Inducing cancer indolence by targeting mitochondrial Complex I is potentiated by blocking macrophage-mediated adaptive responses

Converting carcinomas in benign oncocytomas has been suggested as a potential anti-cancerstrategy. One of the oncocytoma hallmarks is the lack of respiratory complex I (CI). Herewe use genetic ablation of this enzyme to induce indolence in two cancer types, andshow this is reversed by allowing the stabilization of Hypoxia Inducible Factor-1 alpha(HIF-1α). We further show that on the long run CI-deficient tumors re-adapt to their inabilityto respond to hypoxia, concordantly with the persistence of human oncocytomas. Wedemonstrate that CI-deficient tumors survive and carry out angiogenesis, despite theirinability to stabilize HIF-1α. Such adaptive response is mediated by tumor associated mac-rophages, whose blockage improves the effect of CI ablation. Additionally, the simultaneouspharmacological inhibition of CI function through metformin and macrophage infiltrationthrough PLX-3397 impairs tumor growth in vivo in a synergistic manner, setting the basisfor an efficient combinatorial adjuvant therapy in clinical trials

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

A New Method for the Validation of Ultraviolet Reactors by Means of Photochromic Materials

The interest in ultraviolet (UV) water sterilization has grown significantly in recent years. The main difficulty in designing a UV reactor is to assess the UV dose delivered. In fact, that dose depends on both the UV radiation field and the flow distribution within the reactor. At the design phase, computational fluid dynamics (CFD) helps to predict the UV dose distribution, but it requires a validation; nowadays, such validation is possible only using the Lagrangian actinometry method. This promising technique, however, requires a complex and expensive equipment, which makes it difficult to apply in most of the real contexts. The purpose of this work is to develop a new method to make the validation of the UV reactor performance a faster, less expensive, and more sustainable procedure. To this aim, we used two photochromic materials, sensitive to the UV-C radiation. Each material has been characterized by relating its color variation with the absorbed UV dose. Samples of such materials, in some cases stuck on supports characterized by different densities, were then inserted within a pilot UV reactor under three different flow rates, to measure the dose distributions. These latter were then compared with the results obtained by the CFD simulations performed on the same reactor geometry, and by biodosimetry analyses. The best results, both in terms of average value and distributions of the UV dose, were obtained from the photochromic amorphous polypropylene samples, having a density similar to that of water. This method emerges then as a promising validation technique, able also to assess the dose distribution of a UV reactor

Health-related quality of life in fibromyalgia patients: a comparison with rheumatoid arthritis patients and the general population using the SF-36 health survey

Objective. To compare health-related quality of life (HRQL) in fibromyalgia (FM) patients with that of patients with rheumatoid arthritis (RA) and the general population, and investigate if the factors are associated with the greater impact of FM. Methods. This cross-sectional study involved 380 patients with FM, 693 patients with RA and 1579 healthy controls. HRQL was evaluated using the Medical Outcome Study Short-Form 36 (SF-36), and the measures included disease-related characteristics, demographic variables and comorbidities. S-scores were calculated for comparisons with the norm, and multivariate analyses were used to assess the relationships between HRQL and clinical and demographic variables. Results. In comparison with the general population, the FM patients showed significant impairment in relation to all of the eight scales of the SF-36(p<0.0001), as well as the physical and mental component summary scores (PCS and MCS) (p<0.0001). The mean PCS and MCS of the FM patients were 38.5 (SD=6.9) and 32.8 (SD=10.9), whereas those of the RA patients were, 33.5 (SD=6.4) (p<0.01) and 40.2 (SD=11.9) (p<0.001). The dimensions typical 67 affected by FM were vitality (s-score, -1.61), mental health (s-score -1.46) and general health (s-score-1.47), whereas physical functioning (s-score-1.63) and role limitations due to physical function (s -score -0.94) were more impaired in the RA patients; the bodily pain scores were similar in the two groups. The PCS was lower than the MCS in the RA patients (s-scores -1.80 vs. -0.62), but the two scores were similar in the FM patients (s-scores -1.20 vs. -1.08). Multiple regression models showed that the physical component of the SF-36 was associated with widespread pain (the SAPS score) (p<0.0001), educational level (p=0.0017), and the body mass index (p=0.007), and the mental component was associated with the widespread pain (p=0.0005), sleep abnormalities (p=0.0033), physical function (p=0.015), fatigue (p=0.029), gender (p=0.014) and a low educational level (p=0.0007). Conclusion. Patients with FM see the disease as having a worse health than RA patients and the general population, especially in terms of mental health

Development and validation of the self-administered Fibromyalgia Assessment Status: a disease-specific composite measure for evaluating treatment effect

The self-administered FAS is a reliable, valid and responsive disease-specific composite measure for assessing treatment effect in patients with FM