Further observations on mechanisms of bone destruction by squamous carcinomas of the head and neck: the role of host stroma.

Mechanisms of bone invasion by squamous carcinomas of the head and neck have been investigated using fresh tumours and established tumour cell lines in an in vitro bone resorption assay with 45Ca-labelled mouse calvaria. Fresh tumours regularly resorb bone in vitro. Activity is consistently reduced by indomethacin. The tumours release E2 prostaglandins (PGE2) in amounts sufficient to account for approximately 50% of the bone resorption observed. Small amounts of non-prostaglandin (indomethacin-resistant) osteolytic factors are also produced. Control non-neoplastic tissues show a variable capacity to resorb bone in vitro; PGE2 levels in these tissues may be related to their content of inflammatory cells. Tumour cell lines also resorb bone in vitro but, for most lines, activity is not significantly blocked by indomethacin and PGE2 levels are generally insufficient to account for the osteolysis observed. Non-prostaglandin bone resorbing factors thus predominate. It is concluded that most squamous cancers of the head and neck are osteolytic in vitro and release a mixture of prostaglandin and non-prostaglandin factors which stimulate osteoclastic bone resorption. These factors are derived from both neoplastic and stromal elements, and are "tumour-associated" rather than "tumour-specific". In vitro bone resorption and prostaglandin release does not correlate with pathological features of the tumour or with post-operative survival

Childhood, adolescent, and adulthood adiposity are associated with risk of PCOS: a Mendelian randomization study with meta-analysis.

Study questionWhat is the influence of body composition during childhood, adolescence, and adulthood, as well as metabolic parameters, on incident polycystic ovary syndrome (PCOS)?Summary answerExcess body fat, even during childhood/adolescence, and metabolic parameters, suggestive of hyperinsulinaemia/insulin resistance, significantly impact the risk of PCOS in a linear fashion.What is known alreadyObservational and Mendelian randomization (MR) data have demonstrated an association between adulthood overweight/obesity and development of PCOS. However, the contribution of body composition in childhood/adolescence to incident PCOS is unclear, as is the influence of childhood overweight/obesity.Study design, size, durationWe conducted a systematic review and meta-analysis and integrated our results with a previously published systematic review. Two blinded investigators screened abstracts published between November 2010 and May 2021. Furthermore, we incorporated summary statistics from genome-wide association study (GWAS) data in subjects of European ancestry. Adult overweight was defined as BMI ≥ 25 kg/m2 and obesity as BMI ≥ 30 kg/m2; in Asian subjects, overweight was defined as BMI ≥ 23 kg/m2 and obesity as BMI ≥ 25 kg/m2.Participants/materials, setting, methodsWe utilized meta-analysis and MR together to allow synthesis of genetic and observational data. For the systematic review, the search revealed 71 studies, of which 63 were included in meta-analysis by calculating odds ratios (ORs) using the random-effects model. Furthermore, we conducted a two-sample MR study of GWAS data to determine the impact of childhood and adult body size (defined categorically by BMI and childhood body size proportions), abnormal body composition and metabolic parameters (higher fasting serum insulin or lower sex hormone-binding globulin (SHBG) concentration) on the odds of incident PCOS via the inverse-variance weighted method.Main results and the role of chanceSignificant associations were shown between body composition and PCOS incidence. From the systematic review/meta-analysis, women with overweight (OR 3.80, 2.87-5.03), obesity (OR 4.99, 3.74-6.67), and central obesity (OR 2.93, 2.08-4.12) had increased odds of PCOS. For adolescents with overweight and/or obesity, the PCOS odds were greater than for adults. From MR, for every standard deviation increase in BMI (4.8 kg/m2), the odds of PCOS increased by 2.76 (2.27-3.35). Childhood body size had an independent effect on PCOS odds after adjusting for adult body size (OR: 2.56, 1.57-4.20). Genetically determined body fat percentage (OR 3.05, 2.24-4.15), whole body fat mass (OR 2.53, 2.04-3.14), fasting serum insulin (OR 6.98, 2.02-24.13), and SHBG concentration (OR 0.74, 0.64-0.87) were all significantly associated with PCOS in a linear relation.Limitations, reasons for cautionThe meta-analysis included studies which were cross-sectional and retrospective, limiting our ability to determine causality. MR was limited by interrogating subjects only of European ancestry and including cases classified by either self-diagnosis or diagnostic criteria.Wider implications of the findingsOur study demonstrates for the first time a critical role of the impact of excess childhood/adolescent adiposity on the pathophysiology of adult PCOS. Our results, driven by genetically determined childhood/adolescent body composition, higher BMI, hyperinsulinaemia, and lower SHBG, clearly favour obesity driving the metabolic, but not reproductive, PCOS phenotype. Overall, effective weight maintenance, even from the early years, is likely to reduce the risk of this reproductive endocrine disorder.Study funding/competing interest(s)S.S.Z. was funded by a National Institute for Health and Care Research (NIHR) Academic Clinical Lectureship. U.A. is chair of the NIHR Steering Committee Trial-CASSANDRA-DN. No other authors declare any sources of funding or relevant conflicts of interest. The authors declare that the research was conducted in the absence of any commercial or financial relations that could be construed as a potential conflict of interest.Trial registration numberN/A

Active to Sterile Neutrino Mixing Limits from Neutral-Current Interactions in MINOS

Results are reported from a search for active to sterile neutrino oscillations in the MINOS long-baseline experiment, based on the observation of neutral-current neutrino interactions, from an exposure to the NuMI neutrino beam of 7.07×10^(20) protons on target. A total of 802 neutral-current event candidates is observed in the Far Detector, compared to an expected number of 754±28(stat)±37(syst) for oscillations among three active flavors. The fraction f_s of disappearing ν_μ that may transition to ν_s is found to be less than 22% at the 90% C.L

Measurement of the underground atmospheric muon charge ratio using the MINOS Near Detector

The magnetized MINOS Near Detector, at a depth of 225 mwe, is used to measure the atmospheric muon charge ratio. The ratio of observed positive to negative atmospheric muon rates, using 301 days of data, is measured to be 1.266±0.001(stat)_(-0.014)^(+0.015)(syst). This measurement is consistent with previous results from other shallow underground detectors and is 0.108±0.019(stat+syst) lower than the measurement at the functionally identical MINOS Far Detector at a depth of 2070 mwe. This increase in charge ratio as a function of depth is consistent with an increase in the fraction of muons arising from kaon decay for increasing muon surface energie

New constraints on muon-neutrino to electron-neutrino transitions in MINOS

This paper reports results from a search for ν_μ → ν_e transitions by the MINOS experiment based on a 7×10^(20) protons-on-target exposure. Our observation of 54 candidate ν_e events in the far detector with a background of 49.1±7.0(stat)±2.7(syst) events predicted by the measurements in the near detector requires 2sin^2(2θ_(13))sin^2θ_(23)<0.12(0.20) at the 90% C.L. for the normal (inverted) mass hierarchy at δ_(CP)=0. The experiment sets the tightest limits to date on the value of θ_(13) for nearly all values of δ_(CP) for the normal neutrino mass hierarchy and maximal sin^2(2θ_(23))

Neutrino and Antineutrino Inclusive Charged-current Cross Section Measurements with the MINOS Near Detector

The energy dependence of the neutrino-iron and antineutrino-iron inclusive charged-current cross sections and their ratio have been measured using a high-statistics sample with the MINOS Near Detector exposed to the NuMI beam from the Main Injector at Fermilab. Neutrino and antineutrino fluxes were determined using a low hadronic energy subsample of charged-current events. We report measurements of neutrino-Fe (antineutrinoFe) cross section in the energy range 3-50 GeV (5-50 GeV) with precision of 2-8% (3-9%) and their ratio which is measured with precision 2-8%. The data set spans the region from low energy, where accurate measurements are sparse, up to the high-energy scaling region where the cross section is well understood.Comment: accepted by PR

Search for sterile neutrino mixing in the MINOS long-baseline experiment

A search for depletion of the combined flux of active neutrino species over a 735 km baseline is reported using neutral-current interaction data recorded by the MINOS detectors in the NuMI neutrino beam. Such a depletion is not expected according to conventional interpretations of neutrino oscillation data involving the three known neutrino flavors. A depletion would be a signature of oscillations or decay to postulated noninteracting sterile neutrinos, scenarios not ruled out by existing data. From an exposure of 3.18×10^(20) protons on target in which neutrinos of energies between ∼500  MeV and 120 GeV are produced predominantly as ν_μ, the visible energy spectrum of candidate neutral-current reactions in the MINOS far detector is reconstructed. Comparison of this spectrum to that inferred from a similarly selected near-detector sample shows that of the portion of the ν_μ flux observed to disappear in charged-current interaction data, the fraction that could be converting to a sterile state is less than 52% at 90% confidence level (C.L.). The hypothesis that active neutrinos mix with a single sterile neutrino via oscillations is tested by fitting the data to various models. In the particular four-neutrino models considered, the mixing angles θ_(24) and θ_(34) are constrained to be less than 11° and 56° at 90% C.L., respectively. The possibility that active neutrinos may decay to sterile neutrinos is also investigated. Pure neutrino decay without oscillations is ruled out at 5.4 standard deviations. For the scenario in which active neutrinos decay into sterile states concurrently with neutrino oscillations, a lower limit is established for the neutrino decay lifetime τ_3/m_3>2.1×10^(-12) s/eV at 90% C.L

Testing Lorentz Invariance and CPT Conservation with NuMI Neutrinos in the MINOS Near Detector

A search for a sidereal modulation in the MINOS near detector neutrino data was performed. If present, this signature could be a consequence of Lorentz and CPT violation as predicted by a class of extensions to the Standard Model. No evidence for a sidereal signal in the data set was found, implying that there is no significant change in neutrino propagation that depends on the direction of the neutrino beam in a sun-centered inertial frame. Upper limits on the magnitudes of the Lorentz and CPT violating terms in these extensions to the Standard Model lie between 0.01-1% of the maximum expected, assuming a suppression of these signatures by factor of $10^{-17}$.