110 research outputs found
Are bisphosphonates effective in the treatment of osteoarthritis pain? A meta-analysis and systematic review.
Osteoarthritis (OA) is the most common form of arthritis worldwide. Pain and reduced function are the main symptoms in this prevalent disease. There are currently no treatments for OA that modify disease progression; therefore analgesic drugs and joint replacement for larger joints are the standard of care. In light of several recent studies reporting the use of bisphosphonates for OA treatment, our work aimed to evaluate published literature to assess the effectiveness of bisphosphonates in OA treatment
Unloading shoes for osteoarthritis of the knee: protocol for the SHARK randomised controlled trial
TGFbeta induces apoptosis and EMT in primary mouse hepatocytes independently of p53, p21Cip1 or Rb status
Melville Trust for the Care and Cure of Cancer to SP and SS.Background: TGF beta has pleiotropic effects that range from regulation of proliferation and apoptosis to morphological changes and epithelial-mesenchymal transition (EMT). Some evidence suggests that these effects may be interconnected. We have recently reported that P53, P21(Cip1) and pRB, three critical regulators of the G1/S transition are variably involved in TGF beta-induced cell cycle arrest in hepatocytes. As these proteins are also involved in the regulation of apoptosis in many circumstances, we investigated their contribution to other relevant TGF beta-induced effects, namely apoptosis and EMT, and examined how the various processes were interrelated. Methods: Primary mouse hepatocytes deficient in p53, p21 and/or Rb, singly or in combination were treated with TGF beta for 24 to 96 hours. Apoptosis was quantified according to morphology and by immunostaining for cleavedcapsase 3. Epithelial and mesenchymal marker expression was studied using immunocytochemistry and real time PCR. Results: We found that TGF beta similarly induced morphological changes regardless of genotype and independently of proliferation index or sensitivity to inhibition of proliferation by TGF beta. Morphological changes were accompanied by decrease in E-cadherin and increased Snail expression but the mesenchymal markers (N-cadherin, SMA alpha and Vimentin) studied remained unchanged. TGF beta induced high levels of apoptosis in p53-/-, Rb-/-, p21(cip1)-/- and control hepatocytes although with slight differences in kinetics. This was unrelated to proliferation or changes in morphology and loss of cell-cell adhesion. However, hepatocytes deficient in both p53 and p21(cip1)were less sensitive to TGF beta-induced apoptosis. Conclusion: Although p53, p21(Cip1) and pRb are well known regulators of both proliferation and apoptosis in response to a multitude of stresses, we conclude that they are critical for TGF beta-driven inhibition of hepatocytes proliferation, but only slightly modulate TGF beta-induced apoptosis. This effect may depend on other parameters such as proliferation and the presence of other regulatory proteins as suggested by the consequences of p53, p21(Cip1) double deficiency. Similarly, p53, p21(Cip1) and pRB deficiency had no effect on the morphological changes and loss of cell adhesion which is thought to be critical for metastasis. This indicates that possible association of these genes with metastasis potential would be unlikely to involve TGF beta-induced EMT.Publisher PDFPeer reviewe
Deficiency of G1 regulators P53, P21Cip1 and/or pRb decreases hepatocyte sensitivity to TGFÎČ cell cycle arrest
<p>Abstract</p> <p>Background</p> <p>TGFÎČ is critical to control hepatocyte proliferation by inducing G1-growth arrest through multiple pathways leading to inhibition of E2F transcription activity. The retinoblastoma protein pRb is a key controller of E2F activity and G1/S transition which can be inhibited in viral hepatitis. It is not known whether the impairment of pRb would alter the growth inhibitory potential of TGFÎČ in disease. We asked how <it>Rb</it>-deficiency would affect responses to TGFÎČ-induced cell cycle arrest.</p> <p>Results</p> <p>Primary hepatocytes isolated from <it>Rb-floxed </it>mice were infected with an adenovirus expressing CRE-recombinase to delete the <it>Rb </it>gene. In control cells treatment with TGFÎČ prevented cells to enter S phase via decreased cMYC activity, activation of P16<sup>INK4A </sup>and P21<sup>Cip </sup>and reduction of E2F activity. In <it>Rb</it>-null hepatocytes, cMYC activity decreased slightly but P16<sup>INK4A </sup>was not activated and the great majority of cells continued cycling. <it>Rb </it>is therefore central to TGFÎČ-induced cell cycle arrest in hepatocytes. However some <it>Rb</it>-null hepatocytes remained sensitive to TGFÎČ-induced cell cycle arrest. As these hepatocytes expressed very high levels of P21<sup>Cip1 </sup>and P53 we investigated whether these proteins regulate pRb-independent signaling to cell cycle arrest by evaluating the consequences of disruption of <it>p53 </it>and <it>p21</it><sup><it>Cip1</it></sup>. Hepatocytes deficient in <it>p53 or p21</it><sup><it>Cip1 </it></sup>showed diminished growth inhibition by TGFÎČ. Double deficiency had a similar impact showing that in cells containing functional pRb; P21<sup>Cip </sup>and P53 work through the same pathway to regulate G1/S in response to TGFÎČ. In <it>Rb</it>-deficient cells however, <it>p53 </it>but not <it>p21</it><sup><it>Cip </it></sup>deficiency had an additive effect highlighting a pRb-independent-P53-dependent effector pathway of inhibition of E2F activity.</p> <p>Conclusion</p> <p>The present results show that otherwise genetically normal hepatocytes with disabled <it>p53</it>, <it>p21</it><sup><it>Cip1 </it></sup>or <it>Rb </it>genes respond less well to the antiproliferative effects of TGFÎČ. As the function of these critical cellular proteins can be impaired by common causes of chronic liver disease and HCC, including viral hepatitis B and C proteins, we suggest that disruption of pRb function, and to a lesser extend P21<sup>Cip1 </sup>and P53 in hepatocytes may represent an additional new mechanism of escape from TGFÎČ-growth-inhibition in the inflammatory milieu of chronic liver disease and contribute to cancer development.</p
Analysis of the candidate 8p21 tumour suppressor, BNIP3L, in breast and ovarian cancer
Loss of heterozygosity (LOH) on the short arm of chromosome 8, at 8p 12-p23, is one of the most frequent genetic events in both breast and ovarian cancer, suggesting the location of a shared tumour suppressor gene. Microcell-mediated chromosome transfer of chromosome 8 suppresses tumorigenicity and growth of colorectal and prostate cancer cell lines, further supporting the presence of a tumour suppressor gene on 8p. We have taken a candidate gene approach to try to identify this tumour suppressor gene at 8p 12-p23. BNIP3L, which has sequence homology to pro-apoptotic proteins and the ability to suppress colony formation in soft agar, is located at 8p21, within a region of ovarian cancer LOH, breast cancer LOH and prostate cancer metastasis suppression. BNIP3L expression was assessed by both RT-PCR and Northern blot analysis in breast and ovarian cancer cell lines and found to be expressed at similar levels relative to expression in their respective normal epithelial cell lines. Genetic analysis of BNIP3L in 40 primary ovarian and 25 primary breast tumours identified one somatic, intronic mutation in one ovarian tumour, as well as several polymorphisms, including one resulting in an amino-acid substitution. These data suggest that BNIP3L is unlikely to be the target of 8p LOH in ovarian or breast cancer
Discrepancies in the diagnosis of intraductal proliferative lesions of the breast and its management implications: results of a multinational survey
To measure discrepancies in diagnoses and recommendations impacting management of proliferative lesions of the breast, a questionnaire of five problem scenarios was distributed among over 300 practicing pathologists. Of the 230 respondents, 56.5% considered a partial cribriform proliferation within a duct adjacent to unequivocal ductal carcinoma in situ (DCIS) as atypical ductal hyperplasia (ADH), 37.7% of whom recommended reexcision if it were at a resection margin. Of the 43.5% who diagnosed the partially involved duct as DCIS, 28.0% would not recommend reexcision if the lesion were at a margin. When only five ducts had a partial cribriform proliferation, 35.7% considered it as DCIS, while if â„20 ducts were so involved, this figure rose to 60.4%. When one duct with a complete cribriform pattern measured 0.5, 1.5, or 4Â mm, a diagnosis of DCIS was made by 22.6, 31.3, and 94.8%, respectively. When multiple ducts with flat epithelial atypia were at a margin, 20.9% recommended reexcision. Much of these discrepancies arise from the artificial separation of ADH and low-grade DCIS and emphasize the need for combining these two under the umbrella designation of ductal intraepithelial neoplasia grade 1 (DIN 1) to diminish the impact of different terminologies applied to biologically similar lesions
Effects of patient selection on the applicability of results from a randomised clinical trial (EORTC 10853) investigating breast-conserving therapy for DCIS
Selection of patients for randomised clinical trials may have a large impact on the applicability of the study results to the general population presenting the same disorder. However, clinical characteristics and outcome data on non-entered patients are usually not available. The effects of patient selection for the EORTC 10853 trial investigating the role of radiotherapy in breast conserving therapy for ductal carcinoma in situ have been studied, in an analysis of all patients treated for ductal carcinoma in situ in five participating institutes. The reasons for not entering patients were evaluated and treatment results of the randomised patients were compared to those not entered. A total of 910 patients were treated for ductal carcinoma in situ. Of these, 477 (52%) were ineligible, with the size of the lesion being the main reason for ineligibility (30% of all ductal carcinoma in situ). Of the 433 eligible patients, 278 (64%) were randomised into the trial. The main reasons for non-entry of eligible patients were either physicians' preference for one of the treatment arms (26%) or patients' refusal (9%). These percentages showed significant variation among the institutes. At 4 years follow-up, those patients not entered in the trial and treated with local excision and radiotherapy, had higher local recurrence rates than the patients randomised in the trial and treated with the same approach, (17 vs 2%, P=0.03). The patients treated with local excision alone had equal local recurrence rates (11% in both groups). Selection of patients may explain the differences in outcome of the randomised patients, and those not-entered. Thus, the results of this trial may not be applicable to all patients with ductal carcinoma in situ
Essential versus accessory aspects of cell death: recommendations of the NCCD 2015
Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as âaccidental cell deathâ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. âRegulated cell deathâ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death
Effects of Hepatitis B Virus S Protein Exposure on Sperm Membrane Integrity and Functions
Background: Hepatitis B is a public health problem worldwide. Viral infection can affect a manâs fertility, but only scant information about the influence of hepatitis B virus (HBV) infection on sperm quality is available. The purpose of this study was to investigate the effect of hepatitis B virus S protein (HBs) on human sperm membrane integrity and functions. Methods/Principal Findings: Reactive oxygen species (ROS), lipid peroxidation (LP), total antioxidant capacity (TAC) and phosphatidylserine (PS) externalization were determined. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays and flow cytometric analyses were performed. (1) After 3 h incubation with 25 mg/ml of HBs, the average rates of ROS positive cells, annexin Vâpositive/propidium iodide (PI)-negative cells, Caspases-3,-8,-9 positive cells and TUNEL-positive cells were significantly increased in the test groups as compared to those in the control groups, while TAC level was decreased when compared with the control. The level of malondialdehyde (MDA) in the sperm cells exposed to 50 mg/ml of HBs for 3 h was significantly higher than that in the control (P,0.05â0.01). (2) HBs increased the MDA levels and the numbers of ROS positive cells, annexin Vâpositive/PI-negative cells, caspases-3,-8,-9 positive cells and TUNEL-positive cells in a dose-dependent manner. (3) HBs monoclonal antibody (MAb) and N-Acetylcysteine (NAC) reduced the number of ROS-positive sperm cells. (4) HBs decreased the TAC levels in sperm cells in a dose-dependent manner. Conclusion: HBs exposure could lead to ROS generation, lipid peroxidation, TAC reduction, PS externalization, activation o
Contesting European Regions
The research on which this paper is based was conducted under an Economic and Social Research Council (ESRC) Professorial Fellowship [grant number RES-051-27-0302].Peer reviewedPublisher PD
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