Παρασκευή 13 Μαΐου 2016

Addition of Rice Bran Arabinoxylan to Curcumin Therapy May Be of Benefit to Patients With Early-Stage B-Cell Lymphoid Malignancies (Monoclonal Gammopathy of Undetermined Significance, Smoldering Multiple Myeloma, or Stage 0/1 Chronic Lymphocytic Leukemia): A Preliminary Clinical Study

Hypothesis. Prior studies on patients with early B-cell lymphoid malignancies suggest that early intervention with curcumin may lead to delay in progressive disease and prolonged survival. These patients are characterized by increased susceptibility to infections. Rice bran arabinoxylan (Ribraxx) has been shown to have immunostimulatory, anti-inflammatory, and proapoptotic effects. We postulated that addition of Ribraxx to curcumin therapy may be of benefit. Study design. Monoclonal gammopathy of undetermined significance (MGUS)/smoldering multiple myeloma (SMM) or stage 0/1 chronic lymphocytic leukemia (CLL) patients who had been on oral curcumin therapy for a period of 6 months or more were administered both curcumin (as Curcuforte) and Ribraxx. Methods. Ten MGUS/SMM patients and 10 patients with stage 0/1 CLL were administered 6 g of curcumin and 2 g Ribraxx daily. Blood samples were collected at baseline and at 2-month intervals for a period of 6 months, and various markers were monitored. MGUS/SMM patients included full blood count (FBC); paraprotein; free light chains/ratio; C-reactive protein (CRP)and erythrocyte sedimentation rate (ESR); B2 microglobulin and immunological markers. Markers monitored for stage 0/1 CLL were FBC, CRP and ESR, and immunological markers. Results. Of 10 MGUS/SMM patients,5 (50%) were neutropenic at baseline, and the Curcuforte/Ribraxx combination therapy showed an increased neutrophil count, varying between 10% and 90% among 8 of the 10 (80%) MGUS/SMM patients. An additional benefit of the combination therapy was the potent effect in reducing the raised ESR in 4 (44%) of the MGUS/SMM patients. Conclusion. Addition of Ribraxx to curcumin therapy may be of benefit to patients with early-stage B-cell lymphoid malignancies.



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Antihepatocellular Carcinoma Potential of Tetramethylpyrazine Induces Cell Cycle Modulation and Mitochondrial-Dependent Apoptosis: Regulation of p53 Signaling Pathway in HepG2 Cells In Vitro

Tetramethylpyrazine (TMP) was originally isolated from a traditional Chinese herbal medicine, Ligusticum chuanxiong. In the present study, TMP exhibits potent antitumor activities in vitro. However, the molecular mechanisms remain to be defined. Hence, this study aims to investigate the antiproliferative and apoptotic effects of TMP on HepG2 and elucidate the underlying mechanisms. Analyses using Cell Counting Kit-8 and real-time cell analyzer indicated that TMP significantly inhibited HepG2 cell proliferation. We also observed that TMP induced cell cycle arrest at the G0/G1 checkpoint and apoptosis, using flow cytometry and high-content screening. Furthermore, our results predicted that TMP could directly decrease mitochondrial membrane potential (m), increase the release of cytochrome c, and increase caspase activation, indicating that mitochondrial pathway apoptosis could be the mechanism for TMP within HepG2 cells. Moreover, TMP altered expression of p53 and the Bcl-2/Bax protein ratio, which revealed that TMP induced cell cycle arrest and caspase-dependent mitochondrial apoptosis in HepG2 cells in vitro. These studies provided mechanistic insights into the antitumor properties of TMP, which may be explored as a potential option for treatment of hepatocellular carcinoma.



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TUSC3 suppresses glioblastoma development by inhibiting Akt signaling

Abstract

Glioblastoma multiform is one of the most common and most aggressive brain tumors in humans. The molecular and cellular mechanisms responsible for the onset and progression of GBM are elusive and controversial. The function of tumor suppressor candidate 3 (TUSC3) has not been previously characterized in GBM. TUSC3 was originally identified as part of an enzyme complex involved in N-glycosylation of proteins, but was recently implicated as a potential tumor suppressor gene in a variety of cancer types. In this study, we demonstrated that the expression levels of TUSC3 were downregulated in both GBM tissues and cells, and also found that overexpression of TUSC3 inhibits GBM cell proliferation and invasion. In addition, the effects of increased levels of methylation on the TUSC3 promoter were responsible for decreased expression of TUSC3 in GBM. Finally, we determined that TUSC3 regulates proliferation and invasion of GBM cells by inhibiting the activity of the Akt signaling pathway.



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Fertility preservation in children, adolescents, and young adults with cancer: Quality of clinical practice guidelines and variations in recommendations

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BACKGROUND

Fertility preservation care for children, adolescents, and young adults (CAYAs) with cancer is not uniform among practitioners. To ensure high-quality care, evidence-based clinical practice guidelines (CPGs) are essential. The authors identified existing CPGs for fertility preservation in CAYAs with cancer, evaluated their quality, and explored differences in recommendations.

METHODS

A systematic search in PubMed (January 2000-October 2014); guideline databases; and Web sites of oncology, pediatric, and fertility organizations was performed. Two reviewers evaluated the quality of the identified CPGs using the Appraisal of Guidelines for Research and Evaluation II Instrument (AGREE II). From high-quality CPGs, the authors evaluated concordant and discordant areas among the recommendations.

RESULTS

A total of 25 CPGs regarding fertility preservation were identified. The average AGREE II domain scores (scale of 0%-100%) varied from 15% on applicability to 100% on clarity of presentation. The authors considered 8 CPGs (32%) to be of high quality, which was defined as scores ≥60% in any 4 domains. Large variations in the recommendations of the high-quality CPGs were observed, with 87.2% and 88.6%, respectively, of discordant guideline areas among the fertility preservation recommendations for female and male patients with cancer.

CONCLUSIONS

Only approximately one-third of the identified CPGs were found to be of sufficient quality. Of these CPGs, the fertility preservation recommendations varied substantially, which can be a reflection of inadequate evidence for specific recommendations, thereby hindering the ability of providers to deliver high-quality care. CPGs including a transparent decision process for fertility preservation can help health care providers to deliver optimal and uniform care, thus improving the quality of life of CAYAs with cancer and cancer survivors. Cancer 2016. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.



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Patient-Derived Prostate Cancer: from Basic Science to the Clinic

Abstract

Systems that model cancer form the backbone of research discovery, and their accuracy and validity are a key determinant to ensure successful translation. In many tumour types, patient-derived specimens are an important model of choice for pre-clinical drug development. In this review, we consider why this has been such a challenge for prostate cancer, resulting in relatively few patient-derived xenografts (PDXs) of prostatic tumours compared to breast cancers, for example. Nevertheless, with only a few patient specimens and PDXs, we exemplify in three vignettes how important new clinical insights were obtained resulting in benefit for future men with prostate cancer.



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Survival in patients with acute myeloblastic leukemia in Germany and the United States: Major differences in survival in young adults

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Abstract

Previous epidemiologic studies on AML have been limited by the rarity of the disease. Here, we present population level data on survival of patients with AML in Germany and the United States (US). Data were extracted from 11 population-based cancer registries in Germany and the Surveillance, Epidemiology, and End Results (SEER13) database in the US. Patients diagnosed with AML in 1997-2011 were included. Period analysis was used to estimate 5-year relative survival (RS) and trends in survival in the early 21st century. Overall 5-year age-adjusted RS for patients with AML in 2007-11 was greater in Germany than in the US at 22.8% and 18.8%, respectively. Five-year RS was higher in Germany than in the US at all ages, with particularly large differences at ages 15-24 for whom 5-year RS was 64.3% in Germany and 55.0% in the US and 35-44, with 5-year RS estimates of 61.8% in Germany and 46.6% in the US. Most of the difference in 5-year RS was due to higher 1-year RS, with overall 1-year RS estimates of 47.0% in Germany and 38.5% in the US. A small increase in RS was observed between 2003-05 and 2009-11 in both countries, but no increase in survival was observed in either country for ages 75+. To our knowledge, this is the first detailed description of AML survival in Germany. Comparison to the US suggests that further analysis into risk factors for poor outcomes in AML in the US may be useful in improving survival. This article is protected by copyright. All rights reserved.



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Impact of immunosuppression and region of birth on risk of cervical intraepithelial neoplasia among migrants living with HIV in Sweden

Abstract

Little is known about the incidence and risk of cervical intraepithelial neoplasia (CIN) grade 3, adenocarcinoma in situ and invasive cervical cancer (CIN3+) among migrants living with HIV in a European setting. We assessed the cumulative incidence (CuI) and hazard ratio (HR) of CIN2+ and CIN3+ in a cohort of women living with HIV (WLWH) (n= 893) identified from the Swedish national HIV register and HIV-negative women (n= 205 842) identified from the Swedish Population Register, matched on region of birth and age. Data was collected between 1993 and 2011 by linking our cohort with the Swedish National Cervical Screening Registry (NKCx), collecting all cytological and histological results since 1993.

The CuI of CIN3+ was 13.1% (95% CI 8.9-17.2) for WLWH and 2.1% (95% CI 2.0-2.2) for HIV-negative after 18 years of follow up. WLWH had more than eight times higher, age and region of birth matched, risk of CIN3+ than HIV-negative (HR 8.8: 95% CI 6.9-11.3). WLWH born in the East region, dominated by Thai women, had a two times higher risk of CIN3+ compared with WLWH born in Sweden (HR 2.47: 95% CI 1.2-5.0), which remained after adjusting for immunosuppression. Our results showed a substantially increased risk of CIN3+ among WLWH, which differed depending on birth region. Early HIV-diagnosis and attendance to cervical cancer screening, with focus on migrants, is of crucial importance to minimize the incidence of cervical intraepithelial neoplasia. This article is protected by copyright. All rights reserved.



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Prospective cohort study of general and central obesity, weight change trajectory, and risk of major cancers among Chinese women

Abstract

General obesity, typically measured using body mass index (BMI), has been associated with an increased risk of several cancers. However, few prospective studies have been conducted in Asian populations. Although central obesity, often measured using waist-hip ratio (WHR), is more predictive for type 2 diabetes and cardiovascular diseases (CVD) risk than BMI, knowledge of its association with cancer incidence is limited. In a cohort of 68, 253 eligible Chinese women, we prospectively investigated the association of BMI, WHR, and weight change during adulthood with risk of overall cancer and major site-specific cancers using multivariate Cox proportional hazard models. Compared to the BMI group of 18.5-22.9 kg/m2, obese (BMI≥30 kg/m2) women were at an increased risk of developing overall cancer (hazard ratio = 1.36, 95% confidence interval = 1.21-1.52), postmenopausal breast cancer (HR: 2.43, 95% CI: 1.73-3.40), endometrial cancer (HR: 5.34, 95% CI: 3.48-8.18), liver cancer (HR: 1.93, 95% CI: 1.14-3.27), and epithelial ovarian cancer (HR: 2.44, 95% CI: 1.37-4.35). Weight gain during adulthood (per 5 kg gain) was associated with increased risk of all cancers combined (HR: 1.05, 95% CI: 1.03-1.08), postmenopausal breast cancer (HR: 1.17, 95% CI: 1.10-1.24), and endometrial cancer (HR: 1.37, 95% CI: 1.27-1.48). On the other hand, WHR was not associated with cancer risk after adjustment for baseline BMI. These findings suggest that obesity may be associated with cancer risk through different mechanisms from those for type 2 diabetes and CVD and support measures of maintaining health body weight to reduce cancer risk in Chinese women. This article is protected by copyright. All rights reserved.



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Impact of statin use on cancer recurrence and mortality in breast cancer: A systematic review and meta-analysis

Abstract

Statins have shown antineoplastic properties in preclinical studies with breast cancer cells. They inhibit the enzyme 'HMG CoA reductase' and the expression of this enzyme in cancer cells has been implicated as a favorable prognostic factor in patients with breast cancer. After a search of MEDLINE and Embase from inception through November 2015, 817 abstracts were reviewed to identify studies that described an association between statin use and outcomes in breast cancer. A total of 14 studies which included 75,684 women were identified. In a meta-analysis of 10 studies, statin use was associated with improved recurrence-free survival (RFS) (HR 0.64; 95% CI 0.53- 0.79, I2= 44%). Furthermore, this RFS benefit appeared to be confined to use of lipophilic statins (HR 0.72; 95% CI 0.59- 0.89) as hydrophilic statin use was not associated with improvement in RFS (HR 0.80; 95% CI 0.44- 1.46). Statin users similarly showed improved overall survival in a meta-analysis with substantial heterogeneity (8 studies, HR 0.66; 95% CI 0.44-0.99, I2= 89%). Statin users also had improved cancer-specific survival, although this relationship was measured with less precision (6 studies, HR 0.70; 95% CI 0.46- 1.06, I2= 86%). In conclusion, breast cancer patients who use statins, or specifically, lipophilic statins show improved recurrence-free survival. Statin users also had improved overall survival and cancer-specific survival. These findings should be assessed in a prospective randomized cohort and the choice of statin, dose and biomarkers that may predict the efficacy of these drugs should be identified. This article is protected by copyright. All rights reserved.



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Timing of breast cancer surgery, menstrual phase, and prognosis: Systematic review and meta-analysis

Publication date: June 2016
Source:Critical Reviews in Oncology/Hematology, Volume 102
Author(s): Hillary Klonoff-Cohen, Ruopeng An, Theodora Fries, Jennifer Le, Georg E. Matt
BackgroundFor over 25 years, there has been a debate revolving around the timing of breast cancer surgery, menstrual cycle, and prognosis.MethodsThis systematic review synthesizes and evaluates the body of evidence in an effort to inform evidence-based practice. A keyword and reference search was performed in PubMed and Web of Science to identify human studies that met the inclusion criteria. A total of 58 studies (48 international and 10 U.S.-based) were identified. We provided a narrative summary on study findings and conducted a meta-analysis on a subset of studies where quantitative information was available.ResultsFindings from both qualitative and quantitative analyses were inconclusive regarding performing breast cancer surgery around a specific phase of the menstrual cycle.ConclusionBased on the Institute of Medicine criteria, evidence is insufficient to recommend a change in current primary breast cancer surgery practice based on menstrual phase.



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Editorial Board

Publication date: June 2016
Source:Critical Reviews in Oncology/Hematology, Volume 102





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The Third Italian Consensus Conference for Malignant Pleural Mesothelioma: State of the art and recommendations

Publication date: Available online 13 May 2016
Source:Critical Reviews in Oncology/Hematology
Author(s): S. Novello, C. Pinto, V. Torri, L. Porcu, M. Di Maio, G. Ceresoli, C. Magnani, S. Silvestri, A. Veltri, M. Papotti, G. Rossi, U. Ricardi, L. Trodella, F. Rea, F. Facciolo, A. Granieri, V. Zagonel, G. Scagliotti
Malignant pleural mesothelioma (MPM) remains a relevant public health issue, and asbestos exposure is the most relevant risk factor. The incidence has considerably and constantly increased over the past two decades in the industrialized countries and is expected to peak in 2020-2025. In Italy, a standardized-rate incidence in 2011 among men was 3.5 and 1.25 per 100,000 in men and women, respectively, and wide differences are noted among different geographic areas. The disease remains challenging in terms of diagnosis, staging and treatment and an optimal strategy has not yet been clearly defined. The Third Italian Multidisciplinary Consensus Conference on Malignant Pleural Mesothelioma was held in Bari (Italy) in January 30-31, 2015. This Consensus has provided updated recommendations on the MPM management for health institutions, clinicians and patients.



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Cancer Mortality Progress Report: Past Success and Future Challenges

ACS 2015 Challenge Goal Progress Chart

By American Cancer Society Chief Medical Officer Otis W. Brawley, MD, FACP and Chief Cancer Control Officer Richard Wender, MD

As leaders of the American Cancer Society, one of our jobs is to look at the big picture; to step back from our day-to-day work and review our nation's collective progress toward ending the cancer problem.

Analyzing the cancer landscape allows us to figure out what's working and what isn't — and to determine what else can be done. Back in the mid-1990s, the American Cancer Society Board of Directors took a hard look at the state of cancer in the United States. Based on what they learned, they challenged the U.S. to cut the cancer mortality rate in half by the year 2015.1 They made the start year 1990.

They knew from the outset that achieving the goal would require the combined efforts of many sectors, and not any one organization.

Today, we are reporting on the nation's progress toward achieving that goal. Here's what we have all accomplished together: The cancer death rate declined 26% over the 25-year period of 1990 to 2015. Though the goal of a 50% reduction was only one-half achieved, we believe this progress should be viewed as a glass half full.

Let's break down this number. From 1990 to 2015, the age-adjusted cancer death rate declined by:

  • 32% among men
  • 22% among women
  • 39% for breast cancer
  • 44% for colorectal cancer among women
  • 47% for colorectal cancer among men
  • 45% for lung cancer among men
  • 53% for prostate cancer among men

These findings and more are published early online today in the American Cancer Society journal, CA: A Cancer Journal for Clinicians.

What these numbers tell us is that while the goal of a 50% decrease in cancer mortality overall was not met, more progress is possible given our current state of medical knowledge. Let us explain.

Speeding up progress in cancers already seeing declines in death rates

Progress is especially possible in cancers for which there is prevention, screening, diagnosis and treatment that we know works. The problem is a large number of Americans do not have access to state-of-the-art care, including preventive services. More cancer deaths could have been prevented by getting adequate high-quality care to more Americans. More lives can be saved in the future by getting adequate high-quality care to more Americans.

Breast Cancer: For example, the 39% decrease in breast cancer death rates was achieved nationally. The successes in breast cancer were due to improvements in screening, awareness, diagnosis and treatment. However, previous American Cancer Society studies showed that there is dramatic variation in breast cancer death rates by state. Death rates declined in 36 states and the District of Columbia, but did not decline in 14 states.3 These 14 states are mainly located in the south and west. There is evidence to show the lack of decline was due to differences in the quality of mammography screening, diagnosis and treatment.

Colorectal Cancer: Similar findings have been documented for colorectal cancer. Effective screening, diagnosis and treatment have led to the significant decline in the colorectal cancer death rate. But the fact that Massachusetts and New York can have a greater than 40% decline over 25 years and Mississippi had no decline means we can do better.4

Lung Cancer: The 45% drop in lung cancer deaths among men is due to the decline in tobacco use. Tobacco has been linked to at least 16 different cancers. Tobacco control efforts led to the steep drop in smoking rates in the U.S. These declines in tobacco use drove much, if the not most, of the 26% decline in deaths from all cancers.

Prostate Cancer: As we have shown, oftentimes we know why we are seeing progress against certain cancers. But sometimes the picture isn't so clear. For example, clinicians and researchers continue to study why the prostate cancer death rate is declining. Increases in early detection and improvements in treatment, as well as other factors, have played a role. We go into this in great detail in the full report. We encourage you to read it if you want to know more.

Focusing on cancers with increasing death rates

While death rates have gone down for a number of cancers and especially for the very common cancers, there are some cancers for which death rates have remained stable or increased. For example:

  • Liver cancer death rates in the past 25 years have nearly doubled from 3.6 to 6.5 per 100,000.
  • There has been a small increase in pancreatic cancer death rates from 10.6 per 100,000 to 11 per 100,000 over the past 25 years.
  • And there has been an increase in uterine cancer deaths from 4.3 to 4.6 per 100,000 over the same time period.

Let's take a look at liver cancer. The death rate for liver cancer increased by about 60% from 1990 to 2015 — a greater increase than for any other cancer type. The two reasons for this increase are both preventable. The biggest cause is chronic hepatitis C infection among "baby boomers" (Americans born between 1945 and 1965). While it is recommended that everyone born in that era get screened for hepatitis C, most of the population hasn't been tested. So partly we have an awareness problem. The other issue is the need for a lower cost drug to treat the infection.

Turning around the obesity epidemic will also be key to stopping the increase in liver cancer deaths — and addressing the nation's weight problem will impact other cancers as well.

Making more discoveries to better understand and treat cancer

While better applying what we already know is a big piece of the puzzle, we still need more options — new discoveries, especially in areas where we have not seen much progress. Sometimes, to make the biggest discoveries, we have to go back to basics. We need to support basic research — learning more about why cancer forms and how it spreads. We also need more clinical research in cancer to get better treatment options to patients.

Of course, to do all of this — and do it as fast as possible — funding is necessary. Right now, only about 10% of all of the good cancer research ideas out there are being funded. Major efforts like the vice president's "cancer moonshot" program in combination with other large-scale investments from all corners of the country hold great promise. And we here at the American Cancer Society remain deeply committed to funding cancer research.

Bottom line

The full report reviews what we can do to better control cancer. Many Americans do not get state-of-the-art care, from screening to diagnosis. Fixing that requires new changes in our systems of providing care, not new science.

While we all support and see a need for more scientific research aimed at finding new and better treatments for cancer, it is both an irony and a shame that so many Americans do not enjoy the fruits of completed research. From 1991 through 2015, more than one million cancer deaths were averted in men and more than 500,000 were averted in women. We've proven that dramatic progress is possible.

We have the opportunity and the moral obligation to do everything possible to speed up progress, to ensure that everyone has a chance to benefit from interventions proven to work and to redouble efforts to find new interventions to prevent and treat all cancers.

Working closely with all segments of society, the American Cancer Society can fuel progress to achieve a greater reduction in our nation's cancer burden.



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CD44 variant-dependent redox status regulation in liver fluke-associated cholangiocarcinoma: a target for CCA treatment

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Summary

CD44 expression, especially the variant isoforms (CD44v) of this major cancer stem cell (CSC) marker, contributes to reactive oxygen species (ROS) defense via stabilizing xCT (a cystine-glutamate transporter) and promoting glutathione (GSH) synthesis. This enhances cancer development and increases chemotherapy resistance. We investigate the role of CD44v in the regulation of the ROS defense system in cholangiocarcinoma (CCA). Immunohistochemical staining of CD44v and p38MAPK (a major ROS target) expression in Opisthorchis viverrini (Ov)-induced hamster CCA tissues (at 60, 90, 120, 180 days) reveals a decreased phospho-p38MAPK signal, whereas the CD44v signal was increased during bile duct transformation. CCA patients showed CD44v overexpression and negative-phospho-p38MAPK patients a significantly shorter survival rate than the low CD44v signal and positive-phospho-p38MAPK patients (p=0. 030). Knockdown of CD44 showed that xCT and GSH levels were decreased, leading to a high level of ROS. We examined xCT-targeted CD44v-CSCs therapy using sulfasalazine (SSZ). Glutathione decreased and ROS increased after the treatment, leading to inhibition of cell proliferation and induction of cell death. Thus, the accumulation of CD44v leads to the suppression of p38MAPK in transforming bile duct cells. The redox status regulation of CCA cells depends on the expression of CD44v to contribute the xCT function and is a link to the poor prognosis of patients. Thus, an xCT inhibitor could inhibit cell growth and activate cell death. This suggests that an xCT-targeting drug may improve CCA therapy by sensitization to the available drug, e.g. gemcitabine, by blocking the mechanism of the cell's ROS defensive system.

This article is protected by copyright. All rights reserved.



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Hematological reference values for stray colony cats of northern Italy

Abstract

In additional to significant dietary, lifestyle and hormonal differences, stray cats may have different hematological parameters from pet cats. The objectives of this study are to determine hematological reference intervals (RIs) from a large population of stray cats in northern Italy, to establish whether published RIs for the general pet feline population are valid in stray cats and to evaluate the effects of age and sex on hematological parameters. Hematological data were analyzed retrospectively from the database of a trap-neuter-release program (performed in 2008–2010 in northern Italy) to generate normal RIs. RIs were determined and compared with established pet cat RIs according to the National Committee for Clinical Laboratory Standard guidelines and the American Society of Veterinary Clinical Pathology guidelines. Data from 90 healthy stray cats from 17 colonies were available for determination of hematological RIs. Based on the results of comparison with published feline RIs, new RIs were proposed for RBC count, Hct, MCV, MCHC, and WBC count in stray cats. Male cats had a statistically significant higher value than did females for RBC count (mean RBC count in females 6.5 × 1012 versus 7.4 × 1012/L in males, P = 0.001), Hb (mean Hb concentration in females 9.9 versus 10.9 g/dL in males, P = 0.004), and Hct (mean Hct in females 24.8 versus 28.2 % in males, P = 0.001). Significant differences in five hematological parameters were found between stray and pet cats, for most of which the most plausible explanation is probably anesthetic effect and infections or parasitism. It can therefore be assumed that there is no need to establish a specific RI for most of the CBC variables in stray cats.



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Disability and all-cause mortality in the older population: evidence from the English Longitudinal Study of Ageing

Abstract

Despite the vast body of literature studying disability and mortality, evidence to support their association is scarce. This work investigates the role of disability in explaining all‐cause mortality among individuals aged 50+ who participated in the English Longitudinal Study of Aging. The aim is to explain the gender paradox in health and mortality by analysing whether the association of disability with mortality differs between women and men. Disability was conceived following the International Classification of Functioning, Disability and Health (ICF), proposed by the WHO, that conceptualizes disability as a combination of three components: impairment, activity limitation and participation restriction. Latent variable models were used to identify domain-specific factors and general disability. The association of the latter with mortality up to 10 years after enrolment was estimated using discrete-time survival analysis. Our work confirms the validity of the ICF framework and finds that disability is strongly associated with mortality, with a time-varying effect among men, and a smaller constant effect for women. Adjusting for demographic, socioeconomic and behavioural factors attenuated the association for both sexes, but overall the effects remained high and significant. These findings confirm the existence of gender paradox by showing that, when affected by disability, women survive longer than men, although if men survive the first years they appear to become more resilient to disability. Sensitivity analyses suggested that the gender paradox cannot be solely explained by gender-specific health conditions: there must be other mechanisms acting within the pathway between disability and mortality that need to be explored.



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The association between attention-deficit/hyperactivity (ADHD) symptoms and self-employment

Abstract

Attention-deficit/hyperactivity (ADHD) symptoms have been associated with the decision to become self-employed. Although these symptoms are generally regarded as disadvantageous, there may also be a bright side. To our knowledge, however, there has been no systematic, epidemiological evidence to support this claim. This paper examines the association between ADHD symptoms and self-employment in a population-based sample from the STAGE cohort of the Swedish Twin Registry (N = 7208). For replication, we used a sample of Dutch students who participated in the Global University Entrepreneurial Spirit Students' Survey (N = 13,112). In the Swedish sample, we found a positive association with self-employment for both general ADHD symptoms [odds ratio (OR) 1.13; 95 % confidence intervals (CI) 1.04–1.23] and hyperactivity symptoms [OR 1.19; 95 % CI 1.08–1.32], whereas no association was found for attention-deficit symptoms [OR 0.99; 95 % CI 0.89–1.10]. The positive association between hyperactivity and self-employment was replicated in the Dutch student sample [OR 1.09; 95 % CI 1.03–1.15]. Our results show that certain aspects of ADHD, in particular hyperactivity, can have a bright side, as they are positively associated with self-employment.



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The effects of bevacizumab on intestinal anastomotic healing in rabbits

Abstract

Purposes

The aim of this study was to investigate the effects of the preoperative administration of BV on the healing process of intestinal anastomosis in a rabbit model.

Methods

Twenty male white rabbits were randomly divided into two groups. The control group received saline 1 week before surgery, and the BV group received intravenous BV 1 week before surgery. Each rabbit underwent an enteroenterostomy and a colocolostomy. On postoperative day 7, the bursting pressures of the anastomoses, CD31 and α-smooth muscle actin (α-SMA) staining by immunohistochemistry, the gene expression of α-SMA, and collagen deposition using Picrosirius Red at the site of anastomosis were evaluated.

Results

The bursting pressure of small bowel anastomoses was significantly lower in the BV group than in the control group (control 184 ± 10 mmHg vs. BV 140 ± 9 mmHg; p = 0.004). The microvessel counts in the anastomotic tissue were significantly lower in the BV group than in the control group in both the small bowel (p = 0.023) and colon (p = 0.008). The expression of α-SMA, and the degree of collagen deposition decreased in the anastomotic tissue in the BV group compared with the control group.

Conclusion

The preoperative use of BV may therefore negatively affect the rigidity of intestinal anastomosis.



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Understanding the role of tariquidar, a potent Pgp inhibitor, in combination trials with cytotoxic drugs: What is missing?



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δ- and γ-tocopherols inhibit phIP/DSS-induced colon carcinogenesis by protection against early cellular and DNA damages

Tocopherols, the major forms of vitamin E, are a family of fat-soluble compounds that exist in alpha (α-T), beta (β-T), gamma (γ-T), and delta (δ-T) variants. A cancer preventive effect of vitamin E is suggested by epidemiological studies. However, past animal studies and human intervention trials with α-T, the most active vitamin E form, have yielded disappointing results. A possible explanation is that the cancer preventive activity of α-T is weak compared to other tocopherol forms. In the present study, we investigated the effects of δ-T, γ-T, and α-T (0.2% in diet) in a novel colon cancer model induced by the meat-derived dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and promoted by dextran sodium sulfate (DSS)-induced colitis in CYP1A-humanized (hCYP1A) mice. PhIP/DSS treatments induced multiple polypoid tumors, mainly tubular adenocarcinomas, in the middle to distal colon of the hCYP1A mice after 10 wk. Dietary supplementation with δ-T and γ-T significantly reduced colon tumor formation and suppressed markers of oxidative and nitrosative stress (i.e., 8-oxo-dG and nitrotyrosine) as well as pro-inflammatory mediators (i.e., NF-κB p65 and p-STAT3) in tumors and adjacent tissues. By administering δ-T at different time periods, we obtained results suggesting that the inhibitory effect of δ-T against colon carcinogenesis is mainly due to protection against early cellular and DNA damages caused by PhIP. α-T was found to be ineffective in inhibiting colon tumors and less effective in attenuating the molecular changes. Altogether, we demonstrated strong cancer preventive effects of δ-T and γ-T in a physiologically relevant model of human colon cancer. © 2016 Wiley Periodicals, Inc.



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Modification of p27 with O-linked N-acetylglucosamine regulates cell proliferation in hepatocellular carcinoma

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The tumor suppressor p27, which is a member of the Cip/Kip family of Cyclin-dependent kinase inhibitory proteins (CKIs), controls anti-proliferative events. The post-translational addition of O-GlcNAc to p27 occurs in HEK293T and HCC (hepatocellular carcinoma) cell lines, and we identified Ser2, Ser106, Ser110, Thr157, and Thr198 as the glycosylation sites of p27 based on the Q-TOF spectrum. Here, immunoprecipitation analysis showed that Ser2 was O-GlcNAcylated and that this modification was associated with the increased phosphorylation of p27 at Ser10, ultimately resulting in p27 accumulation in the cytoplasm and increased p27 ubiquitination. In addition, O-GlcNAcylation at Ser2 suppressed Cyclin/CDK complex-p27 interactions by promoting the nuclear export of p27, thus facilitating cell cycle progression. Cell proliferation was negatively regulated when Ser2 of p27 was replaced with Ala. Furthermore, western blot and immunohistochemical analyses of HCC tissues and their corresponding nontumorous tissues were performed, and we found that O-GlcNAcylated p27 correlated with cell proliferation in HCC. Together, our results indicate that the dynamic interplay between O-GlcNAcylation and p27 phosphorylation coordinates and regulates cell proliferation in hepatocellular carcinoma. © 2016 Wiley Periodicals, Inc.



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Exploring Big Data in Hematological Malignancies: Challenges and Opportunities

Abstract

Secondary analysis of large datasets has become a useful alternative to address research questions outside the reach of clinical trials. It is increasingly utilized in hematology and oncology. In this review, we provided an overview of some examples of commonly used large datasets in the USA and described common research themes that can be pursued using such a methodology. We selected a sample of 14 articles on adult hematologic malignancies published in 2015 and highlighted their contributions as well as limitations.



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Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in patients receiving carboplatin-based chemotherapy

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BACKGROUND

Rolapitant, a novel neurokinin-1 receptor antagonist, provided effective protection against chemotherapy-induced nausea and vomiting (CINV) in a randomized, double-blind phase 3 trial of patients receiving moderately emetogenic chemotherapy or an anthracycline and cyclophosphamide regimen. The current analysis explored the efficacy and safety of rolapitant in preventing CINV in a subgroup of patients receiving carboplatin.

METHODS

Patients were randomized 1:1 to receive oral rolapitant (180 mg) or a placebo 1 to 2 hours before chemotherapy administration; all patients received oral granisetron (2 mg) on days 1 to 3 and oral dexamethasone (20 mg) on day 1. A post hoc analysis examined the subgroup of patients receiving carboplatin in cycle 1. The efficacy endpoints were as follows: complete response (CR), no emesis, no nausea, no significant nausea, complete protection, time to first emesis or use of rescue medication, and no impact on daily life.

RESULTS

In the subgroup administered carboplatin-based chemotherapy (n = 401), a significantly higher proportion of patients in the rolapitant group versus the control group achieved a CR in the overall phase (0-120 hours; 80.2% vs 64.6%; P < .001) and in the delayed phase (>24-120 hours; 82.3% vs 65.6%; P < .001) after chemotherapy administration. Superior responses were also observed by the measures of no emesis, no nausea, and complete protection in the overall and delayed phases and by the time to first emesis or use of rescue medication. The incidence of treatment-emergent adverse events was similar for the rolapitant and control groups.

CONCLUSIONS

Rolapitant provided superior CINV protection to patients receiving carboplatin-based chemotherapy in comparison with the control. These results support rolapitant use as part of the antiemetic regimen in carboplatin-treated patients. Cancer 2016. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.



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FLIP L is critical for aerobic glycolysis in hepatocellular carcinoma

Abstract

Background

Tumor cells use aerobic glycolysis to rapidly generate ATP and growth substrate which expenses a large amount of glucose. However, how tumor cells take in enough glucose from the tumor microenvironment of insufficient blood supply remains poorly understood. The cellular FLICE-like inhibitory protein (FLIP), a cell apoptosis inhibiting molecule, is highly expressed in hepatocellular carcinoma (HCC) and is implicated in HCC development.

Methods

The effects of FLIPL (the long form of FLIP) on aerobic glycolysis and glucose uptake were assessed in HCC cells and xenograft tumors. The correlations between FLIPL expression and sodium/glucose cotransporter 1 (SGLT1) expression in clinical HCC tissues were analyzed. The consequences of FLIPL-induced regulation of SGLT1 at the transcription and translation levels and the interaction between FLIPL and SGLT1 were examined. FLIPL-mediated tolerance upon glucose limitation and its mechanism were detected.

Results

We report a novel role for FLIPL in promoting the aerobic glycolysis of HCC cells. FLIPL overexpression induced a significant increase in cell aerobic glycolysis indexes including glucose uptake, glucose consumption, and lactate production. FLIPL co-localized and interacted with SGLT1, a major active glucose transporter in HCC cells. FLIPL increased the stability of SGLT1 protein by inhibiting its ubiquitination and degradation. The expression level of FLIPL was positively correlated with the expression level of SGLT1 in 79 HCC tissues from surgical operation. Furthermore, FLIPL increased cell tolerance ability and decreased cell apoptosis to low glucose by regulating SGLT1.

Conclusions

Our results indicate that FLIPL plays an essential role in HCC aerobic glycolysis and that SGLT1 is required for FLIPL-modulated tumor proliferation under low glucose conditions. Targeting the actions of FLIPL in cell glucose-dependent aerobic glycolysis may provide an attractive strategy for therapeutic intervention in HCC.



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Olfactomedin 4 expression and functions in innate immunity, inflammation, and cancer

Abstract

Olfactomedin 4 (OLFM4) is an olfactomedin domain-containing glycoprotein. Multiple signaling pathways and factors, including NF-κB, Wnt, Notch, PU.1, retinoic acids, estrogen receptor, and miR-486, regulate its expression. OLFM4 interacts with several other proteins, such as gene associated with retinoic-interferon-induced mortality 19 (GRIM-19), cadherins, lectins, nucleotide oligomerization domain-1 (NOD1) and nucleotide oligomerization domain-2 (NOD2), and cathepsins C and D, known to regulate important cellular functions. Recent investigations using Olfm4-deficient mouse models have provided important clues about its in vivo biological functions. Olfm4 inhibited Helicobacter pylori-induced NF-κB pathway activity and inflammation and facilitated H. pylori colonization in the mouse stomach. Olfm4-deficient mice exhibited enhanced immunity against Escherichia coli and Staphylococcus aureus infection. Olfm4 deletion in a chronic granulomatous disease mouse model rescued them from S. aureus infection. Olfm4 deletion in mice treated with azoxymethane/dextran sodium sulfate led to robust intestinal inflammation and intestinal crypt hyperplasia. Olfm4 deletion in Apc Min/+ mice promoted intestinal polyp formation as well as adenocarcinoma development in the distal colon. Further, Olfm4-deficient mice spontaneously developed prostatic epithelial lesions as they age. OLFM4 expression is correlated with cancer differentiation, stage, metastasis, and prognosis in a variety of cancers, suggesting its potential clinical value as an early-stage cancer marker or a therapeutic target. Collectively, these data suggest that OLFM4 plays important roles in innate immunity against bacterial infection, gastrointestinal inflammation, and cancer. In this review, we have summarized OLFM4's initial characterization, expression, regulation, protein interactions, and biological functions.



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Quercetin blocks t-AUCB-induced autophagy by Hsp27 and Atg7 inhibition in glioblastoma cells in vitro

Abstract

We previously demonstrated that the acquired resistance because of Hsp27 activation weakens the cytotoxic effect of t-AUCB on glioblastoma cells. Since autophagy is regarded as a survival mechanism for cells exposed to cytotoxic agents, the aim of this study is to investigate whether t-AUCB induces autophagy and whether Hsp27 and autophagy are interacted with each other. Our data demonstrated that t-AUCB induces autophagy in glioblastoma cells and regulates multiple autophagy related-gene expression. t-AUCB induces overexpression of Atg7, which is downstream of Hsp27 and participates in the resistance of glioblastoma cells to t-AUCB treatment. Hsp27 inhibitor quercetin suppresses Atg7 expression and strengthens t-AUCB-induced cell death by autophagy blockage. We concluded that combination of quercetin and t-AUCB might be a potential strategy for glioblastoma treatment.



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Genetic Polymorphism of SUMO-Specific Cysteine Proteases − SENP1 and SENP2 in Breast Cancer

Abstract

SENP proteases take part in post-translational modification of proteins known as sumoylation. They catalyze three distinct processes during sumoylation: processing of SUMO protein, deconjugation of SUMO from the target protein, and chain editing which mentions to the dismantling of SUMO chain. Many proteins that are involved in the basic processes of cells, such as regulation of transcription, DNA repair or cell cycle control, are sumoylated. The aim of these studies was to investigate an association between polymorphic variants (SNPs) of the SENP1 gene (c.1691 + 36C > T, rs12297820) and SENP2 gene (c.902C > A, p.Thr301Lys, rs6762208) and a risk of breast cancer occurrence. We performed a case-control study in 324 breast cancer cases and 335 controls using PCR-RLFP. In the case of the SENP1 gene polymorphism we did not find any association between this polymorphism and breast cancer risk. In the case of SENP2 gene polymorphism we observed higher risk of breast cancer for carriers of the A allele (OR =1.33; 95 % CI 1.04–1.69). Our analysis also showed the genotype C/C (OR =0.67, 95 % CI 0.48–0.93) and the allele C (OR =0.75, 95 % CI 0.59–0.69) of this polymorphism decrease a risk of breast cancer. We also checked the distribution of genotypes and frequency of alleles of the SENP1 and SENP2 genes polymorphisms in groups of patients with different hormone receptor status, patients with positive and negative lymph node status and patients with different tumor grade. Odds ratio analysis showed a higher risk of metastases in women with the genotype C/C (OR =2.07, 95 % CI 1.06–4.05) and allele C (OR =2.10 95 % CI 1.10–4.01) of the c.1691 + 36C > T SENP1 gene polymorphism. Moreover, we observed reduced risk in women with the allele T (OR =0.48, 95 % CI 0.25–0.91) in this polymorphic site. In the case of SENP2 gene polymorphism we observed that the A/A genotype correlated with the lack of estrogen receptor (OR =1.94, 95 % CI 1.04–3.62). Our results suggest that the variability of the SENP1 and SENP2 genes may play a role in breast cancer occurrence. Further studies are needed to clarify their biological functions in breast cancer.



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Enhanced immunity in a mouse model of malignant glioma is mediated by a therapeutic ketogenic diet

Abstract

Background

Glioblastoma multiforme is a highly aggressive brain tumor with a poor prognosis, and advances in treatment have led to only marginal increases in overall survival. We and others have shown previously that the therapeutic ketogenic diet (KD) prolongs survival in mouse models of glioma, explained by both direct tumor growth inhibition and suppression of pro-inflammatory microenvironment conditions. The aim of this study is to assess the effects of the KD on the glioma reactive immune response.

Methods

The GL261-Luc2 intracranial mouse model of glioma was used to investigate the effects of the KD on the tumor-specific immune response. Tumor-infiltrating CD8+ T cells, CD4+ T cells and natural killer (NK) cells were analyzed by flow cytometry. The expression of immune inhibitory receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) on CD8+ T cells were also analyzed by flow cytometry. Analysis of intracellular cytokine production was used to determine production of IFN, IL-2 and IFN- in tumor-infiltrating CD8+ T and natural killer (NK) cells and IL-10 production by T regulatory cells.

Results

We demonstrate that mice fed the KD had increased tumor-reactive innate and adaptive immune responses, including increased cytokine production and cytolysis via tumor-reactive CD8+ T cells. Additionally, we saw that mice maintained on the KD had increased CD4 infiltration, while T regulatory cell numbers stayed consistent. Lastly, mice fed the KD had a significant reduction in immune inhibitory receptor expression as well as decreased inhibitory ligand expression on glioma cells.

Conclusions

The KD may work in part as an immune adjuvant, boosting tumor-reactive immune responses in the microenvironment by alleviating immune suppression. This evidence suggests that the KD increases tumor-reactive immune responses, and may have implications in combinational treatment approaches.



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Heme oxygenase is not involved in the anti-proliferative effects of statins on pancreatic cancer cells

Abstract

Background

Pancreatic cancer is recognized as one of the most fatal tumors due to its aggressiveness and resistance to therapy. Statins were previously shown to inhibit the proliferation of cancer cells via various signaling pathways. In healthy tissues, statins activate the heme oxygenase pathway, nevertheless the role of heme oxygenase in pancreatic cancer is still controversial. The aim of this study was to evaluate, whether anti-proliferative effects of statins in pancreatic cancer cells are mediated via the heme oxygenase pathway.

Methods

In vitro effects of various statins and hemin, a heme oxygenase inducer, on cell proliferation were evaluated in PA-TU-8902, MiaPaCa-2 and BxPC-3 human pancreatic cancer cell lines. The effect of statins on heme oxygenase activity was assessed and heme oxygenase-silenced cells were used for pancreatic cancer cell proliferation studies. Cell death rate and reactive oxygen species production were measured in PA-TU-8902 cells, followed by evaluation of the effect of cerivastatin on GFP-K-Ras trafficking and expression of markers of invasiveness, osteopontin (SPP1) and SOX2.

Results

While simvastatin and cerivastatin displayed major anti-proliferative properties in all cell lines tested, pravastatin did not affect the cell growth at all. Strong anti-proliferative effect was observed also for hemin. Co-treatment of cerivastatin and hemin increased anti-proliferative potential of these agents, via increased production of reactive oxygen species and cell death compared to individual treatment. Heme oxygenase silencing did not prevent pancreatic cancer cells from the tumor-suppressive effect of cerivastatin or hemin. Cerivastatin, but not pravastatin, protected Ras protein from trafficking to the cell membrane and significantly reduced expressions of SPP1 (p < 0.05) and SOX2 (p < 0.01).

Conclusions

Anti-proliferative effects of statins and hemin on human pancreatic cancer cell lines do not seem to be related to the heme oxygenase pathway. While hemin triggers reactive oxygen species-induced cell death, cerivastatin targets Ras protein trafficking and affects markers of invasiveness.



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Nuclear grade based on transbronchial cytology is an independent prognostic factor in patients with advanced, unresectable non-small cell lung cancer

BACKGROUND

In patients with resected non-small cell lung cancer (NSCLC), the prognostic value of nuclear grade has been demonstrated. However, among patients with advanced, unresectable NSCLC, the prognostic usefulness of cytological nuclear grade to the authors' knowledge remains unknown. In the current study, the authors used transbronchial cytology to investigate whether nuclear morphometry correlated with clinical outcomes in patients with advanced NSCLC.

METHODS

The authors reviewed patients with advanced, unresectable NSCLC who were diagnosed on transbronchial cytology and were treated at the study institution from 2007 through 2015 (97 patients). Nuclear morphometry (including major diameter) was assessed by an image analysis system and small lymphocytes were used as a reference. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, and multivariate analyses were performed using the Cox proportional hazards regression model.

RESULTS

In the multivariate analysis, according to the nuclear major diameter as assessed by an image analysis system, a nuclear major diameter >15 μm was an independent prognostic factor of worse OS (hazard ratio [HR], 1.05; P = .003) and PFS (HR, 1.04; P = 0.011). According to the nuclear major diameter as assessed by small lymphocytes, a major diameter of >5 small lymphocytes was an independent prognostic factor of worse OS (HR, 1.32; P<.001) and PFS (HR, 1.20; P = 0.001). A moderately significant correlation between nuclear diameter measurements by an image analysis system and small lymphocytes was observed (P<.001; correlation coefficient, 0.662).

CONCLUSIONS

Nuclear grade based on nuclear diameter was found to be independently associated with prognosis in patients with advanced, unresectable NSCLC. Cancer Cytopathol 2016. © 2016 American Cancer Society.



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Quantitative phase imaging to improve the diagnostic accuracy of urine cytology

BACKGROUND

A definitive diagnosis of urothelial carcinoma in urine cytology is often challenging and subjective. Many urine cytology samples receive an indeterminate diagnosis. Ancillary techniques such as fluorescence in situ hybridization (FISH) have been used to improve the diagnostic sensitivity, but FISH is not approved as a routine screening test, and the complex fluorescent staining protocol also limits its widespread clinical use. Quantitative phase imaging (QPI) is an emerging technology allowing accurate measurements of the single-cell dry mass. This study was undertaken to explore the ability of QPI to improve the diagnostic accuracy of urine cytology for malignancy.

METHODS

QPI was performed on unstained, ThinPrep-prepared urine cytology slides from 28 patients with 4 categories of cytological diagnoses (negative, atypical, suspicious, and positive for malignancy). The nuclear/cell dry mass, the entropy, and the nucleus-to-cell mass ratio were calculated for several hundred cells for each patient, and they were then correlated with the follow-up diagnoses.

RESULTS

The nuclear mass and nuclear mass entropy of urothelial cells showed significant differences between negative and positive groups. These data showed a progressive increase from patients with negative diagnosis, to patients with atypical/suspicious and positive cytologic diagnosis. Most importantly, among the patients in the atypical and suspicious diagnosis, the nuclear mass and its entropy were significantly higher for those patients with a follow-up diagnosis of malignancy than those patients without a subsequent follow-up diagnosis of malignancy.

CONCLUSIONS

QPI shows potential for improving the diagnostic accuracy of urine cytology, especially for indeterminate cases, and should be further evaluated as an ancillary test for urine cytology. Cancer Cytopathol 2016. © 2016 American Cancer Society.



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The value of a transformation zone component in anal cytology to detect HSIL

BACKGROUND

In a cytology-based screening program intended to prevent anal cancer, the anal transformation zone (TZ) should be adequately sampled because it is the site most susceptible to the development of the cancer precursor, high-grade squamous intraepithelial lesion (HSIL). An adequate TZ component is defined as comprising at least 10 rectal columnar or squamous metaplastic cells. In the current study, the authors examined whether the presence of a TZ component in anal cytology correlated with the detection of histological HSIL.

METHODS

In a natural history study of anal human papillomavirus infection in homosexual men, all participants underwent liquid-based cytology and high-resolution anoscopy (HRA) with or without biopsy at each visit. True-negative cytology (negative cytology with non-HSIL biopsy or negative HRA), false-negative cytology (negative cytology with HSIL biopsy), and true-positive cytology (abnormal cytology with HSIL biopsy) were compared with regard to the presence or absence of a TZ component.

RESULTS

Of 617 participants, baseline results included 155 true-positive results, 191 true-negative results, and 31 false-negative results. The absence of an adequate TZ component was found to be significantly higher for false-negative (32.3%) than for either true-positive (11.0%; P = .0034) or true-negative (13.1%; P = .0089) results.

CONCLUSIONS

Significantly more false-negative cases lacked a TZ component compared with either true-positive or true-negative cases. TZ cells may be an important indicator of sample quality for anal cytology because, unlike cervical sampling, the anal canal is not visualized during cytology sampling. Cancer Cytopathol 2016. © 2016 American Cancer Society.



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2016 publication schedule



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Merchants of mayhem



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Issue Information



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Small non-coding RNA biomarkers in sputum for lung cancer diagnosis

Abstract

The early detection of lung cancer can reduce the mortality. However, there is no effective means in clinical settings for noninvasively detecting lung cancer. We previously developed 3 sputum miRNA biomarkers and 2 sputum small nucleolar RNA (snoRNA) biomarkers that can potentially be used for noninvasively diagnosing lung cancer. Here we evaluate the individual and combined applications of the two types of biomarkers in different sets of lung cancer patients and controls. Combined analysis of the miRNAs and snoRNAs has a synergistic effect with 89 % sensitivity and 89 % specificity, and may provide a useful tool for lung cancer early detection.



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Issue Information — UICC



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Issue Information — Information for Authors



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Issue Information — Table of Contents



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Reconstruction with double pedicel fibular graft and ankle arthrodesis for aggressive chondroblastoma in the distal tibia

Abstract

Background

Aggressive chondroblastoma of the distal tibia is rare, and below-knee amputation had been the standard surgical procedure.

Case presentation

We reported an additional case and reviewed the existing literature. A 20-year-old man with a 2-month history of right ankle pain and swelling underwent distal tibia wide resection, double pedicle fibular, autogenous iliac bone graft, and ankle arthrodesis. He had no pain, no limitation in daily activities, and no evidence of local recurrence and infection; the Musculoskeletal Tumour Society Score (MSTS) is 86 % at the final follow-up.

Conclusions

Double pedicel fibular graft and ankle arthrodesis may be an effective and economical alternative method for aggressive chondroblastoma in the distal tibia.



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A Pathway Through the Bundle Jungle [Editorial]



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Fractionation spares mice from radiation-induced reductions in weight gain but does not prevent late oligodendrocyte lineage side effects

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Publication date: Available online 12 May 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Sage Begolly, Peter G. Shrager, John A. Olschowka, Jacqueline P. Williams, M. Kerry O'Banion
PurposeTo determine the late effects of fractionated versus single dose cranial radiation on murine white matter.Methods and MaterialsMice were exposed to 0 Gy, 6x6 Gy, or 1x20 Gy cranial irradiation at 10-12 weeks of age. Endpoints were assessed through 18 months from exposure using immunohistochemistry, electron microscopy, and electrophysiology.ResultsWeight gain was temporarily reduced after irradiation; greater loss was seen after single versus fractionated doses. Oligodendrocyte progenitor cells were reduced early and late after both single and fractionated irradiation. Both protocols also increased myelin g-ratio, reduced the number of nodes of Ranvier, and promoted a shift in the proportion of small, unmyelinated versus large, myelinated axon fibers.ConclusionsFractionation does not adequately spare normal white matter from late radiation side effects.

Teaser

Although fractionation reduced cranial radiation-related effects on weight gain, patterns of early and late oligodendrocyte progenitor cell depletion and late white matter pathology and dysfunction were similar following both single and fractionated irradiation. This indicates that fractionation fails to reduce late white matter side effects of radiation in adult mice.


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Geographic disparity in the use of hypofractionated radiotherapy among elderly women undergoing breast conservation for invasive breast cancer

Publication date: Available online 12 May 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Erin F. Gillespie, Rayna K. Matsuno, Beibei Xu, Daniel P. Triplett, Lindsay Hwang, Isabel J. Boero, John P. Einck, Catheryn Yashar, James D. Murphy
PurposeResearch demonstrates that the use of short-course (hypofractionated) radiotherapy (RT) breast cancer in the US has lagged behind other countries, despite evidence from randomized trials. This study evaluates geographic heterogeneity in the delivery of hypofractionated radiotherapy among Medicare beneficiaries across the US.MethodsWe identified 190,193 patients from the Centers for Medicare and Medicaid Services (CMS) Chronic Conditions Warehouse. The study included patients over age 65 diagnosed with invasive breast cancer treated with breast conservation surgery followed by radiation diagnosed between 2000 and 2012. We analyzed data by hospital referral region based on patient residency zip code. The proportion of women who received hypofractionated RT within each region was analyzed over the study period. Multivariable logistic regression models identified predictors of hypofractionated RT.ResultsOver the entire study period we found substantial geographic heterogeneity in the use of hypofractionated radiotherapy. The proportion of women receiving hypofractionated breast RT in individual hospital referral regions varied from 0% to 61%. We found no correlation between the use of hypofractionated RT and urban/rural setting or general geographic region. The proportion of hypofractionated RT increased in regions with higher density of radiation oncologists, as well as lower total Medicare reimbursements.ConclusionsThis study demonstrates substantial geographic heterogeneity in the use of hypofractionated radiotherapy among elderly women with invasive breast cancer treated with lumpectomy in the US. This heterogeneity persists despite clinical data from multiple randomized trials proving efficacy and safety compared to standard fractionation, and highlights possible inefficiency in healthcare delivery.

Teaser

Among 190,193 women age 65 and older undergoing breast conservation for invasive breast cancer in the United States from 2000-2012, the proportion of women receiving hypofractionated radiotherapy (3-4 weeks) varied from 0% to 61%. In the setting of strong data from randomized clinical trials showing efficacy and safety compared to conventionally fractionated breast radiotherapy (5-7 weeks), the slow uptake of hypofractionated breast radiotherapy coupled with geographic heterogeneity suggests inefficiency in our health care system.


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Heterogeneity in Tumors and Resistance to EGFR TKI Therapy—Letter



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5hmC at CGIs Predicts Promoter Hypermethylation in HCC

Aberrant hypermethylation of CpG islands (CGI) in human tumors occurs predominantly at repressed genes in the host tissue, but the preceding events driving this phenomenon are poorly understood. In this study, we temporally tracked epigenetic and transcriptomic perturbations that occur in a mouse model of liver carcinogenesis. Hypermethylated CGI events in the model were predicted by enrichment of the DNA modification 5-hydroxymethylcytosine (5hmC) and the histone H3 modification H3K27me3 at silenced promoters in the host tissue. During cancer progression, selected CGIs underwent hypo-hydroxymethylation prior to hypermethylation, while retaining H3K27me3. In livers from mice deficient in Tet1, a tumor suppressor involved in cytosine demethylation, we observed a similar loss of promoter core 5hmC, suggesting that reduced Tet1 activity at CGI may contribute to epigenetic dysregulation during hepatocarcinogenesis. Consistent with this possibility, mouse liver tumors exhibited reduced Tet1 protein levels. Similar to humans, DNA methylation changes at CGI in mice did not appear to be direct drivers of hepatocellular carcinoma progression, rather, dynamic changes in H3K27me3 promoter deposition correlated strongly with tumor-specific activation and repression of transcription. Overall, our results suggest that loss of promoter-associated 5hmC in liver tumors licenses reprograming of DNA methylation at silent CGI during progression. Cancer Res; 76(10); 3097–108. ©2016 AACR.

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Heterogeneity in Tumors and Resistance to EGFR TKI Therapy—Response



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Radiation-Induced Translational Control of Gene Expression

Changes in polysome-bound mRNA (translatome) are correlated closely with changes in the proteome in cells. Therefore, to better understand the processes mediating the response of glioblastoma to ionizing radiation (IR), we used polysome profiling to define the IR-induced translatomes of a set of human glioblastoma stem-like cell (GSC) lines. Although cell line specificity accounted for the largest proportion of genes within each translatome, there were also genes that were common to the GSC lines. In particular, analyses of the IR-induced common translatome identified components of the DNA damage response, consistent with a role for the translational control of gene expression in cellular radioresponse. Moreover, translatome analyses suggested that IR enhanced cap-dependent translation processes, an effect corroborated by the finding of increased eIF4F–cap complex formation detected after irradiation in all GSC lines. Translatome analyses also predicted that Golgi function was affected by IR. Accordingly, Golgi dispersal was detected after irradiation of each of the GSC lines. In addition to the common responses seen, translatome analyses predicted cell line–specific changes in mitochondria, as substantiated by changes in mitochondrial mass and DNA content. Together, these results suggest that analysis of radiation-induced translatomes can provide new molecular insights concerning the radiation response of cancer cells. More specifically, they suggest that the translational control of gene expression may provide a source of molecular targets for glioblastoma radiosensitization. Cancer Res; 76(10); 3078–87. ©2016 AACR.

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HDACs and Homologous Recombination in Melanoma

DNA-damaging anticancer drugs remain a part of metastatic melanoma therapy. Epigenetic reprogramming caused by increased histone deacetylase (HDAC) activity arising during tumor formation may contribute to resistance of melanomas to the alkylating drugs temozolomide, dacarbazine, and fotemustine. Here, we report on the impact of class I HDACs on the response of malignant melanoma cells treated with alkylating agents. The data show that malignant melanomas in situ contain a high level of HDAC1/2 and malignant melanoma cells overexpress HDAC1/2/3 compared with noncancer cells. Furthermore, pharmacologic inhibition of class I HDACs sensitizes malignant melanoma cells to apoptosis following exposure to alkylating agents, while not affecting primary melanocytes. Inhibition of HDAC1/2/3 caused sensitization of melanoma cells to temozolomide in vitro and in melanoma xenografts in vivo. HDAC1/2/3 inhibition resulted in suppression of DNA double-strand break (DSB) repair by homologous recombination because of downregulation of RAD51 and FANCD2. This sensitized cells to the cytotoxic DNA lesion O6-methylguanine and caused a synthetic lethal interaction with the PARP-1 inhibitor olaparib. Furthermore, knockdown experiments identified HDAC2 as being responsible for the regulation of RAD51. The influence of class I HDACs on DSB repair by homologous recombination and the possible clinical implication on malignant melanoma therapy with temozolomide and other alkylating drugs suggests a combination approach where class I HDAC inhibitors such as valproic acid or MS-275 (entinostat) appear to counteract HDAC- and RAD51/FANCD2-mediated melanoma cell resistance. Cancer Res; 76(10); 3067–77. ©2016 AACR.

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Genetic Nrf2 Activation in Chemical Lung Carcinogenesis

Nrf2 activation promotes resistance to chemical carcinogenesis in animal models, but activating mutations in Nrf2 also confer malignant characters to human cells by activating antioxidative/detoxifying enzymes and metabolic reprogramming. In this study, we examined how these contradictory activities of Nrf2, cancer chemoprevention and cancer cell growth enhancement, can be reconciled in an established mouse model of urethane-induced lung carcinogenesis. Using Keap1-knockdown (kd) mice, which express high levels of Nrf2, we found that urethane was rapidly excreted into the urine, consistent with an upregulation in the expression of urethane detoxification genes. Consequently, urethane-induced tumors were significantly smaller and less frequent in Keap1-kd mice than in wild-type mice. In contrast, tumor cells derived from Keap1-kd mice and transplanted into nude mice exhibited higher tumorigenicity compared with cells derived from wild-type mice. To identify the factors contributing to the tumor growth phenotype in the transplantation model, we performed a microarray analysis and found that many antioxidative stress genes were upregulated in the Keap1-kd–derived tumors. Therefore, we suggest that Nrf2 activation in cancer cells enhances their tumorigenicity, but global Nrf2 activation, as in Keap1-kd mice, simultaneously enhances anticancer immunity, thereby suppressing the growth potential of Keap1-kd tumors. Our findings provide relevant insight into the dual role of Nrf2 in cancer and warrant further studies of Nrf2 function during different stages of carcinogenesis. Cancer Res; 76(10); 3088–96. ©2016 AACR.

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CD73 and Radiation-Induced Lung Fibrosis

Radiation-induced pulmonary fibrosis is a severe side effect of thoracic irradiation, but its pathogenesis remains poorly understood and no effective treatment is available. In this study, we investigated the role of the extracellular adenosine as generated by the ecto-5′-nucleotidase CD73 in fibrosis development after thoracic irradiation. Exposure of wild-type C57BL/6 mice to a single dose (15 Gray) of whole thorax irradiation triggered a progressive increase in CD73 activity in the lung between 3 and 30 weeks postirradiation. In parallel, adenosine levels in bronchoalveolar lavage fluid (BALF) were increased by approximately 3-fold. Histologic evidence of lung fibrosis was observed by 25 weeks after irradiation. Conversely, CD73-deficient mice failed to accumulate adenosine in BALF and exhibited significantly less radiation-induced lung fibrosis (P < 0.010). Furthermore, treatment of wild-type mice with pegylated adenosine deaminase or CD73 antibodies also significantly reduced radiation-induced lung fibrosis. Taken together, our findings demonstrate that CD73 potentiates radiation-induced lung fibrosis, suggesting that existing pharmacologic strategies for modulating adenosine may be effective in limiting lung toxicities associated with the treatment of thoracic malignancies. Cancer Res; 76(10); 3045–56. ©2016 AACR.

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