIL receptors and increased sensitivity to TRAIL receptor agonists. Dietary methionine deprivation enhanced the antitumor effects of lexatumumab in an orthotopic metastatic TNBC model.

Conclusions: Methionine depletion exposes a targetable defect in TNBC cells by increasing TRAIL-R2 expression. Our findings provide the foundation for a clinical trial combining dietary methionine restriction and TRAIL-R2 agonists. Clin Cancer Res; 21(12); 2780–91. ©2015 AACR.
A Phase I First-in-Human Study of Enoticumab (REGN421), a Fully Human Delta-like Ligand 4 (Dll4) Monoclonal Antibody in Patients with Advanced Solid Tumors
Authors: Chiorean Elena Gabriela , LoRusso Patricia , Strother Robert Matthew , Diamond Jennifer R. , Younger Anne , Messersmith Wells A. , Adriaens Lieve , Liu Liming , Kao Richard J. , DiCioccio Albert Thomas , Kostic Ana , Leek Russell , Harris Adrian , Jimeno Antonio
Published: February 2015

Purpose: Enoticumab (REGN421) is a fully human IgG1 monoclonal antibody that binds human Dll4 and disrupts Notch-mediated signaling. The main objectives of this trial were to determine the safety, dose-limiting toxicities (DLT), pharmacokinetics (PK), and recommended phase II dose (RP2D) of enoticumab.

Experimental Design: Enoticumab was administered intravenously, with dose escalations from 0.25 to 4 mg/kg every 3 weeks (Q3W) and 0.75 to 3 mg/kg every 2 weeks (Q2W).

Results: Of 53 enrolled patients, 31 patients were treated Q3W and 22 patients were treated Q2W. Two DLTs occurred: grade 3 nausea (0.5 mg/kg Q3W) and grade 3 abdominal pain (1 mg/kg Q2W). An MTD was not reached on either schedule. The most frequent adverse events (AE) were fatigue, nausea, vomiting, hypertension, headache, and anorexia. Six treatment-related serious AEs were reported in 4 patients: brain natriuretic peptide (BNP) increase (0.25 mg/kg Q3W, Gr1), troponin I increase (4 mg/kg Q3W, Gr3), right ventricular dysfunction and pulmonary hypertension (1.5 mg/kg Q2W, both Gr3), and left ventricular dysfunction and pulmonary hypertension (3 mg/kg Q2W, both Gr3). Enoticumab was characterized by nonlinear, target-mediated PK, and had a terminal half-life of 8 to 9 days. With multiple Q2W or Q3W dosing, accumulation was not observed. Antitumor activity included two partial responses (non–small cell lung cancer bronchoalveolar-type with a β-catenin mutation, and ovarian cancer) and 16 patients with stable disease (3> 6 months).

Conclusions: Enoticumab was tolerated, with RP2D of 4 mg/kg Q3W and 3 mg/kg Q2W based on PK profile and clinical activity. Responses and SD were noted in ovarian cancer and other solid tumors. Clin Cancer Res; 21(12); 2695–703. ©2015 AACR.
A Phase I/II Study of the mTOR Inhibitor Everolimus in Combination with HyperCVAD Chemotherapy in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia
Authors: Daver Naval , Boumber Yanis , Kantarjian Hagop , Ravandi Farhad , Cortes Jorge , Rytting Michael E. , Kawedia Jitesh D. , Basnett Jordan , Culotta Kirk S. , Zeng Zhihong , Lu Hongbo , Richie Mary Ann , Garris Rebecca , Xiao Lianchun , Liu Wenbin , Baggerly Keith A. , Jabbour Elias , O'Brien Susan , Burger Jan , Bendall Linda J. , Thomas Deborah , Konopleva Marina
Published: February 2015

Purpose: Previous studies suggest a potential therapeutic role for mTOR inhibition in lymphoid malignancies. This single-center phase I/II study was designed to test the safety and efficacy of the mTOR inhibitor everolimus in combination with HyperCVAD chemotherapy in relapsed/refractory acute lymphoblastic leukemia (ALL).

Experimental Design: Twenty-four patients were treated; 15 received everolimus 5 mg/day and 9 received 10 mg/day with HyperCVAD.

Results: The median age of patients was 25 years (range, 11–64) and median number of prior treatments was 2 (range, 1–7). Grade 3 mucositis was the dose-limiting toxicity and the maximum tolerated everolimus dose was 5 mg/day. Responses included complete remission (CR) in 6 patients (25%), CR without platelet recovery (CRp) in 1 (4%), and CR without recovery of counts (CRi) in 1 (4%), for an overall response rate of 33%. In addition, partial response (PR) was noted in 2 patients (8%). Seven of 11 patients treated in first salvage achieved CR/CRp (64%). The median OS was 29 weeks for patients in first salvage versus 15 weeks for patients in second salvage and beyond (P ≤ 0.001). A response was noted in 5 of 10 (50%) heavily pretreated T-ALL patients (median of 4 prior salvage regimens). Everolimus significantly inhibited phosphorylation of S6RP, but this did not correlate with response. No significant decreases in p4EBP1 and pAkt levels were noted. Responders had higher everolimus dose-adjusted area under the curve (P = 0.025) and lower clearance (P = 0.025) than nonresponders.

Conclusions: The combination of HyperCVAD and everolimus is well tolerated and moderately effective in relapsed ALL, specifically T-ALL. Clin Cancer Res; 21(12); 2704–14. ©2015 AACR.
Radiation Enhancement of Head and Neck Squamous Cell Carcinoma by the Dual PI3K/mTOR Inhibitor PF-05212384
Authors: Leiker Andrew J. , DeGraff William , Choudhuri Rajani , Sowers Anastasia L. , Thetford Angela , Cook John A. , Van Waes Carter , Mitchell James B.
Published: February 2015

Purpose: Radiation remains a mainstay for the treatment of nonmetastatic head and neck squamous cell carcinoma (HNSCC), a malignancy characterized by a high rate of PI3K/mTOR signaling axis activation. We investigated the ATP-competitive dual PI3K/mTOR inhibitor, PF-05212384, as a radiosensitizer in preclinical HNSCC models.

Experimental Design: Extent of radiation enhancement of two HNSCC cell lines (UMSCC1-wtP53 and UMSCC46-mtP53) and normal human fibroblast (1522) was assessed by in vitro clonogenic assay with appropriate target inhibition verified by immunoblotting. Radiation-induced DNA damage repair was evaluated by γH2AX Western blots with the mechanism of DNA double-strand break repair abrogation investigated by cell cycle analysis, immunoblotting, and RT-PCR. PF-05212384 efficacy in vivo was assessed by UMSCC1 xenograft tumor regrowth delay, xenograft lysate immunoblotting, and tissue section immunohistochemistry.

Results: PF-05212384 effectively inhibited PI3K and mTOR, resulting in significant radiosensitization of exponentially growing and plateau-phase cells with 24-hour treatment following irradiation, and variable radiation enhancement with 24-hour treatment before irradiation. Tumor cells radiosensitized to a greater extent than normal human fibroblasts. Postirradiation PF-05212384 treatment delays γH2AX foci resolution. PF-05212384 24-hour exposure resulted in an evident G1–S phase block in p53-competent cells. Fractionated radiation plus i.v. PF-05212384 synergistically delayed nude mice bearing UMSCC1 xenograft regrowth, with potential drug efficacy biomarkers identified, including pS6, pAkt, p4EBP1, and Ki67.

Conclusions: Taken together, our results of significant radiosensitization both in vitro and in vivo validate the PI3K/mTOR axis as a radiation modification target and PF-05212384 as a potential clinical radiation modifier of nonmetastatic HNSCC. Clin Cancer Res; 21(12); 2792–801. ©2015 AACR.
High Turnover of Tissue Factor Enables Efficient Intracellular Delivery of Antibody–Drug Conjugates
Authors: de Goeij Bart E.C.G. , Satijn David , Freitag Claudia M. , Wubbolts Richard , Bleeker Wim K. , Khasanov Alisher , Zhu Tong , Chen Gary , Miao David , van Berkel Patrick H.C. , Parren Paul W.H.I.
Published: February 2015

Antibody–drug conjugates (ADC) are emerging as powerful cancer treatments that combine antibody-mediated tumor targeting with the potent cytotoxic activity of toxins. We recently reported the development of a novel ADC that delivers the cytotoxic payload monomethyl auristatin E (MMAE) to tumor cells expressing tissue factor (TF). By carefully selecting a TF-specific antibody that interferes with TF:FVIIa-dependent intracellular signaling, but not with the procoagulant activity of TF, an ADC was developed (TF-011-MMAE/HuMax-TF-ADC) that efficiently kills tumor cells, with an acceptable toxicology profile. To gain more insight in the efficacy of TF-directed ADC treatment, we compared the internalization characteristics and intracellular routing of TF with the EGFR and HER2. Both in absence and presence of antibody, TF demonstrated more efficient internalization, lysosomal targeting, and degradation than EGFR and HER2. By conjugating TF, EGFR, and HER2-specific antibodies with duostatin-3, a toxin that induces potent cytotoxicity upon antibody-mediated internalization but lacks the ability to induce bystander killing, we were able to compare cytotoxicity of ADCs with different tumor specificities. TF-ADC demonstrated effective killing against tumor cell lines with variable levels of target expression. In xenograft models, TF-ADC was relatively potent in reducing tumor growth compared with EGFR- and HER2-ADCs. We hypothesize that the constant turnover of TF on tumor cells makes this protein specifically suitable for an ADC approach. Mol Cancer Ther; 14(5); 1130–40. ©2015 AACR.
Frequent Loss of NISCH Promotes Tumor Proliferation and Invasion in Ovarian Cancer via Inhibiting the FAK Signal Pathway
Authors: Li Jing , He Xiaoying , Dong Ruofan , Wang Yuan , Yu Jinjin , Qiu Haifeng
Published: February 2015

NISCH encodes the imidazoline receptor Nischarin and is a known tumor suppressor in many human malignancies; however, its roles in ovarian cancer are still largely unknown. Here, we aim to investigate the biologic functions of NISCH in ovarian cancer. We found that NISCH was significantly downregulated, which correlated considerably with advanced tumor stage, poor differentiation, lymph node metastasis, and the serous/mucinous subtypes in a panel of ovarian cancer tissues. Moreover, NISCH gene silencing was mainly the product of promoter hypermethylation, which could be reversed by treatment with 5-aza-dC. In vitro, NISCH overexpression suppressed cell proliferation and colony formation by hindering cell-cycle progression, whereas the opposite was observed in NISCH knockdown counterparts. In vivo, abundant NISCH expression hindered the growth of HO8910 xenografts, whereas NISCH knockdown accelerated the growth of SKOV3 xenografts. In addition, NISCH significantly attenuated cell invasion by inhibiting the phosphorylation of FAK and ERK, which could be neutralized by PF-562271 (a FAK/Pyk2 inhibitor). Accordingly, NISCH knockdown xenografts exhibited increased peritoneal/pelvic metastases that were not present in counterparts treated with PF-562271. Furthermore, NISCH expression in primary ovarian cancer cells predicted a cellular resistance to PF-562271. In conclusion, we showed that NISCH was frequently silenced by promoter hypermethylation in human ovarian cancer. NISCH manipulated cellular proliferation and invasion by arresting cell cycle and inhibiting the FAK signal. Our findings revealed the biologic functions of NISCH in ovarian cancer, and might be useful for treating patients with aberrant expression of NISCH. Mol Cancer Ther; 14(5); 1202–12. ©2015 AACR.
βIII-Tubulin Regulates Breast Cancer Metastases to the Brain
Authors: Kanojia Deepak , Morshed Ramin A. , Zhang Lingjiao , Miska Jason M. , Qiao Jian , Kim Julius W. , Pytel Peter , Balyasnikova Irina V. , Lesniak Maciej S. , Ahmed Atique U.
Published: February 2015

Brain metastases occur in about 10% to 30% of breast cancer patients, which culminates in a poor prognosis. It is, therefore, critical to understand the molecular mechanisms underlying brain metastatic processes to identify relevant targets. We hypothesized that breast cancer cells must express brain-associated markers that would enable their invasion and survival in the brain microenvironment. We assessed a panel of brain-predominant markers and found an elevation of several neuronal markers (βIII-tubulin, Nestin, and AchE) in brain metastatic breast cancer cells. Among these neuronal predominant markers, in silico analysis revealed overexpression of βIII-tubulin (TUBB3) in breast cancer brain metastases (BCBM) and its expression was significantly associated with distant metastases. TUBB3 knockdown studies were conducted in breast cancer models (MDA-Br, GLIM2, and MDA-MB-468), which revealed significant reduction in their invasive capabilities. MDA-Br cells with suppressed TUBB3 also demonstrated loss of key signaling molecules such as β3 integrin, pFAK, and pSrc in vitro. Furthermore, TUBB3 knockdown in a brain metastatic breast cancer cell line compromised its metastatic ability in vivo, and significantly improved survival in a brain metastasis model. These results implicate a critical role of TUBB3 in conferring brain metastatic potential to breast cancer cells. Mol Cancer Ther; 14(5); 1152–61. ©2015 AACR.
The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression
Authors: Rabender Christopher S. , Alam Asim , Sundaresan Gobalakrishnan , Cardnell Robert J. , Yakovlev Vasily A. , Mukhopadhyay Nitai D. , Graves Paul , Zweit Jamal , Mikkelsen Ross B.
Published: February 2015

Here, evidence suggests that nitric oxide synthases (NOS) of tumor cells, in contrast with normal tissues, synthesize predominantly superoxide and peroxynitrite. Based on high-performance liquid chromatography analysis, the underlying mechanism for this uncoupling is a reduced tetrahydrobiopterin:dihydrobiopterin ratio (BH4:BH2) found in breast, colorectal, epidermoid, and head and neck tumors compared with normal tissues. Increasing BH4:BH2 and reconstitution of coupled NOS activity in breast cancer cells with the BH4 salvage pathway precursor, sepiapterin, causes significant shifts in downstream signaling, including increased cGMP-dependent protein kinase (PKG) activity, decreased β-catenin expression, and TCF4 promoter activity, and reduced NF-κB promoter activity. Sepiapterin inhibited breast tumor cell growth in vitro and in vivo as measured by a clonogenic assay, Ki67 staining, and 2[18F]fluoro-2-deoxy-d-glucose–deoxyglucose positron emission tomography (FDG-PET). In summary, using diverse tumor types, it is demonstrated that the BH4:BH2 ratio is lower in tumor tissues and, as a consequence, NOS activity generates more peroxynitrite and superoxide anion than nitric oxide, resulting in important tumor growth–promoting and antiapoptotic signaling properties.

Implications: The synthetic BH4, Kuvan, is used to elevate BH4:BH2 in some phenylketonuria patients and to treat diseases associated with endothelial dysfunction, suggesting a novel, testable approach for correcting an abnormality of tumor metabolism to control tumor growth. Mol Cancer Res; 13(6); 1034–43. ©2015 AACR.
Clinicopathologic Features of IgA-Dominant Infection-Associated Glomerulonephritis: A Pooled Analysis of 78 Cases
Authors: Bu Ru , Li Qian , Duan Zhi-yu , Wu Jie , Chen Pu , Chen Xiang-mei , Cai Guang-yan
Published: March 2015

Backgrounds: IgA-dominant infection-associated glomerulonephritis (IgA-dominant IAGN) is a unique form of glomerulonephritis. There are numerous case reports in the literature. However, the risk factors, treatment approach, and outcomes of the disease are not clearly characterized. Methods: We completed a pooled analysis based on published literature. Clinical features, laboratory findings, and histopathological changes were analyzed. A logistic regression model was employed to identify the determinants of disease outcome, for example, end-stage renal disease (ESRD) or death. Results: Seventy-eight patients with IgA-dominant IAGN from 28 reports were analyzed. All of these patients showed granular IgA deposits predominantly along the glomerular peripheral capillary walls using immunofluorescence and majority showed subepithelial ‘hump-shaped' electron-dense deposits using electron microscopy. The majority of patients had hematuria (76/78), proteinuria (75/78), acute kidney injury (AKI) (66/78) and hypocomplementemia (43/75) without a previous history of renal disease. All of the patients had clinical infections at the time of presentation. Skin infections (19/78) and visceral abscesses (15/78) were frequently encountered, and staphylococcus was the most common pathogen. After treatment with antibiotics and/or supportive therapy, the renal function of 42 patients (54.5%) improved, 9 patients (11.7%) had persistent renal dysfunction, 15 patients (19.5%) progressed to ESRD, and 11 patients (14.3%) died. A multivariate regression analysis revealed that age (odds ratio [OR], 30.71; 95% confidence interval [CI], 2.53-373.07; p = 0.007) and diabetes mellitus (DM) (OR, 16.65; 95% CI, 1.18-235.84; p = 0.038) were independent risk factors for ESRD or death. Conclusions: IgA-dominant IAGN has unique clinicopathological manifestations and treatment responses. Age and DM are independent risk factors associated with an unfavorable prognosis for IgA-dominant IAGN.
American Heart Association's Life's Simple 7 and Risk of Venous Thromboembolism: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study
Authors: Olson Nels C. , Cushman Mary , Judd Suzanne E. , McClure Leslie A. , Lakoski Susan G. , Folsom Aaron R. , Safford Monika M. , Zakai Neil A.
Published: February 2015

Background

The American Heart Association's Life's Simple 7 metric is being used to track the population's cardiovascular health (
CVH
) toward a 2020 goal for improvement. The metric includes body mass index (
BMI
), blood pressure, cholesterol, glucose, physical activity (
PA
), cigarette smoking, and diet. We hypothesized a lower risk of venous thromboembolism (
VTE
) with favorable Life's Simple 7 scores.

Methods and Results

REGARDS
recruited 30 239 black and white participants ≥45 years of age across the United States in 2003–2007. A 14‐point summary score for Life's Simple 7 classified participants into inadequate (0 to 4 points), average (5 to 9 points), and optimal (10 to 14 points) categories. Hazard ratios (
HR
s) of incident
VTE
were calculated for these categories, adjusting for age, sex, race, income, education, and region of residence. For comparison,
HR
s of
VTE
were calculated using the Framingham 10‐year coronary risk score. There were 263 incident
VTE
cases over 5.0 years of follow‐up; incidence rates per 1000 person‐years declined from 2.9 (95% confidence interval [
CI
], 2.3 to 3.7) among those in the inadequate category to 1.8 (95%
CI
, 1.4 to 2.4) in the optimal category. Compared to the inadequate category, participants in the average category had a 38% lower
VTE
risk (95%
CI
, 11 to 57) and participants in the optimal category had a 44% lower risk (95%
CI
, 18 to 62). The individual score components related to lower
VTE
risk were ideal
PA
and
BMI
. There was no association of Framingham Score with
VTE
.

Conclusions

Life's Simple 7, a
CVH
metric, was associated with reduced
VTE
risk. Findings suggest that efforts to improve the population's
CVH
may reduce
VTE
incidence.
Bored to Death: Entertainment, Violence and a Sacramental Approach to Teaching Peace
Authors: Haitch Russell
Published: March 2015

This article focuses on the nexus of boredom and violence in the human spirit, and the nexus between the aim of peacemaking and the activity of Baptism and the Lord's Supper, in the relationality of human spirit to Holy Spirit. To elucidate the first nexus, I turn to Erich Fromm's classic study of aggression, and to elucidate the second I turn to both Orthodox and Anabaptist sacramental perspectives, which though different supplement each other.
Is Jesus my Superhero?
Authors: Stirrup Andy
Published: March 2015

This paper considers an implicit trend in youth ministry to present Jesus as the archetypal superhero and asks if this is a valid and a helpful approach. The paper examines the relationship between the biblical category of hero and the contemporary notion of superhero and a broader appreciation of the use of myth for communicating Christian apologetics as seen in Lewis and Tolkien. The starting point for the paper is that an arguable starting point for the creation of Superman is in the epic character of Hercules and the biblical hero Samson. Through an examination of biblical and other Near East material the paper calls for a deeper and more nuanced appreciation of the relevance of modern western myth in the task of communicating theological narratives and concepts.
A new species of Erythroxylum (Erythroxylaceae) from Colombia and emendation of Erythroxylum plowmanianum
Authors: Jara Orlando Adolfo
Published: March 2015

The description of Erythroxylum plowmanianum is emended, and the new species Erythroxylum cogolloi is described. Both species are endemics to the sub-montane forest of Colombia’s Middle Magdalena River Basin. Diagnostic characters are discussed, notes on distribution and illustration are provided for each species.
Tinnitus Holistic Simplified Classification (THoSC)
Authors: Cianfrone Giancarlo , Mazzei Filippo , Salviati Massimo , Turchetta Rosaria , Orlando Maria Patrizia , Testugini Valeria , Carchiolo Laura , Cianfrone Francesca , Altissimi Giancarlo
Published: February 2015

Objective:

One of the most debated topics in tinnitus is its standard and practical classification. The most popular classification distinguishes subjective from objective tinnitus. Other classifications are based on different features. On the whole, they seem incomplete, and the diagnostic and therapeutic algorithms are often difficult for practical purposes. The aim of this work is to develop a new diagnostic and therapeutic algorithm.

Methods:

Our model is based on 10 years of experience. In particular, the starting point is the data retrieved from 212 consecutive patients in our Tinnitus Unit between May and December 2013: We found a clear auditory disorder in 74.5% of the population, muscolo-skeletal disorders and/or trigeminal disease in 57.1%, and psychiatric comorbidities in 43.8%. Different features coexisted in 59.9% of the population.

Results:

Following such data we propose the Tinnitus Holistic Simplified Classification, which takes into account the different tinnitogenic mechanisms and the interactions between them. It differentiates tinnitus that arises from: (1) auditory alterations (Auditory Tinnitus), (2) complex auditory-somatosensory interactions (Somatosensory Tinnitus), (3) psychopathological-auditory interactions (Psychopathology-related Tinnitus), and (4) 2 or all of the previous mechanisms (Combined Tinnitus).

Conclusions:

In our opinion this classification provides an accurate and easy tailored path to manage tinnitus patients.
Salivary cortisol and cortisone responses to tetracosactrin (synacthen)
Authors: Cornes Michael P , Ashby Helen L , Khalid Yasmeen , Buch Harit N , Ford Clare , Gama Rousseau
Published: February 2015

Background

To establish cutoff values for salivary liquid chromatography tandem mass spectroscopy cortisol and cortisone in defining adequate adrenocortical function during a standard synacthen test.

Methods

We compared salivary liquid chromatography tandem mass spectroscopy cortisol and cortisone responses to those of serum cortisol measured on the Roche E170 immunoassay analyser and the Abbott Architect i2000 before and 30 min and 60 min following 0.25 mg of intravenous synacthen.

Results

Correlations of salivary cortisol and cortisone were bimodal and linear, respectively. Based on these correlations, adequate salivary cortisol and cortisone responses to synacthen were extrapolated from a serum cortisol (Roche) cut-off of 550 nmol/L and defined as 15 nmol/L and 45 nmol/L, respectively. The Abbott method correlated well with the Roche but gave results that were about 20% lower than the Roche method.

Conclusions

Measurement of salivary cortisol and cortisone responses offers an alternative to those of serum cortisol during a synacthen test in the investigation of adrenal hypofunction.
Pediatricians Transitioning Practices, Youth With Special Health Care Needs in New York State
Authors: Davidson Lynn F. , Chhabra Rosy , Cohen Hillel W. , Lechuga Claudia , Diaz Patricia , Racine Andrew
Published: February 2015

Objective. To assess current practices of New York State pediatricians as they transition youth with special health care needs to adult-oriented medical care. Methods. A survey of New York State pediatricians included 6 critical steps from 2002 consensus statement, 11 essential steps adapted from recent literature, and questions targeting age of starting transition and availability of transition policy. Results. Of 181 respondents, only 11% have a transition policy. Most assist patients in transition process; identify an adult provider (92%); and create portable medical summary (57%). Only 3% start planning process at recommended age. No respondents are compliant with all 6 critical steps; subspecialists were more likely to report compliance to more than 4 steps. Conclusions. Participating pediatricians are making gains, yet effort is needed, to incorporate the essential steps into practice for transitioning youth with special health care needs. Recognition of barriers, use of electronic tools, and clarifying subspecialist’s approach, may improve compliance with transition recommendations.
The Association Between Psychopathic Personality Traits and Criminal Justice Outcomes: Results From a Nationally Representative Sample of Males and Females
Authors: Beaver Kevin M. , Boutwell Brian B. , Barnes J. C. , Vaughn Michael G. , DeLisi Matt
Published: March 2015

There has been a great deal of research revealing that psychopathy is related to criminal involvement and other measures of antisocial behavior. However, the generalizability of these findings is limited because of some potential problems with measurement and because of the overreliance on forensic samples and the relative lack of psychopathy measures in national samples. The current study addresses these gaps in the existing psychopathy literature by examining the association between a Five-Factor Model–based measure of psychopathic personality traits and criminal justice outcomes in a nationally representative sample of males and females. Analysis of data drawn from the National Longitudinal Study of Adolescent to Adult Health (Add Health) revealed that psychopathic personality traits predicted the probability of being arrested, of being incarcerated, and of being sentenced to probation for both males and females. Additional analyses revealed that the psychopathic personality traits scale was also associated with a self-reported delinquency scale. We concluded by discussing the importance of the concept of psychopathy and psychopathic personality traits to criminological theory and research.
Promotion of Dental Pulp Cell Migration and Pulp Repair by a Bioceramic Putty Involving FGFR-mediated Signaling Pathways
Authors: Zhang J. , Zhu L.X. , Cheng X. , Lin Y. , Yan P. , Peng B.
Published: February 2015

Mineral trioxide aggregate is the currently recommended material of choice for clinical pulp repair despite several disadvantages, including handling inconvenience. Little is known about the signaling mechanisms involved in bioceramic-mediated dental pulp repair—particularly, dental pulp cell (DPC) migration. This study evaluated the effects of iRoot BP Plus, a novel ready-to-use nanoparticulate bioceramic putty, on DPC migration in vitro and pulp repair in vivo, focusing on possible involvement of fibroblast growth factor receptor (FGFR)–related signaling, including mitogen-activated protein kinase and Akt pathways. Treatment with iRoot BP Plus extracts enhanced horizontal and vertical migration of DPCs, which was comparable with the effects induced by mineral trioxide aggregate extracts. The DPCs exposed to iRoot BP Plus extracts demonstrated no evident apoptosis. Importantly, treatment with iRoot BP Plus extracts resulted in rapid activation of FGFR, p38 mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK) 1/2, c-Jun-N-terminal kinase (JNK), and Akt signaling in DPCs. Confocal immunofluorescence staining revealed that iRoot BP Plus stimulated focal adhesion formation and stress fiber assembly in DPCs, in addition to upregulating the expression of focal adhesion molecules, including p–focal adhesion kinase, p-paxillin, and vinculin. Moreover, activation of FGFR, ERK, JNK, and Akt were found to mediate the upregulated expression of focal adhesion molecules, stress fiber assembly, and enhanced DPC migration induced by iRoot BP Plus. Consistent with the in vitro results, we observed induction of homogeneous dentin bridge formation and expression of p–focal adhesion kinase, p-FGFR, p-ERK 1/2, p-JNK, and p-Akt near injury sites by iRoot BP Plus in an in vivo pulp repair model. These data demonstrate that iRoot BP Plus can promote DPC migration and pulp repair involving the FGFR-mediated ERK 1/2, JNK, and Akt pathways. These findings provide valuable insights into the signaling mechanisms underlying nanoparticulate bioceramic-mediated pulp repair.
Women, work and industrial relations in Australia in 2014
Authors: Charlesworth Sara , Macdonald Fiona
Published: February 2015

This paper provides a review of Australian policy and regulatory developments in 2014 that influence the working conditions of over 5.4 million women. After an assessment of progress against key gender equality indicators, we focus on two key components of the current gender equality ‘architecture’: employment regulation and policy and the work and care infrastructure that supports working women and gender equality more broadly. We review key developments in regulation providing minimum labour standards and anti-discrimination protections for women workers. We then turn to recent developments in the work and care infrastructure, including childcare, paid parental leave and equal pay. Despite having better regulatory and institutional arrangements than exist in some other developed economies, we conclude that without an explicit national gender equality policy framework, progress towards decent work for Australian working women is likely to be incremental at best.
Employer and employer association matters in Australia in 2014
Authors: Sheldon Peter , Thornthwaite Louise
Published: February 2015

This article examines the industrial relations issues at the forefront of employer and employer association attention in Australia in 2014. We examine their ambitions for legislative change and frustrations with parliamentary gridlock, as well as their engagement in the four-year Modern Award Review, the annual Minimum Wage Review, and policy discussion on 457 Visas. As well, we look at the involvement of employers and their associations in several positive social policy agendas, and developments in the employer association world during the year. As 2014 draws to a close without their long-sought modifications to the Fair Work system, the public policy rhetoric of employers and their associations is shifting once again towards the advocacy of larger-scale industrial relations change.
The Australian labour market in 2014: Still ill?
Authors: Healy Joshua
Published: February 2015

The Australian labour market remained in a subdued state during 2014. Participation and employment rates fell, while unemployment and underemployment rates rose. Of the limited employment growth that did occur, most was in the part-time workforce and concentrated on prime-aged and older workers. After exhibiting serious weakness in 2013, the youth labour market deteriorated further in 2014. A rise in job vacancies was a sign of possible improvement, but employers’ confidence has not yet recovered to nearly the extent necessary to end the labour market slowdown of recent years.
Developments in the Practice of Forensic Medicine
Authors: Simpson Keith
Published: February 2015

The world-famous pathologist reviews progress and the present state of forensic medicine in England and Wales.
The Responsibilities of Rank in the Police Service
Authors: Smith C. R.
Published: February 2015

We congratulate Inspector Smith on winning The Queen's Gold Medal Essay Competition for 1969 with the following essay. Mr Smith was a student on the Special Course at the Police College in 1967 and is at present in his third year as a Bramshill Scholar at the University of Birmingham.
French Police Training
Authors: Ingleton R.
Published: February 2015

Chief Inspector Ingleton is the officer in charge of Folkestone Sub-Division of the Kent Constabulary. As a result of his being so near to the coast and the fact that he is French-speaking he has been given certain responsibilities for liaison with the French and Belgian Police. He has been on several official visits to France, particularly in the Pas de Calais area and recently made, at the invitation of the Directeur des Ecoles et Techniques in Paris, a short study tour of police training establishments in France.