Reduced glutamate in white matter of male neonates exposed to alcohol in utero : a 1 H-magnetic resonance spectroscopy study

Abstract

In utero exposure to alcohol leads to a spectrum of fetal alcohol related disorders (FASD). However, few studies used have used proton magnetic resonance spectroscopy (¹H-MRS) to understand how neurochemical disturbances relate to the pathophysiology of FASD. Further, no studies to date have assessed brain metabolites in infants exposed to alcohol in utero. We hypothesize that neonates exposed to alcohol in utero will show decreased glutamatergic activity, pre-emptive of their clinical diagnosis or behavioural phenotype. Single voxel ¹H-MRS data, sampled in parietal white and gray matter, were acquired from 36 neonates exposed to alcohol in utero, and 31 control unexposed healthy neonates, in their 2nd-4th week of life. Metabolites relative to creatine with phosophocreatine and metabolites absolute concentrations using a water reference are reported. Male infants exposed to alcohol in utero were found to have reduced concentration of glutamate with glutamine (Glx) in their parietal white matter (PWM), compared to healthy male infants (p = 0.02). Further, male infants exposed to alcohol in utero had reduced concentration and ratio for glutamate (Glu) in their PWM (p = 0.02), compared to healthy male infants and female infants exposed to alcohol in utero. Female infants showed higher relative Glx and Glu ratios for parietal gray matter (PGM, p < 0.01), compared to male infants. We speculate that the decreased Glx and Glu concentrations in PWM are a result of delayed oligodendrocyte maturation, which may be a result of dysfunctional thyroid hormone activity in males exposed to alcohol in utero. Further study is required to elucidate the relationship between Glx and Glu, thyroid hormone activity, and oligodendrocyte maturation in infants exposure to alcohol in utero.

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The expression and prognostic value of protein tyrosine kinase 6 in early-stage cervical squamous cell cancer

Abstract

Background

Protein tyrosine kinase 6 (PTK6) is overexpressed in many epithelial tumors and predicts poor prognosis. However, PTK6 expression status and its role in cervical squamous cell cancer are unknown. This study aimed to investigate the expression level and clinical significance of PTK6 in early-stage cervical squamous cell cancer.

Methods

Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting analysis were performed to detect PTK6 mRNA and protein expression levels in 10 freshly frozen, early-stage cervical squamous cell cancer specimens and adjacent non-tumorous cervical tissues. The expression of PTK6 was detected using immunohistochemical staining in 150 formalin-fixed, paraffin-embedded, early-stage cervical squamous cell cancer sections and 10 normal cervical tissue sections.

Results

The mRNA and protein levels of PTK6 in cancer tissues were higher than those in adjacent non-tumorous cervical tissues. Immunohistochemical analysis showed that PTK6 was not expressed in normal cervical tissues but was overexpressed in the cytoplasm of cervical squamous cell cancer cells. The level of PTK6 expression was significantly associated with tumor grade (P = 0.020). The 5-year overall survival rate of patients with high PTK6 expression was lower than that of patients with low PTK6 expression (81.3% vs. 96.2%, P = 0.008). Multivariate Cox regression analysis showed that the expression level of PTK6 in cervical squamous cell cancer was an independent prognostic factor for patient survival (hazard ratio = 5.999, 95% confidence interval 1.622–22.191, P < 0.05).

Conclusions

PTK6 is overexpressed in cervical squamous cell cancer. Increased PTK6 expression is associated with reduced 5-year overall survival. PTK6 expression is an independent prognostic predictor for cervical cancer.

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Molecular profiles to biology and pathways: a systems biology approach

Abstract

Interpreting molecular profiles in a biological context requires specialized analysis strategies. Initially, lists of relevant genes were screened to identify enriched concepts associated with pathways or specific molecular processes. However, the shortcoming of interpreting gene lists by using predefined sets of genes has resulted in the development of novel methods that heavily rely on network-based concepts. These algorithms have the advantage that they allow a more holistic view of the signaling properties of the condition under study as well as that they are suitable for integrating different data types like gene expression, gene mutation, and even histological parameters.

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Inequalities in cancer screening participation: examining differences in perceived benefits and barriers

Abstract

Objective

Inequalities exist in colorectal cancer (CRC) screening uptake, with people from lower socioeconomic status backgrounds less likely to participate. Identifying the facilitators and barriers to screening uptake is important to addressing screening disparities. We pooled data from two trials to examine educational differences in psychological constructs related to guaiac Fecal Occult Blood testing (gFOBt).

Methods

Patients (n = 8,576) registered at seven general practices in England, within 15 years of the eligible age range for screening (45-59.5 years), were invited to complete a questionnaire. Measures included perceived barriers (emotional and practical) and benefits of screening, screening intentions, and participant characteristics including education.

Results

After data pooling, 2,181 responses were included. People with high school education or no formal education reported higher emotional and practical barriers, and were less likely to definitely intend to participate in screening, compared with university graduates in analyses controlling for study arm and participant characteristics. The belief that one would worry more about colorectal cancer after screening, and concerns about tempting fate were strongly negatively associated with education. In a model including education and participant characteristics, respondents with low emotional barriers, low practical barriers, and high perceived benefits were more likely to definitely intend to take part in screening.

Conclusions

In this analysis of adults approaching the CRC screening age, there was a consistent effect of education on perceived barriers towards gFOB testing, which could affect screening decision-making. Interventions should target specific barriers to reduce educational disparities in screening uptake and avoid exacerbating inequalities in CRC mortality.

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Links between personality, time perspective and intention to practice physical activity during cancer treatment: an exploratory study

Abstract

Objective

The purpose of the study was to analyze links between personality, time perspective and intention to practice physical activity during cancer treatment.

Method

143 patients participated in survey by questionnaire. Intention to practice physical activity, time perspective using Zimbardo Time Perspective Inventory, and personality with the Big Five Inventory were measured. Structural equation models using Lisrel were developed to examine hypothetical links between the variables.

Results

The adjusted model evidenced an excellent fit (Comparative fit index (CFI) = .92; Root mean squared error of approximation (RMSEA) = .076; p value = .014). Results showed that intention to practice exercise was positively linked with openness to experience and negatively with present fatalist time perspective. Moreover, conscientiousness and neuroticism were found to be linked with future time perspective, which was positively related with intention to practice physical activity.

Conclusion

The present exploratory study with patients suffering from cancer underlined the importance of considering jointly time perspective dimensions and personality factors for health behavior recommendations. Based on our results, we propose some reflections on practice to help nurses and physicians increase patient's motivation to be physically active. Taking into account patients' personality and time perspective, we would be able to propose specific awareness messages and offer short interventions to have an impact on patients' motivation to practice.

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MicroRNA-155-3p promotes hepatocellular carcinoma formation by suppressing FBXW7 expression

Abstract

Background

MicroRNAs (miRNAs) are small non-coding RNAs frequently dysregulated in human malignant tumors. In the present study, we analyzed the role miR-155-3p plays in Hepatocellular carcinoma (HCC), which has been reported participation in some other types of cancer.

Methods

qRT-PCR was used to measure the levels of miR-155-3p in HCC specimens and HCC cell lines. Overexpression of miR-155-3p and miR-155-3p inhibitor were transfected into HCC cell lines to investigate its role in HCC. Colony formation assay and 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assays were used to analyses cell proliferation in vitro. In vivo tumor formation assays were performed in BALB/c nude mice. Luciferase reporter assay was carried out to measure the translation of F-Box and WD repeat romain containing 7 (FBXW7).

Results

We found that miR-155-3p was remarkably upregulated both in HCC tissue and cell lines. Overexpression of miR-155-3p enhanced HCC cell proliferation in vitro and tumorigenesis in vivo. In addition, overexpression of miR-155-3p is correlated with decreased levels FBXW7 mainly through inhibiting the expression of FBXW7.

Conclusions

Our studies suggest that miR-155-3p plays an important role in the pathogenesis of HCC and implicates its potential applications in the treatment of HCC cancer.

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Evaluation of the effect of necitumumab on the corrected QT interval in patients with advanced solid tumors

Abstract

Purpose

Necitumumab is a second-generation, recombinant, human immunoglobulin G1 monoclonal antibody that blocks the ligand binding site of the epidermal growth factor receptor. The primary objective of this phase 2 study, conducted in accordance with International Conference on Harmonisation E14 guidance, was to determine the effect of necitumumab treatment on QT/QTc interval in patients with advanced solid tumors.

Methods

Patients received necitumumab monotherapy at an absolute dose of 800 mg, once per week for each 6-week cycle. Triplicate electrocardiogram readings were taken at pretreatment (baseline) and then weekly at multiple timepoints that were time-matched with blood samples to determine necitumumab concentrations.

Results

Seventy-five patients received treatment. Overall, the upper bound of the two-sided 90 % confidence interval for mean change from baseline in QTc in cycle 1 did not exceed 10 ms. No patients had a mean QTcF interval >500 ms, and no patients had an increase of >60 ms. Necitumumab concentration–QTc analysis also showed that necitumumab is unlikely to cause QTc prolongation.

Conclusions

The results demonstrate lack of effect of necitumumab on the QTc interval in heavily pretreated patients with advanced solid tumors, suggesting that QT prolongation is not a major safety concern for necitumumab at the recommended therapeutic dose. The safety profile was consistent with the known safety profile of necitumumab.

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Evaluation of the effect of necitumumab on the corrected QT interval in patients with advanced solid tumors

Abstract

Purpose

Necitumumab is a second-generation, recombinant, human immunoglobulin G1 monoclonal antibody that blocks the ligand binding site of the epidermal growth factor receptor. The primary objective of this phase 2 study, conducted in accordance with International Conference on Harmonisation E14 guidance, was to determine the effect of necitumumab treatment on QT/QTc interval in patients with advanced solid tumors.

Methods

Patients received necitumumab monotherapy at an absolute dose of 800 mg, once per week for each 6-week cycle. Triplicate electrocardiogram readings were taken at pretreatment (baseline) and then weekly at multiple timepoints that were time-matched with blood samples to determine necitumumab concentrations.

Results

Seventy-five patients received treatment. Overall, the upper bound of the two-sided 90 % confidence interval for mean change from baseline in QTc in cycle 1 did not exceed 10 ms. No patients had a mean QTcF interval >500 ms, and no patients had an increase of >60 ms. Necitumumab concentration–QTc analysis also showed that necitumumab is unlikely to cause QTc prolongation.

Conclusions

The results demonstrate lack of effect of necitumumab on the QTc interval in heavily pretreated patients with advanced solid tumors, suggesting that QT prolongation is not a major safety concern for necitumumab at the recommended therapeutic dose. The safety profile was consistent with the known safety profile of necitumumab.

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Cancers, Vol. 8, Pages 56: Targeted Vaccination against Human α-Lactalbumin for Immunotherapy and Primary Immunoprevention of Triple Negative Breast Cancer

We have proposed that safe and effective protection against the development of adult onset cancers may be achieved by vaccination against tissue-specific self-proteins that are "retired" from expression at immunogenic levels in normal tissues as we age, but are overexpressed in emerging tumors. α-Lactalbumin is an example of a "retired" self-protein because its expression in normal tissues is confined exclusively to the breast during late pregnancy and lactation, but is also expressed in the vast majority of human triple negative breast cancers (TNBC)—the most aggressive and lethal form of breast cancer and the predominant form that occurs in women at high genetic risk including those with mutated BRCA1 genes. In anticipation of upcoming clinical trials, here we provide preclinical data indicating that α-lactalbumin has the potential as a vaccine target for inducing safe and effective primary immunoprevention as well as immunotherapy against TNBC.

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ACR Appropriateness Criteria Hodgkin Lymphoma-Unfavorable Clinical Stage I and II.

These guidelines review the historical evolution of treatment for early-stage Hodgkin lymphoma (HL) with current standards that rely on prognostic factors to risk stratify and direct current treatment schemes that includes differentiation of favorable and unfavorable presentations. The major clinical trials for unfavorable early-stage HL are reviewed. Patients in this heterogenous subgroup of classic HL are best managed with sequential chemotherapy and radiotherapy. The role of imaging response assessment as a means to modify therapy is a strategy under investigation. Tailoring the radiation treatment volume and radiation dose prescription along with selective use of modern conformal techniques is expected to help reduce long-term toxicities. Many patients are well served receiving involved-site radiotherapy to 30 Gy after appropriate systemic therapy intensity; but, there are nuances for which some variations in the chemotherapy and radiotherapy specifics are appropriately individualized. Following a discussion of the current evidence-based treatment algorithms, several different example cases are reviewed to help physicians make appropriate treatment decisions. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Prognostic Significance of Nodal Ratio in Patients Undergoing Adjuvant Chemoradiotherapy After Curative Resection for Ampullary Cancer.

Objectives: To analyze the outcome of patients with ampullary cancer who had undergone curative surgery followed by adjuvant chemoradiotherapy and to identify the prognostic factors for these patients Methods: Between January 1991 and August 2006, 71 patients with ampullary cancer underwent curative resection followed by adjuvant radiotherapy. There were 38 males and 33 females, and median age was 56 years (range, 28 to 77 y). Postoperative radiotherapy was delivered to tumor bed and regional lymph nodes up to 40 to 50 Gy at 2 Gy/fraction; 67 patients also received intravenous 5-fluorouracil as a radiosensitizer. Median follow-up duration was 72 months for survivors. Results: There were 5 isolated locoregional recurrences, 20 isolated distant metastases, and 11 combined locoregional and distant relapses. The 5-year locoregional relapse-free and overall survival rates were 76.2% and 64.5%, respectively. On multivariate analysis, nodal ratio and histologic differentiation were significant prognostic factors for overall survival (P=0.0382 and 0.0331, respectively). Conclusions: Adjuvant chemoradiotherapy after curative resection can achieve a long-term survival rate in patients with ampullary cancer. Nodal ratio and histologic differentiation are independent prognostic factors for these patients. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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States, cities raise age for tobacco purchase

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Issue Information – TOC – Masthead

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New genetic test reduces chemotherapy use in patients with early-stage breast cancer

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New guidelines for long-term needs of head and neck cancer survivors

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Latanoprost and Dorzolamide for the Treatment of Pediatric Glaucoma: The Glaucoma Italian Pediatric Study (Gipsy), Design and Baseline Characteristics

Abstract

Introduction

To investigate the efficacy of a treatment strategy with latanoprost and dorzolamide in primary pediatric glaucoma patients partially responsive to surgery.

Methods

Single arm, prospective, interventional multicenter study. Primary pediatric glaucoma patients younger than 13 years after a single surgical procedure with IOP between 22 and 26 mmHg were considered eligible. At baseline, patients were allocated to latanoprost monotherapy once daily. Depending on intraocular pressure (IOP) reduction at first visit, the patients were allocated to one of three groups: continuation of latanoprost monotherapy, addition of dorzolamide twice daily, or switch to dorzolamide three times daily. The same approach for allocation in medication groups was used in all subsequent visits. Patients in the dorzolamide monotherapy group with IOP reduction <20% from baseline were considered non-responders and withdrawn. Study treatment and patient follow-up will continue for 3 years or until treatment failure. The primary endpoint is the percentage of responders. Secondary endpoints are time to treatment failure and frequency of adverse events.

Results

A total of 37 patients (69 eyes) were enrolled. The mean age was 4.0 ± 3.8 years, the female/male ratio was 1/1.7, and the majority of patients were Caucasian. Eighty percent of patients had bilateral glaucoma. Goniotomy was the most frequently performed surgery (38.6%), followed by trabeculotomy (22.8%), trabeculectomy (21.1%), and trabeculectomy plus trabeculotomy (17.5%). The baseline IOP was 23.6 ± 1.5 mmHg.

Conclusion

The study population is representative of patients frequently encountered after the first surgery for primary pediatric glaucoma. The study will produce evidence on the medium-term efficacy of a defined pharmacological approach.

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Comprehensive Study of Patients’ Compliance with Sublingual Immunotherapy in House Dust Mite Perennial Allergic Rhinitis

Abstract

Introduction

Allergen immunotherapy is a long-term treatment that has been associated with patient adherence issues. The aim of the study was to increase the knowledge on compliance of patients allergic to house dust mites, receiving sublingual immunotherapy (SLIT).

Methods

A retrospective observational study was performed in 53 Spanish allergy units. We enrolled patients undergoing the SLIT treatment for house dust mites including a scheduled control visit 12 months after initiating the therapy. We conducted a comprehensive assessment of compliance using three methods. In the first step, an allergist evaluated the patients according to the results of an interview and the existing medical records. The subjects taking more than 80% of the overall prescription were defined as compliant. The remaining noncompliant patients were divided into groups taking less than 25%, 25–50%, and 50–80% of the prescribed SLIT. In the second stage, we conducted the Morisky–Green test. Finally, the noncompliant patients were asked to fill a self-report assessment form. Data were stratified into age groups. The potential factors affecting compliance were also investigated.

Results

Overall, 380 subjects participated in the study. The compliance rate was 79.7%, and the treatment discontinuation rate was 22.5%, while 66.8% of patients were adherent (both compliant and continuing with the treatment). The results showed that children were the most compliant and adolescents the least compliant (86.6% and 60.9%, respectively). The main reason for noncompliance was "forgetting some doses" in 31.0% of the children, 48.0% of the adolescents, and 53.2% of the adults. Compliance was associated with the following factors: age, number of annual control visits, and reduction in symptomatic medication.

Conclusion

Our results showed that two out of three patients with house dust mite-induced allergic rhinitis adhered to the SLIT treatment. Multidisciplinary and integral solutions are needed to improve the compliance, with special attention paid to adolescents.

Funding

Stallergenes Greer Spain.

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Remarkable response in 2 cases of Advanced Poorly Differentiated Thyroid Carcinoma with liposomal doxorubicin plus cisplatin.

Remarkable response in 2 cases of Advanced Poorly Differentiated Thyroid Carcinoma with liposomal doxorubicin plus cisplatin.

Cancer Biol Ther. 2016 Jun 14;:0

Authors: Yang H, Chen Z, Wu M, Lei T, Yu H, Ge M

Abstract
BACKGROUND: Poorly Differentiated Thyroid Carcinoma (PDTC), especially advanced PDTC, is an aggressive disease and displays a much poorer prognosis compared with well differentiated thyroid carcinoma. Surgery is the recommended treatment in the early stage of PDTC, however, no effective treatment modalities are currently available for advanced PDTC.
METHODS: Two advanced PDTC patients with no radioiodine uptake adopted a cytotoxic chemotherapy with liposomal doxorubicin (35 mg/m(2), day 1) plus cisplatin (75 mg/m(2), day1-3) every 3 weeks. Computer tomography (CT) was performed after 6 cycles (case 1) or 5 cycles (case 2) of chemotherapy.
RESULTS: Our patients achieved remarkable response with one a Complete Remission (CR) and the other a very good Partial Remission (PR).
CONCLUSION: Our findings indicate that liposomal doxorubicin-based chemotherapy regimens might produce response in PDTC patients, and improve their overall survival and quality of life. Hence we believe this result is very important for oncologists in treating PDTC.

PMID: 27302615 [PubMed - as supplied by publisher]

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Remarkable response in 2 cases of Advanced Poorly Differentiated Thyroid Carcinoma with liposomal doxorubicin plus cisplatin.

Remarkable response in 2 cases of Advanced Poorly Differentiated Thyroid Carcinoma with liposomal doxorubicin plus cisplatin.

Cancer Biol Ther. 2016 Jun 14;:0

Authors: Yang H, Chen Z, Wu M, Lei T, Yu H, Ge M

Abstract
BACKGROUND: Poorly Differentiated Thyroid Carcinoma (PDTC), especially advanced PDTC, is an aggressive disease and displays a much poorer prognosis compared with well differentiated thyroid carcinoma. Surgery is the recommended treatment in the early stage of PDTC, however, no effective treatment modalities are currently available for advanced PDTC.
METHODS: Two advanced PDTC patients with no radioiodine uptake adopted a cytotoxic chemotherapy with liposomal doxorubicin (35 mg/m(2), day 1) plus cisplatin (75 mg/m(2), day1-3) every 3 weeks. Computer tomography (CT) was performed after 6 cycles (case 1) or 5 cycles (case 2) of chemotherapy.
RESULTS: Our patients achieved remarkable response with one a Complete Remission (CR) and the other a very good Partial Remission (PR).
CONCLUSION: Our findings indicate that liposomal doxorubicin-based chemotherapy regimens might produce response in PDTC patients, and improve their overall survival and quality of life. Hence we believe this result is very important for oncologists in treating PDTC.

PMID: 27302615 [PubMed - as supplied by publisher]

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Remarkable response in 2 cases of Advanced Poorly Differentiated Thyroid Carcinoma with liposomal doxorubicin plus cisplatin.

Remarkable response in 2 cases of Advanced Poorly Differentiated Thyroid Carcinoma with liposomal doxorubicin plus cisplatin.

Cancer Biol Ther. 2016 Jun 14;:0

Authors: Yang H, Chen Z, Wu M, Lei T, Yu H, Ge M

Abstract
BACKGROUND: Poorly Differentiated Thyroid Carcinoma (PDTC), especially advanced PDTC, is an aggressive disease and displays a much poorer prognosis compared with well differentiated thyroid carcinoma. Surgery is the recommended treatment in the early stage of PDTC, however, no effective treatment modalities are currently available for advanced PDTC.
METHODS: Two advanced PDTC patients with no radioiodine uptake adopted a cytotoxic chemotherapy with liposomal doxorubicin (35 mg/m(2), day 1) plus cisplatin (75 mg/m(2), day1-3) every 3 weeks. Computer tomography (CT) was performed after 6 cycles (case 1) or 5 cycles (case 2) of chemotherapy.
RESULTS: Our patients achieved remarkable response with one a Complete Remission (CR) and the other a very good Partial Remission (PR).
CONCLUSION: Our findings indicate that liposomal doxorubicin-based chemotherapy regimens might produce response in PDTC patients, and improve their overall survival and quality of life. Hence we believe this result is very important for oncologists in treating PDTC.

PMID: 27302615 [PubMed - as supplied by publisher]

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Issue Information — Table of Contents

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Issue Information — UICC

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Issue Information — Information for Authors

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Ototoxicity of 12 mg/kg cisplatin in the Fischer 344/NHsd rat using multiple dosing strategies.

Ototoxicity continues to be a major dose-limiting side effect of cis-diamminedichloroplatinum(II) (cisplatin). With an ongoing need to develop pharmaceutical protection strategies for cisplatin's ototoxicity, there is also a need to develop stable in-vivo mammalian models of cisplatin ototoxicity. The current study examined the difference in ototoxicity of a cumulative 12 mg/kg dose of cisplatin in the Fischer 344/NHsd rat when administered over four different dosing protocols. Hearing sensitivity was measured using free-field auditory brainstem response thresholds under anesthesia. Rats were divided into four groups. The first group was administered 12 mg/kg of cisplatin in a single bolus infusion. The second group was administered two 6 mg/kg infusions separated by 7 days. The third group was administered 3 mg/kg injections once per day for 4 consecutive days. The fourth group was administered 3 mg/kg injections in four injections separated by 3 days each. Hearing thresholds and body weights were measured at 3 and 7 days after the final cisplatin exposure. Postmortem sensory cell counts were used to confirm injury to the auditory system. The 4 consecutive days of 3 mg/kg induced a greater mortality rate and greater hearing loss at day 3 than the other experimental protocols. The 3 mg/kg administered every 3 days induced less sensory cell loss than the other conditions. The findings indicate that 4 consecutive days of 3 mg/kg cisplatin is not a viable ototoxicity model in the Fischer 344/NHsd rat, but that the other models are all effective in inducing comparable cochlear injuries. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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