Quick, non-invasive and quantitative assessment of small fiber neuropathy in patients receiving chemotherapy

Abstract

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common, potentially severe and dose-limiting adverse effect; however, it is poorly investigated at an early stage due to the lack of a simple assessment tool. As sweat glands are innervated by small autonomic C-fibers, sudomotor function testing has been suggested for early screening of peripheral neuropathy. This study aimed to evaluate Sudoscan, a non-invasive and quantitative method to assess sudomotor function, in the detection and follow-up of CIPN. Eighty-eight patients receiving at least two infusions of Oxaliplatin only (45.4 %), Paclitaxel only (14.8 %), another drug only (28.4 %) or two drugs (11.4 %) were enrolled in the study. At each chemotherapy infusion the accumulated dose of chemotherapy was calculated and the Total Neuropathy Score clinical version (TNSc) was carried out. Small fiber neuropathy was assessed using Sudoscan (a 3-min test). The device measures the Electrochemical Skin Conductance (ESC) of the hands and feet expressed in microSiemens (µS). For patients receiving Oxaliplatin mean hands ESC changed from 73 ± 2 to 63 ± 2 and feet ESC from 77 ± 2 to 66 ± 3 µS (p < 0.001) while TNSc changed from 2.9 ± 0.5 to 4.3 ± 0.4. Similar results were observed in patients receiving Paclitaxel or another neurotoxic chemotherapy. During the follow-up, ESC values of both hands and feet with a corresponding TNSc < 2 were 70 ± 2 and 73 ± 2 µS respectively while they were 59 ± 1.4 and 64 ± 1.5 µS with a corresponding TNSc ≥ 6 (p < 0.0001 and p = 0.0003 respectively). This preliminary study suggests that small fiber neuropathy could be screened and followed using Sudoscan in patients receiving chemotherapy.

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Investigation of FIH-1 and SOCS3 expression in KRAS mutant and wild-type patients with colorectal cancer

Abstract

Colorectal cancer (CRC) is a multistep process based on the accumulation of somatic mutations in genes such as APC and KRAS. Data on the presence of mutations in KRAS gene in CRC and its relationship with clinicopathological parameters and expression of genes involved in tumor progression are scarce. We unbiasedly examined the KRAS status in samples from 99 patients and its correlation with clinicopathological parameters such as age, sex, tumor location, lymph node metastasis, tumor stage, tumor grade, and vascular invasion. Consistent with reports of other researchers, 38.4 % of our samples harbored KRAS mutation in their genomes with preferential mutation in codon 12 (89.4 %). Nevertheless, unlike previous reports, we were not able to correlate KRAS status with clinicopathological parameters (P > 0.05) except for vascular invasion. Patients with KRAS mutation have more vascular invasion compared with patient having wild-type KRAS. Next, we investigated the expression of two tumor suppressor genes, factor-inhibiting hypoxia-inducible factor 1 (FIH-1) and suppressor of cytokine signaling (SOCS3), in both KRAS mutant and wild-type groups and looked for any correlation between their expression and clinicopathological parameters. Although the expression of both genes was not regular, none of the clinicopathological parameters were associated with the expressions of FIH-1 and SOCS3 at mRNA level (P > 0.05). However, decline in FIH-1 expression at protein level in KRAS mutant group was correlated with stage IV and grade 2 of tumor (P ≤ 0.05). Our results demonstrated that there is no or low correlation between KRAS status, FIH-1, and SOCS3 expression with epidemiologic and clinicpathological characteristics in CRC.

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E2F1: a promising regulator in ovarian carcinoma

Abstract

E2F is a family of transcription factors that recognized to regulate the expression of genes essential for a wide range of cellular functions, including cell cycle progression, DNA repair, DNA replication, differentiation, proliferation, and apoptosis. E2F1, the most classic member of the E2F family, exhibits a complex role in tumor development regulation. In recent years, a growing body of data suggested an intimate relationship between E2F1 and ovarian carcinoma. And E2F1 was well identified to play dual functions and serve as a useful prognostic indicator in ovarian carcinoma. However, the mechanism underlying E2F1 associated with ovarian carcinoma remains elusive. It is necessary to clarify the fundamental role of E2F1 in ovarian carcinoma. In this review, we tried to sum up the knowledge of E2F1, including its structure and related mechanism. We also attempt to absorb the research achievements and collect the mechanism of E2F1 in ovarian carcinoma.

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Evaluation of RIP1K and RIP3K expressions in the malignant and benign breast tumors

Abstract

Receptor-interacting protein kinase 1 (RIP1K) and RIP3K belong to RIPK family, which regulate cell survival and cell death. In the present investigation, the expression levels of RIP1K and RIP3K were evaluated in the 30 malignant, 15 benign, and 20 normal breast tissues, and their correlation with clinicopathological characteristics was also studied. The expression levels of RIP1K and RIP3K were determined, by western blot analysis. The relative RIP1K expression was significantly higher in the malignant and benign tumors when compared to those of normal tissues (P < 0.0001 and P < 0.001, respectively). However, the expression level of RIP3K was significantly lower in the malignant tumors than those of normal and benign values (P < 0.001 and P < 0.01, respectively). Positive significant correlation was found for RIP1K expression with tumor size (P < 0.001), grades (P < 0.0001), and c-erbB2 (P < 0.001), but negative significant correlation was detected with patient's age (P < 0.001), estrogen receptor (ER) (P < 0.001), progesterone receptor (PR) (P < 0.01), and P53 (P<0.01) status. RIP3K expression was significantly lower in the pre-menopauses (P < 0.01), grade III (P < 0.05), ER-negative (P < 0.05), and c-erbB2-negative malignant tumors, but no correlation was detected with tumor size, PR, and P53 status. No significant correlation was observed for RIP1K and RIP3K expressions with Ki67 and Her2. Based on the present results, it is concluded that reduction of RIP3K expression in the malignant breast tumor might be an important evidence to support the antitumor activity of this enzyme in vivo. However, RIP1K expression was shown to be higher in the malignant breast tumors than those of normal and benign breast tissues, which probably designates as a poor prognostic factor.

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TIMP3 regulates osteosarcoma cell migration, invasion, and chemotherapeutic resistances

Abstract

Tissue inhibitors of metalloproteinases (TIMPs) inhibit matrix metalloproteinases (MMPs) to limit degradation of the extracellular matrix. Low levels of TIMP3 have been demonstrated in cancer tissues at advanced clinical stages, with positive distant metastasis and chemotherapeutic resistance. We examined the role of TIMP3 in osteosarcoma (OS) cell invasiveness and chemoresistance. TIMP3 was overexpressed or knocked down in the human OS cell lines Saos2 and MG63. Cell migration and invasion capacities were then evaluated using Transwell assays, and resistance to cisplatin was assessed by CCK-8 assay and flow cytometry. Real-time PCR and western blotting were used to investigate activation of signaling pathways downstream of TIMP3. Overexpression of TIMP3 inhibited the migration and invasion of Saos2 and MG63 cells, while knockdown of TIMP3 had the opposite effect. Cell survival after exposure to cisplatin was inhibited by TIMP3 overexpression in both Saos2 and MG63 cells. Consistently, downregulation of TIMP3 gene expression significantly decreased the sensitivity of OS cells to cisplatin treatment. MMP1, MMP2, Bcl-2, and Akt1 were all downregulated following TIMP3 overexpression, while Bax and cleaved caspase-3 were upregulated. TIMP3 knockdown had opposite effects on the regulation of these genes. Taken together, our findings suggest TIMP3 as a new target for inhibition of OS progression and chemotherapeutic resistance.

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Zinc Carnosine Inhibits Lipopolysaccharide-Induced Inflammatory Mediators by Suppressing NF-κb Activation in Raw 264.7 Macrophages, Independent of the MAPKs Signaling Pathway

Abstract

This study aimed to investigate the role of the mitogen-activated protein kinases (MAPKs) signaling pathway in the anti-inflammatory effects of zinc carnosine (ZnC) in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Cells were pretreated with ZnC (0–100 μM) for 2 h prior to the addition of LPS (1 μg/ml). Following 24 h of treatment, ZnC was found not to be cytotoxic to RAW 264.7 cells up to the concentration of 100 μM. Our current findings showed that ZnC did not protect RAW 264.7 cells from LPS-induced "respiratory burst". Significant increment in intracellular glutathione (GSH) level and reduction in thiobarbituric acid reactive substances (TBARS) concentration can only be observed in cell pretreated with high doses of ZnC only (50 and 100 μM for GSH and 100 μM only for TBARS). On the other hand, pretreatment of cells with ZnC was able to inhibit LPS-induced inducible nitric oxide synthase and cyclooxygenase-2 expression significantly. Furthermore, results from immunoblotting showed that ZnC was able to suppress nuclear factor-kappaB (NF-κB) activation, and highest suppression can be observed at 100 μM of ZnC pretreatment. However, pretreatment of ZnC did not inhibit the early activation of MAPKs. In conclusion, pretreatment with ZnC was able to inhibit the expression of inflammatory mediators in LPS-induced RAW 264.7 cells, mainly via suppression of NF-κB activation, and is independent of the MAPKs signaling pathway.

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Effects of Dietary Copper-Methionine on Matrix Metalloproteinase-2 in the Lungs of Cold-Stressed Broilers as an Animal Model for Pulmonary Hypertension

Abstract

The objective of the present study was to investigate the effects of different levels of copper (as supplemental copper-methionine) on ascites incidence and matrix metalloproteinase-2 (MMP-2) changes in the lungs of cold-stressed broilers. For this purpose, 480 1-day-old Ross 308 broiler chickens were randomly assigned to six treatments. Treatments consisted of two ambient temperatures (thermoneutral and cold stress) each combined with 0, 100, and 200 mg supplemental copper/kg as copper-methionine in a 2 × 3 factorial arrangement in a completely randomized design with four replicates. Ascites was diagnosed based on abdominal and pericardial fluid accumulation at 45 days of age. Fourty-eight broilers were killed at 38 and 45 days of age, and their lungs were collected for biological analysis. Results showed that MMP-2 increased in the lungs of ascitic broilers and that copper-methionine supplementation significantly reduced MMP-2 in cold-stressed broiler chickens. Treatments did not affect tissue inhibitor of metalloproteinase-2 (TIMP-2) at 38 and 45 days of age, and no difference was observed between 100 and 200 mg/kg copper-methionine treatments. In conclusion, copper-methionine at higher than conventional levels of supplementation decreased ascites incidence in low temperature through reduced MMP-2 concentration. Further research is warranted to investigate the effect of copper on MMP-2 concentrations in other tissues with high oxygen demand.

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