Feasibility of recruitment to an oral dysplasia trial in the United Kingdom

Background: Oral epithelial dysplasia (OED) has a malignant potential. Therapeutic options for OED remain both limited and without good evidence. Despite surgery being the most common method of treating OED, recurrence and potentially significant morbidity remain problematic. Consequently, there has been much interest in non-surgical treatments for OED. Cyclo-oxygenase (COX) up-regulation is known to occur in the dysplasia-carcinoma sequence and evidence now exists that COX-2 is a prognostic marker of malignant transformation in OED. COX-inhibitors are therefore considered a potential therapeutic strategy for treating this condition. We aimed to provide both proof of principal evidence supporting the effect of topical COX inhibition, and determine the feasibility of recruitment to an OED chemoprevention trial in the UK. Methods: Recruitment of 40 patients with oral leukoplakia to 4 study arms was planned. The total daily dose of Aspirin would increase in each group and be used in the period between initial diagnostic and follow-up biopsies. Results: During the 15-month recruitment period, 15/50 screened patients were eligible for recruitment, and 13 (87%) consented. Only 1 had OED diagnosed on biopsy. 16 patients were intolerant of, or already taking Aspirin and 16 patients required no biopsy. Initial recruitment was slow, as detection relied on clinicians identifying potentially eligible patients. Pre-screening new patient letters and directly contacting patients listed for biopsies improved screening of potentially eligible patients. However, as the incidence of OED was so low, it had little impact on trial recruitment. The trial was terminated, as recruitment was unlikely to be achieved in a single centre. Conclusion: This feasibility trial has demonstrated the low incidence of OED in the UK and the difficulties in conducting a study because of this. With an incidence of around 1.5/100,000/year and a high proportion of those patients already taking or intolerant of Aspirin, a large multi-centred trial would be required to fulfil the recruitment for this study. The ability of topical non-steroidal anti-inflammatory drugs to modify COX and prostaglandin expression remains an important but unanswered question. Collaboration with centres in other parts of the world with higher incidences of the disease may be required to ensure adequate recruitment. ISRCTN: 31503555

Isothermal grain growth and ferroelectric behavior of a fully dense lanthanum doped lead zirconate-lead titanate ceramic

Theoretically dense PLZT specimens with average grain diameters were fabricated by a pressure-sintering technique. Specimens were characterized with respect to their electrical and electromechanical properties

Minimum Cost of Transport in Asian Elephants: Do We Really Need a Bigger Elephant?

Body mass is the primary determinant of an animal’s energy requirements. At their optimum walking speed, large animals have lower mass-specific energy requirements for locomotion than small ones. In animals ranging in size from 0.8 g (roach) to 260 kg (zebu steer), the minimum cost of transport (COTmin) decreases with increasing body size roughly as COTmin∝body mass (Mb)–0.316±0.023 (95% CI). Typically, the variation of COTmin with body mass is weaker at the intraspecific level as a result of physiological and geometric similarity within closely related species. The interspecific relationship estimates that an adult elephant, with twice the body mass of a mid-sized elephant, should be able to move its body approximately 23% cheaper than the smaller elephant. We sought to determine whether adult Asian and sub-adult African elephants follow a single quasi-intraspecific relationship, and extend the interspecific relationship between COTmin and body mass to 12-fold larger animals. Physiological and possibly geometric similarity between adult Asian elephants and sub-adult African elephants caused body mass to have a no effect on COTmin (COTmin∝Mb0.007±0.455). The COTmin in elephants occurred at walking speeds between 1.3 and ∼1.5 m s–1, and at Froude numbers between 0.10 and 0.24. The addition of adult Asian elephants to the interspecific relationship resulted in COTmin∝M –0.277±0.046b. The quasi-intraspecific relationship between body mass and COTmin among elephants caused the interspecific relationship to underestimate COTmin in larger elephants

Laser cooling a membrane-in-the-middle system close to the quantum ground state from room temperature

Many protocols in quantum science and technology require initializing a system in a pure quantum state. In the context of the motional state of massive resonators, this enables studying fundamental physics at the elusive quantum–classical transition, and measuring force and acceleration with enhanced sensitivity. Laser cooling has been a method of choice to prepare mechanical resonators in the quantum ground state, one of the simplest pure states. However, to overcome the heating and decoherence by the thermal bath, this usually has to be combined with cryogenic cooling. Here, we laser-cool an ultracoherent, soft-clamped mechanical resonator close to the quantum ground state directly from room temperature. To this end, we implement the versatile membrane-in-the-middle setup with one fiber mirror and one phononic crystal mirror, which reaches a quantum cooperativity close to unity already at room temperature. We furthermore introduce a powerful combination of coherent and measurement-based quantum control techniques, which allows us to mitigate thermal intermodulation noise. The lowest occupancy we reach is 30 phonons, limited by measurement imprecision. Doing away with the necessity for cryogenic cooling should further facilitate the spread of optomechanical quantum technologies

A model for hysteretic magnetic properties under the application of noncoaxial stress and field

Although descriptions of the effect of stress on spontaneous magnetization within a single domain already exist, there remains no adequate mathematical model for the effects of noncoaxial magnetic field and stress on bulk magnetization in a multidomained specimen. This article addresses the problem and provides a phenomenological theory that applies to the case of bulk isotropic materials. The magnetomechanical hysteresis model of Sablik and Jiles is thus extended to treat magnetic properties in the case of noncoaxial stress and magnetic field in an isotropic, polycrystalline medium. In the modeling, noncollinearity between magnetization and magnetic field is taken into account. The effect of roll‐axis anisotropy is also considered. Both magnetic and magnetostrictive hysteresis are describable by the extended model. Emphasis in this article is on describing properties like coercivity, remanence,hysteresis loss, maximum flux density, and maximum differential permeability as a function of stress for various angular orientations between field and stress axis. The model predictions are compared with experimental results

Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer

Background Selective cyclooxygenase inhibitors may retard the progression of cancer, but they have enhanced thrombotic potential. We report on cardiovascular adverse events in patients receiving rofecoxib to reduce rates of recurrence of colorectal cancer. Methods All serious adverse events that were cardiovascular thrombotic events were reviewed in 2434 patients with stage II or III colorectal cancer participating in a randomized, placebo-controlled trial of rofecoxib, 25 mg daily, started after potentially curative tumor resection and chemotherapy or radiotherapy as indicated. The trial was terminated prematurely owing to worldwide withdrawal of rofecoxib. To examine possible persistent risks, we examined cardiovascular thrombotic events reported up to 24 months after the trial was closed. Results The median duration of active treatment was 7.4 months. The 1167 patients receiving rofecoxib and the 1160 patients receiving placebo were well matched, with a median follow-up period of 33.0 months (interquartile range, 27.6 to 40.1) and 33.4 months (27.7 to 40.4), respectively. Of the 23 confirmed cardiovascular thrombotic events, 16 occurred in the rofecoxib group during or within 14 days after the treatment period, with an estimated relative risk of 2.66 (from the Cox proportional-hazards model; 95% confidence interval [CI], 1.03 to 6.86; P = 0.04). Analysis of the Antiplatelet Trialists’ Collaboration end point (the combined incidence of death from cardiovascular, hemorrhagic, and unknown causes; of nonfatal myocardial infarction; and of nonfatal ischemic and hemorrhagic stroke) gave an unadjusted relative risk of 1.60 (95% CI, 0.57 to 4.51; P = 0.37). Fourteen more cardiovascular thrombotic events, six in the rofecoxib group, were reported within the 2 years after trial closure, with an overall unadjusted relative risk of 1.50 (95% CI, 0.76 to 2.94; P = 0.24). Four patients in the rofecoxib group and two in the placebo group died from thrombotic causes during or within 14 days after the treatment period, and during the follow-up period, one patient in the rofecoxib group and five patients in the placebo group died from cardiovascular causes. Conclusions Rofecoxib therapy was associated with an increased frequency of adverse cardiovascular events among patients with a median study treatment of 7.4 months’ duration. (Current Controlled Trials number, ISRCTN98278138.

A titanium-nitride near-infrared kinetic inductance photon-counting detector and its anomalous electrodynamics

We demonstrate single-photon counting at 1550 nm with titanium-nitride (TiN) microwave kinetic inductance detectors. Energy resolution of 0.4 eV and arrival-time resolution of 1.2 microseconds are achieved. 0-, 1-, 2-photon events are resolved and shown to follow Poisson statistics. We find that the temperature-dependent frequency shift deviates from the Mattis-Bardeen theory, and the dissipation response shows a shorter decay time than the frequency response at low temperatures. We suggest that the observed anomalous electrodynamics may be related to quasiparticle traps or subgap states in the disordered TiN films. Finally, the electron density-of-states is derived from the pulse response.Comment: 4 pages, 3 figure

Oestrogen inactivation in the colon: analysis of the expression and regulation of 17 β -hydroxysteroidehydrogenase isozymes in normal colon and colonic cancer

Epidemiological data suggest that oestrogen contributes to the aetiology of colonic cancer. Furthermore, recent studies have suggested that local hormone metabolism may play a key role in determining colonic responsiveness to oestrogen. To further clarify this mechanism we have characterized the expression and regulation of isozymes of 17β-hydroxysteroid dehydrogenase (17β-HSD) in vitro and in situ. Immunohistochemistry was used to confirm expression of the type 2 and 4 isozymes of 17β-HSD (17β-HSD2 and 4) in normal colonic epithelial cells. Parallel studies suggested that both isozymes were abnormally expressed in colonic tumours and this was confirmed by Western blot analyses. Abnormal expression of 17β-HSD2 and 4 proteins was also observed in Caco-2, HT-29 and SW620 colonic cancer cell lines, although the overall pattern of oestrogen metabolism in these cells was similar to that seen in primary colonic mucosal tissue. The predominant activity (conversion of oestradiol to oestrone) was highest in Caco-2>SW620>HT-29, which correlated inversely with the rate of proliferation of the cell lines. Regulatory studies using SW620 cells indicated that the most potent stimulator of oestradiol to oestrone inactivation was the antiproliferative agent 1,25-dihydroxyvitamin D 3(1,25D 3), whilst oestradiol itself inhibited 17β-HSD activity. Both oestradiol and 1,25D 3 decreased mRNA for 17β-HSD2 and 4. Data indicate that the high capacity for inactivation of oestrogens in the colon is associated with the presence of 17β-HSD2 and 4 in epithelial cells. Abnormal expression of both isozymes in colonic cancer cells and the stimulation of oestrogen inactivation by the antiproliferative agent 1,25D 3 highlights a possible role for 17β-HSD isozymes as modulators of colonic cell proliferation. © 2000 Cancer Research Campaig

PHYOX2: a pivotal randomized study of nedosiran in primary hyperoxaluria type 1 or 2

Chronic kidney disease; Pediatric nephrology; UrologyMalaltia renal crònica; Nefrologia pediàtrica; UrologiaEnfermedad renal crónica; Nefrología pediátrica; UrologíaNedosiran is an investigational RNA interference agent designed to inhibit expression of hepatic lactate dehydrogenase, the enzyme thought responsible for the terminal step of oxalate synthesis. Oxalate overproduction is the hallmark of all genetic subtypes of primary hyperoxaluria (PH). In this double-blind, placebo-controlled study, we randomly assigned (2:1) 35 participants with PH1 (n = 29) or PH2 (n = 6) with eGFR ≥30 mL/min/1.73 m2 to subcutaneous nedosiran or placebo once monthly for 6 months. The area under the curve (AUC) of percent reduction from baseline in 24-hour urinary oxalate (Uox) excretion (primary endpoint), between day 90–180, was significantly greater with nedosiran vs placebo (least squares mean [SE], +3507 [788] vs −1664 [1190], respectively; difference, 5172; 95% CI 2929–7414; P < 0.001). A greater proportion of participants receiving nedosiran vs placebo achieved normal or near-normal (<0.60 mmol/24 hours; <1.3 × ULN) Uox excretion on ≥2 consecutive visits starting at day 90 (50% vs 0; P = 0.002); this effect was mirrored in the nedosiran-treated PH1 subgroup (64.7% vs 0; P < 0.001). The PH1 subgroup maintained a sustained Uox reduction while on nedosiran, whereas no consistent effect was seen in the PH2 subgroup. Nedosiran-treated participants with PH1 also showed a significant reduction in plasma oxalate versus placebo (P = 0.017). Nedosiran was generally safe and well tolerated. In the nedosiran arm, the incidence of injection-site reactions was 9% (all mild and self-limiting). In conclusion, participants with PH1 receiving nedosiran had clinically meaningful reductions in Uox, the mediator of kidney damage in PH

Prospective, double-blind, placebo-controlled randomized trial of cimetidine in gastric cancer

Cimetidine is thought to inhibit suppressor T-lymphocyte function and preliminary evidence from a randomized trial indicated that it might prolong survival for patients with operable and inoperable gastric cancer. The British Stomach Cancer Group conducted a randomized, double-blind, placebo-controlled trial examining the effects of cimetidine (400 mg or 800 mg twice a day) on the survival of patients with early (stages I, II and III: n = 229) and advanced (stages IVa and IVb: n = 201) gastric cancer. The primary end point was death. A total of 442 patients were randomized by 59 consultants in 39 hospitals between February 1990 and March 1995. Log-rank survival analysis was used to assess differences between the groups. Three hundred and forty patients died during the study: 166 (49%) in the cimetidine treatment groups and 174 (51%) in the placebo groups. Median survival for patients receiving cimetidine was 13 months (95% confidence interval (CI) 9–16 months) and 11 months in the placebo arm (95% CI 9–14 months). There was no significant difference in survival between the two treatment groups (P = 0.42) or between different doses of cimetidine tablets (P = 0.46). Five-year survival of those patients randomized to cimetidine was 21% compared to 18% for those patients randomized to placebo. Cimetidine at a dose of 400 mg or 800 mg twice a day does not have a significant influence on the survival of patients with gastric cancer compared to placebo. © 1999 Cancer Research Campaig