Δευτέρα 19 Σεπτεμβρίου 2016

γ-Aminobutyric acid inhibits the proliferation and increases oxaliplatin sensitivity in human colon cancer cells

Abstract

γ-Aminobutyric acid (GABA) is a natural non-protein amino acid, which broadly exists in many plant parts and is widely used as an ingredient in the food industry. In mammals, it is widely distributed in central nervous system and non-neural tissues. In addition to a primary inhibitory neurotransmitter in the central nervous system, endogenous GABA content has been found to be elevated in neoplastic tissues in colon cancer. However, the effect of extraneous GABA on colon cancer has rarely been reported. In this study, we found the inhibitory effects of GABA on the proliferation of colon cancer cells (CCCs). The amino acid also suppressed metastasis of SW480 and SW620 cells. To further study the correlated mechanism, we analyzed the changes in cell cycle distribution and found that GABA suppressed cell cycle progression through G2/M or G1/S phase. Furthermore, RNA sequencing analysis revealed GABA-induced changes in the mRNA expression of 30 genes, including EGR1, MAPK4, NR4A1, Fos, and FosB, in all the three types of CCC. Importantly, GABA enhanced the anti-tumor efficacy of oxaliplatin (OXA) in subcutaneous xenograft tumor model in nude mice. The data suggest that GABA inhibits colon cancer cell proliferation perhaps by attenuating EGR1-NR4A1 axis, EGR1-Fos axis, and by disrupting MEK-EGR1 signaling pathway. This work reveals the pharmacological value of GABA derived from food and suggests that exogenous GABA might play an auxiliary role in polychemotherapy of colon cancer.



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A monomer purified from Paris polyphylla (PP-22) triggers S and G2/M phase arrest and apoptosis in human tongue squamous cell carcinoma SCC-15 by activating the p38/cdc25/cdc2 and caspase 8/caspase 3 pathways

Abstract

Recent studies have shown that the aqueous, ethanolic extracts and a monomer compound of Paris polyphylla exhibit anticancer activity toward several types of cancer cell lines, but the anticancer activity of (3β,17α,25R)-spirost-5-ene-3,17-diol 3-O-α-l-rhamnopyranosyl-(1 → 2)-β-d-glucopyranoside, a monomer isolated from P. polyphylla (PP), named PP-22, has not been reported previously. In this study, we investigated the effect of PP-22 on human tongue squamous cell carcinoma SCC-15 cells in vitro. MTT assays showed that PP-22 inhibited the growth of SCC-15 cells and had no obvious inhibitory effects on human liver L02 cells. Flow cytometry assays showed that the percentages of apoptotic cells were increased. In addition, cleaved caspase-8, cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP) could be detected by Western blotting. Flow cytometry also showed that PP-22 triggered S and G2/M phases arrest in SCC-15 cells, and on the other hand, the expression of cyclin A, cyclin E2, cyclin B1, phospho-cell division cycle2 (p-cdc2)(Tyr15), p-Wee1, Myt1, and p53 was upregulated. Moreover, p-p38 levels increased, p-extracellular signal-regulated kinase (ERK) levels decreased, and cdc25B expression was inhibited. Furthermore, the p38/mitogen-activated protein kinase (MAPK) inhibitor SB203580 reversed the increase of the expression level of p38, p-cdc2 (Tyr15), cleaved caspase 3, cleaved PARP, p-p53, and p53 and reversed the decrease in cdc25B expression. In conclusion, these results demonstrated that PP-22 activated p38, inhibited cdc25B, increased p-cdc2 (Tyr15), and triggered S and G2/M phase arrest, as well as activated p53 through the p38-p53 pathway, inhibited the MAPK/ERK pathway, activated the caspase 8/caspase 3 pathway, and triggered the extrinsic apoptotic pathway in SCC-15 cells.



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Endocan reduces the malign grade of gastric cancer cells by regulating associated protein expression

Abstract

Endocan, which has been identified to be low expressed in gastric cancer, was found to be positively related to the differentiation level of gastric cancer in vivo and in vitro. In the present study, we aimed to investigate the role of endocan in gastric adenocarcinoma cell line SGC7901 by artificially upregualting or downregulating endocan expression using endocan recombinant vector or specific small interfering RNA (siRNA)-targeting endocan gene, respectively. The effects of endocan recombinant vector-mediated over-expressing and siRNA-mediated endocan silencing on the differentiation, migration, and apoptosis of SGC7901 cells were assessed. Furthermore, the primary molecular mechanisms of endocan were explored by testing the expression alterations of associated protein in SGC7901 along endocan over-expression or knockdown. We found that over-expression of endocan reduced the migration but promoted the differentiation and apoptosis of SGC7901 cells. While, knockdown of endocan did just the opposite. Some molecules were found to participate in endocan-mediated anti-tumor effects, such as p53, caspase 3, and MMP-9. In conclusion, our findings suggest that endocan plays an anti-carcinogenic role in gastric cancer development and progression and might serve as a prognostic biomarker as well as a potential therapeutic target for gastric cancer.



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FABP5 correlates with poor prognosis and promotes tumor cell growth and metastasis in cervical cancer

Abstract

Fatty acid-binding protein 5 (FABP5) was found in our previous study to be a potential biomarker for lymph node metastasis of cervical cancer. However, the roles of FABP5 in cervical cancer remain unclear. In the present study, FABP5 expression was found to be significantly upregulated in cervical cancer tissues, and high FABP5 expression was significantly correlated with lymph node metastasis, lymphovascular space invasion, the International Federation of Gynecology and Obstetrics (FIGO) stage, and tumor size. Moreover, FABP5 was an independent factor for poor prognosis in cervical cancer patients. Silencing of FABP5 inhibited cell proliferation, colony formation, cell migration, and invasion in vitro. Furthermore, FABP5 silencing significantly reduced tumor growth and lung metastases in a murine allograft model in vivo. In addition, FABP5 silencing decreased the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in vitro and in vivo. Collectively, these findings indicated that FABP5 plays an important role in the carcinogenesis and metastasis of cervical cancer, and FABP5 may be a novel predictor for prognostic assessment of cervical cancer patients.



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Overexpression of pyruvate kinase M2 predicts a poor prognosis for patients with osteosarcoma

Abstract

It is stated that high expression of pyruvate kinase (PKM2) emerges as a significant player in the metabolism and progression of various human malignancies. However, the expression of PKM2 and its association with the prognosis of osteosarcoma had not yet been studied. In the present study, the expression and biological significance of PKM2 in osteosarcoma were investigated. We found that PKM2 expression was elevated in the cancerous tissues and it was more abundant than the adjacent normal tissues (60.2 vs 26.1 %, p < 0.001). Moreover, we showed that high PKM2 expression was positively correlated with Enneking stage (p = 0.006) and distant metastasis (p = 0.007) but not with the age, gender, tumor site, tumor size, histologic grade, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and local pain of the patients. Furthermore, Kaplan–Meier analysis revealed that the overall survival (OS) for patients with high PKM2 expression was significantly lower than those with low PKM2 expression (p < 0.001). Finally, multivariate analysis revealed that high PKM2 expression was an independent prognostic factor for osteosarcoma patients (p = 0.004). Collectively, these data indicated that elevated PKM2 might serve as a novel target for the treatment of osteosarcoma.



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Dysregulation of TTP and HuR plays an important role in cancers

Abstract

Defects in the adenosine-uridine (AU)-rich elements (AREs), which mediate post-transcriptional regulation, play important roles in cancers. Both tristetraprolin (TTP, also known as TIS11 and ZFP36) and human antigen R (HuR, also known as ELAVL1) are two important and closely related AU-rich RNA-binding proteins (ARE-BPs). High-expression or aberrant nuclear/cytoplasmic distribution of HuR and decreased TTP have been found in many types of cancers. TTP mediates the decay of target mRNAs, whereas HuR generally stabilizes target transcripts and promotes translation of certain mRNAs. Furthermore, thousands of overlapping binding sites of TTP and HuR were found in more than 1300 genes. RNA-IP experiments also indicated that TTP can bind directly to and destabilize HuR mRNA. The dysregulation of TTP and HuR has been found to play an important role in the progression of cancers, including inflammation-related cancer, as well as in proliferation, apoptosis, angiogenesis, metastasis, invasion, and chemotherapy resistance. In this review, we provided an overview of the role of TTP and HuR, as well as the underlying mechanisms of the TTP-HuR axis in cancers.



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Novel long non-coding RNA GACAT3 promotes gastric cancer cell proliferation through the IL-6/STAT3 signaling pathway

Abstract

Long non-coding RNAs (lncRNAs) play an important role in cancer occurrence and development. We previously demonstrated that lncRNA gastric cancer-associated transcript 3 (GACAT3) was positively correlated with TNM stages, tumor size, and distant metastasis of patients with gastric cancer. However, the role of GACAT3 in gastric cancer remains unclear. In this study, to investigate its function, we synthesized small interference RNAs (siRNAs) against GACTA3 and developed a GACAT3 overexpression vector (pcDNA3-GACAT3), respectively. The siRNA-mediated knockdown of GACAT3 significantly decreased cell proliferation of the gastric cancer HGC-27 cells, in which GACAT3 is overexpressed. Furthermore, GACAT3 overexpression in gastric cancer SGC-7901 cells promoted cell growth. Moreover, GACAT3 expression in HGC-27 cells was greatly upregulated by IL-6 treatment in a concentration-dependent manner. In contrast, siRNA-mediated knockdown of STAT3 decreased GACAT3 expression even in the presence of IL-6. These results demonstrated that as a downstream target of the IL6/STAT3 signaling, lncRNA GACAT3 promotes gastric cancer cell growth suggesting that GACAT3 is an inflammatory response gene and may be served as a valuable potential target for the treatment of gastric cancer.



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Long non-coding RNA IRAIN suppresses apoptosis and promotes proliferation by binding to LSD1 and EZH2 in pancreatic cancer

Abstract

Long non-coding RNA (lncRNA) modulates gene expression, while lncRNA dysregulation is associated with human cancer. Furthermore, while recent studies have shown that lncRNA IRAIN plays an important role in other malignancies, the role of IRAIN in pancreatic cancer (PC) progression remains unclear. In this study, we found that upregulation of lncRNA IRAIN was significantly correlated with tumor size, TNM stage, and lymph node metastasis in a cohort of 37 PC patients. In vitro experiments showed that knockdown of IRAIN by small interfering RNA (siRNA) significantly induced cell apoptosis and inhibited cell proliferation in both BxPC-3 and PANC-1 cells. Further mechanism study showed that, by binding to histone demethylase lysine-specific demethylase 1 (LSD1), an enhancer of zeste homolog 2 (EZH2), IRAIN reduced PC tumor cell apoptosis and induced growth arrest by silencing the expression of Kruppel-like factor 2 (KLF2) and P15. Moreover, IRAIN expression was inversely correlated with that of KLF2 and P15 in PC tissues. To our knowledge, this is the first report elucidating the role and mechanism of IRAIN in PC progression.



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Comparison of clinical outcomes of squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma of the uterine cervix after definitive radiotherapy: a population-based analysis

Abstract

Purpose

To evaluate the clinical outcomes in patients with International Federation of Gynecology and Obstetrics (FIGO) stage I to IVA squamous cell carcinoma (SCC), adenocarcinoma (AC), and adenosquamous carcinoma (ASC) of the uterine cervix after definitive radiotherapy.

Methods

Patients with a primary diagnosis of FIGO stage I–IVA SCC, AC, and ASC of the uterine cervix who had undergone definitive beam radiation with implants or isotopes between 1988 and 2013 were identified using the Surveillance, Epidemiology, and End Results database. Univariate and multivariate Cox regression analyses were performed to analyze the effect of histologic subtype on cause-specific survival (CSS) and overall survival (OS).

Results

A total of 8751 were identified, and 86.0, 10.6, and 3.4 % of patients were SCC, AC, and ASC, respectively. AC patients were more often well differentiated, while more patients were poorly/undifferentiated in ASC subtype. A higher percentage of AC and ASC patients were stage I, and fewer had stage III compared to SCC. Univariate and multivariate Cox analyses showed that histologic subtype was an independent prognostic factor for CSS and OS. SCC subtype had a better CSS and OS compared to AC and ASC subtype. The survival between AC and ASC had no significant difference. The impact of the histologic subtype on CSS and OS was not affected by FIGO stage and the year of diagnosis.

Conclusion

AC and ASC subtypes are independent prognostic factors for cervical cancer patients treated with definitive radiotherapy. AC and ASC subtypes are associated with poor survival outcomes than those with SCC.



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Perilipin 1 is a highly specific marker for adipocytic differentiation in sarcomas with intermediate sensitivity

Abstract

Purpose

Liposarcomas are the most common soft tissue sarcomas of adults. The identification of lipoblastic cells in soft tissue sarcomas is mandatory for the diagnosis of most subtypes of liposarcomas but may be difficult in conventional histology. The present study focuses on the expression and possible diagnostic impact of two PAT family proteins, perilipin 1/perilipin and perilipin 2/adipophilin in human liposarcomas.

Methods

Eighty-seven cases of liposarcomas and 30 cases of non-lipomatous sarcomas were investigated immunohistochemically for perilipin 1 and 2 using entire tissue sections. Statistical analyses were performed using appropriate tests.

Results

Most liposarcomas and non-lipomatous sarcomas displayed positivity for perilipin 2. In contrast, while more than two-thirds of liposarcomas presented perilipin 1 positivity, all non-lipomatous sarcomas studied were negative for this marker, with statistical significance (p < 0.001). Perilipin 1 expression increased with adipocytic differentiation of liposarcoma subtypes showing statistical significance (p < 0.001). Non-lipomatous sarcomas demonstrated variable expression levels of perilipin 2. The expression level of perilipin 2 appeared to be correlated with tumor cell degeneration, e.g., through hypoxia.

Conclusions

Perilipin 2 is not well suitable for distinction between liposarcomas and non-lipomatous sarcomas. However, perilipin 1 appeared to be a highly specific marker for liposarcoma and adipocytic differentiation in sarcomas with intermediate sensitivity.



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Simultaneous existence of acute myeloid leukemia and chronic lymphocytic leukemia: a case report

Abstract

Background

The simultaneous Occurrence of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) has been rarely reported. Most of these cases have been occurring more frequently as a secondary event in patients receiving chemotherapeutic agents for CLL.

Case presentation

We describe a case of a 77-year-old man who presented with fatigue, pallor and lower limb pain and weakness. Initial laboratory studies showed Hb 7.7 g/dl, WBC 279.6 × 109/1, PLT 143× 109/1. The peripheral blood (PB) smear examination showed circulating blast cells (20 %) cells and 50 % lymphocytes, with smudge cells.

A bone marrow examination showed infiltration by two discrete abnormal cell populations, one represents the leukemic blast cells (60 %) and the other represents small mature lymphocytes (30 %). The immunologic phenotype of blasts was characterized by the co-expression of CD13, CD33, CD14, CD4, CD15, CD64, HLA-DR, CD11c. Lymphocytes were characterized by a typical CLL immunophenotype: CD19+, CD5+, CD23+, CD20+ (dim) and negative for FMC7, CD34, CD10 and TdT. Cytogenetic studies were negative for CLL and AML panels. PCR assays for AML specific genetic abnormalities were negative. Immunoglobulin gene analysis established the clonal nature of the B-cell expansion. A final diagnosis of concomitant CLL and AML(FAB: M5) was made.

Conclusion

We have reported a case in which there was simultaneous presentation of AML and CLL. Both forms of leukemia were well documented by morphology, cytometric analysis and molecular studies. Our findings support the idea that this rare concurrence of AML and untreated CLL may represent two separate disease processes.



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Novel long non-coding RNA GACAT3 promotes gastric cancer cell proliferation through the IL-6/STAT3 signaling pathway

Abstract

Long non-coding RNAs (lncRNAs) play an important role in cancer occurrence and development. We previously demonstrated that lncRNA gastric cancer-associated transcript 3 (GACAT3) was positively correlated with TNM stages, tumor size, and distant metastasis of patients with gastric cancer. However, the role of GACAT3 in gastric cancer remains unclear. In this study, to investigate its function, we synthesized small interference RNAs (siRNAs) against GACTA3 and developed a GACAT3 overexpression vector (pcDNA3-GACAT3), respectively. The siRNA-mediated knockdown of GACAT3 significantly decreased cell proliferation of the gastric cancer HGC-27 cells, in which GACAT3 is overexpressed. Furthermore, GACAT3 overexpression in gastric cancer SGC-7901 cells promoted cell growth. Moreover, GACAT3 expression in HGC-27 cells was greatly upregulated by IL-6 treatment in a concentration-dependent manner. In contrast, siRNA-mediated knockdown of STAT3 decreased GACAT3 expression even in the presence of IL-6. These results demonstrated that as a downstream target of the IL6/STAT3 signaling, lncRNA GACAT3 promotes gastric cancer cell growth suggesting that GACAT3 is an inflammatory response gene and may be served as a valuable potential target for the treatment of gastric cancer.



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Hypoxia-induced NIPP1 activation enhances metastatic potential and predicts poor prognosis in hepatocellular carcinoma

Abstract

Hypoxia is known to promote hepatocellular carcinoma (HCC) invasion and metastasis and nuclear inhibitor of protein phosphatase 1 (NIPP1) overexpression contributes to the malignant phenotype in HCC. The aim of this study was to investigate the role of NIPP1 in HCC development under hypoxia. We first conducted a study with 106 cases to explore the association of NIPP1 and/or enhancer of zeste homolog 2 (EZH2) expression with poor prognosis in HCC. Then additional 352 independent cases were recruited to validate the results in the first stage. Hypoxia was induced by culturing HCC cells in 1 % O2 or of the treatment with hypoxic agent. The expression levels of NIPP1/EZH2 in both HCC tissues and HCC cell lines were detected by RT-PCR, Western blot, or immunohistochemistry. We also studied the effects of the loss of function of NIPP1 and EZH2 on malignant phenotypes, downstream pathway, and inflammatory factors activities using gene silencing strategy. Overall, we found that NIPP1 and EZH2 were overexpressed in both HCC tissue samples and HCC cell lines. High expression of HIPP1 was associated with poor prognosis and clinicopathological features in patients with advanced HCC. HIPP1 expression positively correlated with the expression of hypoxia marker (carbonic anhydrase IX). Hypoxia induced high expression of NIPP1. NIPP1/EZH2 knockdown in HCC cell lines under hypoxia suppressed the malignant phenotypes, reduced the expression of hypoxia-inducible Factor 1α, downstream molecules of EZH2, and inhibit the activity of inflammatory factors. In conclusion, we found that NIPP1 could be activated by hypoxia and contributed to hypoxia-induced invasive and metastatic potential in HCC.



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Endocan reduces the malign grade of gastric cancer cells by regulating associated protein expression

Abstract

Endocan, which has been identified to be low expressed in gastric cancer, was found to be positively related to the differentiation level of gastric cancer in vivo and in vitro. In the present study, we aimed to investigate the role of endocan in gastric adenocarcinoma cell line SGC7901 by artificially upregualting or downregulating endocan expression using endocan recombinant vector or specific small interfering RNA (siRNA)-targeting endocan gene, respectively. The effects of endocan recombinant vector-mediated over-expressing and siRNA-mediated endocan silencing on the differentiation, migration, and apoptosis of SGC7901 cells were assessed. Furthermore, the primary molecular mechanisms of endocan were explored by testing the expression alterations of associated protein in SGC7901 along endocan over-expression or knockdown. We found that over-expression of endocan reduced the migration but promoted the differentiation and apoptosis of SGC7901 cells. While, knockdown of endocan did just the opposite. Some molecules were found to participate in endocan-mediated anti-tumor effects, such as p53, caspase 3, and MMP-9. In conclusion, our findings suggest that endocan plays an anti-carcinogenic role in gastric cancer development and progression and might serve as a prognostic biomarker as well as a potential therapeutic target for gastric cancer.



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FABP5 correlates with poor prognosis and promotes tumor cell growth and metastasis in cervical cancer

Abstract

Fatty acid-binding protein 5 (FABP5) was found in our previous study to be a potential biomarker for lymph node metastasis of cervical cancer. However, the roles of FABP5 in cervical cancer remain unclear. In the present study, FABP5 expression was found to be significantly upregulated in cervical cancer tissues, and high FABP5 expression was significantly correlated with lymph node metastasis, lymphovascular space invasion, the International Federation of Gynecology and Obstetrics (FIGO) stage, and tumor size. Moreover, FABP5 was an independent factor for poor prognosis in cervical cancer patients. Silencing of FABP5 inhibited cell proliferation, colony formation, cell migration, and invasion in vitro. Furthermore, FABP5 silencing significantly reduced tumor growth and lung metastases in a murine allograft model in vivo. In addition, FABP5 silencing decreased the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in vitro and in vivo. Collectively, these findings indicated that FABP5 plays an important role in the carcinogenesis and metastasis of cervical cancer, and FABP5 may be a novel predictor for prognostic assessment of cervical cancer patients.



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Dysregulation of TTP and HuR plays an important role in cancers

Abstract

Defects in the adenosine-uridine (AU)-rich elements (AREs), which mediate post-transcriptional regulation, play important roles in cancers. Both tristetraprolin (TTP, also known as TIS11 and ZFP36) and human antigen R (HuR, also known as ELAVL1) are two important and closely related AU-rich RNA-binding proteins (ARE-BPs). High-expression or aberrant nuclear/cytoplasmic distribution of HuR and decreased TTP have been found in many types of cancers. TTP mediates the decay of target mRNAs, whereas HuR generally stabilizes target transcripts and promotes translation of certain mRNAs. Furthermore, thousands of overlapping binding sites of TTP and HuR were found in more than 1300 genes. RNA-IP experiments also indicated that TTP can bind directly to and destabilize HuR mRNA. The dysregulation of TTP and HuR has been found to play an important role in the progression of cancers, including inflammation-related cancer, as well as in proliferation, apoptosis, angiogenesis, metastasis, invasion, and chemotherapy resistance. In this review, we provided an overview of the role of TTP and HuR, as well as the underlying mechanisms of the TTP-HuR axis in cancers.



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γ-Aminobutyric acid inhibits the proliferation and increases oxaliplatin sensitivity in human colon cancer cells

Abstract

γ-Aminobutyric acid (GABA) is a natural non-protein amino acid, which broadly exists in many plant parts and is widely used as an ingredient in the food industry. In mammals, it is widely distributed in central nervous system and non-neural tissues. In addition to a primary inhibitory neurotransmitter in the central nervous system, endogenous GABA content has been found to be elevated in neoplastic tissues in colon cancer. However, the effect of extraneous GABA on colon cancer has rarely been reported. In this study, we found the inhibitory effects of GABA on the proliferation of colon cancer cells (CCCs). The amino acid also suppressed metastasis of SW480 and SW620 cells. To further study the correlated mechanism, we analyzed the changes in cell cycle distribution and found that GABA suppressed cell cycle progression through G2/M or G1/S phase. Furthermore, RNA sequencing analysis revealed GABA-induced changes in the mRNA expression of 30 genes, including EGR1, MAPK4, NR4A1, Fos, and FosB, in all the three types of CCC. Importantly, GABA enhanced the anti-tumor efficacy of oxaliplatin (OXA) in subcutaneous xenograft tumor model in nude mice. The data suggest that GABA inhibits colon cancer cell proliferation perhaps by attenuating EGR1-NR4A1 axis, EGR1-Fos axis, and by disrupting MEK-EGR1 signaling pathway. This work reveals the pharmacological value of GABA derived from food and suggests that exogenous GABA might play an auxiliary role in polychemotherapy of colon cancer.



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A monomer purified from Paris polyphylla (PP-22) triggers S and G2/M phase arrest and apoptosis in human tongue squamous cell carcinoma SCC-15 by activating the p38/cdc25/cdc2 and caspase 8/caspase 3 pathways

Abstract

Recent studies have shown that the aqueous, ethanolic extracts and a monomer compound of Paris polyphylla exhibit anticancer activity toward several types of cancer cell lines, but the anticancer activity of (3β,17α,25R)-spirost-5-ene-3,17-diol 3-O-α-l-rhamnopyranosyl-(1 → 2)-β-d-glucopyranoside, a monomer isolated from P. polyphylla (PP), named PP-22, has not been reported previously. In this study, we investigated the effect of PP-22 on human tongue squamous cell carcinoma SCC-15 cells in vitro. MTT assays showed that PP-22 inhibited the growth of SCC-15 cells and had no obvious inhibitory effects on human liver L02 cells. Flow cytometry assays showed that the percentages of apoptotic cells were increased. In addition, cleaved caspase-8, cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP) could be detected by Western blotting. Flow cytometry also showed that PP-22 triggered S and G2/M phases arrest in SCC-15 cells, and on the other hand, the expression of cyclin A, cyclin E2, cyclin B1, phospho-cell division cycle2 (p-cdc2)(Tyr15), p-Wee1, Myt1, and p53 was upregulated. Moreover, p-p38 levels increased, p-extracellular signal-regulated kinase (ERK) levels decreased, and cdc25B expression was inhibited. Furthermore, the p38/mitogen-activated protein kinase (MAPK) inhibitor SB203580 reversed the increase of the expression level of p38, p-cdc2 (Tyr15), cleaved caspase 3, cleaved PARP, p-p53, and p53 and reversed the decrease in cdc25B expression. In conclusion, these results demonstrated that PP-22 activated p38, inhibited cdc25B, increased p-cdc2 (Tyr15), and triggered S and G2/M phase arrest, as well as activated p53 through the p38-p53 pathway, inhibited the MAPK/ERK pathway, activated the caspase 8/caspase 3 pathway, and triggered the extrinsic apoptotic pathway in SCC-15 cells.



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Transcription factor HIF1A: downstream targets, associated pathways, polymorphic hypoxia response element (HRE) sites, and initiative for standardization of reporting in scientific literature

Abstract

Hypoxia-inducible factor-1α (HIF-1α) has crucial role in adapting cells to hypoxia through expression regulation of many genes. Identification of HIF-1α target genes (HIF-1α-TGs) is important for understanding the adapting mechanism. The aim of the present study was to collect known HIF-1α-TGs and identify their associated pathways. Targets and associated genomics data were retrieved using PubMed, WoS (http://ift.tt/1nH7FC5), HGNC (http://ift.tt/S6f76j), NCBI (http://ift.tt/MfJzKA), Ensemblv.84 (http://ift.tt/MFiHTY), DAVID Bioinformatics Resources (http://ift.tt/20M50EQ/), and Disease Ontology database (http://ift.tt/1ln5iSD). From 51 papers, we collected 98 HIF-1α TGs found to be associated with 20 pathways, including metabolism of carbohydrates and pathways in cancer. Reanalysis of genomic coordinates of published HREs (hypoxia response elements) revealed six polymorphisms within HRE sites (HRE-SNPs): ABCG2, ACE, CA9, and CP. Due to large heterogeneity of results presentation in scientific literature, we also propose a first step towards reporting standardization of HIF-1α-target interactions consisting of ten relevant data types. Suggested minimal checklist for reporting will enable faster development of a complete catalog of HIF-1α-TGs, data sharing, bioinformatics analyses, and setting novel more targeted hypotheses. The proposed format for data standardization is not yet complete but presents a baseline for further optimization of the protocol with additional details, for example, regarding the experimental validation.



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Cutaneous Complications of Targeted Melanoma Therapy

Opinion statement

The landscape of advanced and metastatic melanoma therapy has shifted dramatically in recent years. Since 2011, eight drugs (ipilimumab, vemurafenib, dabrafenib, trametinib, cometinib, pembrolizumab, nivolumab, and talimogene laherparepvec) have received FDA approval for the treatment of advanced or metastatic melanoma, including combination regimens of both small molecule kinase and immune checkpoint inhibitors. These therapies have revolutionized the management of unresectable regional nodal and distant melanoma, providing hope of extended survival to patients. As the use of novel agents has increased, so have the cutaneous toxicities associated with these medications. While most skin reactions are low-grade and can be managed conservatively with topical therapies, malignant lesions and more serious or life-threatening drug reactions can arise during therapy, requiring prompt dermatologic recognition and treatment in order to improve patient outcome. Given the survival benefit attributed to these new agents, treating skin toxicity and maintaining patient quality of life is of paramount importance. Oncologists should be aware of the common cutaneous toxicities associated with these medications and should be encouraged to involve dermatologists in the collaborative care of advanced melanoma patients. Close communication between oncologists and dermatologists can help to avoid unnecessary dose reduction or treatment discontinuation and identify situations when treatment cessation is truly warranted.



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Transcription factor HIF1A: downstream targets, associated pathways, polymorphic hypoxia response element (HRE) sites, and initiative for standardization of reporting in scientific literature

Abstract

Hypoxia-inducible factor-1α (HIF-1α) has crucial role in adapting cells to hypoxia through expression regulation of many genes. Identification of HIF-1α target genes (HIF-1α-TGs) is important for understanding the adapting mechanism. The aim of the present study was to collect known HIF-1α-TGs and identify their associated pathways. Targets and associated genomics data were retrieved using PubMed, WoS (http://ift.tt/1nH7FC5), HGNC (http://ift.tt/S6f76j), NCBI (http://ift.tt/MfJzKA), Ensemblv.84 (http://ift.tt/MFiHTY), DAVID Bioinformatics Resources (http://ift.tt/20M50EQ/), and Disease Ontology database (http://ift.tt/1ln5iSD). From 51 papers, we collected 98 HIF-1α TGs found to be associated with 20 pathways, including metabolism of carbohydrates and pathways in cancer. Reanalysis of genomic coordinates of published HREs (hypoxia response elements) revealed six polymorphisms within HRE sites (HRE-SNPs): ABCG2, ACE, CA9, and CP. Due to large heterogeneity of results presentation in scientific literature, we also propose a first step towards reporting standardization of HIF-1α-target interactions consisting of ten relevant data types. Suggested minimal checklist for reporting will enable faster development of a complete catalog of HIF-1α-TGs, data sharing, bioinformatics analyses, and setting novel more targeted hypotheses. The proposed format for data standardization is not yet complete but presents a baseline for further optimization of the protocol with additional details, for example, regarding the experimental validation.



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Combined large cell neuroendocrine carcinoma and endometrioid carcinoma of the endometrium: a shared gene mutation signature between the two histological components

Abstract

A 61-year-old Japanese woman was diagnosed with FIGO Stage IB endometrioid cancer (EC) combined with large cell neuroendocrine carcinoma (LCNEC). Metastasis to the lymph nodes in the right bronchopulmonary area, mediastinum and brain were also identified. The patient eventually developed pleuritis and pericarditis carcinomatosa, and died of cancer at 51 months after surgery. Because gene aberrations in uterine neuroendocrine carcinoma are still not well understood, we examined alterations in the mutational hotspots of 50 selected cancer-associated genes. The EC and LCNEC components shared identical alterations in PTEN, PIK3CA and FGFR3. Both the EC and LCNEC components had heterozygous SBSs on CTNNB1 but at different codons (G34R in EC, and T41A in LCNEC). The altered gene signature raised a possibility that the EC and LCNEC components were derived from a common precursor lesion. The LCNEC independently obtained a significant CTNNB1 mutation and the lymph node metastasis originated from this component. Because the LCNEC component seemed to bring about the aggressive course of the disease and defined the patient outcome, further investigations are needed to elucidate the mechanism of NE carcinoma development in the endometrium.



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Healthcare resource utilization and G‑CSF use in patients with solid tumors or hematological malignancies hospitalized for febrile neutropenia in Bulgaria, Czech Republic and Slovakia

Summary

Background

Febrile neutropenia (FN) is a common side effect of chemotherapy that frequently necessitates hospitalization and healthcare resource utilization (HCRU), but is poorly studied in Eastern European countries. We investigated HCRU and granulocyte colony-stimulating factor (G-CSF) use in patients hospitalized for FN in Bulgaria, Czech Republic, and Slovakia.

Patients and methods

This was a multicenter retrospective cohort study. Eligible patients were ≥18 years old, had received chemotherapy for solid tumors or hematological malignancies of any stage, and had been hospitalized for FN. The primary objective was to evaluate FN-related HCRU; secondary objectives included the description of chemotherapy treatment patterns and G‑CSF use. Data were analyzed by participating country.

Results

Data of 156 patients from Bulgaria and 79 patients each from the Czech Republic and Slovakia were analyzed. The most frequent solid tumors were breast (n = 28) and testicular cancer (n = 13), and the most common hematological malignancies were non-Hodgkin B‑cell lymphoma (n = 51) and acute myeloid leukemia (n = 35). In general, G‑CSF was used to treat FN rather than as prophylaxis. Most patients had a single FN episode, predominantly in cycle 1. The mean duration of FN-related hospitalization was 7–9 days, with longer stays in patients with hematological malignancies.

Conclusions

Results indicate considerable FN-related HCRU in all countries. Frequent lack of G‑CSF primary prophylaxis was observed, particularly in Slovakia.



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Novel strategies in the management of chronic lymphocytic leukemia (CLL)

Summary

This review discusses promising new approaches in the management of chronic lymphocytic leukemia (CLL) that were recently presented at the annual meeting of the American Society of Hematology meeting in 2015. In total, 405 abstracts concerning biological and clinical aspects of CLL were presented. The review concentrates on clinical data regarding improved treatment strategies for treatment-naïve patients as well as those with relapsed/refractory disease.



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Focus on multiple myeloma at ASH 2015

Summary

Multiple myeloma was prominently featured during the American Society of Hematology 2015 meeting. Important presentations were related to standards of first-line therapy of myeloma, disease assessment, and treatment of relapsed disease. New innovative treatments for myeloma are emerging, which will likely open new therapeutic avenues in the near future. This review aims to give a brief overview of the topic, focusing on presentations with relevance for clinical practice.



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The effect of cyclophosphamide on the immune system: implications for clinical cancer therapy

Abstract

Cyclophosphamide is an alkylating agent belonging to the group of oxazaphosporines. As cyclophosphamide is in clinical use for more than 40 years, there is a lot of experience using this drug for the treatment of cancer and as an immunosuppressive agent for the treatment of autoimmune and immune-mediated diseases. Besides antimitotic and antireplicative effects, cyclophosphamide has immunosuppressive as well as immunomodulatory properties. Cyclophosphamide shows selectivity for T cells and is therefore now frequently used in tumour vaccination protocols and to control post-transplant allo-reactivity in haplo-identical unmanipulated bone marrow after transplantation. The schedule of administration is of special importance for the immunological effect: while cyclophosphamide can be used in high-dose therapy for the complete eradication of haematopoietic cells, lower doses of cyclophosphamide are relatively selective for T cells. Of special interest is the fact that a single administration of low-dose cyclophosphamide is able to selectively suppress regulatory T cells (Tregs). This effect can be used to counteract immunosuppression in cancer. However, cyclophosphamide can also increase the number of myeloid-derived suppressor cells. Combination of cyclophosphamide with other immunomodulatory agents could be a promising approach to treat different forms of advanced cancer.



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The effect of cyclophosphamide on the immune system: implications for clinical cancer therapy

Abstract

Cyclophosphamide is an alkylating agent belonging to the group of oxazaphosporines. As cyclophosphamide is in clinical use for more than 40 years, there is a lot of experience using this drug for the treatment of cancer and as an immunosuppressive agent for the treatment of autoimmune and immune-mediated diseases. Besides antimitotic and antireplicative effects, cyclophosphamide has immunosuppressive as well as immunomodulatory properties. Cyclophosphamide shows selectivity for T cells and is therefore now frequently used in tumour vaccination protocols and to control post-transplant allo-reactivity in haplo-identical unmanipulated bone marrow after transplantation. The schedule of administration is of special importance for the immunological effect: while cyclophosphamide can be used in high-dose therapy for the complete eradication of haematopoietic cells, lower doses of cyclophosphamide are relatively selective for T cells. Of special interest is the fact that a single administration of low-dose cyclophosphamide is able to selectively suppress regulatory T cells (Tregs). This effect can be used to counteract immunosuppression in cancer. However, cyclophosphamide can also increase the number of myeloid-derived suppressor cells. Combination of cyclophosphamide with other immunomodulatory agents could be a promising approach to treat different forms of advanced cancer.



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Influence of glioblastoma contact with the lateral ventricle on survival: a meta-analysis

Abstract

The ventricular-subventricular zone (V-SVZ), which lies in the walls of the lateral ventricles (LV), is the largest neurogenic niche within the adult brain. Whether radiographic contact with the LV influences survival in glioblastoma (GBM) patients remains unclear. We assimilated and analyzed published data comparing survival in GBM patients with (LV+GBM) and without (LV-GBM) radiographic LV contact. PubMed, EMBASE, and Cochrane electronic databases were searched. Fifteen studies with survival data on LV+GBM and LV-GBM patients were identified. Their Kaplan–Meier survival curves were digitized and pooled for generation of median overall (OS) and progression free (PFS) survivals and log-rank hazard ratios (HRs). The log-rank and reported multivariate HRs after accounting for the common predictors of GBM survival were analyzed separately by meta-analyses. The calculated median survivals (months) from pooled data were 12.95 and 16.58 (OS), and 4.54 and 6.25 (PFS) for LV+GBMs and LV-GBMs, respectively, with an overall log-rank HRs of 1.335 [1.204–1.513] (OS) and 1.387 [1.225–1.602] (PFS). Meta-analysis of log-rank HRs resulted in summary HRs of 1.58 [1.35–1.85] (OS, 10 studies) and 1.41 [1.22–1.64] (PFS, 5 studies). Meta-analysis of multivariate HRs resulted in summary HRs of 1.35 [1.14–1.58] (OS, 6 studies) and 1.64 [0.88–3.05] (PFS, 3 studies). Patients with GBM contacting the LV have lower survival. This effect may be independent of the common predictors of GBM survival, suggesting a clinical influence of V-SVZ contact on GBM biology.



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Considerations in radiation therapy for pregnant women with malignancy

Abstract

Treatment of pregnant women with cancer with radiation presents medical, technical, and ethical challenges. Cancer during pregnancy occurs in 1 out of 1000 cases. The most common cancers are those that are common in females of childbearing age, including breast cancer, cervical cancer, melanoma, Hodgkin lymphoma, and leukemia. The in utero radiation exposure of a developing fetus through diagnostic radiology/nuclear medicine and radiation therapy is always a concern for healthcare providers and parents. Radiation exposure to the fetus seems to be associated with increased incidences of childhood cancer at any fetal dose. However, there also seem to be threshold doses for non-cancer adverse outcomes such as intellectual disability, organ malformation, and fetal death. The fetal radiation exposure from diagnostic radiology and nuclear medicine studies is far smaller than these threshold levels. On the other hand, fetal doses from radiation therapy for treatment of maternal cancers depend largely on gestational age and distance of fetus from the treatment field. Treatment of cancers in head and neck or extremities is relatively safe, while that of pelvic organs, such as cervical cancer, is not compatible with pregnancy. It is important to note that the "threshold" doses were calculated based on observational data and therefore should be used with careful considerations in individual clinical scenarios. Ultimately, it is the frank discussion between the pregnant mother and her family with the entire medical team, including her oncologist, the obstetrician, the neonatologist, the psychologist, and the social worker, that will lead to the best individualized management plan.



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Radiotherapy-related outcomes in pediatric patients with atypical teratoid thabdoid tumor of the central nervous system

Abstract

Objective

Atypical teratoid/rhabdoid tumor (ATRT) of the central nervous system (CNS) is a rare, highly malignant tumor of early childhood. Current protocols favor multimodality treatment, but practice guidelines differ with regard to radiotherapy. The aim of this study was to evaluate outcomes and prognostic factors in pediatric ATRT receiving multimodality treatment including postoperative radiation.

Methods

Pediatric subjects with CNS ATRT treated at our institution between 2000 and 2014 were retrospectively evaluated. Kaplan-Meier method was used to estimate progression free survival (PFS) and overall survival (OS) over time. Log-rank tests were used to examine associations of demographic and treatment factors with PFS and OS.

Results

Twenty pediatric subjects (median age 23.5 months; range 4–99 months) were eligible for analysis. All underwent surgical resection, adjuvant radiotherapy, and intensive multi-agent chemotherapy. PFS at 1 year was 63.3 % (95 % CI, 38.1–80.6 %) and 2 years was 46.1 % (95 % CI, 22.9–66.5 %). OS at both 1 and 2 years was 73.0 % (95 % CI, 46.7–87.8 %). Infratentorial disease, localized disease at diagnosis, and gross total tumor resection were identified as beneficial prognostic factors in PFS and OS. Progressive disease after radiation was identified as a poor prognostic factor in OS. Radiation modality (proton versus x-ray) did not affect disease-related outcomes.

Conclusion

Modern treatment for ATRT with intensive multimodality therapy including radiotherapy results in a significant portion of subjects with long-term disease control. Initial evidence demonstrates that focal proton therapy in very young subjects is feasible with limited toxicities. Prognosis appears to be improved in localized, completely resected disease.



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Evaluation of the Impact of Cancer Treatment on the Adoption and Consolidation of Pro-Health Attitudes in the Field of Cancer in Treated Patients with Colon Cancer

Abstract

Colorectal cancer is the second most common cause of cancer deaths worldwide. Although progress in the development of new drugs over the last two decades has expanded treatment options for this disease, many significant problems relating to their optimization remain to be solved. Data on the cancer knowledge and the healthy behavior and lifestyle in patients with colorectal cancer in Poland is missing. We analyzed the course and results of treatment of first-line chemotherapy in 165 patients diagnosed with colorectal cancer treated between May 2010 and December 2013. The respondent's knowledge in the field of cancer and their lifestyle before and after the treatment were rated. The results were compared with a control group. Mean age was 60.89 ± 8.69 years, median 59 years. The general knowledge about cancer and the level of healthy lifestyle before treatment were low. After treatment, both the knowledge about cancer and the level of healthy lifestyle increased compared to the control group. There was a clear relationship between the level of knowledge about cancer and the willingness to adopt attitudes and healthy behavior by patients. In our analysis, the overall quality of life in patients treated with first-line palliative chemotherapy of colorectal cancer did not change during treatment. Our results indicate the need to implement an educational program on cancer prevention in treated patients, and the analysis of quality of life and other factors than treatment effect remains controversial.



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Clinical significance of prophylactic central compartment neck dissection in the treatment of clinically node-negative papillary thyroid cancer patients

Abstract

Background

Lymph nodal involvement is very common in differentiated thyroid cancer, and in addition, cervical lymph node micrometastases are observed in up to 80 % of papillary thyroid cancers. During the last decades, the role of routine central lymph node dissection (RCLD) in the treatment of papillary thyroid cancer (PTC) has been an object of research, and it is now still controversial. Nevertheless, many scientific societies and referral authors have definitely stated that even if in expert hands, RCLD is not associated to higher morbidity; it should be indicated only in selected cases.

Main body

In order to better analyze the current role of prophylactic neck dissection in the surgical treatment of papillary thyroid cancers, an analysis of the most recent literature data was performed. Prophylactic or therapeutic lymph node dissection, selective, lateral or central lymph node dissection, modified radical neck dissection, and papillary thyroid cancer were used by the authors as keywords performing a PubMed database research. Literature reviews, PTCs large clinical series and the most recent guidelines of different referral endocrine societies, inhering neck dissection for papillary thyroid cancers, were also specifically evaluated. A higher PTC incidence was nowadays reported in differentiated thyroid cancer (DTC) clinical series. In addition, ultrasound guided fine-needle aspiration citology allowed a more precocious diagnosis in the early phases of disease. The role of prophylactic neck dissection in papillary thyroid cancer management remains controversial especially regarding indications, approach, and surgical extension. Even if morbidity rates seem to be similar to those reported after total thyroidectomy alone, RCLD impact on local recurrence and long-term survival is still a matter of research. Nevertheless, only a selective use in high-risk cases is supported by more and more scientific data.

Conclusions

In the last years, higher papillary thyroid cancer incidence and more precocious diagnoses were worldwide reported. Among endocrine and neck surgeons, there is agreement about indications to prophylactic treatment of node-negative "high-risk" patients. A recent trend toward RCLD avoiding radioactive treatment is still debated, but nevertheless, prophylactic dissections in low-risk cases should be avoided. Prospective randomized trials are needed to evaluate the benefits of different approaches and allow to drawn definitive conclusions.



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Aberrant methylation of protocadherin 17 and its prognostic value in pediatric acute lymphoblastic leukemia

Abstract

Background

The outcome of approximately 20% of patients with acute lymphoblastic leukemia (ALL) remains poor because of disease recurrence. We examined whether DNA methylation of cadherin superfamily genes is a useful biomarker for ALL relapse.

Procedure

We used Infinium Methylation 450K Arrays to assess genome-wide DNA methylation status. The methylation status of each individual gene was then determined by a combination of bisulfite restriction analysis and genome bisulfite sequencing. mRNA expression was evaluated by reverse-transcriptase PCR (RT-PCR) and quantitative real-time PCR.

Results

Cadherin superfamily genes including cadherin (CDH) 1, protocadherin (PCDH) 8, and PCDH17 were selected for analysis of methylation status. In 40 patient samples with B-cell precursor (BCP) ALL at diagnosis, the methylation frequencies of CDH1, PCDH8, and PCDH17 were 62.5, 55, and 30%, respectively. CDH1 and PCDH8 methylation was also detected in 80 and 20% of control bone marrow (BM) samples, respectively. On the contrary, PCDH17 was unmethylated in all control BM samples. There was a significant correlation between the methylation status of PCDH17 (but not CDH1 and PCDH8) and event-free survival or overall survival. Univariate and multivariate analyses showed that only PCDH17 methylation was associated with an increased risk for relapse and mortality in patients with BCP ALL.

Conclusion

PCDH17 methylation at diagnosis was closely related to poor prognosis and thus could be used as a new biomarker to predict relapse in patients with BCP ALL.



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Elective cholecystectomy reduces morbidity of cholelithiasis in pediatric sickle cell disease

Abstract

Background

Cholelithiasis is a frequent complication in pediatric sickle cell disease (SCD). Though it is standard practice to perform a cholecystectomy in pediatric SCD patients with symptoms of cholelithiasis, the use of elective cholecystectomy for asymptomatic patients remains controversial.

Procedure

Records of 191 pediatric sickle cell patients with cholelithiasis who underwent cholecystectomy were retrospectively reviewed. Patients classified as follows: (i) elective—no preoperative symptoms, cholelithiasis on screening ultrasound, comprehensive preoperative plan; (ii) symptomatic—preoperative symptoms of cholelithiasis on diagnostic ultrasound, comprehensive preoperative plan; or (iii) emergent—hospitalization for acute cholecystitis symptoms, cholelithiasis on diagnostic ultrasound, limited preoperative preparation. We compared the morbidity of cholecystectomy by examining pre- and post-cholecystectomy hospital admission days, length of stay for cholecystectomy, and surgical complications.

Results

Patients with SCD underwent a total of 191 cholecystectomies over a 10-year period: 51 elective, 110 symptomatic, and 30 emergent. Patients who required emergent cholecystectomy had a longer postoperative hospitalization time than elective or symptomatic cholecystectomy (7.3 vs 4.3, P < 0.001). Baseline values for total bilirubin and aspartate aminotransferase (AST) were significantly elevated (P < 0.02 and P < 0.07, respectively) in patients requiring emergent cholecystectomy.

Conclusions

This represents the largest reported retrospective review of pediatric cholelithiasis and cholecystectomy in SCD to date. These data strongly suggest that elective cholecystectomy decreases morbidity associated with emergent cholecystectomy. The overall outcomes for symptomatic and elective patients are favorable. However, our study indicates the need for prospective studies to identify clinical indicators for those emergent patients.



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Alcohol Consumption and Prostate Cancer Incidence and Progression: A Mendelian Randomization Study

Abstract

Prostate cancer is the most common cancer in men in developed countries, and is a target for risk reduction strategies. The effects of alcohol consumption on prostate cancer incidence and survival remain unclear, potentially due to methodological limitations of observational studies. In the current study we investigated the associations of genetic variants in alcohol-metabolising genes with prostate cancer incidence and survival. This article is protected by copyright. All rights reserved.



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Evaluation of the Impact of Cancer Treatment on the Adoption and Consolidation of Pro-Health Attitudes in the Field of Cancer in Treated Patients with Colon Cancer

Abstract

Colorectal cancer is the second most common cause of cancer deaths worldwide. Although progress in the development of new drugs over the last two decades has expanded treatment options for this disease, many significant problems relating to their optimization remain to be solved. Data on the cancer knowledge and the healthy behavior and lifestyle in patients with colorectal cancer in Poland is missing. We analyzed the course and results of treatment of first-line chemotherapy in 165 patients diagnosed with colorectal cancer treated between May 2010 and December 2013. The respondent's knowledge in the field of cancer and their lifestyle before and after the treatment were rated. The results were compared with a control group. Mean age was 60.89 ± 8.69 years, median 59 years. The general knowledge about cancer and the level of healthy lifestyle before treatment were low. After treatment, both the knowledge about cancer and the level of healthy lifestyle increased compared to the control group. There was a clear relationship between the level of knowledge about cancer and the willingness to adopt attitudes and healthy behavior by patients. In our analysis, the overall quality of life in patients treated with first-line palliative chemotherapy of colorectal cancer did not change during treatment. Our results indicate the need to implement an educational program on cancer prevention in treated patients, and the analysis of quality of life and other factors than treatment effect remains controversial.



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What do people fear about cancer? A systematic review and meta-synthesis of cancer fears in the general population

Abstract

Objective

Cancer has long inspired fear but the effect of fear is not well understood; it seems both to facilitate and deter early diagnosis behaviours. To elucidate fear's behavioural effects, we systematically reviewed and synthesised qualitative literature to explore what people fear about cancer.

Methods

We searched Medline, Embase, PsycInfo, Web of Science, AnthroSource, and Anthrobase for studies on cancer fear in breast, cervical, and colorectal cancer screening, and analysed 102 studies from 26 countries using thematic synthesis.

Results

Fears of cancer emanated from a core view of cancer as a vicious, unpredictable, and indestructible enemy, evoking fears about its proximity, the (lack of) strategies to keep it at bay, the personal and social implications of succumbing, and fear of dying from cancer.

Conclusions

This view of cancer as "an enemy" reprises the media's "war on cancer" theme, and may affect the acceptance of cancer early detection and prevention messages, since cancer's characteristics influenced whether "fight" or "flight" was considered appropriate. This article is protected by copyright. All rights reserved.



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Systematic review and meta-analysis of collaborative care interventions for depression in patients with cancer

Abstract

Objective

Previous systematic reviews have found limited evidence for the effectiveness of pharmacological and psychological interventions for the management of depression in patients with cancer. This paper provides the first meta-analysis of newer collaborative care interventions, which may include both types of treatment, as well as integrated delivery and follow-up. Meta-analyses of pharmacological and psychological interventions are included as a comparison.

Methods

A search of MEDLINE, EMBASE, PsycINFO, and the Cochrane Library from July 2005 to January 2015 for randomized controlled trials of depression treatments for cancer patients diagnosed with a major depressive disorder, or who met a threshold on a validated depression rating scale was conducted. Meta-analyses were conducted using summary data.

Results

Key findings included 8 reports of 4 collaborative care interventions, 8 pharmacological, and 9 psychological trials. A meta-analysis demonstrated that collaborative care interventions were significantly more effective than usual care (standardized mean difference = -0.49, p = 0.003), and depression reduction was maintained at 12 months. By comparison, short-term (up to 12 weeks), but not longer-term effectiveness was demonstrated for both pharmacological and psychological interventions.

Conclusions

Collaborative care interventions have newly emerged as multi-disciplinary care delivery models, which may result in more long-term depression remission. This review also updates previous findings of modest evidence for the effectiveness of both pharmacological and psychological interventions for threshold depression in cancer patients. Research designs focusing on combined treatments and delivery systems may best further the limited evidence-base for the management of depression in cancer. This article is protected by copyright. All rights reserved.



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Towards understanding problems in the parent-practitioner relationship when a child has cancer: meta-synthesis of the qualitative literature

Abstract

Objective

This review aimed to synthesise qualitative research on problems in the parent-practitioner relationship in childhood cancer, to understand how these problems arise, how they are conceptualised and how they might be resolved.

Methods

A systematic search of five electronic databases identified 2,863 articles. After screening, 81 full text papers were assessed for eligibility, and four were included in the review. Six further papers were identified through searching reference lists and citation tracking. Synthesis of these 10 papers drew on the meta-study approach, involving analysis, comparison and integration of findings, methods and theoretical influences.

Results

All papers but one conceptualised problems in the parent-practitioner relationship as conflict or relational problems, attributing these to differences between parents and practitioners in roles and perspectives, or in power and authority. The remaining paper focussed on parents' emotional needs as the basis for relationship problems. Our approach to synthesis exposed researchers' prior assumptions and the influence of these on the methods, analysis and findings of the studies.

Conclusions

The current literature gives little attention to how interpersonal problems with practitioners may reflect the emotional needs of parents. Understanding these problems as an expression of the distress and fear parents experienced because of their child's condition may offer new ways of helping parents. Future research needs to address the limitations of previous studies, including ensuring that the study design and analysis allow contextual factors and intrapersonal factors to be explored, and that researchers are open to their perspectives being altered by their data.



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Gender differences in clinicopathological features and prognosis of squamous cell carcinoma of the esophagus

Abstract

Background

Esophageal squamous cell carcinoma (ESCC) is more frequent in male, and female ESCC patients have better prognosis and tend to diagnose at an earlier stage than male. Regarding these female advantages, gender differences of immunological reaction and sex hormone relations were investigated previously. However, the gender differences of clinicopathological features and prognostic factors of ESCC remain well unknown.

Methods

A total of consecutive 170 Japanese patients, including 28 females with ESCC who newly diagnosed and underwent esophagectomy between January 2004 and March 2013 in our institute, were examined. Clinicopathological features and p53 expression, a potent biomarker reflecting chemoresistance and prognosis, were compared. Prognostic factors were analyzed using a multivariate analysis.

Results

The rates of current drinking, flusher, smoking habits, and Brinkman index in female were lower than those in male (p < 0.001). Tumor location, tumor differentiation, T factor, N factor, clinical stage, and contents of initial treatment had no gender differences. Especially, in the population that received neoadjuvant chemotherapy, excellent pathological effectiveness (>Grade2) was seen much more in female significantly (36.1:66.7 %, p = 0.048). Immunohistostaining revealed positive rates of p53 expression were significantly high in male (50.4:30.5 %, p = 0.007). Postoperative complication occurred more frequently in male than female (52.8:28.6 %, p = 0.024). Estimated 5-year disease-specific survivals by Kaplan–Meier method were worse in male than female at rates of 46.2 and 76.7 %, respectively (p = 0.045). Multivariate analysis by Cox's proportional hazards model showed that female gender (HR: 0.508, p = 0.023) and tumor depth (HR: 0.572, p = 0.018) were independent prognostic factors of ESCC after resection.

Conclusions

Female ESCC showed prefer prognosis to male ESCC. Low p53 imunohistochemical expression in the female ESCC patients might be related with higher sensitivity to neoadjuvant chemotherapy.



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New water-soluble palladium(II) complexes of lidocaine and phenylcyanamide derivative ligands: cytotoxicity and cellular response mechanisms

Summary

Three new palladium(II) complexes of lidocaine and phenylcyanamide derivative ligands of formula K[Pd(2,6-Me2pcyd)2(LC)], 1, K[Pd(2,6-Et2pcyd)2(LC)], 2, K[Pd(2,6-Cl2pcyd)2(LC)], 3 (LC: lidocaine, 2,6-Me2pcyd: 2,6-dimethyl phenylcyanamide, 2,6-Et2pcyd: 2,6-diethyl phenylcyanamide, 2,6-Cl2pcyd: 2,6-dichloro phenylcyanamide) have been synthesized and fully characterized. The complexes 13 revealed a significant in vitro antiproliferative activity against human ovarian carcinoma (A2780), colorectal adenocarcinoma (HT29), breast (MCF-7), liver hepatocellular carcinoma (HepG-2) and lung adenocarcinoma (A549) cancer cell lines. All the complexes are more active than cisplatin and follow the trend 2 > 1 > 3. Mechanistic studies showed that the trend in cytotoxicity of the Pd(II) complexes is mainly consistent with their ability to accumulate into cancer cells and to increase intracellular basal reactive oxygen species levels, which consequently results in the loss of mitochondrial membrane potential and apoptosis induction.



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Is blue dye still required during sentinel lymph node biopsy for breast cancer?

Mirjam CL Peek, Tibor Kovacs, Rose Baker, Hisham Hamed, Ash Kothari and Michael Douek

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Value of routine staging imaging studies for patients with stage III breast cancer

Background and Objectives

Routine staging imaging studies (RSIS) are optional in stage III breast cancer (BC). The impact of RSIS on treatment decisions and patient outcomes has not been extensively studied. The goal of this study was to determine whether RSIS in stage III BC affected treatment or patient outcomes.

Methods

Stage III BC patients from 2000 to 2010 were retrospectively identified. RSIS results and treatment plan in response to RSIS results were recorded. Univariate and multivariate Cox proportional hazards regression models with time-dependent covariates were used to assess associations between RSIS use and recurrence-free survival (RFS).

Results

Of 420 patients, 362 (86.2%) received RSIS. RSIS were negative in 264 (72.9%), indeterminate in 77 (18.3%), and positive in 21 patients (5.0%) for metastatic disease. Treatment was altered in 21 (5.8%) patients based on RSIS results (20 with metastatic disease, 1 with indeterminate disease). There was no difference in RFS with RSIS use on multivariate analysis (hazard ratio 1.3; 95% confidence interval 0.73–2.5, P = 0.32).

Conclusions

Most stage III BC patients underwent RSIS, but RSIS results infrequently affected treatment decisions. There was no significant difference in RFS with RSIS use. RSIS to identify metastatic disease for stage III BC has limited value. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.



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Surgical excision margin for primary acral melanoma

Background and Objectives

This study aimed to evaluate treatment outcomes of acral melanoma (AM) based on the excision margin.

Methods

A retrospective cohort study was conducted for patients with primary AM, analyzing recurrence rates, local and in-transit recurrence-free survival (LITRFS), disease-free survival (DFS), and melanoma-specific survival (MSS).

Results

Data from 129 patients of AM were analyzed. In 53 patients with thin AM (thickness ≤1 mm), neither recurrence nor mortality occurred regardless of whether the excision margin was >1 cm or not. Seventy-six patients had thick AM (thickness >1 mm), including 36 treated with a <2 cm excision margin and 40 with a 2 cm margin. Multivariate analyses revealed that a 2 cm margin was associated with a reduced rate of local recurrence (HR, 0.120; P-value = 0.023) and LITR (HR, 0.187; P-value = 0.013) compared with a <2 cm margin. DFS and MSS did not differ between the two groups.

Conclusions

Thin AM were successfully treated with a 1 cm excision margin. For thick AM, a 2 cm excision margin provided improved local control, compared with a <2 cm margin; however, this benefit did not translate into a survival gain. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.



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Distance to the anal verge is associated with pathologic complete response to neoadjuvant therapy in locally advanced rectal cancer

Background and Objectives

Achieving a pathologic complete response (pCR) after neoadjuvant therapy has been associated with better prognosis in rectal cancer patients. The objective of this study was to investigate the relationship between distance to the anal verge (DTAV) and pCR.

Methods

Review of a prospectively maintained database of patients with locally advanced rectal cancer who received neoadjuvant treatment was completed. Uni- and multivariate analysis assessed the association between DTAV and pCR after neoadjuvant therapy.

Results

Of 827 included patients, 20% had a pCR. We found that pCR rates were 11% for tumors <4 cm, 24% for tumors 4–6 cm, 30% for tumors at 6–8 cm, 17% for tumors 8–10 cm, and 14% for tumors >10 cm from the anal verge (P = 0.002). Multivariate analysis also showed a strong association between DTAV and pCR (P = 0.008). The bimodal distribution of pCR resulted in a lower odds ratio of pCR for tumors <4 and >8 cm from the anal verge.

Conclusions

Patients with low tumors (<4 cm) and higher tumors (>8 cm), were less likely to have a pCR. Further investigation is warranted to determine if these observations are related to tumor biology or possibly differences in radiation technique. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.



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Prognostic value of occult tumor cells obtained by peritoneal lavage in patients with resectable pancreatic cancer and no ascites: A systematic review

The poor survival of patients with resectable pancreatic cancer might be related to the presence of occult peritoneal tumor cells (OPTC). This systematic review studies the prognostic value of cytology and carcinoembryonic antigen (CEA) by real-time polymerase chain reaction in peritoneal fluid. The results suggest that presence of OPTC is related to a worse survival in patients with resectable pancreatic cancer. Future studies should investigate its possible role in selecting patients for specific treatment strategies. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.



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Reviewer List 2015



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