Expediting Oncology Drug Approvals: The Public Backlash Against the FDA and Opportunities to Reform

The FDA has made great strides over the past twenty years in loosening drug approval regulations to speed important, life-saving treatments to market. However, recent controversies involving anti-depressants for children and the withdrawal of two popular arthritis drugs and a multiple sclerosis therapy have created fears within the cancer community that the FDA will revert to a more cautious, conservative approval policy. Although cancer patient advocates have legitimate concerns about the pendulum swinging back to a more conservative agency stance, the FDA and the Oncologic Drugs Advisory Committee (ODAC) do not appear to have embraced a more risk-averse philosophy. Instead, the public backlash against the FDA presents the agency with an excellent opportunity to facilitate improvements to the accelerated approval and fast-track regulations for the benefit of cancer patients

Cell-cell communication enhances the capacity of cell ensembles to sense shallow gradients during morphogenesis

Collective cell responses to exogenous cues depend on cell-cell interactions. In principle, these can result in enhanced sensitivity to weak and noisy stimuli. However, this has not yet been shown experimentally, and, little is known about how multicellular signal processing modulates single cell sensitivity to extracellular signaling inputs, including those guiding complex changes in the tissue form and function. Here we explored if cell-cell communication can enhance the ability of cell ensembles to sense and respond to weak gradients of chemotactic cues. Using a combination of experiments with mammary epithelial cells and mathematical modeling, we find that multicellular sensing enables detection of and response to shallow Epidermal Growth Factor (EGF) gradients that are undetectable by single cells. However, the advantage of this type of gradient sensing is limited by the noisiness of the signaling relay, necessary to integrate spatially distributed ligand concentration information. We calculate the fundamental sensory limits imposed by this communication noise and combine them with the experimental data to estimate the effective size of multicellular sensory groups involved in gradient sensing. Functional experiments strongly implicated intercellular communication through gap junctions and calcium release from intracellular stores as mediators of collective gradient sensing. The resulting integrative analysis provides a framework for understanding the advantages and limitations of sensory information processing by relays of chemically coupled cells.Comment: paper + supporting information, total 35 pages, 15 figure

Quasi-phase-matched Faraday rotation in semiconductor waveguides with a magnetooptic cladding for monolithically integrated optical isolators

Strategies are developed for obtaining nonreciprocal polarization mode conversion, also known as Faraday rotation, in waveguides in a format consistent with silicon-on-insulator or III–V semiconductor photonic integrated circuits. Fabrication techniques are developed using liftoff lithography and sputtering to obtain garnet segments as upper claddings, which have an evanescent wave interaction with the guided light. A mode solver approach is used to determine the modal Stokes parameters for such structures, and design considerations indicate that quasi-phase-matched Faraday rotation for optical isolator applications could be obtained with devices on the millimeter length scale

TIM: a time interval machine for audio-visual action recognition

Diverse actions give rise to rich audio-visual signals in long videos. Recent works showcase that the two modalities of audio and video exhibit different temporal extents of events and distinct labels. We address the interplay between the two modalities in long videos by explicitly modelling the temporal extents of audio and visual events. We propose the Time Interval Machine (TIM) where a modality-specific time interval poses as a query to a transformer encoder that ingests a long video input. The encoder then attends to the specified interval, as well as the surrounding context in both modalities, in order to recognise the ongoing action. We test TIM on three long audio-visual video datasets: EPIC-KITCHENS, Perception Test, and AVE, reporting state-of-the-art (SOTA) for recognition. On EPICKITCHENS, we beat previous SOTA that utilises LLMs and significantly larger pre-training by 2.9% top-1 action recognition accuracy. Additionally, we show that TIM can be adapted for action detection, using dense multi-scale interval queries, outperforming SOTA on EPIC-KITCHENS-100 for most metrics, and showing strong performance on the Perception Test. Our ablations show the critical role of integrating the two modalities and modelling their time intervals in achieving this performance. Code and models at: https://github.com/JacobChalk/TIM

Enrichment of n-3 containing ether phospholipids in plasma after 30 days of krill oil compared with fish oil supplementation

There are conflicting findings over the bioavailability of long-chain n-3 polyunsaturated fatty acids (n-3 PUFA) from krill oil (KO) compared with fish oil (FO) in short- and long-term studies. The aim of this study was to compare the effects of KO versus FO on the enrichment of molecular species of plasma phospholipids in young women following a 30-day consumption of the n-3 oils. Eleven healthy women aged 18–45 years consumed seven capsules of KO per day (containing a total of 1.27 g n-3 PUFA) or five capsules of FO per day (total of 1.44 g n-3 PUFA) for 30 days in a randomized crossover study, separated by at least a 30-day washout period. Fasting blood samples were collected at day zero (baseline), day 15 and day 30 and analyzed by HPLC-MS/MS for molecular species of phospholipids. Supplementation increased n-3 PUFA in main phospholipids classes in both groups. After 30 days of supplementation, 35 out of 70 molecular species containing eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPAn-3) had a significantly greater concentration in KO group compared with the FO treated group. The majority (89%) of the differentiated molecular species were choline and ethanolamine ether-phospholipids. These data reveal that analysis of plasma phospholipids following 30 days of consumption of KO (a marine oil rich in phospholipids, including ether phospholipids) resulted in an enrichment of n-3 PUFA in molecular species of ether-phospholipids compared with FO (a triacylglycerol-rich marine oil)

Elevated fasting insulin predicts the future incidence of metabolic syndrome: a 5-year follow-up study

<p>Abstract</p> <p>Background</p> <p>There is controversy about the specific pathophysiology of metabolic syndrome (MS) but several authors have argued that hyperinsulinemia is a key feature of the cluster. We aimed to assess whether the baseline insulin levels could predict the development of MS in a well characterised cohort of otherwise healthy adults who were followed over a five year period.</p> <p>Methods</p> <p>We identified 2, 350 Koreans subjects who did not have MS in 2003 and who were followed up in 2008. The subjects were divided into 4 groups according to the baseline quartiles of fasting insulin, and the predictors of the incidence of MS were analyzed using multivariate regression analysis.</p> <p>Results</p> <p>Over the follow up period, 8.5% of the cohort developed MS. However, 16.4% of the subjects in the highest quartile of the insulin levels developed MS. In a model that included gender, age, the smoking status, the exercise level, alcohol consumption and the systolic blood pressure, the subjects in the highest quartile of the insulin levels had more than a 5 times greater risk of developing MS compared that of the subjects in the lowest quartile. This predictive importance remained significant even after correcting for all the individual features of MS.</p> <p>Conclusions</p> <p>These data suggest that high baseline fasting insulin levels are independent determinants for the future development of MS.</p

Linearization of homogeneous, nearly-isotropic cosmological models

Homogeneous, nearly-isotropic Bianchi cosmological models are considered. Their time evolution is expressed as a complete set of non-interacting linear modes on top of a Friedmann-Robertson-Walker background model. This connects the extensive literature on Bianchi models with the more commonly-adopted perturbation approach to general relativistic cosmological evolution. Expressions for the relevant metric perturbations in familiar coordinate systems can be extracted straightforwardly. Amongst other possibilities, this allows for future analysis of anisotropic matter sources in a more general geometry than usually attempted. We discuss the geometric mechanisms by which maximal symmetry is broken in the context of these models, shedding light on the origin of different Bianchi types. When all relevant length-scales are super-horizon, the simplest Bianchi I models emerge (in which anisotropic quantities appear parallel transported). Finally we highlight the existence of arbitrarily long near-isotropic epochs in models of general Bianchi type (including those without an exact isotropic limit).Comment: 31 pages, 2 figures. Submitted to CQ