Prostatic Adenocarcinoma Incognito Manifestation as Generalized Lymphadenopathy: a Rare Case Report

Abstract

Generalized lymphadenopathy is a rare manifestation of carcinoma prostate. Here, we report a case of a 73-year-old male who presented with left supraclavicular lymphadenopathy along with hoarseness of voice and weight loss. His CT neck, chest, abdomen, and subsequently18F-FDG PET CT were suggestive of generalized lymphadenopathy with skeletal involvement. He was not having any urinary or bone symptoms. The biopsy of supraclavicular lymph node revealed metastatic adenocarcinoma, whose prostatic origin was suggested by IHC staining of PSA. The diagnosis was confirmed by prostatic biopsy along with markedly raised serum PSA. We emphasize that in men with adenocarcinoma of undetermined origin, a suspicion of prostate cancer is important for accurate diagnosis and therapeutic approach.

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Isolated Port Site Metastases in Carcinoma Gallbladder: Does it Represent Better Prognosis?

Abstract

Port site metastasis (PSM) is a known sequela of laparoscopic cholecystectomy in carcinoma gallbladder. While they are associated with poor prognosis, isolated PSM may represent a subset with better outcomes. We conducted a clinical audit of 33 cases of PSMs treated over a 6-year period. This included 26 cases of isolated PSM and 7 cases of PSM with systemic metastases. The mean time interval between index surgery and appearance of PSM was longer in the patients with isolated PSM (33.11 vs 25.5 months, p = 0.041). Isolated PSMs were treated with surgery and chemotherapy while the others were treated with palliative chemotherapy only. Two out of 27 cases (7 %) of isolated PSM had disease progression during therapy while 3 out of the 6 cases (50 %) of PSM with other sites of recurrences had disease progression while on treatment. Time to disease progression was significant more in cases of isolated PSM (17.14 vs 7.66 months, p = 0.034). The mean survival time too was significantly more in these cases (25.33 vs 15.66 months, p = 0.015). Isolated PSMs in case of gallbladder cancer may represent a distinct disease entity. Aggressive surgical management in addition to systemic chemotherapy may result in a reasonable survival advantage.

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Overexpression of LARP1 predicts poor prognosis of colorectal cancer and is expected to be a potential therapeutic target

Abstract

This study investigated the significance of La-related protein 1 (LARP1) in the development and progression of colorectal cancer (CRC). Quantitative real-time polymerase chain reaction and Western blot analyses were carried out to determine the mRNA and protein expression of LARP1 in CRC tumor tissues and paired adjacent normal mucosa. The expression of LARP1 was upregulated in CRC. Immunohistochemical analysis using tissue microarray was performed. A positive correlation between LARP1 and proliferating cell nuclear antigen (PCNA) in the area of proliferation was observed using the Spearman's correlation coefficient test (r = 0.332, P < 0.01). The elevated expression of LARP1 significantly correlated with T stage (P = 0.02), N stage (P = 0.006), M stage (P < 0.001), American Joint Committee on Cancer (AJCC) stage (P = 0.04), differentiation rank (P < 0.001), and PCNA level (P < 0.001). In addition, the inhibitory effect of LARP1 knockdown on CRC cell proliferation was demonstrated using Cell Counting Kit-8 (CCK8) and colony-forming cell (CFC) assays. Multivariate analysis showed that LARP1 was an independent prognostic factor for overall survival (OS; hazard rate (HR) = 0.244; 95 % confidence interval (CI), 0.078–0.769; P = 0.016) and disease-free survival (DFS; HR = 0.281; 95 % CI, 0.086–0.917; P = 0.035) in CRC patients. LARP1 plays an important role in the proliferation of colorectal cancer and represents a new prognostic indicator.

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NETs in cancer

Abstract

Many aspects of neutrophil hyperactivity and its role in numerous immune responses still remain a mystery. A new neutrophil mechanism was discovered recently, i.e., the formation of neutrophil extracellular traps (NETs). These structures, composed of DNA strands and neutrophil granule proteins, are an element of the non-specific immune response and bind pathogens to prevent their spread and ensure increased local concentrations of toxic factors. Research on this phenomenon shows that tumor-associated neutrophils (TANs) also form and release NETs. Reports on the role of NETs in the course of cancer are scarce, and the opinions on the involvement of extracellular traps in the disease are divided, indicating a dual function. There is speculation about the anti-cancer properties of NETs connected with direct killing of cancer cells or stimulation of the immune system. On the other hand, the trap structures might promote migration and immune escape of cancer cells or constitute a physical barrier between cancer cells and immune-competent cells. This article summarizes our knowledge about the proven roles of NETs in the course of cancer with particular focus on the significance of NETs as prognosis biomarkers in the course of the neoplastic process and their potential use in therapy.

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Cryopreserved NK cells in the treatment of haematological malignancies: preclinical study

Abstract

Background

Leukaemia is an aggressive cancer of haematopoiesis. Despite increasing treatment success, the relapse rate is still high. Natural killer (NK) cells play a key role in the immune response to malignancies; thus, it is conceivable that NK cell-based immunotherapy may control relapses, while extending the disease-free survival. In our study, we investigated whether cryopreserved NK cells are able to kill the leukaemic K562 cell line, the necessity of IL-2 co-application and the association of activation marker expression (NKp44, NKG2D and CD25) with cytotoxic potential.

Materials and methods

K562 cells were added to NK cell cultures in different ratios, i.e. 1:5, 1:10 and 1:20 (K562/NK), immediately after thawing NK cells or after 3–6–12–24 h of re-cultivation with or without IL-2.

Results

Our results demonstrated the ability of cryopreserved NK cells to kill K562 in all ratios, times and culture conditions. The number of dead K562 cells depended on the number of NK cells and on the presence of IL-2. NK cells cytotoxic potential decreased gradually in the culture without IL-2. In contrast, NK cell-mediated cytotoxicity remained the same during the entire re-culture period after IL-2 re-application.

Conclusion

Our study proved the efficacy of using cryopreserved ready-for-use NK cells in relapse treatment and the need for simultaneous administration of IL-2.

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The circular RNA ciRS-7 (Cdr1as) acts as a risk factor of hepatic microvascular invasion in hepatocellular carcinoma

Abstract

Purpose

Circular RNAs (circRNA) represent a novel class of widespread and diverse endogenous RNAs that regulate gene expression in mammals. microRNA-7 (miR-7) is a well-demonstrated suppressor of hepatocellular carcinoma (HCC). Recent studies have showed that one such circRNA, ciRS-7 (also termed as Cdr1as) was the inhibitor and sponge of miR-7 in the embryonic zebrafish midbrain and islet cells. However, the relationships among ciRS-7, miR-7 and clinical features of HCC remain to be clarified.

Methods

Expression levels of ciRS-7, miR-7 and three miR-7-targeted mRNAs in 108 pairs of HCC and their matched non-tumor tissues were examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The protein production of these three miR-7-targeted mRNAs was further verified by Western blot. The relationship between ciRS-7 level and clinicopathological features as well as the recurrence of HCC patients was analyzed. The univariate and multivariate logistic regression analyses were used to detect the risk factors of hepatic microvascular invasion (MVI). The correlation among ciRS-7, miR-7 and miR-7-targeted mRNAs was evaluated using Spearman's correlation test.

Results

There was no significant difference of ciRS-7 expression levels between the HCC tissues and the matched non-tumor tissues (0.67 ± 1.49 vs. 0.44 ± 0.45, p = 0.13), and the ciRS-7 levels in more than half of HCC tissues (65 out of 108, 60.2 %) were down-regulated when compared with their matched non-tumor tissues. However, the expression of ciRS-7 was significantly correlated with the following three clinicopathological characteristics of HCC patients: age <40 years (p = 0.02), serum AFP ≥400 ng/µl (p < 0.01) and hepatic MVI (p = 0.03). Meanwhile, up-regulated ciRS-7 expression was not only an independent risk factor of hepatic MVI but also had a capable predictive ability for MVI (AUC = 0.68, p = 0.001) at the cut-off value of 0.135. Furthermore, the expression of ciRS-7 in HCC tissues with concurrent MVI was inversely correlated with that of miR-7 (r = −0.39, p = 0.007) and positively related with that of two miR-7-targeted genes [PIK3CD (r = 0.55, p < 0.001) and p70S6K (r = 0.34, p = 0.021)]. In addition, the median recurrent time of patients from higher ciRS-7 level group was shorter than that of lower ciRS-7 group (18 vs. 25 months), but no significant difference was observed (p = 0.38).

Conclusions

The expression levels of ciRS-7 were comparable between HCC and matched non-tumor tissues. However, the highly ciRS-7 expression in HCC tissues was significantly correlated with hepatic MVI, AFP level and younger age and thus partly related with the deterioration of HCC. Especially, ciRS-7 was one of the independent factors of hepatic MVI. These data suggested that ciRS-7 may be a promising biomarker of hepatic MVI and a novel therapy target for restraining MVI.

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Blue Ribbon Panel Report: The Power of the Cancer Community Coming Together

Listening to the presentation of the Cancer Moonshot Blue Ribbon Panel report at the National Cancer Advisory Board (NCAB) meeting earlier this week, I was moved and inspired by this culmination of 5 months of work. The report demonstrates the power of the cancer community coming together as it never has before to deliver a promise of progress against cancer. The time, energy, dedication, and ideas that went into the report's creation have been nothing short of extraordinary, and I'd like to thank the cancer community for participating in this collaborative and important undertaking.

This report represents the collaboration of science, technology, advocacy, social science, and big data to solve some of cancer's greatest challenges. At the core of the report are 10 bold yet feasible initiatives that can benefit patients by changing the trajectory of our understanding of how cancer develops, how to prevent it, and how to treat it. I am honored to deliver this compelling report to Vice President Biden and my federal colleagues on the Cancer Moonshot Task Force for inclusion in their reports to the President later this fall.

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Histone deacetylase inhibitors enhance CD1d-dependent NKT cell responses to lymphoma

Abstract

Histone deacetylases (HDACs) are a family of enzymes that influence expression of genes implicated in tumor initiation, progression, and anti-tumor responses. In addition to their canonical role in deacetylation of histones, HDACs regulate many non-canonical targets, such as Signal Transducer and Activator of Transcription 3 (STAT3). We hypothesize that tumors use epigenetic mechanisms to dysregulate CD1d-mediated antigen presentation, thereby impairing the ability of natural killer T (NKT) cells to recognize and destroy malignant cells. In this study, we pre-treated CD1d-expressing tumor cells with HDAC inhibitors (HDACi) and assessed CD1d-dependent NKT cell responses to mantle cell lymphoma (MCL). Pre-treatment with Trichostatin-A, a pan-HDACi, rapidly enhanced both CD1d- and MHC class II-mediated antigen presentation. Similarly, treatment of MCL cells with other HDACi resulted in enhanced CD1d-dependent NKT cell responses. The observed changes are due, at least in part, to an increase in both CD1D mRNA and CD1d cell surface expression. Mechanistically, we found that HDAC2 binds to the CD1D promoter. Knockdown of HDAC2 in tumor cells resulted in a significant increase in CD1d-mediated antigen presentation. In addition, treatment with HDACi inhibited STAT3 and STAT3-regulated inflammatory cytokine secretion by MCL cells. We demonstrated that MCL-secreted IL-10 inhibits CD1d-mediated antigen presentation and pre-treatment with TSA abrogates secretion of IL-10 by MCL. Taken together, our studies demonstrate the efficacy of HDACi in restoring anti-tumor responses to MCL through both cell-intrinsic and cell-extrinsic mechanisms and strongly implicate a role for HDACi in enhancing immune responses to cancer.

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Conditioned media from differentiating craniofacial bone marrow stromal cells influence mineralization and proliferation in periodontal ligament stem cells

Abstract

Previous reports have mainly focused on the behavioral responses of human periodontal ligament stem cells (hPDLSCs) in interaction with tibia bone marrow stromal cells (BMSCs). However, there is little study on the biologic features of hPDLSCs under the induction of maxilla BMSCs (M-BMSCs) at different phases of osteogenic differentiation. We hypothesized that M-BMSCs undergoing osteogenic differentiation acted on the proliferation, differentiation, and bone-forming capacity of hPDLSCs. In this paper, primary hPDLSCs and human M-BMSCs (hM-BMSCs) were expanded in vitro. After screening of surface markers for characterization, hPDLSCs were cocultured with different phases of differentiating hM-BMSCs. Cell proliferation and alkaline phosphatase activity were examined, and mineralization-associated markers such as osteocalcin and runt-related transcription factor 2 of hPDLSCs in coculture with uninduced/osteoinduced hM-BMSCs were evaluated. hPDLSCs in hM-BMSCs-conditioned medium (hM-BMSCs-CM) group showed a reduction in proliferation compared with untreated hPDLSCs, while osteoinduced hM-BMSCs for 10 day-conditioned medium (hM-BMSCs-CM-10ds) and osteoinduced hM-BMSCs for 15 day-conditioned medium (hM-BMSCs-CM-15ds) enhance the proliferation of hPDLSCs. hM-BMSCs of separate differentiation stages temporarily inhibited osteogenesis of hPDLSCs in the early days. Upon extending time periods, uninduced/osteoinduced hM-BMSCs markedly enhanced osteogenesis of hPDLSCs to different degrees. The transplantation results showed hM-BMSCs-CM-15ds treatment promoted tissue regeneration to generate cementum/periodontal ligament-like structure characterized by hard-tissue formation. This research supported the notion that hM-BMSCs triggered osteogenesis of hPDLSCs suggesting important implications for periodontal engineering.

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Exosomes secreted from human colon cancer cells influence the adhesion of neighboring metastatic cells: Role of microRNA-210.

Exosomes secreted from human colon cancer cells influence the adhesion of neighboring metastatic cells: Role of microRNA-210.

Cancer Biol Ther. 2016 Aug 11;:1-8

Authors: Bigagli E, Luceri C, Guasti D, Cinci L

Abstract
Cancer-secreted exosomes influence tumor microenvironment and support cancer growth and metastasis. MiR-210 is frequently up-regulated in colorectal cancer tissues and correlates with metastatic disease. We investigated whether exosomes are actively released by HCT-8 colon cancer cells, the role of exosomal miR-210 in the cross-talk between primary cancer cells and neighboring metastatic cells and its contribution in regulating epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET). After 7 d of culture, a subpopulation of viable HCT-8 cells detached the monolayer and started to grow in suspension, suggesting anoikis resistance and a metastatic potential. The expression of key proteins of EMT revealed that these cells were E-cadherin negative and vimentin positive further confirming their metastatic phenotype and the acquisition of anoikis resistance. Metastatic cells, in the presence of adherently growing HCT-8, continued to grow in suspension whereas only if seeded in cell-free wells, were able to adhere again and to form E-cadherin positive and vimentin negative new colonies, suggesting the occurrence of MET. The chemosensitivity to 5 fluorouracil and to FOLFOX-like treatment of metastatic cells was significantly diminished compared to adherent HCT-8 cells. Of note, adherent new colonies undergoing MET, were insensitive to both chemotherapeutic strategies. Electron microscopy analysis demonstrated that adherently growing HCT-8, actually secreted exosomes and that exosomes in turn were taken up by metastatic cells. When exosomes secreted by adherently growing HCT-8 were administered to metastatic cells, MET was significantly inhibited. miR-210 was significantly upregulated in exosomes compared to its intracellular levels in adherently growing HCT-8 cells and correlated to anoikis resistance and EMT markers. Exosomes containing miR-210 might be considered as EMT promoting signals that preserve the local cancer-growth permissive milieu and also guide metastatic cells to free, new sites of dissemination.

PMID: 27611932 [PubMed - as supplied by publisher]

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Long time response with chemotherapy in ROS1 NSCLC patient with unusual metastatic site.

Long time response with chemotherapy in ROS1 NSCLC patient with unusual metastatic site.

Cancer Biol Ther. 2016 Aug 12;:1-5

Authors: Franchina T, Russo A, Ricciardi GR, Liguori G, Herberg A, Normanno N, Adamo V

Abstract
During the last decade the therapeutic landscape of Non Small Cell Lung Cancer (NSCLC) has profoundly changed with the identification of actionable genetic alterations that defined molecularly selected subgroups of patients with specific clinic-pathological characteristics and increased sensitivity to specific targeted agents. The presence of ROS1 rearrangements defines a small subgroup of lung adenocarcinomas (∼1-2%) with peculiar clinic-pathological characteristics and increased sensitivity to Crizotinib. It has been reported that ROS1-tranlslocated NSCLCs may also respond well to Pemetrexed-based chemotherapy. Moreover, patients with oncogene-addicted NSCLC may present peculiar pattern of metastatization and, in some instances, are associated with unusual site of metastases. Herein, we present a case of a young woman with bilateral ovarian metastases from a ROS1-positive adenocarcinoma of the lung with a lengthy progression-free survival on Pemetrexed-containing chemotherapy.

PMID: 27611848 [PubMed - as supplied by publisher]

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Novel BCR-ABL1 fusion and leukemic mutations of SETBP1, PAX5, and TP53 detected by next generation sequencing in chronic myeloid leukemia.

Novel BCR-ABL1 fusion and leukemic mutations of SETBP1, PAX5, and TP53 detected by next generation sequencing in chronic myeloid leukemia.

Cancer Biol Ther. 2016 Aug 12;:1-7

Authors: Fu S, Hu Y, Fu Y, Chen F, Liu X, Zhang M, Wang X, Tu S, Zhang J

Abstract
Patients with BCR-ABL1 fusion genes are potential candidates for targeted therapy with tyrosine kinase inhibitor (TKI) imatinib. However, novel BCR-ABL1 fusion variants can be undetected by qRT-PCR-based routine molecular screening, affecting immediate patient management and proper treatment selection. In this study, we describe a case of chronic myeloid leukemia (CML) harboring a novel BCR-ABL1 variant gene. Although Fluorescent In situ Hybridization (FISH) analysis suggested Philadelphia (Ph) translocation, qRT-PCR screening failed to detect the presence of a functional fusion transcript, which is critical for selecting targeted therapy against BCR-ABL1 fusion with aberrant kinase activity. Meanwhile, G-band cytogenetic analysis was performed twice without a solid conclusion. To overcome the uncertainty whether TKIs should be used to treat this patient effectively, we performed whole genome sequencing (WGS) in a next-generation sequencing (NGS) platform and discovered an unusual e13a2-like BCR-ABL1 fusion with 9 ABL1 intron 1 nucleotides incorporated into the broken BCR exon 13 to form a novel chimeric exon, which has never been described previously based on the best of our knowledge. Based on FISH and NGS results, the patient was treated with imatinib, showing significant improvement. Moreover, we also detected novel genetic mutations in the known leukemic genes SETBP1, PAX5, and TP53, while their role in the leukemogenesis remains to be determined. In summary, we have identified BCR-ABL1 fusion and other genetic mutations in a diagnostically difficult case of CML, demonstrating that NGS is a powerful diagnostic tool when routine procedures are challenged.

PMID: 27611742 [PubMed - as supplied by publisher]

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Exosomes secreted from human colon cancer cells influence the adhesion of neighboring metastatic cells: Role of microRNA-210.

Exosomes secreted from human colon cancer cells influence the adhesion of neighboring metastatic cells: Role of microRNA-210.

Cancer Biol Ther. 2016 Aug 11;:1-8

Authors: Bigagli E, Luceri C, Guasti D, Cinci L

Abstract
Cancer-secreted exosomes influence tumor microenvironment and support cancer growth and metastasis. MiR-210 is frequently up-regulated in colorectal cancer tissues and correlates with metastatic disease. We investigated whether exosomes are actively released by HCT-8 colon cancer cells, the role of exosomal miR-210 in the cross-talk between primary cancer cells and neighboring metastatic cells and its contribution in regulating epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET). After 7 d of culture, a subpopulation of viable HCT-8 cells detached the monolayer and started to grow in suspension, suggesting anoikis resistance and a metastatic potential. The expression of key proteins of EMT revealed that these cells were E-cadherin negative and vimentin positive further confirming their metastatic phenotype and the acquisition of anoikis resistance. Metastatic cells, in the presence of adherently growing HCT-8, continued to grow in suspension whereas only if seeded in cell-free wells, were able to adhere again and to form E-cadherin positive and vimentin negative new colonies, suggesting the occurrence of MET. The chemosensitivity to 5 fluorouracil and to FOLFOX-like treatment of metastatic cells was significantly diminished compared to adherent HCT-8 cells. Of note, adherent new colonies undergoing MET, were insensitive to both chemotherapeutic strategies. Electron microscopy analysis demonstrated that adherently growing HCT-8, actually secreted exosomes and that exosomes in turn were taken up by metastatic cells. When exosomes secreted by adherently growing HCT-8 were administered to metastatic cells, MET was significantly inhibited. miR-210 was significantly upregulated in exosomes compared to its intracellular levels in adherently growing HCT-8 cells and correlated to anoikis resistance and EMT markers. Exosomes containing miR-210 might be considered as EMT promoting signals that preserve the local cancer-growth permissive milieu and also guide metastatic cells to free, new sites of dissemination.

PMID: 27611932 [PubMed - as supplied by publisher]

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Long time response with chemotherapy in ROS1 NSCLC patient with unusual metastatic site.

Long time response with chemotherapy in ROS1 NSCLC patient with unusual metastatic site.

Cancer Biol Ther. 2016 Aug 12;:1-5

Authors: Franchina T, Russo A, Ricciardi GR, Liguori G, Herberg A, Normanno N, Adamo V

Abstract
During the last decade the therapeutic landscape of Non Small Cell Lung Cancer (NSCLC) has profoundly changed with the identification of actionable genetic alterations that defined molecularly selected subgroups of patients with specific clinic-pathological characteristics and increased sensitivity to specific targeted agents. The presence of ROS1 rearrangements defines a small subgroup of lung adenocarcinomas (∼1-2%) with peculiar clinic-pathological characteristics and increased sensitivity to Crizotinib. It has been reported that ROS1-tranlslocated NSCLCs may also respond well to Pemetrexed-based chemotherapy. Moreover, patients with oncogene-addicted NSCLC may present peculiar pattern of metastatization and, in some instances, are associated with unusual site of metastases. Herein, we present a case of a young woman with bilateral ovarian metastases from a ROS1-positive adenocarcinoma of the lung with a lengthy progression-free survival on Pemetrexed-containing chemotherapy.

PMID: 27611848 [PubMed - as supplied by publisher]

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Novel BCR-ABL1 fusion and leukemic mutations of SETBP1, PAX5, and TP53 detected by next generation sequencing in chronic myeloid leukemia.

Novel BCR-ABL1 fusion and leukemic mutations of SETBP1, PAX5, and TP53 detected by next generation sequencing in chronic myeloid leukemia.

Cancer Biol Ther. 2016 Aug 12;:1-7

Authors: Fu S, Hu Y, Fu Y, Chen F, Liu X, Zhang M, Wang X, Tu S, Zhang J

Abstract
Patients with BCR-ABL1 fusion genes are potential candidates for targeted therapy with tyrosine kinase inhibitor (TKI) imatinib. However, novel BCR-ABL1 fusion variants can be undetected by qRT-PCR-based routine molecular screening, affecting immediate patient management and proper treatment selection. In this study, we describe a case of chronic myeloid leukemia (CML) harboring a novel BCR-ABL1 variant gene. Although Fluorescent In situ Hybridization (FISH) analysis suggested Philadelphia (Ph) translocation, qRT-PCR screening failed to detect the presence of a functional fusion transcript, which is critical for selecting targeted therapy against BCR-ABL1 fusion with aberrant kinase activity. Meanwhile, G-band cytogenetic analysis was performed twice without a solid conclusion. To overcome the uncertainty whether TKIs should be used to treat this patient effectively, we performed whole genome sequencing (WGS) in a next-generation sequencing (NGS) platform and discovered an unusual e13a2-like BCR-ABL1 fusion with 9 ABL1 intron 1 nucleotides incorporated into the broken BCR exon 13 to form a novel chimeric exon, which has never been described previously based on the best of our knowledge. Based on FISH and NGS results, the patient was treated with imatinib, showing significant improvement. Moreover, we also detected novel genetic mutations in the known leukemic genes SETBP1, PAX5, and TP53, while their role in the leukemogenesis remains to be determined. In summary, we have identified BCR-ABL1 fusion and other genetic mutations in a diagnostically difficult case of CML, demonstrating that NGS is a powerful diagnostic tool when routine procedures are challenged.

PMID: 27611742 [PubMed - as supplied by publisher]

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Exosomes secreted from human colon cancer cells influence the adhesion of neighboring metastatic cells: Role of microRNA-210.

Exosomes secreted from human colon cancer cells influence the adhesion of neighboring metastatic cells: Role of microRNA-210.

Cancer Biol Ther. 2016 Aug 11;:1-8

Authors: Bigagli E, Luceri C, Guasti D, Cinci L

Abstract
Cancer-secreted exosomes influence tumor microenvironment and support cancer growth and metastasis. MiR-210 is frequently up-regulated in colorectal cancer tissues and correlates with metastatic disease. We investigated whether exosomes are actively released by HCT-8 colon cancer cells, the role of exosomal miR-210 in the cross-talk between primary cancer cells and neighboring metastatic cells and its contribution in regulating epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET). After 7 d of culture, a subpopulation of viable HCT-8 cells detached the monolayer and started to grow in suspension, suggesting anoikis resistance and a metastatic potential. The expression of key proteins of EMT revealed that these cells were E-cadherin negative and vimentin positive further confirming their metastatic phenotype and the acquisition of anoikis resistance. Metastatic cells, in the presence of adherently growing HCT-8, continued to grow in suspension whereas only if seeded in cell-free wells, were able to adhere again and to form E-cadherin positive and vimentin negative new colonies, suggesting the occurrence of MET. The chemosensitivity to 5 fluorouracil and to FOLFOX-like treatment of metastatic cells was significantly diminished compared to adherent HCT-8 cells. Of note, adherent new colonies undergoing MET, were insensitive to both chemotherapeutic strategies. Electron microscopy analysis demonstrated that adherently growing HCT-8, actually secreted exosomes and that exosomes in turn were taken up by metastatic cells. When exosomes secreted by adherently growing HCT-8 were administered to metastatic cells, MET was significantly inhibited. miR-210 was significantly upregulated in exosomes compared to its intracellular levels in adherently growing HCT-8 cells and correlated to anoikis resistance and EMT markers. Exosomes containing miR-210 might be considered as EMT promoting signals that preserve the local cancer-growth permissive milieu and also guide metastatic cells to free, new sites of dissemination.

PMID: 27611932 [PubMed - as supplied by publisher]

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Long time response with chemotherapy in ROS1 NSCLC patient with unusual metastatic site.

Long time response with chemotherapy in ROS1 NSCLC patient with unusual metastatic site.

Cancer Biol Ther. 2016 Aug 12;:1-5

Authors: Franchina T, Russo A, Ricciardi GR, Liguori G, Herberg A, Normanno N, Adamo V

Abstract
During the last decade the therapeutic landscape of Non Small Cell Lung Cancer (NSCLC) has profoundly changed with the identification of actionable genetic alterations that defined molecularly selected subgroups of patients with specific clinic-pathological characteristics and increased sensitivity to specific targeted agents. The presence of ROS1 rearrangements defines a small subgroup of lung adenocarcinomas (∼1-2%) with peculiar clinic-pathological characteristics and increased sensitivity to Crizotinib. It has been reported that ROS1-tranlslocated NSCLCs may also respond well to Pemetrexed-based chemotherapy. Moreover, patients with oncogene-addicted NSCLC may present peculiar pattern of metastatization and, in some instances, are associated with unusual site of metastases. Herein, we present a case of a young woman with bilateral ovarian metastases from a ROS1-positive adenocarcinoma of the lung with a lengthy progression-free survival on Pemetrexed-containing chemotherapy.

PMID: 27611848 [PubMed - as supplied by publisher]

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Novel BCR-ABL1 fusion and leukemic mutations of SETBP1, PAX5, and TP53 detected by next generation sequencing in chronic myeloid leukemia.

Novel BCR-ABL1 fusion and leukemic mutations of SETBP1, PAX5, and TP53 detected by next generation sequencing in chronic myeloid leukemia.

Cancer Biol Ther. 2016 Aug 12;:1-7

Authors: Fu S, Hu Y, Fu Y, Chen F, Liu X, Zhang M, Wang X, Tu S, Zhang J

Abstract
Patients with BCR-ABL1 fusion genes are potential candidates for targeted therapy with tyrosine kinase inhibitor (TKI) imatinib. However, novel BCR-ABL1 fusion variants can be undetected by qRT-PCR-based routine molecular screening, affecting immediate patient management and proper treatment selection. In this study, we describe a case of chronic myeloid leukemia (CML) harboring a novel BCR-ABL1 variant gene. Although Fluorescent In situ Hybridization (FISH) analysis suggested Philadelphia (Ph) translocation, qRT-PCR screening failed to detect the presence of a functional fusion transcript, which is critical for selecting targeted therapy against BCR-ABL1 fusion with aberrant kinase activity. Meanwhile, G-band cytogenetic analysis was performed twice without a solid conclusion. To overcome the uncertainty whether TKIs should be used to treat this patient effectively, we performed whole genome sequencing (WGS) in a next-generation sequencing (NGS) platform and discovered an unusual e13a2-like BCR-ABL1 fusion with 9 ABL1 intron 1 nucleotides incorporated into the broken BCR exon 13 to form a novel chimeric exon, which has never been described previously based on the best of our knowledge. Based on FISH and NGS results, the patient was treated with imatinib, showing significant improvement. Moreover, we also detected novel genetic mutations in the known leukemic genes SETBP1, PAX5, and TP53, while their role in the leukemogenesis remains to be determined. In summary, we have identified BCR-ABL1 fusion and other genetic mutations in a diagnostically difficult case of CML, demonstrating that NGS is a powerful diagnostic tool when routine procedures are challenged.

PMID: 27611742 [PubMed - as supplied by publisher]

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Topiramate induces acute intracellular acidification in glioblastoma

Abstract

Reversal of the intracellular/extracellular pH gradient is a hallmark of malignant tumors and is an important consideration in evaluating tumor growth potential and the effectiveness of anticancer therapies. Glioblastoma multiforme (GBM) brain tumors have increased expression of the carbonic anhydrase (CA) isozymes CAII, CAIX and CAXII that contribute to the altered regulation of intracellular pH (pH_i). The anti-epileptic drug topiramate (TPM) inhibits CA action and may acidify the tumor intracellular compartment. In-vivo detection of acute tumor acidification could aid in cancer diagnosis and monitoring treatment response. Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) has been used to measure tissue pH. Using a recently developed CEST-MRI method called amine/amide concentration independent detection (AACID), we have previously shown intracellular acidification caused by single dose of lonidamine. The current study aims to evaluate the intracellular acidification induced by a single dose of the clinically approved drug TPM. Brain tumors were induced in NU/NU mice by injecting 10⁵ U87 human glioblastoma multiforme cells into the right frontal lobe. Using a 9.4T MRI scanner AACID measurements were acquired, before and after administration of TPM (dose: 120 mg/kg, intraperitoneal), 15 ± 2 days after tumor cell implantation. TPM administration induced acute intracellular acidification (average ± SD: baseline AACID = 1.14 ± 0.05; post AACID = 1.19 ± 0.05, paired ttest p = 0.02) in implanted brain tumors. In contrast, contralateral tissue showed no change in AACID value. These results suggest that topiramate can rapidly induce a tumor specific physiological change detectable by AACID CEST. This pH challenge paradigm could be exploited to aid in tumor detection and monitoring treatment response.

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Selective Inducible Nitric Oxide Synthase Inhibitor Reversed Zinc Chloride-Induced Spatial Memory Impairment via Increasing Cholinergic Marker Expression

Abstract

Zinc, an essential micronutrient and biochemical element of the human body, plays structural, catalytic, and regulatory roles in numerous physiological functions. In the current study, the effects of a pretraining oral administration of zinc chloride (10, 25, and 50 mg/kg) for 14 consecutive days and post-training bilateral intra-hippocampal infusion of 1400W as a selective inducible nitric oxide synthase (iNOS) inhibitor (10, 50, and 100 μM/side), alone and in combination, on the spatial memory retention in Morris water maze (MWM) were investigated. Animals were trained for 4 days and tested 48 h after completion of training. Also, the molecular effects of these compounds on the expression of choline acetyltransferase (ChAT), as a cholinergic marker in the CA1 region of the hippocampus and medial septal area (MSA), were evaluated. Behavioral and molecular findings of this study showed that a 2-week oral administration of zinc chloride (50 mg/kg) impaired spatial memory retention in MWM and decreased ChAT expression. Immunohistochemical analysis of post-training bilateral intra-hippocampal infusion of 1400W revealed a significant increase in ChAT immunoreactivity. Furthermore, post-training bilateral intra-hippocampal infusion of 1400W into the CA1 region of the hippocampus reversed zinc chloride-induced spatial memory impairment in MWM and significantly increased ChAT expression in comparison with zinc chloride-treated animals. Taken together, these results emphasize the role of selective iNOS inhibitors in reversing zinc chloride-induced spatial memory deficits via modulation of cholinergic marker expression.

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Bis(maltolato)oxovanadium(IV) (BMOV) Attenuates Apoptosis in High Glucose-Treated Cardiac Cells and Diabetic Rat Hearts by Regulating the Unfolded Protein Responses (UPRs)

Abstract

Endoplasmic reticulum stress (ERS)-induced unfolded protein response (UPR) and the subsequent cell deaths are essential steps in the pathogenesis of diabetic cardiomyopathy (DCM), a main cause of diabetics' morbidity and mortalities. The bis(maltolato)oxovanadium(IV) (BMOV), a potent oral vanadium complex with anti-diabetic properties and insulin-mimicking effects, was shown to improve cardiac dysfunctions in diabetic models. Here, we examined the effects of BMOV on UPR pathway protein expression and apoptotic cell deaths in both high glucose-treated cardiac H9C2 cells and in the hearts of diabetic rats. We show that in both the high glucose-treated cardiac cells and in the hearts of streptozotocin (STZ) diabetic rats, there was an overall activation of the UPR signaling, including both apoptotic (e.g., the cascades of PERK/EIf2α/ATF4/CHOP and of IRE1/caspase 12/caspase 3) and pro-survival (GRP78 and XBP1) signaling. A high amount of apoptotic cell deaths was also detected in both diabetic conditions. The administration of BMOV suppressed both the apoptotic and pro-survival UPR signaling and significantly attenuated apoptotic cell deaths in both conditions. The overall suppression of UPR signaling by BMOV suggests that the drug protects diabetic cardiomyopathy by counteracting reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress. Our findings lend support to promote the use of BMOV in the treatment of diabetic heart diseases.

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Biological Silicon Stimulates Collagen Type 1 and Osteocalcin Synthesis in Human Osteoblast-Like Cells Through the BMP-2/Smad/RUNX2 Signaling Pathway

Abstract

Silicon is essential for bone formation. A low-silicon diet leads to bone defects, and numerous animal models have demonstrated that silicon supplementation increases bone mineral density (BMD) and reduces bone fragility. However, the exact mechanism of this action has not been characterized. In this study, we aimed to determine the role of biological silicon in the induction of osteoblast differentiation and the possible underlying mechanism. We examined whether orthosilicic acid promotes collagen type 1 (COL-1) and osteocalcin synthesis through the bone morphogenetic protein-2 (BMP-2)/Smad1/5/runt-related transcription factor 2 (RUNX2) signaling pathway by investigating its effect in vitro at several concentrations on COL-1 and osteocalcin synthesis in human osteosarcoma cell lines (MG-63 and U2-OS). The expression of relevant proteins was detected by Western blotting following exposure to noggin, an inhibitor of BMP-2. In MG-63 cells, immunofluorescence methods were applied to detect changes in the expression of BMP-2, phosphorylated Smad1/5 (P-Smad1/5), and RUNX2. Furthermore, rat bone mesenchymal stem cells (BMSCs) were used to determine the effect of orthosilicic acid on osteogenic differentiation. Exposure to 10 μM orthosilicic acid markedly increased the expression of BMP-2, P-Smad1/5, RUNX2, COL-1, and osteocalcin in osteosarcoma cell lines. Enhanced ALP activity and the formation of mineralized nodules were also observed under these conditions. Furthermore, preconditioning with noggin inhibited the silicon-induced upregulation of P-Smad1/5, RUNX2, and COL-1 expression. In conclusion, the BMP-2/Smad1/5/RUNX2 signaling pathway participates in the silicon-mediated induction of COL-1 and osteocalcin synthesis, and orthosilicic acid promotes the osteogenic differentiation of rat BMSCs.

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Effects of Fluoride on the Expression of p38MAPK Signaling Pathway-Related Genes and Proteins in Spleen Lymphocytes of Mice

Abstract

This study investigated the effects of sodium fluoride on the expression of p38MAPK signaling pathway-related genes and proteins in the spleen lymphocytes of mice, revealing the mechanism of the toxicity of fluoride to the immune system. The spleen lymphocytes, isolated from mice consuming different NaF doses (0, 50, 100, and 150 mg/L) for 60 days, were cultured in medium with bacteria lipopolysaccharide, and the cells' proliferation ability was analyzed through MTT; real-time PCR detected the change of MLK3/MKK6/p38MAPK/MSK1/ATF1 on mRNA, and the difference of protein expression of MKK6/p38MAPK were detected through the Western blotting. The results suggested that the proliferation ability of spleen lymphocytes isolated from mice consuming different NaF doses is lower, and the expression of genes and proteins of MKK6/p38MAPK showed a decreasing trend. These results demonstrate that fluoride can suppress the activation of p38MAPK pathway in mice spleen lymphocytes and further influences the function of the immune system.

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Developmental Hypothyroxinemia and Hypothyroidism Reduce Parallel Fiber–Purkinje Cell Synapses in Rat Offspring by Downregulation of Neurexin1/Cbln1/GluD2 Tripartite Complex

Abstract

Iodine is a significant micronutrient. Iodine deficiency (ID)-induced hypothyroxinemia and hypothyroidism during developmental period can cause cerebellar dysfunction. However, mechanisms are still unclear. Therefore, the present research aims to study effects of developmental hypothyroxinemia caused by mild ID and hypothyroidism caused by severe ID or methimazole (MMZ) on parallel fiber–Purkinje cell (PF-PC) synapses in filial cerebellum. Maternal hypothyroxinemia and hypothyroidism models were established in Wistar rats using ID diet and deionized water supplemented with different concentrations of potassium iodide or MMZ water. Birth weight and cerebellum weight were measured. We also examined PF-PC synapses using immunofluorescence, and western blot analysis was conducted to investigate the activity of Neurexin1/cerebellin1 (Cbln1)/glutamate receptor d2 (GluD2) tripartite complex. Our results showed that hypothyroxinemia and hypothyroidism decreased birth weight and cerebellum weight and reduced the PF-PC synapses on postnatal day (PN) 14 and PN21. Accordingly, the mean intensity of vesicular glutamate transporter (VGluT1) and Calbindin immunofluorescence was reduced in mild ID, severe ID, and MMZ groups. Moreover, maternal hypothyroxinemia and hypothyroidism reduced expression of Neurexin1/Cbln1/GluD2 tripartite complex. Our study supports the hypothesis that developmental hypothyroxinemia and hypothyroidism reduce PF-PC synapses, which may be attributed to the downregulation of Neurexin1/Cbln1/GluD2 tripartite complex.

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Different Zinc Sources Have Diverse Impacts on Gene Expression of Zinc Absorption Related Transporters in Intestinal Porcine Epithelial Cells

Abstract

This study was conducted to investigate the effects of zinc sources on gene expression of zinc-related transporters in intestinal porcine epithelial cells (IPEC-1). IPEC-1 cells were treated with zinc glycine chelate (Zn-Gly), zinc methionine (Zn-Met), and zinc sulfate (ZnSO₄), respectively, for measurement of cell viability. Then, the relative expression of zinc-related transporters in IPEC-1 in response to different zinc sources (50 μmol/L zinc) was measured. Zinc transporter SLC39A4 (ZIP4) expression was selectively silenced to assess the function of ZIP4 in inorganic and organic zinc absorption. The result showed that Zn-Gly and Zn-Met had lower cell damage compared with ZnSO₄ on the same zinc levels. Different zinc sources improved the expression of metallothionein1 (MT1) and zinc transporter SLC30A1 (ZnT1) messenger RNA (mRNA) compared with the control (P < 0.05), while ZIP4 decreased (P < 0.05) in response to zinc addition. MT1 and ZnT1 mRNA expressions in Zn-Gly and Zn-Met were higher than those in ZnSO₄, and ZIP4 mRNA expression in Zn-Met was the lowest among three kinds of zinc sources (P < 0.05). Expression of divalent metal transporter 1 (DMT1) mRNA in control was significantly higher (P < 0.05) than added different zinc sources groups. Silencing of ZIP4 significantly decreased MT1 mRNA expression in ZnSO₄ and Zn-Gly treatments, reduced zinc absorption rate, and increased DMT1 mRNA expression in ZnSO₄ compared with negative control. In summary, different zinc sources could improve zinc status on IPEC-1 cells and organic zinc had lower cell damage compared with ZnSO₄. Moreover, Zn-Gly and Zn-Met are more efficient on zinc absorption according to the expression of various zinc-related transporters MT1, ZIP4, ZnT1, and DMT1. ZIP4 played a direct role in inorganic zinc uptake, and the absorption of zinc in Zn-Gly depends on ZIP4 partly, while absorption of Zn-Met is less dependent on ZIP4.

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Refractive Errors in Northern China Between the Residents with Drinking Water Containing Excessive Fluorine and Normal Drinking Water

Abstract

The purpose of this study was to evaluate the refractive errors and the demographic associations between drinking water with excessive fluoride and normal drinking water among residents in Northern China. Of the 1843 residents, 1415 (aged ≥40 years) were divided into drinking-water-excessive fluoride (DWEF) group (>1.20 mg/L) and control group (≤1.20 mg/L) on the basis of the fluoride concentrations in drinking water. Of the 221 subjects in the DWEF group, with 1.47 ± 0.25 mg/L (fluoride concentrations in drinking water), the prevalence rates of myopia, hyperopia, and astigmatism were 38.5 % (95 % confidence interval [CI] = 32.1–45.3), 19.9 % (95 % CI = 15–26), and 41.6 % (95 % CI = 35.1–48.4), respectively. Of the 1194 subjects in the control group with 0.20 ± 0.18 mg/L, the prevalence of myopia, hyperopia, and astigmatism were 31.5 % (95 % CI = 28.9–34.2), 27.6 % (95 % CI = 25.1–30.3), and 45.6 % (95 % CI = 42.8–48.5), respectively. A statistically significant difference was not observed in the association of spherical equivalent and fluoride concentrations in drinking water (P = 0.84 > 0.05). This report provides the data of the refractive state of the residents consuming drinking water with excess amounts of fluoride in northern China. The refractive errors did not result from ingestion of mild excess amounts of fluoride in the drinking water.

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Copper-Induced Spermatozoa Head Malformation Is Related to Oxidative Damage to Testes in CD-1 Mice

Abstract

The molecular mechanism for copper toxicity on spermatozoa quality in mice is not well understood. In a 4-week experiment, we challenged 24, 6-week-old male CD-1 mice with twice-a-week intraperitoneal copper chloride injections and evaluated spermatozoa quality, copper levels in the testes, serum testosterone, the expression of key antioxidant glutathione peroxidase 5 (GPx5), and the regulated androgen receptor (AR) in the mice testes. We compared these outcomes for four groups of six mice given doses of 0, 1.25, 2.5, 5.0 mg/kg weight copper chloride twice a week for 4 weeks. The mice demonstrated a copper increase spermatozoa head malformation in a dose-response manner. However, we observed no changes in spermatozoa viability and acrosome integrity in the ratio of mouse body weight to testes weight or in the histomorphology of the testes as the average copper level increased. Results of our RT-PCR assays, immunohistochemical tests, ELISA, and histochemistry analyses indicated that testis GPx5 expression was increased, AR expression in the testes was decreased, serum testosterone was decreased, and the activity of 3β-hydroxysteroid dehydrogenase was decreased as the copper dose increased. In conclusion, these data show that sublethal exposure to copper induces spermatozoa head malformation and influences both mRNA and protein levels of GPx5 and AR which is related to copper resides in the testes.

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Dietary High Fluorine Alters Intestinal Microbiota in Broiler Chickens

Abstract

This study investigated the effects of dietary high fluorine on ileal and cecal microbiota in broiler chickens. Two hundred eighty 1-day-old broiler chickens were randomly assigned to four groups and raised for 42 days. The control group was fed a corn-soybean basal diet (fluorine 22.6 mg/kg). The other three groups were fed the same basal diet, but supplemented with 400, 800, and 1200 mg/kg fluorine (high fluorine groups I, II, and III), administered in the form of sodium fluoride. The microbiota of ileal and cecal digesta was assessed with plate counts and polymerase chain reaction-based denaturing gradient gel electrophoresis (PCR-DGGE). It was found that, compared with those in the control group, the counts of Lactobacillus spp. and Bifidobacterium spp. were markedly decreased (P < 0.01 or P < 0.05), whereas the counts of Escherichia coli and Enterococcus spp. were significantly increased (P < 0.01 or P < 0.05) in the high fluorine groups II and III. PCR-DGGE analysis showed that the number of DGGE bands, similarity, and Shannon index of ileal and cecal bacteria were markedly reduced in the high fluorine groups II and III from 21 to 42 days. Sequencing analysis revealed that the composition of the intestinal microbiota was altered in the high fluorine groups. In conclusion, dietary fluorine in the range of 800–1200 mg/kg obviously altered the bacterial counts, and the diversity and composition of intestinal microbiota in broiler chickens, a finding which implies that dietary high fluorine can disrupt the natural balance and structure of the intestinal microbiota.

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Selenium Deficiency Activates Heat Shock Protein Expression in Chicken Spleen and Thymus

Abstract

Heat shock proteins (Hsps) are protective proteins present in nearly all species; they are used as biomarkers of various stress conditions in humans, animals, and birds. Selenium (Se) deficiency, which can depress the production of Hsps, can cause chicken tissue injuries. To investigate Hsp production, mRNA, and protein levels in Se-deficient chicken spleens and thymuses, a total of 180 1-day-old sea blue white laying hens (90 chickens/group) were harvested in two groups (the control group and the Se-deficient group) in 15, 25, 35, 45, and 55 days, respectively. The results showed that mRNA levels of Hsp27, Hsp40, Hsp60, Hsp70, and Hsp90 were significantly increased in the spleens and thymuses of the Se-deficient group compared to the control group. Further protein levels of Hsp60, Hsp70, and Hsp90 were also significantly increased in the spleen and thymus of the Se-deficient group compared to the control group. Meanwhile, the spleen expression ratio of Hsp40 mRNA level and Hsp70 protein level were higher in the Se-deficient group than other proteins. In the thymus, the Hsp90 mRNA level and Hsp60 protein expression level were the highest level in the Se-deficient group among other proteins. Based on these results, we concluded that Se deficiency could induce a protective stress response in chicken by means of promoting the mRNA and protein expression of Hsps, thus easing the effects of Se deficiency to some extent.

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Serum Copper Status in School-Age Children and Pregnant Women in China Nutrition and Health Survey 2010–2012

Abstract

Serum copper is an insensitive but reliable biomarker reflecting the change of copper nutritional status in both depleted and replete populations. The current study aimed to establish the reference values of serum copper in school-age children and pregnant women in China and to explore the adequate range of serum copper for both these two categories of people. A multistage, stratified, random sampling combined with probability proportionate to regional size sampling method was employed. A total of 4019 subjects (2736 school-age children and 1283 pregnant women) were selected from China Nutrition and Health Survey 2010–2012 (CNHS 2010–2012). The concentration of serum copper was determined by sector field inductively coupled plasma mass spectrometry (SF-ICP-MS). The adequate range of serum copper was determined by the logistic sigmoid saturation curve of the median derivatives. The median concentration of serum copper was 1140.9 μg/L with a range of 746.7–1677.6 μg/L for school-age children and 1933.4 μg/L with a range of 947.4–3391.4 μg/L for pregnant women. The adequate range of serum copper was 905.7–1440.7 μg/L for school-age children and 1308.8–2537.8 μg/L for pregnant women. These parameters represent an essential prerequisite for the assessment of copper nutritional status, as well as nutrition interventions.

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Selenium Plays a Protective Role in Staphylococcus aureus -Induced Endometritis in the Uterine Tissue of Rats

Abstract

The essential trace element selenium (Se) modulates the functions of many regulatory proteins in signal transduction, conferring benefits in inflammatory diseases. Endometritis is a reproductive obstacle disease both in humans and animals. Staphylococcus aureus is the major pathogen that causes endometritis. The present study analyzes the protection and mechanism of Se-methylselenocysteine (MSC) and methylseleninic acid (MSA) on S. aureus-induced endometritis. An atomic fluorescence spectrophotometry study showed that the uterine Se content increased with the addition of MSC and MSA. Histopathology observation and TUNEL detection showed that Se supplementation displayed a greater defense against uterine inflammatory damage. The quantitative PCR (qPCR) and ELISA analyses showed that the expressions of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) increased with S. aureus infection and decreased with the addition of MSC and MSA. The Toll-like receptor 2 (TLR2) expression showed the same status as the inflammatory cytokines. The Western blot results showed that the increased phosphorylation of IκBα and NF-κB p65 was also reduced by the addition of MSC and MSA. The qPCR and Western blot results also showed that the transcription expressions and the protein dissociation of caspase-9, caspase-3, caspase-7, caspase-6, and poly(ADP-ribose) polymerase (PARP), which were increased by S. aureus infection, were inhibited by Se supplementation. All of the results displayed that the protection conferred by MSC was stronger than MSA. The present study indicated the Se supplementation might be a potential prevention and control measure for S. aureus-induced endometritis.

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The Toxicity of Aluminum Chloride on Kidney of Rats

Abstract

This study investigated the toxicity of aluminum chloride (AlCl₃) exposure in the rat kidney. Forty male Wistar rats (5 weeks old), weighing 110–120 g, were randomly divided into four groups: control group (CG, 0 g/L AlCl₃), low dose group (LG, 0.4 g/L AlCl₃), mid dose group (MG, 0.8 g/L AlCl₃), and high dose group (HG, 1.6 g/L AlCl₃). Rats were administered AlCl₃ in their drinking water for 120 days. A variety of measurements were taken including superoxide dismutase (SOD) and glutathione peroxidase (GSH-P_X) activities, malondialdehyde (MDA) concentration in the kidney and blood urea nitrogen (BUN), and cystatin C (Cys-C) concentrations in the serum. In addition, Al and β₂-microglobulin (β₂-MG) concentrations and the activity of N-acetyl-β-d-glucosaminidase (NAG) in the urine were determined. The results showed that in the AlCl₃-treated groups SOD and GSH-P_X activities were decreased, while NAG activity and Al, MDA, BUN, Cys-C, and β₂-MG concentrations were increased, compared with the CG. This study indicates that AlCl₃ exposure induces oxidative stress and suppresses kidney function.

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Effects of Corticosterone on Immune Functions of Cultured Rat Splenic Lymphocytes Exposed to Aluminum Trichloride

Abstract

Aluminum (Al) exposure is toxic to immune system. Studies have implicated that glucocorticoids (GCs) exert the dual regulation effect on the immune function depending on the concentration. However, it is unknown whether a dual effect of GCs exists in the AlCl₃-treated lymphocytes. Corticosterone (Cort) is one kind of GCs. To investigate the effect of different concentration Cort on AlCl₃-treated lymphocytes, rat splenic lymphocyte was isolated and cultured with 0.55 mmol/L AlCl₃, simultaneously administrated Cort at final concentration of 0 (control group, CG), 10⁻⁸ (low-level group, LG), and 10⁻⁶ (high-level group, HG) mol/L, respectively. Another group without AlCl₃ and Cort served as the blank group (BG). We found that low concentration Cort increased the T and B lymphocyte proliferation rate, proportions of CD4⁺ T lymphocyte subset, IgG, IL-2, and TNF-α contents, whereas high concentration Cort decreased those in AlCl₃-treated lymphocytes. In conclusion, the results of this study indicated that low concentration Cort relieves the immunotoxicity of AlCl₃ on the splenic lymphocytes, whereas high concentration Cort aggravates it.

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Effects of Dietary Zinc Pectin Oligosaccharides Chelate Supplementation on Growth Performance, Nutrient Digestibility and Tissue Zinc Concentrations of Broilers

Abstract

The experiment was conducted to investigate the effects of zinc pectin oligosaccharides (Zn-POS) chelate on growth performance, nutrient digestibility, and tissue zinc concentrations of Arbor Acre broilers aged from 1 to 42 days. A total of 576 1-day-old broilers were randomly assigned into 4 groups with 9 replicates per group and 16 chicks per replicate. Chicks were fed either a basal diet (control) or basal diet supplemented with Zn-POS at 300 (Zn-POS-300), 600 (Zn-POS-600), or 900 mg/kg (Zn-POS-900), respectively, for 42 days. A 3-day metabolism trial was conducted during the last week of the experiment feeding. The average daily gain and the average daily feed intake of Zn-POS-600 were significantly higher (P < 0.05) than those of either the control, Zn-POS-300, or Zn-POS-900. Zn-POS-600 had the highest apparent digestibility of dry matter, crude protein, and metabolic energy among all groups. The control group had the lowest apparent digestibility of dry matter (P < 0.05), whereas the apparent digestibility of dry matter in Zn-POS-600 was higher (P < 0.05) than that of Zn-POS-300. The apparent digestibility of crude protein in Zn-POS-600 or Zn-POS-900 was higher (P < 0.05) compared to Zn-POS-300 or the control. The apparent digestibility of metabolic energy in Zn-POS-600 or Zn-POS-900 was higher (P < 0.05) than that of Zn-POS-300. Zn-POS-600 had the highest liver zinc concentrations (P < 0.05), while Zn-POS-900 had the highest pancreatic zinc concentrations (P < 0.05). Our data suggest that the supplementation of 600 mg/kg Zn-POS is optimal in improving the average daily gain and the average daily feed intake, utilization of dietary dry matter and crude protein, and increasing tissue zinc concentrations in liver and pancreas of broilers.

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Phase I dose-escalation study of plitidepsin in combination with bevacizumab in patients with refractory solid tumors.

This phase I trial evaluated the toxicity profile and maximum tolerated dose of the combination between the marine derived cyclodepsipeptide plitidepsin and bevacizumab in advanced cancer patients. Thirteen patients were enrolled and treated with plitidepsin at three dose levels (2.8 mg/m2, n=3; 3.8 mg/m2, n=4; and 4.8 mg/m2, n=6) with a fixed dose of bevacizumab (10 mg/kg). Both agents were administered intravenously at D1 and D15 of a 28-day cycle. All 13 patients were evaluable for safety and toxicity. Dose-limiting toxicities occurred in two out of six patients treated at the maximum dose tested (plitidepsin 4.8 mg/m2 and bevacizumab 10 mg/kg) and consisted of grade 3 fatigue, grade 3 myalgia, and two grade 2/3 alanine aminotransferase increases lasting for more than 7 days or leading to subsequent cycle delay greater than 2 weeks (n=1 each). The recommended dose for the combination of plitidepsin with bevacizumab was 3.8 mg/m2 for plitidepsin and 10 mg/kg for bevacizumab every 2 weeks. Most frequent treatment-related adverse events were nausea, vomiting, fatigue, epistaxis, and headache. Relevant hematological toxicity was minimal. Objective disease responses were not observed; however, stable disease (>3 months) was observed in four patients with colorectal cancer, renal cancer, and cervical cancer. Combining plitidepsin with bevacizumab combination is feasible. Stable disease was the best response obtained. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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