Deep Divergence-Based Approach to Clustering

A promising direction in deep learning research consists in learning representations and simultaneously discovering cluster structure in unlabeled data by optimizing a discriminative loss function. As opposed to supervised deep learning, this line of research is in its infancy, and how to design and optimize suitable loss functions to train deep neural networks for clustering is still an open question. Our contribution to this emerging field is a new deep clustering network that leverages the discriminative power of information-theoretic divergence measures, which have been shown to be effective in traditional clustering. We propose a novel loss function that incorporates geometric regularization constraints, thus avoiding degenerate structures of the resulting clustering partition. Experiments on synthetic benchmarks and real datasets show that the proposed network achieves competitive performance with respect to other state-of-the-art methods, scales well to large datasets, and does not require pre-training steps

Advances in Biologically Inspired Reservoir Computing

The interplay between randomness and optimization has always been a major theme in the design of neural networks [3]. In the last 15 years, the success of reservoir computing (RC) showed that, in many scenarios, the algebraic structure of the recurrent component is far more important than the precise fine-tuning of its weights. As long as the recurrent part of the network possesses a form of fading memory of the input, the dynamics of the neurons are enough to efficiently process many spatio-temporal signals, provided that their activations are sufficiently heterogeneous. Even if today it is feasible to fully optimize deep recurrent networks, their implementation still requires a vast degree of experience and practice, not to mention vast computational resources, limiting their applicability in simpler architectures (e.g., embedded systems) or in areas where time is of key importance (e.g., online systems). Not surprisingly, then, RC remains a powerful tool for quickly solving dynamical problems, and it has become an invaluable tool for modeling and analysis in neuroscience

Replacing meat with alternative plant-based products (RE-MAP):a randomized controlled trial of a multicomponent behavioral intervention to reduce meat consumption

BACKGROUND: Reducing meat consumption could protect the environment and human health. OBJECTIVES: We tested the impact of a behavioral intervention to reduce meat consumption. METHODS: Adult volunteers who regularly consumed meat were recruited from the general public and randomized 1:1 to an intervention or control condition. The intervention comprised free meat substitutes for 4 weeks, information about the benefits of eating less meat, success stories, and recipes. The control group received no intervention or advice on dietary change. The primary outcome was daily meat consumption after 4 weeks, assessed by a 7-day food diary, and repeated after 8 weeks as a secondary outcome. Other secondary and exploratory outcomes included the consumption of meat substitutes, cardiovascular risk factors, psychosocial variables related to meat consumption, and the nutritional composition of the diet. We also estimated the intervention's environmental impact. We evaluated the intervention using generalized linear mixed-effects models. RESULTS: Between June 2018 and October 2019, 115 participants were randomized. The baseline meat consumption values were 134 g/d in the control group and 130 g/d in the intervention group. Relative to the control condition, the intervention reduced meat consumption at 4 weeks by 63 g/d (95% CI: 44–82; P < 0.0001; n = 114) and at 8 weeks by 39 g/d (95% CI: 16–62; P = 0.0009; n = 113), adjusting for sex and baseline consumption. The intervention significantly increased the consumption of meat substitutes without changing the intakes of other principal food groups. The intervention increased intentions, positive attitudes, perceived control, and subjective norms of eating a low-meat diet and using meat substitutes, and decreased attachment to meat. At 8 weeks, 55% of intervention recipients identified as meat eaters, compared to 89% of participants in the control group. CONCLUSIONS: A behavioral program involving free meat substitutes can reduce meat intake and change psychosocial constructs consistent with a sustained reduction in meat intake

Comparison of bioelectrical impedance analysis and dual-energy X-ray absorptiometry for the assessment of appendicular body composition in anorexic women

Objective: To establish the accuracy of bioelectrical impedance analysis (BIA) for the assessment of appendicular body composition in anorexic women. Design: Cross-sectional study. Setting: Outpatient University Clinic. Subjects: A total of 39 anorexic and 25 control women with a mean (s.d.) age of 21 (3) y. Methods: Total, arm and leg fat-free mass (FFM) were measured by dual-energy X-ray absorptiometry and predicted from total and segmental BIA at 50 kHz. The predictor variable was the resistance index (Rl), that is, the ratio of height 2 to body resistance for the whole body and the ratio of length2/limb resistance for the arm and leg. Results: Predictive equations developed on controls overestimated total, arm and leg FFM in anorexics (Po0.0001). Populationspecific equations gave a satisfactory estimate of total and appendicular FFM in anorexics (P\ubcNS) but had higher percent root mean square errors (RMSEs%) as compared to those developed on controls (8% vs 5% for whole body, 12% vs 10% for arm and 10% vs 8% for leg). The accuracy of the estimate of total and leg FFM in anorexics was improved by adding body weight (Wt) as a predictor with Rl (RMSE%\ubc5% vs 8% and 7% vs 10%, respectively). However, the same accuracy was obtained using Wt alone, suggesting that in anorexics, BIA at 50 kHz is not superior to Wt for assessing total and leg FFM. Conclusion: BIA shows some potential for the assessment of appendicular body composition in anorexic women. However, Wt is preferable to BIA at 50 kHz on practical grounds. Further studies should consider whether frequencies 450 kHz give better estimates of appendicular composition in anorexics as compared to Wt

The Networks of Genes Encoding Palmitoylated Proteins in Axonal and Synaptic Compartments Are Affected in PPT1 Overexpressing Neuronal-Like Cells

CLN1 disease (OMIM # 256730) is an early childhood ceroid-lipofuscinosis associated with mutated CLN1, whose product Palmitoyl-Protein Thioesterase 1 (PPT1) is a lysosomal enzyme involved in the removal of palmitate residues from S-acylated proteins. In neurons, PPT1 expression is also linked to synaptic compartments. The aim of this study was to unravel molecular signatures connected to CLN1. We utilized SH-SY5Y neuroblastoma cells overexpressing wild type CLN1 (SH-p. wtCLN1) and five selected CLN1 patients' mutations. The cellular distribution of wtPPT1 was consistent with regular processing of endogenous protein, partially detected inside Lysosomal Associated Membrane Protein 2 (LAMP2) positive vesicles, while the mutants displayed more diffuse cytoplasmic pattern. Transcriptomic profiling revealed 802 differentially expressed genes (DEGs) in SH-p. wtCLN1 (as compared to empty-vector transfected cells), whereas the number of DEGs detected in the two mutants (p. L222P and p. M57Nfs * 45) was significantly lower. Bioinformatic scrutiny linked DEGs with neurite formation and neuronal transmission. Specifically, neuritogenesis and proliferation of neuronal processes were predicted to be hampered in the wtCLN1 overexpressing cell line, and these findings were corroborated by morphological investigations. Palmitoylation survey identified 113 palmitoylated protein-encoding genes in SH-p. wtCLN1, including 25 ones simultaneously assigned to axonal growth and synaptic compartments. A remarkable decrease in the expression of palmitoylated proteins, functionally related to axonal elongation (GAP43, CRMP1 and NEFM) and of the synaptic marker SNAP25, specifically in SH-p. wtCLN1 cells was confirmed by immunoblotting. Subsequent, bioinformatic network survey of DEGs assigned to the synaptic annotations linked 81 DEGs, including 23 ones encoding for palmitoylated proteins. Results obtained in this experimental setting outlined two affected functional modules (connected to the axonal and synaptic compartments), which can be associated with an altered gene dosage of wtCLN1. Moreover, these modules were interrelated with the pathological effects associated with loss of PPT1 function, similarly as observed in the Ppt1 knockout mice and patients with CLN1 disease.Peer reviewe

ORIGINAL COMMUNICATION Comparison of bioelectrical impedance analysis and dual-energy X-ray absorptiometry for the assessment of appendicular body composition in anorexic women

Objective: To establish the accuracy of bioelectrical impedance analysis (BIA) for the assessment of appendicular body composition in anorexic women. Design: Cross-sectional study. Setting: Outpatient University Clinic. Subjects: A total of 39 anorexic and 25 control women with a mean (s.d.) age of 21 (3) y. Methods: Total, arm and leg fat-free mass (FFM) were measured by dual-energy X-ray absorptiometry and predicted from total and segmental BIA at 50 kHz. The predictor variable was the resistance index (Rl), that is, the ratio of height 2 to body resistance for the whole body and the ratio of length 2 /limb resistance for the arm and leg. Results: Predictive equations developed on controls overestimated total, arm and leg FFM in anorexics (Po0.0001). Populationspecific equations gave a satisfactory estimate of total and appendicular FFM in anorexics (P ¼ NS) but had higher percent root mean square errors (RMSEs%) as compared to those developed on controls (8% vs 5% for whole body, 12% vs 10% for arm and 10% vs 8% for leg). The accuracy of the estimate of total and leg FFM in anorexics was improved by adding body weight (Wt) as a predictor with Rl (RMSE% ¼ 5% vs 8% and 7% vs 10%, respectively). However, the same accuracy was obtained using Wt alone, suggesting that in anorexics, BIA at 50 kHz is not superior to Wt for assessing total and leg FFM. Conclusion: BIA shows some potential for the assessment of appendicular body composition in anorexic women. However, Wt is preferable to BIA at 50 kHz on practical grounds. Further studies should consider whether frequencies 450 kHz give better estimates of appendicular composition in anorexics as compared to Wt

Carbohydrate Intake in the Etiology of Crohn's Disease and Ulcerative Colitis

Background: Diet may have a role in the etiology of inflammatory bowel disease. In previous studies, the associations between increased intakes of carbohydrates, sugar, starch, and inflammatory bowel disease are inconsistent. However, few prospective studies have investigated the associations between these macronutrients and incident Crohn's disease (CD) or ulcerative colitis (UC). Methods: A total of 401,326 men and women were recruited between 1991 and 1998. At recruitment, dietary intakes of carbohydrate, sugar, and starch were measured using validated food frequency questionnaires. The cohort was monitored identifying participants who developed incident CD or UC. Cases were matched with 4 controls, and odds ratios were calculated for quintiles of total carbohydrate, sugar, and starch intakes adjusted for total energy intake, body mass index, and smoking. Results: One hundred ten participants developed CD, and 244 participants developed UC during follow-up. The adjusted odds ratio for the highest versus the lowest quintiles of total carbohydrate intake for CD was 0.87, 95% CI = 0.24 to 3.12 and for UC 1.46, 95% CI = 0.62 to 3.46, with no significant trends across quintiles for either (CD, Ptrend = 0.70; UC, Ptrend = 0.41). Similarly, no associations were observed with intakes of total sugar (CD, Ptrend = 0.50; UC, Ptrend = 0.71) or starch (CD, Ptrend = 0.69; UC, Ptrend = 0.17). Conclusions: The lack of associations with these nutrients is in agreement with many case–control studies that have not identified associations with CD or UC. As there is biological plausibility for how specific carbohydrates could have an etiological role in inflammatory bowel disease, future epidemiological work should assess individual carbohydrates, although there does not seem to be a macronutrient effect

The role of sentinel node tumor burden in modeling the prognosis of melanoma patients with positive sentinel node biopsy: an Italian melanoma intergroup study (N = 2,086)

Background The management of melanoma patients with metastatic melanoma in the sentinel nodes (SN) is evolving based on the results of trials questioning the impact of completion lymph node dissection (CLND) and demonstrating the efficacy of new adjuvant treatments. In this landscape, new prognostic tools for fine risk stratification are eagerly sought to optimize the therapeutic path of these patients. Methods A retrospective cohort of 2,086 patients treated with CLND after a positive SN biopsy in thirteen Italian Melanoma Centers was reviewed. Overall survival (OS) was the outcome of interest; included independent variables were the following: age, gender, primary melanoma site, Breslow thickness, ulceration, sentinel node tumor burden (SNTB), number of positive SN, non-sentinel lymph nodes (NSN) status. Univariate and multivariate survival analyses were performed using the Cox proportional hazard regression model. Results The 3-year, 5-year and 10-year OS rates were 79%, 70% and 54%, respectively. At univariate analysis, all variables, except for primary melanoma body site, were found to be statistically significant prognostic factors. Multivariate Cox regression analysis indicated that older age (P &lt; 0.0001), male gender (P = 0.04), increasing Breslow thickness (P &lt; 0.0001), presence of ulceration (P = 0.004), SNTB size (P &lt; 0.0001) and metastatic NSN (P &lt; 0.0001) were independent negative predictors of OS. Conclusion The above results were utilized to build a nomogram in order to ease the practical implementation of our prognostic model, which might improve treatment personalization

Optimized EGFR blockade strategies in <i>EGFR</i> addicted gastroesophageal adenocarcinomas

Purpose: Gastric and gastroesophageal adenocarcinomas represent the third leading cause of cancer mortality worldwide. Despite significant therapeutic improvement, the outcome of patients with advanced gastroesophageal adenocarcinoma is poor. Randomized clinical trials failed to show a significant survival benefit in molecularly unselected patients with advanced gastroesophageal adenocarcinoma treated with anti-EGFR agents.Experimental Design: We performed analyses on four cohorts: IRCC (570 patients), Foundation Medicine, Inc. (9,397 patients), COG (214 patients), and the Fondazione IRCCS Istituto Nazionale dei Tumori (206 patients). Preclinical trials were conducted in patient-derived xenografts (PDX).Results: The analysis of different gastroesophageal adenocarcinoma patient cohorts suggests that EGFR amplification drives aggressive behavior and poor prognosis. We also observed that EGFR inhibitors are active in patients with EGFR copy-number gain and that coamplification of other receptor tyrosine kinases or KRAS is associated with worse response. Preclinical trials performed on EGFR-amplified gastroesophageal adenocarcinoma PDX models revealed that the combination of an EGFR mAb and an EGFR tyrosine kinase inhibitor (TKI) was more effective than each monotherapy and resulted in a deeper and durable response. In a highly EGFR-amplified nonresponding PDX, where resistance to EGFR drugs was due to inactivation of the TSC2 tumor suppressor, cotreatment with the mTOR inhibitor everolimus restored sensitivity to EGFR inhibition.Conclusions: This study underscores EGFR as a potential therapeutic target in gastric cancer and identifies the combination of an EGFR TKI and a mAb as an effective therapeutic approach. Finally, it recognizes mTOR pathway activation as a novel mechanism of primary resistance that can be overcome by the combination of EGFR and mTOR inhibitors