Donor-Derived T-Cell Large Granular Lymphocytic Leukemia in a Patient With Peripheral T-Cell Lymphoma

T-cell large granular lymphocytic (T-LGL) leukemia after hematopoietic stem cell transplantation (SCT) is rare and its natural history and clinical outcome have not been well described. We report the clinical, morphologic, immunophenotypic, and molecular features of a case of donor-derived T-LGL leukemia in a 16-year-old man who received allogeneic SCT for peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). The patient presented with persistent neutropenia and splenomegaly 9 months after SCT when the chimerism study showed a 100% donor pattern. A splenectomy revealed T-LGL leukemia. Flow cytometric analysis showed an aberrant T-cell population positive for CD3, CD5 (dim, subset), CD7, CD8, CD16 (subset), CD57, CD94 (dim, partial), and T-cell receptor (TCR) αβ, and negative for CD4, CD26, CD56, and TCR. Molecular studies showed monoclonal TCRβ and TCR gene rearrangements. Both the immunophenotype and molecular profile of the T-LGL leukemia were different from the pre-SCT PTCL. Sequencing analysis for STAT3 exon 21 did not reveal any mutation in both pre-SCT and post-SCT specimens. The patient did not receive any treatment for T-LGL leukemia; however, his count progressively increased after splenectomy, despite the presence of persistent T-LGL leukemia in the bone marrow. There was no evidence of recurrent PTCL. We propose an algorithm to diagnose this rare post-SCT neoplasm.

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Predictors of In-Hospital Mortality in Patients With Metastatic Cancer Receiving Specific Critical Care Therapies

Background: In-hospital mortality is high for critically ill patients with metastatic cancer. To help patients, families, and clinicians make an informed decision about invasive medical treatments, we examined predictors of in-hospital mortality among patients with metastatic cancer who received critical care therapies (CCTs). Patients and Methods: We used the 2010 California Healthcare Cost and Utilization Project: State Inpatient Databases to identify admissions of patients with metastatic cancer (age ≥18 years) who received CCTs, including invasive mechanical ventilation (IMV), tracheostomy, percutaneous endoscopic gastrostomy (PEG) tube, acute use of dialysis, and total parenteral nutrition (TPN). We first described the characteristics and outcomes of patients who received any CCTs. We then used multivariable logistic regression models with generalized estimating equations (to account for clustering within hospitals) to identify predictors of in-hospital mortality among patients who received any CCTs. Results: For 2010, we identified 99,085 admissions among patients with metastatic cancer. Of these, 9,348 (9.4%) received any CCT during hospitalization; 50% received IMV, 15% PEG tube, 8% tracheostomy, 40% TPN, and 8% acute dialysis. Inpatient mortality was 30%. Of patients who received any CCT and survived to discharge, 27% were discharged to a skilled nursing facility. Compared with patients who died, costs of care were $3,019 higher for admissions in which patients survived the hospitalization. Predictors of in-hospital mortality included non-white race (vs whites), lack of insurance (vs Medicare), unscheduled admissions, principal diagnosis of infections (vs cancer-related), greater burden of comorbidities, end-stage renal disease, liver disease and lung cancer (vs other cancers). Conclusions: Although more studies are needed to better understand risks and benefits of specific treatments in the setting of specific cancer types, these data will help to inform decision-making for patients with metastatic cancer who become critically ill.

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NCCN Guidelines Insights: Melanoma, Version 3.2016

The NCCN Guidelines for Melanoma have been significantly revised over the past few years in response to emerging data on a number of novel agents and treatment regimens. These NCCN Guidelines Insights summarize the data and rationale supporting extensive changes to the recommendations for systemic therapy in patients with metastatic or unresectable melanoma.

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Associations Between End-of-Life Cancer Care Patterns and Medicare Expenditures

Background: The purpose of this study was to examine the extent to which patterns of intensive end-of-life care explain geographic variation in end-of-life care expenditures among cancer decedents. Methods: Using the SEER-Medicare database, we identified 90,465 decedents who were diagnosed with cancer in 2004–2011. Measures of intensive end-of-life care included chemotherapy received within 14 days of death; more than 1 emergency department visit, more than 1 hospitalization, or 1 or more intensive care unit (ICU) admissions within 30 days of death; in-hospital death; and hospice enrollment less than 3 days before death. Using hierarchical generalized linear models, we estimated risk-adjusted expenditures in the last month of life for each hospital referral region and identified key contributors to variation in expenditures. Results: The mean expenditure per cancer decedent in the last month of life was $10,800, ranging from $8,300 to $15,400 in the lowest and highest expenditure quintile areas, respectively. There was considerable variation in the percentage of decedents receiving intensive end-of-life care intervention, with 41.7% of decedents receiving intensive care in the lowest quintile of expenditures versus 57.9% in the highest quintile. Regional patterns of late chemotherapy or late hospice use explained only approximately 1% of the expenditure difference between the highest and lowest quintile areas. In contrast, the proportion of decedents who had ICU admissions within 30 days of death was a major driver of variation, explaining 37.6% of the expenditure difference. Conclusions: Promoting appropriate end-of-life care has the potential to reduce geographic variation in end-of-life care expenditures.

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NCCN's Commitment to Medication Safety: The Vincristine Initiative

The mission of NCCN is to improve the quality, effectiveness, and efficiency of cancer care so that patients can live better lives. Improving medication safety is an important aspect of fulfilling this mission. In September 2014, the NCCN Best Practices Committee began a medication safety initiative to improve the safe use of vincristine. This article describes and discusses this initiative.

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Biomarkers in Colorectal Cancer Screening

Colorectal cancer (CRC) is the third most common cause of cancer death in men and women in the United States. The main goals of screening are to prevent carcinogenesis (via adenoma detection and removal) and detect cancer at an early, curable stage. CRC mortality is steadily dropping in the United States, partly because of greater screening utilization. However, nearly 1 in 3 average-risk people are not up to date with standard CRC screening recommendations. This review surveys a wide range of CRC biomarkers in various stages of development, which may offer attractive risk stratification tools; a few have reached the commercial stage. If widely accepted, these tools may contribute to shift CRC screening practices away from 1-step colonoscopy to a 2-step risk stratification process of predictive biomarker measurements followed by colonoscopy for lower-risk patients with a positive result. Such strategies could potentially increase the rate of CRC screening.

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NCCN Framework for Resource Stratification: A Framework for Providing and Improving Global Quality Oncology Care

More than 14 million new cancer cases and 8.2 million cancer deaths are estimated to occur worldwide on an annual basis. Of these, 57% of new cancer cases and 65% of cancer deaths occur in low- and middle-income countries. Disparities in available resources for health care are enormous and staggering. The WHO estimates that the United States and Canada have 10% of the global burden of disease, 37% of the world's health workers, and more than 50% of the world's financial resources for health; by contrast, the African region has 24% of the global burden of disease, 3% of health workers, and less than 1% of the world's financial resources for health. This disparity is even more extreme with cancer. NCCN has developed a framework for stratifying the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) to help health care systems in providing optimal care for patients with cancer with varying available resources. This framework is modified from a method developed by the Breast Health Global Initiative. The NCCN Framework for Resource Stratification (NCCN Framework) identifies 4 resource environments: basic resources, core resources, enhanced resources, and NCCN Guidelines, and presents the recommendations in a graphic format that always maintains the context of the NCCN Guidelines. This article describes the rationale for resource-stratified guidelines and the methodology for developing the NCCN Framework, using a portion of the NCCN Cervical Cancer Guideline as an example.

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Counterpoint: Wealth, Health Expenditure, and Cancer--Translating Research Into Efficient Policies

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Depletion of Dicer promotes epithelial ovarian cancer progression by elevating PDIA3 expression

Abstract

Dicer is an essential component of the microRNA (miRNA) processing machinery whose low expression is associated with advanced stage and poor clinical outcome in epithelial ovarian cancer. To investigate the functional relevance of Dicer in epithelial ovarian cancer and to identify its downstream effectors, two-dimensional gel electrophoresis combined with mass spectrometry was used for proteomic profiling. Dicer depletion promoted ovarian cancer cell proliferation and migration accompanied by a global upregulation of proteins. Twenty-six proteins, 7 upregulated and 19 downregulated, were identified. The functions of the identified proteins and their interactions were bioinformatically analyzed. Among them, protein disulfide-isomerase A3 (PDIA3) was considered to be a potential target protein of Dicer. PDIA3 repression by siRNA could significantly relieve the proliferation- and migration-promoting effect mediated by Dicer depletion in vitro and in vivo. Moreover, the miRNAs targeting PDIA3 were decreased in cells with Dicer depletion. In summary, low Dicer expression contributes to epithelial ovarian cancer progression by elevating PDIA3 expression.

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MicroRNA-137 represses FBI-1 to inhibit proliferation and in vitro invasion and migration of hepatocellular carcinoma cells

Abstract

The pro-oncogene factor that binds to inducer of short transcripts-1 (FBI-1), which is encoded by ZBTB7A gene and belongs to POK (POZ/BTB and KrÜppel) protein family, has been shown to enhance hepatocellular carcinoma (HCC) cells proliferation and multi-drug resistance (MDR) process. However, the possibility that FBI-1 is a therapeutic target for further HCC treatment remains poorly determined. In the current study, two microRNA (miRNA) target prediction programs (TargetScan and MiRanda) were used to identify miR-137 as a potential regulator of FBI-1. Our results showed that expression of miR-137 was downregulated, while FBI-1 was upregulated in clinical HCC specimens, compared with paired non-tumor specimens. Overexpression of miR-137 via adenoviral vector inhibited the proliferation and anchorage-independent growth of HCC cells, HepG2 and MHCC-97H. Our data also showed that miR-137 repressed endogenous expression level of FBI-1, as well as Notch-1 and Survivin. MiR-137 also inhibited in vitro invasion and migration of HCC cells and attenuated their epithelial-mesenchymal transition (EMT) process. Moreover, miR-137 suppressed the growth rate of HepG2 cells in nude mice model. Overexpression of miR-137 via its adenoviral vector enhanced the sensitivity of HepG2 cells to anti-tumor drugs and attenuated the MDR process of a resistance cell line HepG2/adriamycin (ADR). Thus, FBI-1 downregulation mediated by miR-137 overexpression may be a potential strategy for HCC treatment.

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Occurrence and outcome of de novo metastatic breast cancer by subtype in a large, diverse population

Abstract

Purpose

To examine the occurrence and outcomes of de novo metastatic (Stage IV) breast cancer, particularly with respect to tumor HER2 expression.

Methods

We studied all 6,268 de novo metastatic breast cancer cases diagnosed from 1 January 2005 to 31 December 2011 and reported to the California Cancer Registry. Molecular subtypes were classified according to HER2 and hormone receptor (HR, including estrogen and/or progesterone receptor) expression. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) of Stage IV versus Stage I–III breast cancer; Cox proportional hazards regression was used to assess relative hazard (RH) of mortality.

Results

Five percent of invasive breast cancer was metastatic at diagnosis. Compared to patients with earlier stage disease, patients with de novo metastatic disease were significantly more likely to have HER2+ tumors (HR+/HER2+: OR 1.29, 95 % CI 1.17–1.42; HR−/HER2+: OR 1.40, 95 %CI 1.25–1.57, vs. HR+/HER2−). Median survival improved over time, but varied substantially across race/ethnicity (Asians: 34 months; African Americans: 6 months), neighborhood socioeconomic status (SES) (highest: 34 months, lowest: 20 months), and molecular subtype (HR+/HER2+: 45 months; triple negative: 12 months). In a multivariable model, triple negative (RH 2.85, 95 % CI 2.50–3.24) and HR−/HER2+ (RH 1.60, 95 % CI 1.37–1.87) had worse, while HR+/HER2+ had similar, risk of all-cause death compared to HR+/HER2− breast cancer.

Conclusions

De novo metastatic breast cancer was more likely to be HER2+. Among metastatic tumors, those that were HER2+ had better survival than other subtypes.

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Curcumin improves episodic memory in cadmium induced memory impairment through inhibition of acetylcholinesterase and adenosine deaminase activities in a rat model

Abstract

Curcumin, the main polyphenolic component of turmeric (Curcuma longa) rhizomes has been reported to exert cognitive enhancing potential with limited scientific basis. Hence, this study sought to evaluate the effect of curcumin on cerebral cortex acetylcholinesterase (AChE) and adenosine deaminase (ADA) activities in cadmium (Cd)-induced memory impairment in rats. Animals were divided into six groups (n = 6): saline/vehicle, saline/curcumin 12.5 mg/kg, saline/curcumin 25 mg/kg, Cd/vehicle, Cd/curcumin 12.5 mg/kg, and Cd/curcumin 25 mg/kg. Rats received Cd (2.5 mg/kg) and curcumin (12.5 and 25 mg/kg, respectively) by gavage for 7 days. The results of this study revealed that cerebral cortex AChE and ADA activities were increased in Cd-poisoned rats, and curcumin co-treatment reversed these activities to the control levels. Furthermore, Cd intoxication increased the level of lipid peroxidation in cerebral cortex with a concomitant decreased in functional sulfuhydryl (−SH) group and nitric oxide (NO), a potent neurotransmitter and neuromodulatory agent. However, the co-treatment with curcumin at 12.5 and 25 mg/kg, respectively increased the non-enzymatic antioxidant status and NO in cerebral cortex with a decreased in malondialdehyde (MDA) level. Therefore, inhibition of AChE and ADA activities as well as increased antioxidant status by curcumin in Cd-induced memory dysfunction could suggest some possible mechanism of action for their cognitive enhancing properties.

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Qualitative Exploration of Sexual Health Among Diverse Breast Cancer Survivors

Abstract

Although the physical and emotional impact of surgical removal of partial or complete removal of the breast as well as effects of breast cancer treatment on the individual have been well documented, little research is available on sexuality and sexual health of breast cancer survivors in a relationship context. Sexual health concerns of breast cancer survivors remain an unmet need for many. The present study consisted of qualitative interviews with 135 racially diverse, female breast cancer survivors who completed treatment to better understand their perspectives on sexual health and management of sexual problems in their potential and existing relationships after breast cancer. Key thematic findings include that breast cancer survivors have to (1) adapt to the physical and emotional traumas of breast cancer surgery and treatment, (2) navigate complicated sexual communications with potential and existing partners, and (3) negotiate intimacy and closeness without sexual intercourse with existing partners. This study demonstrates the need for healthcare providers to discuss sexual health after breast cancer with all of their patients as it is a concern that faces single and partnered breast cancer survivors months and years after treatment.

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International Cancer Education Conference 2016 Program and Abstracts

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How well Informed are Cancer Patients Prior to a Life Cycle of Injectable Chemotherapy Drug Treatment?

Abstract

Cancer patient dissatisfaction, due to a long waiting time for chemotherapy treatment, is a common complaint. To improve patient satisfaction, our pharmaceutical team was prompted to design a series of information tools for injectable chemotherapy drug treatment (ICDT) patients. This study was based on French Health Authorities recommendations. All three stages were monitored: the preparation stage using a 204 patient survey, the design stage, and the assessment stage with a 12 point questionnaire patient evaluation. An information brochure and a 10-min film were designed which chronologically described key stages in the life cycle of ICDT. Both tools were assessed by 29 and 84 patients respectively. The questionnaire confirmed that this approach met the needs of more than 90 % of patients. The brochure and the film also accurately met the objectives and improved the understanding of the chemotherapy long waiting time which resulted in higher patient satisfaction. The designed tools will continue to evolve with changes in oncology practices based on various indicators defined in the study. Our study proposes an original method to assist health professionals to better inform cancer patients regarding the preparation of ICDT. It is also a part of a continuous quality program to assure quality outpatient healthcare.

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Qualitative Exploration of Sexual Health Among Diverse Breast Cancer Survivors

Abstract

Although the physical and emotional impact of surgical removal of partial or complete removal of the breast as well as effects of breast cancer treatment on the individual have been well documented, little research is available on sexuality and sexual health of breast cancer survivors in a relationship context. Sexual health concerns of breast cancer survivors remain an unmet need for many. The present study consisted of qualitative interviews with 135 racially diverse, female breast cancer survivors who completed treatment to better understand their perspectives on sexual health and management of sexual problems in their potential and existing relationships after breast cancer. Key thematic findings include that breast cancer survivors have to (1) adapt to the physical and emotional traumas of breast cancer surgery and treatment, (2) navigate complicated sexual communications with potential and existing partners, and (3) negotiate intimacy and closeness without sexual intercourse with existing partners. This study demonstrates the need for healthcare providers to discuss sexual health after breast cancer with all of their patients as it is a concern that faces single and partnered breast cancer survivors months and years after treatment.

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International Cancer Education Conference 2016 Program and Abstracts

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How well Informed are Cancer Patients Prior to a Life Cycle of Injectable Chemotherapy Drug Treatment?

Abstract

Cancer patient dissatisfaction, due to a long waiting time for chemotherapy treatment, is a common complaint. To improve patient satisfaction, our pharmaceutical team was prompted to design a series of information tools for injectable chemotherapy drug treatment (ICDT) patients. This study was based on French Health Authorities recommendations. All three stages were monitored: the preparation stage using a 204 patient survey, the design stage, and the assessment stage with a 12 point questionnaire patient evaluation. An information brochure and a 10-min film were designed which chronologically described key stages in the life cycle of ICDT. Both tools were assessed by 29 and 84 patients respectively. The questionnaire confirmed that this approach met the needs of more than 90 % of patients. The brochure and the film also accurately met the objectives and improved the understanding of the chemotherapy long waiting time which resulted in higher patient satisfaction. The designed tools will continue to evolve with changes in oncology practices based on various indicators defined in the study. Our study proposes an original method to assist health professionals to better inform cancer patients regarding the preparation of ICDT. It is also a part of a continuous quality program to assure quality outpatient healthcare.

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Invasive micropapillary carcinoma of the breast had poor clinical characteristics but showed no difference in prognosis compared with invasive ductal carcinoma

Abstract

Background

It is controversial for prognosis of invasive micropapillary carcinoma (IMPC) compared with invasive ductal carcinoma (IDC) of the breast. To better understand the difference between IMPC and IDC prognoses, we conducted this retrospective study.

Methods

Data from 33 patients with IMPC were retrospectively reviewed, and the clinicopathologic characteristics and survival status were compared with those of 347 patients with IDC who were treated during the same period.

Results

The IMPC cases were of larger tumor size, greater proportion of nodal involvement, and an increased incidence of lymphovascular invasion compared with IDC cases. The overall survival (OS), local relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and failure-free survival (FFS) rates were not significantly different between IMPC and IDC. The 3-year OS rate was 97 vs 94.2 % for the IMPC and IDC patients, respectively. The 3-year FFS rate was 87.9 vs 86.2 % for the IMPC and IDC patients, respectively. For IMPC patients, the 3-year LRFS rate was 93.9 % and in IDC patients was 89.0 %. The 3-year DMFS rates of IMPC patients was 90.9 % and IDC patients was 89 %.

Conclusions

IMPC had poor clinical characteristics, but it showed no difference in OS, FFS, LRFS, and DMFS compare with IDC.

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Outcomes of abdominoperineal resection for management of anal cancer in HIV-positive patients: a national case review

Abstract

Background

The incidence of anal cancer in human immunodeficiency virus (HIV)-positive individuals is increasing, and how co-infection affects outcomes is not fully understood. This study sought to describe the current outcome disparities between anal cancer patients with and without HIV undergoing abdominoperineal resection (APR).

Methods

A retrospective review of all US patients diagnosed with anal squamous cell carcinoma, undergoing an APR, was performed. Cases were identified using a weighted derivative of the Healthcare Utilization Project's National Inpatient Sample (2000–2011). Patients greater than 60 years old were excluded after finding a skewed population distribution between those with and without HIV infection. Multivariable logistic regression and generalized linear modeling analysis examined factors associated with postoperative outcomes and cost. Perioperative complications, in-hospital mortality, length of hospital stay, and hospital costs were compared for those undergoing APR with and without HIV infection.

Results

A total of 1725 patients diagnosed with anal squamous cell cancer undergoing APR were identified, of whom 308 (17.9 %) were HIV-positive. HIV-positive patients were younger than HIV-negative patients undergoing APR for anal cancer (median age 47 years old versus 51 years old, p < 0.001) and were more likely to be male (95.1 versus 30.6 %, p < 0.001). Postoperative hemorrhage was more frequent in the HIV-positive group (5.1 versus 1.5 %, p = 0.05). Mortality was low in both groups (0 % in HIV-positive versus 1.49 % in HIV-negative, p = 0.355), and length of stay (LOS) (10+ days; 75th percentile of patient data) was similar (36.9 % with HIV versus 29.8 % without HIV, p = 0.262).

Greater hospitalization costs were associated with patients who experienced a complication. However, there was no difference in hospitalization costs seen between HIV-positive and HIV-negative patients (p = 0.66).

Conclusions

HIV status is not associated with worse postoperative recovery after APR for anal cancer as measured by length of stay or hospitalization cost. Further study may support APRs to be used more aggressively in HIV-positive patients with anal cancer.

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Inconsistent results in the analysis of ALK rearrangements in non-small cell lung cancer

Abstract

Background

Identification of targetable EML4-ALK fusion proteins has revolutionized the treatment of a minor subgroup of non-small cell lung cancer (NSCLC) patients. Although fluorescence in situ hybridization (FISH) is regarded as the gold standard for detection of ALK rearrangements, ALK immunohistochemistry (IHC) is often used as screening tool in clinical practice. In order to unbiasedly analyze the diagnostic impact of such a screening strategy, we compared ALK IHC with ALK FISH in three large representative Swedish NSCLC cohorts incorporating clinical parameters and gene expression data.

Methods

ALK rearrangements were detected using FISH on tissue microarrays (TMAs), including tissue from 851 NSCLC patients. In parallel, ALK protein expression was detected using IHC, applying the antibody clone D5F3 with two different protocols (the FDA approved Ventana CDx assay and our in house Dako IHC protocol). Gene expression microarray data (Affymetrix) was available for 194 patients.

Results

ALK rearrangements were detected in 1.7 % in the complete cohort and 2.0 % in the non-squamous cell carcinoma subgroup. ALK protein expression was observed in 1.8 and 1.4 % when applying the Ventana assay or the in house Dako protocol, respectively. The specificity and accuracy of IHC was high (> 98 %), while the sensitivity was between 69 % (Ventana) and 62 % (in house Dako protocol). Furthermore, only 67 % of the ALK IHC positive cases were positive with both IHC assays. Gene expression analysis revealed that 6/194 (3 %) tumors showed high ALK gene expression (≥ 6 AU) and of them only three were positive by either FISH or IHC.

Conclusion

The overall frequency of ALK rearrangements based on FISH was lower than previously reported. The sensitivity of both IHC assays was low, and the concordance between the FISH and the IHC assays poor, questioning current strategies to screen with IHC prior to FISH or completely replace FISH by IHC.

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A nomogram for predicting pathological complete response in patients with human epidermal growth factor receptor 2 negative breast cancer

Abstract

Background

The response to neoadjuvant chemotherapy has been proven to predict long-term clinical benefits for patients. Our research is to construct a nomogram to predict pathological complete response of human epidermal growth factor receptor 2 negative breast cancer patients.

Methods

We enrolled 815 patients who received neoadjuvant chemotherapy from 2003 to 2015 and divided them into a training set and a validation set. Univariate logistic regression was performed to screen for predictors and construct the nomogram; multivariate logistic regression was performed to identify independent predictors.

Results

After performing the univariate logistic regression analysis in the training set, tumor size, hormone receptor status, regimens of neoadjuvant chemotherapy and cycles of neoadjuvant chemotherapy were the final predictors for the construction of the nomogram. The multivariate logistic regression analysis demonstrated that T4 status, hormone receptor status and receiving regimen of paclitaxel and carboplatin were independent predictors of pathological complete response. The area under the receiver operating characteristic curve of the training set and the validation set was 0.779 and 0.701, respectively.

Conclusions

We constructed and validated a nomogram to predict pathological complete response in human epidermal growth factor receptor 2 negative breast cancer patients. We also identified tumor size, hormone receptor status and paclitaxel and carboplatin regimen as independent predictors of pathological complete response.

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A radiosensitizing effect of RAD51 inhibition in glioblastoma stem-like cells

Abstract

Background

Radioresistant glioblastoma stem cells (GSCs) contribute to tumor recurrence and identification of the molecular targets involved in radioresistance mechanisms is likely to enhance therapeutic efficacy. This study analyzed the DNA damage response following ionizing radiation (IR) in 10 GSC lines derived from patients.

Methods

DNA damage was quantified by Comet assay and DNA repair effectors were assessed by Low Density Array. The effect of RAD51 inhibitor, RI-1, was evaluated by comet and annexin V assays.

Results

While all GSC lines displayed efficient DNA repair machinery following ionizing radiation, our results demonstrated heterogeneous responses within two distinct groups showing different intrinsic radioresistance, up to 4Gy for group 1 and up to 8Gy for group 2. Radioresistant cell group 2 (comprising 5 out of 10 GSCs) showed significantly higher RAD51 expression after IR. In these cells, inhibition of RAD51 prevented DNA repair up to 180 min after IR and induced apoptosis. In addition, RAD51 protein expression in glioblastoma seems to be associated with poor progression-free survival.

Conclusion

These results underscore the importance of RAD51 in radioresistance of GSCs. RAD51 inhibition could be a therapeutic strategy helping to treat a significant number of glioblastoma, in combination with radiotherapy.

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A retrospective analysis of Victorian and South Australian clinical registries for prostate cancer: trends in clinical presentation and management of the disease

Abstract

Background

Prostate cancer (PCa) is the most commonly diagnosed malignancy reported to Australian cancer registries with numerous studies from individual registries summarizing diagnostic and treatment characteristics. The aim of this study was to describe annual trends in clinical and treatment characteristics, and changes in surveillance practice within a large combined cohort of men with PCa in South Australia (SA) and Victoria, Australia in 2008–2013.

Methods

Common data items from clinical registries in SA and Victoria were merged to develop a cross-jurisdictional dataset consisting of 13,598 men with PCa. Frequencies were used to describe these variables using the National Comprehensive Cancer Network risk of disease progression categories in 10 year age groups. A logistic regression analysis was performed to assess the impact of a number of factors (both individually and together) on the likelihood of men receiving no active treatment within twelve months of the diagnosis (i.e. managed with active surveillance/watchful waiting).

Results

Trend analysis showed that over time: (1) men in SA and Victoria are being diagnosed at older age in 2013, 66.1 (SD = 9.7) years compared to 2009 (64.5 (SD = 9.7)); (2) diagnostic methods and characteristics have changed with time; and (3) types of the treatments have changed, with more men having no active treatment. The majority of men were diagnosed with Prostate-Specific Antigen (PSA) <10 ng/mL (66 %) and Grade Group < 4 (65 %). Nearly seventy percent received radical treatment within 12 months of diagnosis, while ~20 % had no active treatment. In 14 % of cases treatment was not recorded or had not commenced. Having no active treatment was strongly associated older age, lower PSA and lower Grade Group at diagnosis, and in 2013 it was offered more frequently (more than 3 times) than in 2009 (OR = 2.63, 95 % CI: 2.16–3.22).

Conclusions

Findings of this study provide the first cross-jurisdictional description of PCa characteristics and management in Australia. These findings will provide benchmarking for ongoing monitoring and feedback of disease management and outcomes of PCa through the Prostate Cancer Outcomes Registry–Australia New Zealand to improve evidence-based practice.

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S6Ks isoforms contribute to viability, migration, docetaxel resistance and tumor formation of prostate cancer cells

Abstract

Background

The S6 Kinase (S6K) proteins are some of the main downstream effectors of the mammalian Target Of Rapamycin (mTOR) and act as key regulators of protein synthesis and cell growth. S6K is overexpressed in a variety of human tumors and is correlated to poor prognosis in prostate cancer. Due to the current urgency to identify factors involved in prostate cancer progression, we aimed to reveal the cellular functions of three S6K isoforms–p70-S6K1, p85-S6K1 and p54-S6K2–in prostate cancer, as well as their potential as therapeutic targets.

Methods

In this study we performed S6K knockdown and overexpression and investigated its role in prostate cancer cell proliferation, colony formation, viability, migration and resistance to docetaxel treatment. In addition, we measured tumor growth in Nude mice injected with PC3 cells overexpressing S6K isoforms and tested the efficacy of a new available S6K1 inhibitor in vitro.

Results

S6Ks overexpression enhanced PC3-luc cell line viability, migration, resistance to docetaxel and tumor formation in Nude mice. Only S6K2 knockdown rendered prostate cancer cells more sensitive to docetaxel. S6K1 inhibitor PF-4708671 was particularly effective for reducing migration and proliferation of PC3 cell line.

Conclusions

These findings demonstrate that S6Ks play an important role in prostate cancer progression, enhancing cell viability, migration and chemotherapy resistance, and place both S6K1 and S6K2 as a potential targets in advanced prostate cancer. We also provide evidence that S6K1 inhibitor PF-4708671 may be considered as a potential drug for prostate cancer treatment.

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MicroRNA-21 promotes proliferation, migration, and invasion of colorectal cancer, and tumor growth associated with down-regulation of sec23a expression

Abstract

Background

MicroRNA-21 (miR-21) is up-regulated in many cancers, including colorectal cancer (CRC). Nevertheless, the function of miR-21 in CRC and the mechanism underlying that function is still unclear.

Methods

After analyzing the expression of miR-21 and Sec23A in CRC cell lines, we transfected the highest miR-21 expressing cell line, SW-480, with a plasmid containing an miR-21 inhibitor and the lowest miR-21 expressing cell line, DLD-1, with a plasmid containing an miR-21 mimic and measured the effects on the expression of Sec23A and on cell proliferation, migration, and invasion. We also evaluated the effect of knocking down Sec23A on miR-21 expression and its effects on cell proliferation, migration, and invasion. Finally, we assessed the effect of miR-21 in a xenograft tumor model in mice. Tumor tissues from these mice were subjected to immunohistochemical staining to detect the expression of Sec23A.

Results

Genetic deletion of miR-21 suppressed the proliferation, migration, and invasion of SW-480 cells, while over-expression of miR-21 promoted proliferation, migration, and invasion of DLD-1 cells. Inhibition of miR-21 increased the expression of Sec23A protein in SW-480 cells while over-expression of miR-21 significantly suppressed the expression of Sec23A protein and Sec23A mRNA in DLD-1 cells. Knockdown of Sec23A increased the expression of miR-21 in SW480 and DLD-1 cells and their proliferation (DLD-1 only), migration, and invasion. Over-expression of miR-21 promoted tumor growth in BALB/c nude mice and suppressed tumor expression of Sec23A.

Conclusion

These findings provide novel insight into the molecular functions of miR-21 in CRC, which may serve as a potential interesting target.

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Feasibility, tolerability and safety of pediatric hyperpolarized 129 Xe magnetic resonance imaging in healthy volunteers and children with cystic fibrosis

Abstract

Background

Hyperpolarized ¹²⁹Xe is a promising contrast agent for MRI of pediatric lung function, but its safety and tolerability in children have not been rigorously assessed.

Objective

To assess the feasibility, safety and tolerability of hyperpolarized ¹²⁹Xe gas as an inhaled contrast agent for pediatric pulmonary MRI in healthy control subjects and in children with cystic fibrosis.

Materials and methods

Seventeen healthy control subjects (ages 6–15 years, 11 boys) and 11 children with cystic fibrosis (ages 8–16 years, 4 boys) underwent ¹²⁹Xe MRI, receiving up to three doses of ¹²⁹Xe gas prepared by either a commercially available or a homebuilt ¹²⁹Xe polarizer. Subject heart rate and SpO₂ were monitored for 2 min post inhalation and compared to resting baseline values. Adverse events were reported via follow-up phone call at days 1 and 30 (range ±7 days) post-MRI.

Results

All children tolerated multiple doses of ¹²⁹Xe, and no children withdrew from the study. Relative to baseline, most children who received a full dose of gas for imaging (10 of 12 controls and 8 of 11 children with cystic fibrosis) experienced a nadir in SpO₂ (mean –6.0 ± standard deviation 7.2%, P≤0.001); however within 2 min post inhalation SpO₂ values showed no significant difference from baseline (P=0.11). There was a slight elevation in heart rate (mean +6.6 ± 13.9 beats per minute [bpm], P=0.021), which returned from baseline within 2 min post inhalation (P=0.35). Brief side effects related to the anesthetic properties of xenon were mild and quickly resolved without intervention. No serious or severe adverse events were observed; in total, four minor adverse events (14.3%) were reported following ¹²⁹Xe MRI, but all were deemed unrelated to the study.

Conclusion

The feasibility, safety and tolerability of ¹²⁹Xe MRI has been assessed in a small group of children as young as 6 years. SpO₂ changes were consistent with the expected physiological effects of a short anoxic breath-hold, and other mild side effects were consistent with the known anesthetic properties of xenon and with previous safety assessments of ¹²⁹Xe MRI in adults. Hyperpolarized ¹²⁹Xe is a safe and well-tolerated inhaled contrast agent for pulmonary MR imaging in healthy children and in children with cystic fibrosis who have mild to moderate lung disease.

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Depletion of Dicer promotes epithelial ovarian cancer progression by elevating PDIA3 expression

Abstract

Dicer is an essential component of the microRNA (miRNA) processing machinery whose low expression is associated with advanced stage and poor clinical outcome in epithelial ovarian cancer. To investigate the functional relevance of Dicer in epithelial ovarian cancer and to identify its downstream effectors, two-dimensional gel electrophoresis combined with mass spectrometry was used for proteomic profiling. Dicer depletion promoted ovarian cancer cell proliferation and migration accompanied by a global upregulation of proteins. Twenty-six proteins, 7 upregulated and 19 downregulated, were identified. The functions of the identified proteins and their interactions were bioinformatically analyzed. Among them, protein disulfide-isomerase A3 (PDIA3) was considered to be a potential target protein of Dicer. PDIA3 repression by siRNA could significantly relieve the proliferation- and migration-promoting effect mediated by Dicer depletion in vitro and in vivo. Moreover, the miRNAs targeting PDIA3 were decreased in cells with Dicer depletion. In summary, low Dicer expression contributes to epithelial ovarian cancer progression by elevating PDIA3 expression.

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Se Enhances MLCK Activation by Regulating Selenoprotein T (SelT) in the Gastric Smooth Muscle of Rats

Abstract

Selenium (Se), a nutritionally essential trace element, is associated with health and disease. Selenoprotein T (SelT) was identified as a redoxin protein with a selenocystein, localizing in the endoplasmic reticulum. The myosin light chain kinase (MLCK) and myosin light chain (MLC) play key roles in the contraction process of smooth muscle. The present study was to detect the effect and mechanism of SelT on the contraction process of gastric smooth muscle. The WT rats were fed with different Se concentration diets, and Se and Ca²⁺ concentrations were detected in the gastric smooth muscle. Western blot and qPCR were performed to determine SelT, CaM, MLCK, and MLC expressions. MLCK activity was measured by identifying the rates of [γ-32P]ATP incorporated into the MLC. The results showed Se and Ca²⁺ concentrations were enhanced with Se intake in gastric smooth muscle tissues. With increasing Se, SelT, CaM, MLCK and MLC expressions increased, and MLCK and MLC activation improved in gastric smooth muscle tissue. The SelT RNA interference experiments showed that Ca²⁺ release, MLCK activation, and MLC phosphorylation were regulated by SelT. Se affected the gastric smooth muscle constriction by regulating Ca²⁺ release, MLCK activation, and MLC phosphorylation through SelT. Se plays a major role in regulating the contraction processes of gastric smooth muscle with the SelT.

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Selenoprotein X Gene Knockdown Aggravated H 2 O 2 -Induced Apoptosis in Liver LO2 Cells

Abstract

To determine the roles of selenoprotein X gene (Selx) in protecting liver cells against oxidative damage, the influences of Selx knockdown on H₂O₂-induced apoptosis in human normal hepatocyte (LO2) cells were studied. pSilencer 3.1 was used to develop knockdown vector targeting the 3′-UTR of human Selx. The Selx knockdown and control cells were further exposed to H₂O₂, and cell viability, cell apoptosis rate, and the expression levels of mRNA and protein of apoptosis-related genes were detected. The results showed that vector targeting the 3′-UTR of Selx successfully silenced mRNA or protein expression of SelX in LO2 cells. Selx knockdown resulted in decreased cell viability, increased percentage of early apoptotic cells, decreased Bcl2A1 and Bcl-2 expression, and increased phosphorylation of P38 in LO2 cells. When Selx knockdown LO2 cells were exposed to H₂O₂, characteristics of H₂O₂-induced cell dysfunctions were further exacerbated. Taken together, our findings suggested that SelX played important roles in protecting LO2 cells against oxidative damage and reducing H₂O₂-induced apoptosis in liver cells.

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Effects of Aqueous Extracts of Chicory and Milk Thistle on Serum Concentrations of Copper, Zinc, and Manganese in Tamoxifen-Treated Rats

Abstract

Some medications may change trace element levels in the body. Extracts of various plants, due to having the several elements, can have beneficial effects. Consumption of herbal extracts with chemical drugs may reduce adverse effects of medication. The goal of this study was to evaluate copper (Cu), zinc (Zn), and manganese (Mn) concentrations in serum of rats treated with tamoxifen, chicory, and/or milk thistle extracts. Therefore, 36 adult female Wistar rats were divided into six groups: normal control, chicory control, milk thistle control, tamoxifen, tamoxifen-chicory, and tamoxifen-milk thistle. At the end of the study, the blood samples were collected and sera isolated by centrifugation and analyzed by the atomic absorption spectrophotometry for Cu, Zn, and Mn levels. The Zn concentration increased in milk thistle-supplemented groups. The Cu level increased in the chicory control group only. Tamoxifen had no affect on Cu, Zn, and Mn levels, but seed extract of milk thistle increased Zn concentration, and chicory root extract increased Cu concentration. Although elevated levels of Cu in rats receiving tamoxifen-chicory were milder than rats treated only with chicory, it seems that the extract and tamoxifen impact on the Cu are in conflict with each other.

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Morphine Attenuated the Cytotoxicity Induced by Arsenic Trioxide in H9c2 Cardiomyocytes

Abstract

Arsenic trioxide (ATO) is an efficient drug for the treatment of the patients with acute promyelocytic leukemia (APL). Inhibition of proliferation as well as apoptosis, attenuation of migration, and induction of differentiation in tumor cells are the main mechanisms through which ATO acts against APL. Despite advantages of ATO in treatment of some malignancies, certain harmful side effects, such as cardiotoxicity, have been reported. It has been well documented that morphine has antioxidant, anti-apoptotic, and cytoprotective properties and is able to attenuate cytotoxicity. Therefore, in this study, we aimed to investigate the protective effects of morphine against ATO toxicity in H9c2 myocytes using multi-parametric assay including thiazolyl blue tetrazolium bromide (MTT) assay, reactive oxygen species (ROS) generation, caspase 3 activity, nuclear factor kappa B (NF-κB) phosphorylation assay, and expression of apoptotic markers. Our results showed that morphine (1 μM) attenuated cytotoxicity induced by ATO in H9c2 cells. Results of this study suggest that morphine may have protective properties in management of cardiac toxicity in patients who receive ATO as an anti-cancer treatment.

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Selenium Deficiency-Induced Inflammation and Increased Expression of Regulating Inflammatory Cytokines in the Chicken Gastrointestinal Tract

Abstract

Selenium (Se), a nutritionally essential trace element, plays an important role in various aspects of health for a wide range of species, including birds. Se deficiency inhibits the growth of immune organs and decreases immune function, leading to many inflammatory diseases. The present study determined the effects and mechanism of dietary Se deficiency on gastrointestinal tract tissue inflammation. The histopathological changes showed that Se deficiency induced inflammatory lesions in the gastrointestinal tract tissues (glandular stomach, gizzard, duodenum, small intestine, and rectum). The expression levels of PTGE (prostagland E synthase), COX-2 (cyclooxygenase-2), TNF-α (tumor necrosis factor α), and NF-κB (nuclear transfer factor κB) in the gastrointestinal tract tissues (glandular stomach, gizzard, duodenum, small intestine, and rectum) were determined by qPCR on days 15, 25, 35, 45, and 55, respectively. The results showed that Se deficiency induced high expression levels of PTGE, COX-2, TNF-α, and NF-κB in the gastrointestinal tract tissues. The effects were more obvious in the duodenum and small intestine than those in the glandular stomach, gizzard, and rectum. In addition, the expression levels of these proteins in the gastrointestinal tract tissue increased in a time-dependent manner with Se deficiency feeding time. Furthermore, Se deficiency induced the production of pro-inflammatory factors, thus aggravating inflammatory lesions in the gastrointestinal tract. The effect of Se deficiency on inflammation and other gastrointestinal tract diseases should be further studied.

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Nickel-Related Intestinal Mucositis in IBS-Like Patients: Laser Doppler Perfusion Imaging and Oral Mucosa Patch Test in Use

Abstract

Nickel (Ni) is often the trigger of irritable bowel syndrome (IBS)-like gastrointestinal disorders: its ingestion may cause allergic contact mucositis, identifiable by means of oral mucosa patch test (omPT). OmPT effectiveness has been proven, but it is still an operator-dependent method. Laser Doppler perfusion imaging (LDPI) was tested to support omPT in Ni allergic contact mucositis diagnosis. Group A: 22 patients with intestinal/systemic symptoms related to the ingestion of Ni-containing foods. Group B: 12 asymptomatic volunteers. Ni-related symptoms and their severity were tested by a questionnaire. All patients underwent Ni omPT with clinical evaluation at baseline (T₀), after 30 min (T₁), after 2 h (T₂), and after 24–48 h (T₃). LDPI was performed to evaluate the mean mucosal perfusion at T₀, T₁, and T₂. Statistical analysis was performed by ANOVA test and Bonferroni multiple-comparison test. All 22 Ni-sensitive patients (group A) presented oral mucosa hyperemia and/or edema at T₂. Eight out of the same 22 patients presented a local delayed vesicular reaction at T₃ (group A1), unlike the remaining 14 out of 22 patients (group A2). All 12 patients belonging to control group B did not show any alteration. The mean mucosal perfusion calculated with LDPI showed an increase in both subgroups A1 and A2. In group B, no significant perfusion variations were observed. LDPI may support omPT for diagnostic purposes in Ni allergic contact mucositis. This also applies to symptomatic Ni-sensitive patients without aphthous stomatitis after 24–48 h from omPT and that could risk to miss the diagnosis.

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Metal Ion Imbalance-Related Oxidative Stress Is Involved in the Mechanisms of Liver Injury in a Rat Model of Chronic Aluminum Exposure

Abstract

The objective of the study is to investigate the effects of chronic aluminum overload on rat liver function and its induction of pathological changes in metal ion levels and oxidative stress in hepatic tissues. Wistar rats were intragastrically administered aluminum gluconate (200 mg Al³⁺/Kg) once a day, 5 days a week, for 20 weeks. HE staining was used to visualize pathological changes in rat liver tissue. A biochemical method was adopted to detect ALT, AST, ALP, and GGT levels, as well as liver SOD activity and blood plasma MDA content. A plasma atomic emission spectrophotometer was used to detect Al, Mn, Fe, Zn, and Cu ion contents in liver tissue. Our results showed obvious vacuolar degeneration, granular degeneration, and spotty necrosis in chronic Al-overload rat hepatocytes. The levels of ALT, AST, ALP, and GGT were significantly increased. Liver SOD activity was significantly decreased, and MDA content was significantly increased. In Al-overload rat liver, Al, Mn, Fe, and Cu contents were significantly increased, and in Al-overload rat serum, Mn, Fe, Zn, and Cu contents were significantly decreased. However, the Al level in Al-overload rat serum was not significantly different from that in control rat serum. These results suggest that chronic aluminum overload causes obvious damage to rat liver and causes imbalances in Al, Mn, Fe, Zn, and Cu levels in rat liver and serum. Metal ion imbalance-related oxidative stress may be involved in the mechanism of chronic liver injury caused by aluminum overload.

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Age-Dependent Changes in Pb Concentration in Human Teeth

Abstract

The result of exposure to Pb is its accumulation in mineralized tissues. In human body, they constitute a reservoir of approx. 90 % of the Pb reserve. The conducted research aimed at determining the accumulation of Pb in calcified tissues of permanent teeth. The concentration of Pb in 390 samples of teeth taken from a selected group of Polish people was determined using the AAS method. Average concentration of Pb in teeth amounted to 14.3 ± 8.18 μg/g, range of changes: 2.21–54.8 μgPb/g. Accumulation of Pb in human body was determined based on changes in Pb concentration in teeth of subjects aged 13–84 years. It was found that in calcified tissues of teeth, the increase in concentration of Pb that occurs with age is a statistically significant process (p = 0.02, the ANOVA Kruskal–Wallis test). It was determined that the annual increase in concentration of Pb in tissues of teeth is approx. 0.1 μg/g. Moreover, a different course of changes in Pb concentration in tissues of teeth in people born in different years was observed. The level of Pb concentration in teeth of the oldest subjects (>60 years) decreased for those born in the 1930s compared to those in the 1950s. Teeth from younger persons (<60 years) were characterized by an increasing level of Pb concentration. The analysis of changes of Pb indicates that for low exposure, a relatively greater accumulation of Pb concentration in calcified tissues of teeth can occur.

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Selenium, Zinc, Copper, and Total Antioxidant Status in the Serum of Patients with Chronic Tonsillitis

Abstract

Antioxidants can play a significant role in chronic inflammatory process. The aim of this study was to evaluate the content of selenium (Se), zinc (Zn), copper (Cu), and total antioxidant status (TAS) of patients with chronic tonsillitis (CT). The study group consisted of 84 patients with CT from 18 to 62 years old and the control group of 67 healthy people aged 19–65 years. Se, Zn, and Cu concentration in serum samples were determined by atomic absorption spectrometry. Serum TAS was measured spectrophotometrically, using the test by Randox Laboratories-Us Ltd. The mean content of Se and Zn in the serum of patients with CT (61.122 ± 12.73 μg/L, 0.887 ± 0.26 mg/L, respectively) was lower compared to the control group (77.969 ± 12.73 μg/L, 0.993 ± 0.32 mg/L, respectively). The mean serum concentration of Cu in patients with CT (1.219 ± 0.35 mg/L) was higher compared to its serum concentration in healthy people (1.033 ± 0.37 mg/L). Serum TAS of patients with CT (1.171 ± 0.33 mmol/L) was lower in comparison with healthy volunteers (1.333 ± 0.42 mmol/L). The serum concentration of Se, Zn, and TAS in patients with CT was lower, whereas the concentration of Cu was higher compared to healthy volunteers. Smoking has an influence on reducing the concentration of Se and TAS of patients with CT.

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Risk Assessment Study of Fluoride Salts: Probability-Impact Matrix of Renal and Hepatic Toxicity Markers

Abstract

The present risk assessment study of fluoride salts was conducted by oral administration of three different doses of sodium and potassium fluorides (NaF, KF) and zinc fluoride tetrahydrate (ZnF₂ •4H₂O) to male Wistar rats. The rats were divided into control and nine experimental groups, to which oral injections of 0.5 mL distilled water and 0.5 mL of fluoride solutions, respectively, were given. The dosage of fluoride compounds was adjusted to contain 2.1 mg (low-dose group, LG), 4.3 mg (mid-dose group, MG), and 5.4 mg fluoride per 200 g rat body weight (high-dose group, HG) corresponding to 5, 10, and 12.5 % of LD₅₀ values for NaF. The 24-h urine volume, N-acetyl-β-D-glucosaminidase (NAG) and creatinine clearance (Ccr) were measured as markers of possible acute renal impact. The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined in serum samples as markers of acute hepatic impact. The levels of serum and urinary fluoride were determined to evaluate fluoride bioavailability. The results reveal that higher doses of NaF, KF, and ZnF₂ induced renal damage as indicated by higher urinary NAG (p < 0.05 with ≥90th percentile of control). High doses of ZnF₂ also induced a significant Ccr decrease (p < 0.05 with ≤10th percentile of control). Low doses of NaF and mid-doses of ZnF₂ induced polyuria (p < 0.05 with ≥90th percentile of control) while medium doses of NaF and low doses of KF also induced liver damage, as indicated by a high level of AST (p < 0.05 with ≥90th percentile of control). These findings suggest that oral administration of fluoride is a potential, dose-dependent risk factor of renal tubular damage.

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Antibacterial and Antibiofilm Effects of Boron on Different Bacteria

Abstract

Boron (B) compounds are used in many fields ranging from medicine to industry. In this study, boric acid (BA) and disodium octaborate tetrahydrate (DOT) were evaluated for their antibacterial effects and antibiofilm capacities on selected strains of clinical and type cultures that are of veterinary concern (Staphylococcus aureus ATCC 25923, Aeromonas hydrophila ATCC 19570, Pseudomonas aeruginosa ATCC 27853, Brucella melitensis Rev1 and field isolates of Vibrio anguillarum, Aeromonas hydrophila, Yersinia ruckeri, Pseudomonas aeruginosa, Lactococcus garvieae, and Brucella abortus). Also, the inhibition of biofilm was monitored by scanning electron microscopy. The lowest MIC values of BA and DOT were measured, by broth method using microdilution, from Pseudomonas aeruginosa ATCC 27853, and were 0.385 and 0.644 mg/ml, respectively. Staphylococcus aureus was the most resistant to both BA and DOT. Using the microplate method, we observed that the strongest positivities for biofilm production were presented by Pseudomonas aeruginosa ATCC 27853 and also a clinical isolate of Lactococcus garviea. Lower values in the MIC scores for both B compounds were tested by measuring the inhibitory effect on biofilm production. We found that all the bacterial strains inhibited biofilm formation with the exception of the Pseudomonas aeruginosa strains for BA only and an isolate of Lactococcus garviea for DOT only. Such effects by BA and DOT are worth discussing in order to find novel approaches for different functions in medicine and industry using the bacteria tested.

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Effects of Sodium Fluoride on Lipid Peroxidation and PARP, XBP-1 Expression in PC12 Cell

Abstract

This study aims to clarify the molecular mechanism of fluorine exposure that leads to nerve injury. PC12 cells were treated with fluorine at different concentrations (0.5, 1.0, 1.5, and 2.0 mM). Cytoactivity was detected at different time points (2, 4, 6, 8, 12, 24, and 48 h). After 2 h, DCF was used to detect and mark the level of reactive oxygen species (ROS) within cells. After 24 h, cellular metamorphosis was observed using an inverted microscope. After 2 h, Hoechst-33342 was used to detect apoptosis. After 24 h, Western blot analysis was performed to detect apoptosis-related poly (ADP-ribose) polymerase (PARP) protein, p-elF, and expression of the endoplasmic reticulum stress-related X-box binding protein 1 (XBP-1). The results showed that Fluorine exposure resulted in a reduction of cell viability, which was negatively correlated with fluorine dose. Within certain fluorine exposure duration, the ROS level within the cell and the apoptotic level are linearly related to fluorine exposure level. XBP-1 and PARP protein are sensitive to variations in fluorine concentration, which indicates that oxidative stress from fluorine exposure can lead to apoptosis. XBP-1 and PARP may be the key proteins during the entire process. These results provide a valid basis for fluorine-induced free radical injury theory.

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Anti-Proliferative Effect of Copper Oxide Nanorods Against Human Cervical Carcinoma Cells

Abstract

Metal oxide nanoparticles have been widely investigated for its use in the pharmacological field. The present study was aimed to investigate the cytotoxicity of copper oxide nanorods in human cervical carcinoma cells. The effect of copper oxide nanorods on cell viability was determined by sulforhodamine-B (SRB) assay. The fluorescence and confocal microscopy analyzes showed the cell rounding and nuclear fragmentation following exposure of copper oxide nanorods. Reactive oxygen species (ROS) was increased and could initiate membrane lipid peroxidation, which in turn regulate cytokinetic movements of cells. The messenger RNA (mRNA) expression of p53 and caspase 3 was increased, which further confirms the occurrence of apoptosis at the transcriptional level. Furthermore, caspase-3 enzyme activity was increased, which also confirms the occurrence of apoptosis in tumor cells at the translational level. Taking all our experimental results together, it may suggest that the copper oxide nanorods could be a potential anti-tumor agent to inhibit cancer cell proliferation.

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Effects of Dietary Selenium Supplementation on Seminiferous Tubules and SelW, GPx4, LHCGR, and ACE Expression in Chicken Testis

Abstract

We investigated the effects of dietary selenium (Se) supplementation on the development of chicken testis and the expression of selenoprotein W (SelW), glutathione peroxidase4 (GPx4), luteinizing hormone/choriogonadotropin receptor (LHCGR), and angiotensin converting enzyme (ACE). Sixty roosters were assigned randomly into the control group fed with a basic diet (containing 0.3 mg Se/kg) and the experimental group fed with a diet (containing 0.6 mg Se/kg). The testes were collected individually at age of 6, 9, and 12 weeks. Se was supplemented in chicken feed for 15 days before sampling. The results indicated that dietary Se affected the number of cells in the seminiferous tubules and viability of Sertoli cells in vitro culture. SelW and GPx4 expression in the testes increased significantly in the experimental group compared to that in the control group. LHCGR expression in the testes increased significantly in the experimental group after 12 weeks compared to that in the control group. In contrast, ACE expression was inhibited in the experimental group compared to that in the control group. These results suggest that dietary supplementation with Se improved development of the seminiferous tubules at the cellular level and that SelW, GPx4, LHCGR, and ACE are involved.

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Iodine Status of Vulnerable Populations in Henan Province of China 2013–2014 After the Implementation of the New Iodized Salt Standard

Abstract

The standard of salt iodine content in China has been adjusted several times since implementation of the universal salt iodization (USI) in 1995. The new standard of iodized salt content was adjusted from 35 ± 15 to 30 ± 9 mg/kg in Henan province in 2012. We aimed to determine whether the vulnerable populations were iodine sufficient after the adjustment of salt iodine content and to provide a guideline for the adjustment of USI policy in China. Two cross-sectional surveys of iodine status in vulnerable populations, including reproductive-age, pregnant and lactating women, infants <2 years, and children aged 8–10 years, were conducted in Henan province in 2013 and 2014. In 2013, the median urinary iodine concentration (mUIC) of reproductive-age women was 200.1 μg/L and that of school children aged 8–10 years was 221.0 μg/L. These mUICs were considered as "more than adequate." The mUICs of reproductive-age women and school children in 2014 showed a significant decline compared to the mUICs in 2013 (P = 0.012 and P = 0.001, respectively). The mUICs of the pregnant women were 204.2 μg/L in 2013 and 202.5 μg/L in 2014, which both met the requirement level recommended by WHO. In 2013, the mUIC of lactating women was 169.1 μg/L and that of infants <2 years was 203.2 μg/L, which were significantly lower than that of 2014 (P < 0.001 and P < 0.001, respectively). The lactating women and infants in 2013 and 2014 were both regarded as "iodine adequate." Iodine status of the vulnerable populations is still adequate as a whole in Henan province after decreasing the salt iodine content. However, the mUIC of school children aged 8–10 years is slightly above the adequate level. To reduce the risk of iodine excess in the general population and prevent the possibility of iodine deficiency of the vulnerable population, it is necessary to explore the appropriate level of iodized salt content.

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Preliminary Study to Test the Feasibility of Sex Identification of Human ( Homo sapiens ) Bones Based on Differences in Elemental Profiles Determined by Handheld X-ray Fluorescence

Abstract

Sex assignment of human remains is a crucial step in forensic anthropological studies. The aim of this study was to examine elemental differences between male and female bones using X-ray fluorescence (XRF) and determine if elemental profiling could be used for sex discrimination. Cranium, humerus, and os coxae of 60 skeletons (30 male, 30 female) from the Chiang Mai University Skeletal Collection were scanned by XRF and differences in elemental profiles between male and female bones determined using discriminant analysis. In the cranium, three elements (S, Ca, Pb) were significantly higher in males and five elements (Si, Mn, Fe, Zn, Ag) plus light elements (atomic number lower than 12) were higher in females. In humerus and os coxae, nine elements were significantly higher in male and one element was higher in female samples. The accuracy rate for sex estimation was 60, 63, and 61 % for cranium, humerus, and os coxae, respectively, and 67 % when data for all three bones were combined. We conclude that there are sex differences in bone elemental profiles; however, the accuracy of XRF analyses for discriminating between male and female samples was low compared to standard morphometric and molecular methods. XRF could be used on small samples that cannot be sexed by traditional morphological methods, but more work is needed to increase the power of this technique for gender assignment.

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Comparative Analysis of the Trace Element Content of the Leaves and Roots of Three Plantago Species

Abstract

The primary objective of this study is to perform a comparative analysis of the trace element content of the leaves and roots of three Plantago species (P. maxima Juss. ex Jacq., P. major L., and P. lanceolata L.). Trace element levels were assessed by inductively coupled plasma mass spectrometry. The data indicate that the leaves of P. lanceolata are characterized by the highest Co, Cr, and Se content, whereas P. maxima leaves contained the greatest levels of Si and Zn. In contrast, the highest concentrations of Co, Cr, Fe, I, Mn, Si, and V were detected in the roots of P. major. Zn content was also higher in P. maxima roots than in the other species analyzed. The toxic trace elements were differentially distributed across the studied species. In particular, P. lanceolata leaves contained significantly higher Al, As, Li, Ni, Pb, and Sr levels, whereas the B and Cd content was elevated in P. major as compared to the other species. Surprisingly, the leaf Hg level was the lowest in P. major, whose levels of Al, As, B, Cd, Ni, Li, and Sr were significantly higher than the other two species. The data indicate that the concentration of most of the essential trace elements was higher in the leaves and roots of P. major and P. lanceolata than in P. maxima, while P. maxima had less toxic metals. The obtained data on trace elements content in Plantago tissues may be taken into account while using plant preparations in practical medicine.

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Cancers, Vol. 8, Pages 75: HPV Associated Head and Neck Cancer

Head and neck cancers (HNCs) are a highly heterogeneous group of tumours that are associated with diverse clinical outcomes. Recent evidence has demonstrated that human papillomavirus (HPV) is involved in up to 25% of HNCs; particularly in the oropharyngeal carcinoma (OPC) subtype where it can account for up to 60% of such cases. HPVs are double-stranded DNA viruses that infect epithelial cells; numerous HPV subtypes, including 16, 18, 31, 33, and 35, drive epithelial cell transformation and tumourigenesis. HPV positive (HPV+) HNC represents a distinct molecular and clinical entity from HPV negative (HPV−) disease; the biological basis for which remains to be fully elucidated. HPV positivity is strongly correlated with a significantly superior outcome; indicating that such tumours should have a distinct management approach. This review focuses on the recent scientific and clinical investigation of HPV+ HNC. In particular, we discuss the importance of molecular and clinical evidence for defining the role of HPV in HNC, and the clinical impact of HPV status as a biomarker for HNC.

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Demand for radiotherapy in Spain

Abstract

Aim

Assessing the demand for radiotherapy in Spain based on existing evidence to estimate the human resources and equipment needed so that every person in Spain has access to high-quality radiotherapy when they need it.

Material and methods

We used data from the European Cancer Observatory on the estimated incidence of cancer in Spain in 2012, along with the evidence-based indications for radiotherapy developed by the Australian CCORE project, to obtain an optimal radiotherapy utilisation proportion (OUP) for each tumour.

Results

About 50.5 % of new cancers in Spain require radiotherapy at least once over the course of the disease. Additional demand for these services comes from reradiation therapy and non-melanoma skin cancer. Approximately, 25–30 % of cancer patients with an indication for radiotherapy do not receive it due to factors that include access, patient preference, familiarity with the treatment among physicians, and especially resource shortages, all of which contribute to its underutilisation.

Conclusions

Radiotherapy is underused in Spain. The increasing incidence of cancer expected over the next decade and the greater frequency of reradiations necessitate the incorporation of radiotherapy demand into need-based calculations for cancer services planning.

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Salvage treatment with irinotecan/cisplatin versus pemetrexed/cisplatin in patients with non-small cell lung cancer pre-treated with a non-platinum-based regimen in the first-line setting: a randomized phase II study of the Hellenic Oncology Research Group (HORG)

Abstract

Background

Platinum-based chemotherapy is the standard front-line treatment for patients with advanced non-small cell lung cancer (NSCLC). However, non-platinum combinations of third-generation chemotherapeutic agents are considered an alternative therapeutic option for patients who cannot tolerate the toxic effects of platinum compounds. In this study, the efficacy and toxicity of the combination of irinotecan plus cisplatin (IC) was compared to pemetrexed plus cisplatin (PC) regimen, in platinum-naïve patients with advanced NSCLC, who had been previously treated with the combination of a taxane plus gemcitabine.

Patients and methods

A total of 124 patients with locally advanced or metastatic NSCLC were randomly assigned to either irinotecan 110 mg/m² on day 1 and 100 mg/m² on day 8 plus cisplatin 80 mg/m² on day 8 every 3 weeks (IC arm) or pemetrexed 500 mg/m² plus cisplatin 80 mg/m² on day 1 every 3 weeks (PC arm). The primary endpoint of the study was the overall response rate (ORR).

Results

The ORR and median progression-free survival (PFS) in the IC arm were 18 % and 3.3 months, respectively, while in the PC arm were 19 % and 4.2 months (p = ns). Median overall survival (OS) was significantly higher in patients with PC (6.9 vs. 10.9; p = 0.013). PC regimen had a better toxicity profile compared to IC, with a statistically significant lower incidence of grade 3/4 neutropenia (3 vs. 31 %; p = 0.0001) and diarrhea (1.6 vs. 14.7 %, p = 0.018).

Conclusions

In patients with advanced NSCLC pretreated with docetaxel/gemcitabine, the combination of pemetrexed/cisplatin is associated with increased OS and is better tolerated than the combination of irinotecan/cisplatin and should be considered as a valid therapeutic option for platinum-naive, previously treated patients.

ClinicalTrials.gov Identifier

NCT00614965.

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MicroRNA-137 represses FBI-1 to inhibit proliferation and in vitro invasion and migration of hepatocellular carcinoma cells

Abstract

The pro-oncogene factor that binds to inducer of short transcripts-1 (FBI-1), which is encoded by ZBTB7A gene and belongs to POK (POZ/BTB and KrÜppel) protein family, has been shown to enhance hepatocellular carcinoma (HCC) cells proliferation and multi-drug resistance (MDR) process. However, the possibility that FBI-1 is a therapeutic target for further HCC treatment remains poorly determined. In the current study, two microRNA (miRNA) target prediction programs (TargetScan and MiRanda) were used to identify miR-137 as a potential regulator of FBI-1. Our results showed that expression of miR-137 was downregulated, while FBI-1 was upregulated in clinical HCC specimens, compared with paired non-tumor specimens. Overexpression of miR-137 via adenoviral vector inhibited the proliferation and anchorage-independent growth of HCC cells, HepG2 and MHCC-97H. Our data also showed that miR-137 repressed endogenous expression level of FBI-1, as well as Notch-1 and Survivin. MiR-137 also inhibited in vitro invasion and migration of HCC cells and attenuated their epithelial-mesenchymal transition (EMT) process. Moreover, miR-137 suppressed the growth rate of HepG2 cells in nude mice model. Overexpression of miR-137 via its adenoviral vector enhanced the sensitivity of HepG2 cells to anti-tumor drugs and attenuated the MDR process of a resistance cell line HepG2/adriamycin (ADR). Thus, FBI-1 downregulation mediated by miR-137 overexpression may be a potential strategy for HCC treatment.

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Laparoscopic Versus Open Resection for Gastrointestinal Stromal Tumors (GISTs)

Abstract

Purpose

Primary gastrointestinal stromal tumors (GISTs) are typically treated with open resection. There is growing interest in laparoscopic GIST resection; however, data is limited. We report our experience with GIST resections using both open and laparoscopic techniques.

Materials and Methods

Twenty-nine GIST patients underwent definitive intent resection at the University of Missouri from 1990 to 2010. Patients who underwent laparoscopic resection (n = 7) were matched on the basis of tumor size, age, tumor location, and National Comprehensive Cancer Network (NCCN) risk stratification with seven patients who underwent open resection. The two groups were compared with respect to age, gender, BMI, tumor size, tumor site, mitotic rate, surgical margins, NCCN risk stratification, estimated blood loss, hospital stay, surgical complications, disease recurrence, and overall survival.

Results

The cohorts did not differ with respect to age, gender, BMI, tumor location, tumor size, or positive margins (p > 0.05). Patients who underwent open resection had more NCCN high-risk patients, but the difference was not statistically significant (p = 0.08). There was significantly less estimated blood loss (median 15 vs. 150 mL, p < 0.05) and significantly shorter hospital stay (median 4 vs. 7 days, p < 0.05) for the laparoscopy group. There were no recurrences in the laparoscopy group, but there was one in the open group with a median follow-up of 55 and 63 months, respectively (p > 0.05). Five-year disease-free survival was 100 % for the laparoscopic group and 83 % for the open resection group.

Conclusions

Laparoscopic resection for appropriately selected GISTs is feasible and associated with significantly less blood loss and shorter hospitalizations compared to open resection. Further studies are needed to better define its role for GIST.

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