Wnt signaling in triple-negative breast cancer.

Wnt signaling regulates a variety of cellular processes, including cell fate, differentiation, proliferation and stem cell pluripotency. Aberrant Wnt signaling is a hallmark of many cancers. An aggressive subtype of breast cancer, known as triple-negative breast cancer (TNBC), demonstrates dysregulation in canonical and non-canonical Wnt signaling. In this review, we summarize regulators of canonical and non-canonical Wnt signaling, as well as Wnt signaling dysfunction that mediates the progression of TNBC. We review the complex molecular nature of TNBC and the emerging therapies that are currently under investigation for the treatment of this disease.

Aggregation of Beta-Amyloid Peptides Proximal to Zwitterionic Lipid Bilayers.

One of the hallmarks of Alzheimers disease is the deposition of amyloid plaques, which consist of ß-amyloid (Aß) peptides in fibrillar states. Nonfibrillar Aß aggregates have been considered as an important intermediate in the pathway of fibrillization, but little is known about the formation mechanism. The on-pathway ß-sheet intermediates of Aß40 peptides can be trapped by incubating the peptides in liposomes formed by zwitterionic lipids. The aggregates of Aß40 peptides have been prepared at a peptide concentration of less than 10 µm. Solid-state NMR spectroscopy data show that the backbone conformation of the aggregates is almost identical to that of the fibrils formed in free solution. In contrast to anionic lipids, zwitterionic lipids, which are typical of neuronal soma, did not induce any significant conformational difference in Aß40 fibrils. This liposome-Aß system may serve as a useful model to study the fibril formation mechanism.

Poor sleep in PCOS; is melatonin the culprit?

STUDY QUESTION: Are daily cycles in urinary melatonin and oxidative stress marker levels (8-hydroxydeoxyguanosine) altered in PCOS, and is this associated with changes in sleep quality? SUMMARY ANSWER: There is an association between elevated nighttime melatonin and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels, and poor sleep quality in our PCOS study group. WHAT IS KNOWN ALREADY: Women with PCOS are known to have poorer sleep. However, there have been few studies examining the possible association between melatonin levels and sleep quality in women with polycystic ovarian syndrome (PCOS). STUDY DESIGN, SIZE, DURATION: This is a case-control study of PCOS (n = 26) and non-PCOS control (n = 26) subjects recruited from a tertiary gynaecological centre. PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were requested to complete sleep questionnaires for a month. In a subgroup from these cohorts (PCOS, n = 15; controls, n = 18), urine samples were also collected at various time points over a 24-h period. In addition, their sleep patterns and lighting environment were monitored for 3 consecutive days and nights using a wrist-mounted Actiwatch device. MAIN RESULTS AND THE ROLE OF CHANCE: PCOS women had significantly elevated night-time urinary levels of the melatonin metabolite 6-sulfatoxymelatonin (aMT6s) and of 8-OHdG (both at P < 0.05), as well as significantly reduced sleep quality (P < 0.05), compared with the controls. LIMITATIONS, REASONS FOR CAUTION: Due to the small sample size of the study, further studies will be required to confirm our findings. WIDER IMPLICATIONS OF THE FINDINGS: Our preliminary work provides a possible new insight into the interactions between melatonin, increased oxidative stress and sleep in women with PCOS. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Faculty of Medicine, University of Southampton.

Performance of the LHCb RICH detector at the LHC.

The LHCb experiment has been taking data at the Large Hadron Collider (LHC) at CERN since the end of 2009. One of its key detector components is the Ring-Imaging Cherenkov (RICH) system. This provides charged particle identification over a wide momentum range, from 2-100 GeV/c. The operation and control, software, and online monitoring of the RICH system are described. The particle identification performance is presented, as measured using data from the LHC. Excellent separation of hadronic particle types (π, K, p) is achieved.

Loss of WT1 expression in the endometrium of infertile PCOS patients: a hyperandrogenic effect?

CONTEXT: In fertile patients the endometrial Wilms tumor suppressor gene (WT1) is expressed during the window of implantation. Polycystic ovary syndrome (PCOS) patients suffer from hyperandrogenemia and infertility and have elevated endometrial androgen receptor (AR) expression. WT1 is known to be down-regulated by AR. Therefore, the expression of WT1 and its targets may be altered in PCOS endometrium. OBJECTIVE: The objective of the study was to assess the expression and regulation of WT1 and selected downstream targets in secretory endometrium from ovulatory PCOS (ovPCOS) and fertile women. DESIGN AND PATIENTS: Endometrial samples were obtained from 25 ovPCOS and 25 fertile patients. MAIN OUTCOME MEASURE: Endometrial expression of WT1 and selected downstream targets were assessed by immunohistochemistry and RT-PCR. The androgen effect on WT1 expression was determined in vitro by immunoblots and RT-PCR. The expression of WT1 and its targets was quantified in fertile and ovPCOS stromal cells in the presence of androgens by RT-PCR. Caspase-3/7 activity was measured to evaluate sensitivity to drug-induced apoptosis. RESULTS: WT1 expression was down-regulated in secretory-phase ovPCOS endometrium. Stromal expression of Bcl-2 and p27 was higher, and epidermal growth factor receptor was lower in ovPCOS than in fertile patients. Endometrial stromal expression of WT1, Bcl-2, Bcl-2-associated X protein, and ß-catenin was regulated by androgens. Apoptosis levels were reduced in ovPCOS samples and androgen-treated fertile samples. CONCLUSION: WT1 expression is down-regulated in ovPCOS endometrium during the window of implantation. Androgens regulate the expression of WT1 and its targets during endometrial decidualization. The altered balance between WT1 and AR in the endometrium of PCOS patients may jeopardize the success of decidualization and endometrial receptivity.

Randomized clinical trial of laparoscopic versus open donor nephrectomy.

BACKGROUND: This randomized controlled trial was designed to determine the safety and efficacy of laparoscopic donor nephrectomy (LDN) in comparison with short-incision open donor nephrectomy (ODN). METHODS: Eighty-four live kidney donors were randomized in a 2 : 1 ratio to LDN (56 patients) or short-incision ODN without rib resection (28). Primary endpoints were pain relief and duration of inpatient stay. RESULTS: There was no donor death or allograft thrombosis in either group. The first warm ischaemic time median (range) 4 (2-7) versus 2 (1-5) min; P = 0.001) and the duration of operation (160 (110-250) versus 150 (90-200); P = 0.004) were longer for LDN. LDN led to a reduction in parenteral morphine requirement 59 (6-136) versus 90 (35-312) mg; P = 0.001) and hospital stay (4 (2-6) versus 6 (2-9) days; P = 0.001), and earlier return to employment (42 (14-84) versus 66.5 (14-112) days; P = 0.004). Postoperative respiratory function was improved after LDN. There were more postoperative complications per donor in the ODN group (0.6(0.7) versus 0.3(0.5); P = 0.033). At a median follow-up of 74 months, there were no differences in renal function or allograft survival between the groups. CONCLUSION: LDN removes some of the disincentives to live donation without compromising the outcome of the recipient transplant.

Inclusive K(S);(0)K(S);(0) resonance production in ep collisions at HERA.

Inclusive K_{S};{0}K_{S};{0} production in ep collisions at the DESY ep collider HERA was studied with the ZEUS detector using an integrated luminosity of 0.5 fb;{-1}. Enhancements in the mass spectrum were observed and are attributed to the production of f_{2}(1270)/a_{2};{0}(1320), f_{2};{'}(1525) and f_{0}(1710). Masses and widths were obtained using a fit which takes into account theoretical predictions based on SU(3) symmetry arguments, and are consistent with the Particle Data Group values. The f_{0}(1710) state, which has a mass consistent with a glueball candidate, was observed with a statistical significance of 5 standard deviations. However, if this state is the same as that seen in gammagamma-->K_{S};{0}K_{S};{0}, it is unlikely to be a pure glueball state.

Tunnelled catheters for the haemodialysis patient.

Haemodialysis depends upon the establishment of a durable means of vascular access. Although the creation of a successful arterio-venous Fistulae (AVF) is the ideal, this is not always possible or practical. Tunnelled catheters play an important role as an interim/bridge technique for emergency access or while an AVF matures, but may be associated with significant morbidity. The aim of this review is to highlight recent evidence based developments in tunnelled catheters, including methods of placement, complications and possible management strategies.

Preservation solutions for solid organ transplantation.

Solid organ transplantation was one of the greatest medical advances of the 20th century. Current preservation technology falls short of maintaining organs ex vivo in perpetuity. This review examines the biochemical basis of organ degradation in response to ischaemia, preservation solution composition and potential future organ preservation technology.

A randomized controlled trial of prophylactic antibiotics (co-amoxiclav) prior to embryo transfer.

BACKGROUND: Bacterial contamination of the transfer catheter during embryo transfer is associated with poor clinical outcomes. Antibiotics at the time of embryo transfer may improve outcomes. We evaluated the effect of co-amoxiclav on the rates of bacterial contamination of transfer catheters and clinical pregnancy. METHODS: On the day of oocyte collection, 350 patients were randomized, with sequentially numbered opaque-sealed envelopes containing treatment allocation assigned randomly by computer, to receive co-amoxiclav on the day before and the day of embryo transfer, or no antibiotics. Following transfer, the catheter tips were cultured and assessed to identify the organism(s) isolated and to quantify the level of the contamination. Couples were followed for 8 weeks to determine whether they had achieved clinical pregnancy. Outcome assessors were blinded to the treatment allocation, and the analysis was by intention to treat. RESULTS: Antibiotics significantly reduced catheter contamination rates (49.4 versus 62.3%, RR = 0.79, 95% CI: 0.64, 0.97, P = 0.03). There was no difference detected in clinical pregnancy rates between the two groups (36.0 versus 35.5%, P = 0.83) although there was a significant (P = 0.03) association between the level of bacterial contamination and clinical pregnancy rates. CONCLUSIONS: Co-amoxiclav reduces catheter contamination, but this is not translated into better clinically relevant outcomes such as clinical pregnancy rates. Our findings do not support the routine use of antibiotics at embryo transfer.

Cetrorelix in women with poor ovarian response in previous assisted reproduction cycles.

Our aim was to compare a gonadotrophin-releasing hormone (GnRH) antagonist protocol with an analogue protocol using high dose gonadotrophins (rFSH) in women with poor ovarian response in order to optimise the management while undergoing assisted reproduction treatment. We recruited 31 consecutive patients over 5 months. The eligibility criteria for the study were: one or more previous cancelled cycle due to or=4,500 IU of rFSH. For the antagonist cycle regimen, we used daily 300 IU of rFSH from day 2 on the menses, and then from day 5 daily 0.25 mg of Cetrorelix until the day of human chorionic gonadotrophin (hCG) administration. We demonstrated that the use of an antagonist cycle was associated with a reduction in cancellation rates from 48% (agonist) to 10% (antagonist) (p < 0.039) allowing women to undergoing oocyte retrieval and embryo transfer with a non-significant improvement in the pregnancy rates.

Pre-incision infiltration of local anesthetic reduces postoperative pain with no effects on bruising and wound cosmesis after thyroid surgery.

Optimizing postoperative pain control is an important aspect in perioperative patient care. The aim of this study was to investigate the efficacy of preincision local anesthetic infiltration in postoperative pain management for thyroid surgery and its relationship to bruising and wound cosmesis. In a randomized single-blinded study, 39 consecutive patients listed for thyroid surgery were assigned into two groups. Group I (n = 19) received subcuticular preincision infiltration with 10 ml of bupivacaine (0.5%) and Group II (n = 20) received no infiltration. Postoperatively, the pain experienced was evaluated by two methods: verbal response scores and linear analogue scores (0-100 mm) at different time intervals following surgery. Bruising and cosmetic effects resulting from surgery were assessed using a linear analogue score at discharge. The two groups were well matched for confounding variables. Pain scores were significantly different at 6 hours post operatively (p = 0.0341) with mean scores Group I = 33 and Group II = 50, but this difference disappeared at 24 hours. No patients (0%) received IV morphine in Group I compared to 5 patients (25%) in Group II. There was no significant difference in the mean bruising scores (p = 0.8864) and mean cosmetic scores (p = 0.3339) at discharge. Preincision infiltration with bupivacaine provides easy and better analgesic control postoperatively in patients following thyroid surgery with no effects on bruising or wound cosmesis.

Evaluation of daclizumab to reduce delayed graft function in non-heart-beating renal transplantation: a prospective, randomized trial.

Daclizumab (DZB), an interleukin-2 receptor blocker, has been shown to reduce the rate of acute rejection, while non-heart-beating kidney recipients have high rates of delayed graft function that may be prolonged by high levels of calcineurin inhibitors. This study assessed whether DZB could safely replace calcineurin inhibitors in the immediate postoperative period and promote recovery from ischemic acute tubular necrosis. Patients were randomized into one of two groups: DZB induction and daily mycophenolate mofetil (MMF; 2 g) with steroids (20 mg prednisone) or standard triple therapy with tacrolimus, MMF, and prednisone. Patients in the DZB arm were converted to the control arm when either the serum creatinine dropped to <350 micromol/L or there was biopsy evidence of acute rejection. Over 2 years, Leicester and Newcastle non-heart-beating donor (NHBD) centers recruited 51 patients. There was one patient death in the DZB arm, during the study period, after a nonfunctioning graft was removed. A total of two (8%) grafts in the DZB arm and three (11.5%) grafts in the control arm failed to function. The overall rate of immediate function improved from around 5% (pre-2001) to 28%. There were no significant differences in the incidence of acute rejection or graft function (GFR) at 3 months. Machine-perfused kidneys in DZB-treated recipients had the highest rates of immediate function (53%, P = .015). We found that a calcineurin-sparing regime is safe and may be beneficial for recipients of machine-perfused grafts damaged by warm ischemia.

Randomized clinical trial of daclizumab induction and delayed introduction of tacrolimus for recipients of non-heart-beating kidney transplants.

BACKGROUND: Kidneys from non-heart-beating donors (NHBDs) have high rates of delayed graft function (DGF). Use of calcineurin inhibitors is associated with a reduction in renal blood flow, which may delay graft recovery from ischaemic acute tubular necrosis. METHODS: To assess whether daclizumab (DZB) could safely replace tacrolimus in the immediate postoperative period, patients were randomized to receive DZB induction and daily mycophenolate mofetil with steroids (DZB group) or standard tacrolimus-based triple therapy (control group). Tacrolimus was given to patients in the DZB group when the serum creatinine level dropped below 350 micromol/l. RESULTS: Fifty-one patients were recruited at two centres over a 2-year interval between 2000 and 2003. The overall rate of immediate function was 28 per cent (13 of 46 grafts), with the highest rate in recipients of machine-perfused kidneys treated with DZB (eight of 15 patients). CONCLUSION: Induction with DZB and delayed introduction of tacrolimus reduced the incidence of DGF in recipients of machine-perfused NHBD kidneys.

Cyclosporine and rapamycin act in a synergistic and dose-dependent manner in a model of immunosuppressant-induced kidney damage.

The combination of cyclosporine (CSA) and rapamycin (RAPA) is a potent and commonly used approach to immunosuppression following solid-organ transplantation. By applying varying doses of CSA and RAPA to the rat salt-depleted model, we aimed to find a dose combination that favored antiproliferation/antifibrosis rather than toxicity. Male Sprague-Dawley rats (350 to 500 g) were salt-depleted for 7 days prior to commencing CSA and RAPA treatment. Serum creatinine and urinary protein/creatinine ratios were measured. Fibrosis was estimated with Sirius red staining of extracellular collagen. mRNA expression of TGF-beta, MMP-2, MMP-9, TIMP-1, and collagen III was assessed with reverse transcriptase PCR. A rise in serum creatinine at 7 and 28 days was observed for CSA 15 mg/kg/d (P = .002) but not CSA 7.5 mg (P = .06) or RAPA 1 mg (P = .69) compared to controls. Twenty-four-hour urinary protein excretion was unchanged compared to controls for all drug doses and combinations. Of the dose combinations, CSA 7.5 mg/d + RAPA 0.5 mg/d produced the lowest serum creatinine for all time points, and inhibited profibrotic TIMP-1 (P = .017), while increasing antifibrotic MMP-2 (P = .009) mRNA expression, compared to CSA treatment alone. Expression of TGF-beta and collagen III was unaltered between groups. CSA treatment produced molecular and biochemical changes indicating renal damage. Addition of RAPA can attenuate this damage, but only with a dose reduction of both agents. The most favorable results were for the dose combination CSA 7.5 mg/kg/d plus RAPA 0.5 mg/kg/d.

Alterations in the practice of open and laparoscopic live donor nephrectomy at renal transplant centers in the UK and Ireland.

Live kidney donor (LKD) activity has increased over recent years. In response, the British Transplantation Society (BTS) has issued guidelines for best practice. This study involved two questionnaires sent to all renal transplant centers in the UK and Ireland to examine practice for the years 2000 and 2002. Findings were compared to BTS guidelines. There was a 100% response rate from 28 centers for both years. Twenty-seven centers performed LKD in the year 2000, falling to 24 in 2002. Consultants reported 356 procedures in 2000, representing 19% of all kidney transplants, and 403 in 2002, representing 23% of all kidney transplants. Three centers offered laparoscopic donor nephrectomy in 2000, and five did so in 2002. The majority of centers organize donor and recipient operations synchronously, and most have a consultant anaesthetist present for the donor procedure. There were variations in the use of thromboprophylaxis, and in donor follow-up. There is widespread practice of live kidney donation in the UK and Ireland, but BTS guidelines are not closely adhered to. Laparoscopic donor nephrectomy is offered at a small number of centers, but many have plans to introduce it.

Laparoscopic donor nephrectomy yields kidneys with structure and function equivalent to those retrieved by open surgery.

The technical challenges of laparosopcic transperitoneal donor nephrectomy (LapDN) have raised concerns over the quality of the procured allografts. This study reports the anatomical and functional outcomes of kidneys retrieved from 60 live donors entered into a randomized controlled trial of open versus laparoscopic procurement. Open and laparoscopic donors were well matched for age (P = .18) and body mass index (P = .49). Operating time (P = .0001) and first warm ischaemic time (P < .001) were longer for the laparoscopic donors but total warm time was not different (P = .52). Left renal vein length (P = .14) and left renal artery length (P = .38) were similar. No differences in right vessel length were observed. Rates of acute rejection did not differ, and recipient renal function was similar in the two groups. This study demonstrates that LapDN yields kidneys that are structurally and functionally equivalent to those acquired by the open operation. This data may go some way towards allaying concerns over the effect of laparoscopic procurement on live donor kidneys.