Zhengrong Yuan

Predictive assessment in pharmacogenetics of XRCC1 gene on clinical outcomes of advanced lung cancer patients treated with platinum-based chemotherapy

Published data have shown inconsistent results about the pharmacogenetics of XRCC1 gene on clinical outcomes of advanced lung cancer patients treated with platinum-based chemotherapy. This meta-analysis aimed to summarize published findings and provide more reliable association. A total of 53 eligible studies including 7433 patients were included. Patients bearing the favorable TrpTrp and TrpArg genotypes of Arg194Trp were more likely to better response rates to platinum-based chemotherapy compared to those with the unfavorable ArgArg genotype (TrpTrp+TrpArg vs. ArgArg: odds ratio (OR) = 2.02, 95% CI, 1.66–2.45). The GlnGln and GlnArg genotypes of Arg399Gln were significantly associated with the poorer response rates compared to those with the ArgArg genotype (GlnGln +GlnArg vs. ArgArg: OR = 0.68, 95% CI, 0.54–0.86). The GlnGln genotype might be more closely associated with shorter survival time and higher risks of death for patients (GlnGln vs. ArgArg: hazard ratio (HR) = 1.14, 95% CI, 0.75–1.75). Our cumulative meta-analyses indicated a distinct apparent trend toward a better response rate for Arg194Trp, but a poorer response rate in Arg399Gln. These findings indicate a predictive role of XRCC1 polymorphisms in clinical outcomes. The use of XRCC1 polymorphisms as predictive factor of clinical outcomes in personalized chemotherapy treatment requires further verification from large well-designed pharmacogenetics studies.

Seasonal Expression of Prolactin Receptor in the Scented Gland of Male Muskrat (Ondatra zibethicus).

Prolactin (PRL) has numerous actions in mammalian biological systems including mammary development and biological processes. The aim of this study was to investigate the seasonal changes of prolactin receptor (PRLR) expression in the scented gland of muskrat during the breeding and nonbreeding seasons. Histologically, glandular cells, interstitial cells and excretory tubules were identified in the scented glands in both seasons, whereas epithelial cells were sparse in the nonbreeding season. PRLR was observed in glandular cells of scented glands during the breeding and nonbreeding seasons with stronger immunostaining during the breeding season. Consistent with the immunohistochemical results, both the mean of protein and mRNA levels of PRLR were higher in the scented glands of the breeding season, and relatively lower level in the nonbreeding season. In addition, differential seasonal changes were also detected in the expression profile of microRNAs (miRNAs) in the scented gland of muskrat. Besides, plasma PRL concentration was remarkably higher in the breeding season than that in the nonbreeding season. These results suggested that muskrat scented gland was the direct target organ of PRL, and stronger expression of PRLR in scented glands during the breeding season indicated that PRL may directly regulate scented glandular function of the muskrats.

Seasonal changes of androgen receptor, estrogen receptors and aromatase expression in the hippocampus of the wild male ground squirrels (Citellus dauricus Brandt)

The wild ground squirrel is a typical seasonal breeder whose annual life cycle can be roughly divided into the breeding season, the post-breeding season and hibernation. Our previous study has reported the seasonal changes in the expressions of androgen receptor (AR), estrogen receptors α and β (ERα and ERβ), and aromatase cytochrome P450 (P450arom) in the hypothalamus of male wild ground squirrels. To further seek evidence of seasonal expression of steroid hormone receptors and steroid hormone synthases in other brain regions, we investigated the protein and mRNA expressions of AR, ERα, ERβ and P450arom in the hippocampus of the male wild ground squirrels during these different reproductive periods. Histological observation showed that the number of pyramidal cells in Cornu Ammonis 1 (CA1) increased in the breeding season. Both protein and mRNA of AR, ERα, ERβ and P450arom were present in CA1 and CA3 of all seasons. There was significant increment in the immune-signal intensity and mRNA level of AR and ERα during the pre-hibernation, whereas those of ERβ and P450arom were higher during the post-breeding season. In addition, the profile of plasma testosterone concentration showed the nadir in the post-breeding season, a marked elevation in the pre-hibernation, and the summit in the breeding season. These findings suggested that the hippocampus may be a direct target of androgen and estrogen; androgen may play important regulatory roles through its receptor and/or the aromatized estrogen in the hippocampus of the wild male ground squirrels.

The expression of prostaglandin-E2 and its receptor in the oviduct of Chinese brown frog (Rana dybowskii).

The Chinese brown frog (Rana dybowskii) has one special physiological phenomenon, which is that its oviduct expands prior to hibernation rather than in the breeding period. In this study, we investigated the immunolocalization and expression levels of prostaglandin-E2 (PGE2), cyclooxygenase (COX)-1 and COX-2, as well as one of its receptor subtypes 4 (EP4) in the oviduct of Rana dybowskii during the pre-hibernation and breeding period. PGE2, COX-1, COX-2 and EP4 have been observed in glandular and epithelial cells in the breeding period, whereas only in the epithelial cells during the pre-hibernation. Consistently, the protein levels of COX-2 and EP4 were higher in the pre-hibernation as compared to the breeding period, but the diversity of COX-1 was not obvious. In addition, oviductal PGE2 concentration was also significantly higher in the pre-hibernation. These results suggested that prostaglandin-E2 may play an important autocrine or paracrine role in oviductal cell proliferation and differentiation of Rana dybowskii during pre-hibernation.

Predictive value of XPG rs2296147T>C polymorphism on clinical outcomes of cancer patients

The Xeroderma pigmentosum complementation group G (XPG) rs2296147T>C polymorphism is suspected to associate with the clinical outcomes of cancer patients. However, the results are inconsistent. This meta-analysis aimed to evaluate the reliable predictive value of XPG rs2296147T>C polymorphism on clinical outcomes of cancer patients. A total of 11 eligible studies were enrolled in this meta-analysis. Our results indicated that the cancer patients with TT and CT genotypes were significantly associated with better respond rates when compared with the CC genotype (TT versus (vs.) CC: odds ratio (OR) = 2.05, 95% confidence intervals (CIs), 1.32-3.20, P = 0.002; TT+CT vs. CC: OR= 1.57, 95% CI, 1.14-2.17, P = 0.005). The TT genotype and/or T allele might be associated with higher survival time for cancer patients than the CC genotype and/or C allele. The cumulative meta-analyses showed an apparent beneficial objective response of TT genotype on cancer patients. In conclusion, this meta-analysis suggests that the XPG rs2296147T>C polymorphism is associated with the clinical outcomes of cancer patients. The XPG rs2296147T>C polymorphism might be a predictive factor of prognosis in cancers patients and contribute to individual treatment in the future.

Seasonal expression of P450c17 and 5α-reductase-2 in the scented gland of male muskrats (Ondatra zibethicus)

Cytochrome P450 17A1 (P450c17) is the key enzyme required for the production of androgenic sex steroids by converting progestogens to androgens. 5α-reductases are enzymes that convert testosterone (T) to dihydrotestosterone (DHT), which has a greater affinity for androgen receptors (AR) and stronger action than T. Our previous studies revealed that the scented glands of male muskrats expressed AR during the breeding and nonbreeding seasons. To further seek evidence of the activities of androgens in scented glands, the expression patterns of P450c17 and 5α-reductase 2 were investigated in the scented glands of male muskrats during the breeding and nonbreeding seasons. The weight and size of scented glands in the breeding season were significantly higher than those of the nonbreeding season. Immunohistochemical data showed that P450c17 and 5α-reductase 2 were presented in the glandular cells and epithelial cells of scented glands in both the seasons. The protein and mRNA expression of P450c17 and 5α-reductase 2 were significantly higher in the scented gland during the breeding season than those during the nonbreeding season. In addition, the levels of DHT and T in the scented gland were remarkably higher during the breeding season. Taken together, these results suggested that the scented glands of male muskrats were capable of locally synthesizing T and DHT, and T and DHT might play an important role in the scented glandular function via an autocrine or paracrine manner.

Immunoreactivities of NF-κB, IL-1β and IL-1R in the skin of Chinese brown frog (Rana dybowskii)

The cytokine interleukin-1 beta (IL-1β) is an evolutionarily conserved molecule that was originally identified in the immune system. Nuclear factor κB (NF-κB) plays a critical role in the activation of immune cells by upregulating the expression of many cytokines. In this study, we investigated the localization and expression level of IL-1β, its functional membrane receptor type I (IL-1R1) and NF-κB in the skin of Rana dybowskii during the breeding period and pre-hibernation. Histologically, the skin of Rana dybowskii consists of epidermis and dermis, and four kinds of cells were identified in the epidermis during the breeding period and pre-hibernation, while the dermis was composed of homogenous gel, mucous glands and granular glands. IL-1β, IL-1R1 and NF-κB were immunolocalized in the epithelial and glandular cells in both periods. Western blotting showed that there was no significant difference in the expression of IL-1β between the breeding period and pre-hibernation, whereas IL-1R1 and NF-κB were significantly higher in the pre-hibernation compared to the breeding period. These results suggested that IL-1β and NF-κB may collectively play important roles in the skin immune system of Rana dybowskii during the breeding period and pre-hibernation.

Seasonal expressions of androgen receptor, P450arom and estrogen receptors in the epididymis of the wild ground squirrel (Citellus dauricus Brandt)

The aim of this study was to investigate the seasonal expressions of androgen receptor (AR), estrogen receptors alpha and beta (ERα and ERβ) and aromatase cytochrome P450 (P450arom) in the epididymis of the wild ground squirrel. Histologically, the epididymis was with larger duct diameter and cell population during the breeding season. AR was presented in the peritubular smooth muscle cells and epithelial cells in the whole epididymis with stronger staining in the breeding period. P450arom was intensely localized in epithelial cells and spermatozoa during the breeding season, absent in the non-breeding season and moderately stained in pre-hibernation. During the breeding season, ERα was intensely expressed in epithelial cytoplasm and/or nucleus, whereas in the non-breeding season and pre-hibernation, weaker staining signal was found in nucleus of epithelial cells. ERβ was absent in the entire annual cycle by immunohistochemical and Real-time PCR detection. The mRNA levels of AR, P450arom and ERα were higher in the epididymis of the breeding season when compared to those of the non-breeding season and pre-hibernation. Taken together, these results suggest that epididymis of the wild ground squirrel is a primary target for androgen and estrogen, and the expression of P450arom represents that epididymis may be a potential source of estrogen.

Seasonal Expression of Oxytocin and Oxytocin Receptor in the Scented Gland of Male Muskrat (Ondatra zibethicus)

Oxytocin (OT) can modulate multiple physiological functions via binding to the widely distributed oxytocin receptor (OTR). In this study, we investigated the seasonal expressions of OT, OTR and extracellular signal regulated kinase (ERK1/2) signaling pathway components in the scented gland of muskrat during the breeding and non-breeding seasons. Histologically, glandular cells, interstitial cells and excretory tubules were identified in the breeding season scented glands, whereas epithelial cells were sparse in the non-breeding season. Immunohistochemical results showed that OTR was present in epithelial cells and interstitial cells while OT, pERK1/2, ERK1/2 and c-fos were expressed in epithelial cells and glandular cells. The protein and mRNA expressions of OTR, OT and c-fos were significantly higher in the scented gland in the breeding season than in the non-breeding season. Importantly, the levels of OT in scented glands and serum were measured by hormone assays, and their concentrations were both significantly higher in the breeding season than in the non-breeding season. Moreover, bioinformatics analysis showed that the predicted targets of the differentially expressed microRNAs might include the genes encoding OTR, ERK1/2 and c-fos. These findings suggested that OT may regulate the function of muskrat scented glands by the locally expressed receptors.

Seasonal expression of luteinizing hormone receptor and follicle stimulating hormone receptor in testes of the wild ground squirrels (Citellus dauricus Brandt)

The objective of this study was to evaluate whether luteinizing hormone (LH), follicle stimulating hormone (FSH) and their receptors luteinizing hormone receptor (LHR) and follicle stimulating hormone receptor (FSHR) play roles in the seasonal spermatogenesis of the wild ground squirrels. To that end, we characterized the testicular immunolocalization of LHR and FSHR, their expression on both mRNA and protein levels, as well as serum concentrations of LH and FSH in male wild ground squirrels throughout the annual reproductive cycle. Histologically, all types of spermatogenic cells including mature spermatozoa were identified in the breeding season (April), while spermatogonia and primary spermatocytes were observed in the non-breeding season (June), and spermatogonia, primary spermatocytes and secondary spermatocytes were found in pre-hibernation (September). LHR was present in Leydig cells during the whole periods with more intense staining in the breeding season; Stronger immunostaining of FSHR was observed in Sertoli cells during the breeding season compared to the non-breeding season and pre-hibernation. Consistently, the mRNA and protein levels of LHR and FSHR were higher in testes of the breeding season, and then decreased to a relatively lower level in the non-breeding season and pre-hibernation. Meanwhile, serum LH and FSH concentrations were significantly higher in the breeding season than those in the non-breeding season and pre-hibernation. These results suggested that gonadotropins and its receptors, LHR and FSHR may be involved in the regulation of seasonal changes in testicular functions of the wild ground squirrels.