Proliferation-dependent expression and phosphorylation of pRB in B cell non-Hodgkin's lymphomas: dependence on RB1 copy number.

Some studies have suggested that a significant fraction of non-Hodgkin's lymphomas (NHL) do not express pRB protein, possibly due to deletions of RB1. We examined RB1/centromere 17 copy number by fluorescent in situ hybridisation, and pRB expression/phosphorylation by immunohistochemistry (IHC) and immunoblotting (IB) in 66 cases of B cell NHL. Thirteen cases had lost one RB1 copy relative to centromere 17 copy number and total DNA content. Case 458/88 had no RB1 copies. pRB levels were heterogeneous as assessed by IB (0.04-1.12 relative units), but all tumours, except for case 458/88, expressed pRB localised to the nucleus in >75% of the tumour cells by IHC. The fraction of phosphorylated pRB was correlated with pRB expression (r(2)= 0.56, P < 0.001). The 14 cases with loss of RB1 had lower pRB expression (median 0.25) than those without (median 0.48, P < 0.001), but a correlation with S phase fraction (r(2) = 0.43, P < 0.001; previously published data for tumour-specific S phase and apoptotic fractions) indicated that the variation in pRB expression was due to differences in proliferative activity. Furthermore, the regression lines for pRB expression vs S phase fraction were not different for the cases with or without loss of one RB1 copy (P = 0.5). Cases 154/88 (one RB1 copy) and 258/88 (two RB1 copies), in addition to case 458/88, had low expression of (hypophosphorylated) pRB (0.04, 0.08 and 0.04), despite their high S phase fractions (21%, 17% and 21%). There was no association between pRB expression/RB1 copy number and apoptotic fraction. Neither pRB expression nor loss of RB1 had prognostic value, but cases 154/88, 258/88, and 458/88 had short survival times (5, 3 and 46 months, respectively) compared to the others (median survival: 44 months, P = 0.03). It is suggested that pRB expression and function are normal in 63 of 66 NHL cases, including 12 of 13 lymphomas with loss of one RB1 allele.     

Association among interleukin-6 gene polymorphism, diabetes and periodontitis in a Chinese population

Objectives:  Diabetics significantly increase risk for periodontitis. Interleukin-6 (IL-6) gene polymorphism may play certain roles in the progression of periodontitis with diabetes. The purpose of this study was to assess the association among IL-6 gene polymorphisms, type 2 diabetes mellitus (T2DM) and chronic periodontitis (CP) in a Chinese population.
Material and methods:  DNA was obtained from 159 patients with CP, 88 patients with T2DM, 110 patients with CP&T2DM and 135 control subjects. The -174/-572/-597 polymorphisms of IL-6 gene were investigated by restriction fragment length polymorphism of polymerase chain reaction products. The results were further confirmed by sequencing. Significance was set at P  < 0.008 after Bonferroni correction.
Results:  Among four groups, CP&T2DM group showed the lowest IL-6-572 CC genotype and C-allele frequencies (54.5% and 74.1%). In this regard, there were significant differences between CP&T2DM group and the control group [ P  = 0.006, odds ratio (OR)  =  0.475, 95% CI: 0.279–0.808 and P  = 0.002, OR = 0.502, 95% CI: 0.319–0.788 respectively]. Logistic regression with adjustment for age, gender, body mass index, smoking and stress showed no significant difference in terms of IL-6-572 genotypes ( P  = 0.058, OR= 0.523, 95% CI: 0.268–1.022).
Conclusions:  The IL-6-572 genotype and allele distributions are unique to subjects with CP&T2DM in a Chinese population.     

Matrix metalloproteinases as mediators of reproductive function

The organs of the adult reproductive system can undergo extensive remodelling, experiencing rapid changes in tissue mass and function. Much of this matrix remodelling is attributed to the action of matrix metalloproteinases. Matrix metalloproteinase family members are expressed in a highly-regulated manner in many reproductive processes, including menstruation, ovulation, implantation, and uterine, breast, and prostate involution. Metalloproteinase concentrations and activity can be regulated by reproductive hormones, as well as by growth factors and cytokines that participate in reproductive events. In addition to playing a role in the loss of connective tissue mass, the metalloproteinases can influence the phenotype of the cellular components of the tissues, altering basic cellular functions such as proliferation, differentiation, and apoptosis. This review focuses on the expression of matrix metalloproteinases in reproductive tissues, and discusses the evidence supporting a role for these enzymes in modulating the structure and function of reproductive organs.      

The Pharmacological Profile of a Novel Highly Potent Bisphosphonate,OX14 (1‐Fluoro‐2‐(Imidazo‐[1,2‐α]Pyridin‐3‐yl)‐Ethyl‐Bisphosphonate)

Bisphosphonates are widely used in the treatment of clinical disorders characterized by increased bone resorption, including osteoporosis, Paget's disease, and the skeletal complications of malignancy. The antiresorptive potency of the nitrogen‐containing bisphosphonates on bone in vivo is now recognized to depend upon two key properties, namely mineral binding affinity and inhibitory activity on farnesyl pyrophosphate synthase (FPPS), and these properties vary independently of each other in individual bisphosphonates. The better understanding of structure activity relationships among the bisphosphonates has enabled us to design a series of novel bisphosphonates with a range of mineral binding properties and antiresorptive potencies. Among these is a highly potent bisphosphonate, 1‐fluoro‐2‐(imidazo‐[1,2 alpha]pyridin‐3‐yl)‐ethyl‐bisphosphonate, also known as OX14, which is a strong inhibitor of FPPS, but has lower binding affinity for bone mineral than most of the commonly studied bisphosphonates. The aim of this work was to characterize OX14 pharmacologically in relation to several of the bisphosphonates currently used clinically. When OX14 was compared to zoledronate (ZOL), risedronate (RIS), and minodronate (MIN), it was as potent at inhibiting FPPS in vitro but had significantly lower binding affinity to hydroxyapatite (HAP) columns than ALN, ZOL, RIS, and MIN. When injected i.v. into growing Sprague Dawley rats, OX14 was excreted into the urine to a greater extent than the other bisphosphonates, indicating reduced short‐term skeletal uptake and retention. In studies in both Sprague Dawley rats and C57BL/6J mice, OX14 inhibited bone resorption, with an antiresorptive potency equivalent to or greater than the comparator bisphosphonates. In the JJN3‐NSG murine model of myeloma‐induced bone disease, OX14 significantly prevented the formation of osteolytic lesions (p < 0.05). In summary, OX14 is a new, highly potent bisphosphonate with lower bone binding affinity than other clinically relevant bisphosphonates. This renders OX14 an interesting potential candidate for further development for its potential skeletal and nonskeletal benefits. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.     

Mechanisms of cancer chemoprevention in hepatic carcinogenesis: modulation of focal lesion growth in mice

Studies in our laboratory have concentrated on further understanding the mechanism by which chemicals induce cancer and the means to prevent or retard this process. Recent investigations have revolved around the role of oxidative stress and oxidative damage in the induction of cancer by nongenotoxic carcinogens. Hepatocarcinogenic compounds including selective chlorinated hydrocarbons appeared to induce oxidative stress in the liver. This oxidative stress and oxidative damage in turn may be responsible for the tumor-promoting activity of these compounds. Reduction of oxidative damage by antioxidants, or dietary-restriction, results in an ablation of the induction of selective cell growth by these agents. The oxidative stress induced by nongenotoxic agents may influence cell proliferation and/or apoptosis in the preneoplastic cells. Our studies with nongenotoxic hepatic carcinogens showed a dose-dependent increase in oxidative stress and an increase in hepatic focal lesion growth. Antioxidant dietary supplementation or caloric restriction prevented the lesion growth. This appeared to be through an increase in apoptosis in the hepatic lesions.      

To prep or not to prep - that is the question: A randomized trial on the use of antiflatulent medication as part of bowel preparation for patients having image guided external beam radiation therapy to the prostate

Introduction

Radiation therapy is a standard treatment option for prostate cancer. With growing use of escalated doses and tighter margins, procedures to limit rectal size variation are needed to reduce prostate motion, increase treatment accuracy, and minimize rectal toxicity. This prospective study was done to determine whether the introduction of an antiflatulent medication would decrease rectal distention at computed tomography (CT) simulation and throughout a course of radiation therapy.

Hysteroscopic findings in postmenopausal abnormal uterine bleeding: a comparison between HRT users and non-users

Objectives: The aim of our study was to investigate hysteroscopic findings in a sample of 410 menopausal women (hormonal replacement therapy, HRT users n=219 and HRT non-users n=191) and to evaluate the relationship between the presence of intrauterine disease, the use of HRT and the presence of AUB. Methods: Two hundred and nineteen women on HRT underwent standard office hysteroscopy by means of the Hamou hysteroscope (in 94 cases for abnormal uterine bleeding (AUB) and in 125 cases for periodic endometrium monitoring). One hundred and ninety-one women who had never received HRT were submitted to office hysteroscopy (154 for AUB and 37 for other reasons). Results: Intrauterine diseases are more frequent in patients who do not use HRT (P=0.02). Endometrial polyps is a frequent disease present in 30% of the sample (23.7% of HRT users and 30.8% of HRT non-users). Myomas were present in 8.7% of all patients examined (6.8% of HRT users and 11% of HRT non-users). Irregular bleeding in menopause is often associated with endouterine abnormalities: in symptomatic patients the frequency of endouterine diseases was 41% while in asymptomatic patients was 28% (P=0.003). In patients taking HRT (n=219) endouterine disease is demonstrated in 37% with AUB and in 26% without AUB (P=0.07). Conclusion: Benign intrauterine diseases (endometrial polyps and submucous myomas) are more frequent in postmenopausal women who do not use HRT. In patients taking HRT irregular bleeding is associated with intrauterine diseases; however, the absence of AUB does not exclude the presence of endometrial polyps or myomas.