Complement Activation Determines the Therapeutic Activity of Rituximab In Vivo

Rituximab is an anti-CD20 chimeric mAb effective for the treatment of B-NHL. It can lyse lymphoma cells in vitro through both C- and Ab-dependent cellular cytotoxicity. The mechanism of action of rituximab in vivo is however still unclear. We have set up a new in vivo model in nonimmunodeficient mice by stable transduction of the human CD20 cDNA in the murine lymphoma line EL4. Animals injected i.v. with the EL4-CD20+ lymphoma cells died within 30 days with evident liver, spleen, and bone marrow involvement, confirmed by immunohistochemistry and PCR analysis. A single injection of rituximab or the murine anti-CD20 Ab 1F5, given i.p. 1 day after the tumor, cured 100% of the animals. Indeed, at week 4 after tumor cell inoculation, CD20+ cells were undetectable in all organs analyzed in rituximab-treated animals, as determined by immunohistochemistry and PCR. Rituximab had no direct effect on tumor growth in vitro. Depletion of either NK cells or neutrophils or both in tumor-injected animals did not affect the therapeutic activity of the drug. Similarly, rituximab was able to eradicate tumor cells in athymic nude mice, suggesting that its activity is T cell independent. In contrast, the protective activity of rituximab or the 1F5 Ab was completely abolished in syngeneic knockout animals lacking C1q, the first component of the classical pathway of C (C1qa−/−). These data demonstrate that C activation is fundamental for rituximab therapeutic activity in vivo

Design, Synthesis, and Anticancer Activity of a Selenium‐Containing Galectin‐3 and Galectin‐9N Inhibitor

Galectins are soluble β‐D‐galactoside‐binding proteins whose implication in cancer progression and disease outcome makes them prominent targets for therapeutic intervention. In this frame, the development of small inhibitors that block selectively the activity of galectins represents an important strategy for cancer therapy which is, however, still relatively underdeveloped. To this end, we designed here a rationally and efficiently novel diglycosylated compound, characterized by a selenoglycoside bond and the presence of a lipophilic benzyl group at both saccharide residues. The relatively high binding affinity of the new compound to the carbohydrate recognition domain of two galectins, galectin 3 and galectin 9, its good antiproliferative and anti‐migration activity towards melanoma cells, as well as its anti‐angiogenesis properties, pave the way for its further development as an anticancer agent

Ultra-processed food consumption and its correlates among Italian children, adolescents and adults from the Italian Nutrition & Health Survey (INHES) cohort study

Objective: To assess ultra-processed food (UPF) consumption and its socio-demographic, psychosocial and behavioural correlates in a general population of Italian children, adolescents and adults. Design: Cross-sectional telephone-based survey Setting: Italy, 2010-2013. Participants: In total, 9078 participants (5-97 years) from the Italian Nutrition & Health Survey. Dietary intakes were collected by a 1-d 24-h dietary recall. UPF was defined by the NOVA classification and expressed as percentage of total energies. Results: Average energy intake from UPF (95 % CI) was 17·3 % (17·1 %, 17·6 %) among adults and 25·9 % (24·8 %, 27·0 %) in children/adolescents. Top sources of UPF were processed meats (32·5 %) and bread substitutes (16·7 %). Among adults, age (β = -3·10; 95 % CI (-4·40, -1·80) for >65 years v. 20-40 years; βs are dimensionless) and residing in Southern Italy (β = -0·73; 95 % CI (-1·32, -0·14) v. Northern) inversely associated with UPF. Screen view during meals was directly linked to UPF, as well as poor self-rated health (β = 5·32; 95 % CI (2·66, 7·99)), adverse life events (β = 2·33; 95 % CI (1·48, 3·18)) and low sleep quality (β = 2·34; 95 % CI (1·45, 3·23)). Boys consumed two-point percent more UPF of the total energy than girls (β = 2·01; 95 % CI (0·20, 3·82)). For all ages, a Mediterranean diet was inversely associated with UPF (β = -4·86; 95 % CI (-5·53, -4·20) for good v. poor adherence in adults and (β = -5·08; 95 % CI (-8·38, -1·77) for kids). Conclusions: UPF contributes a modest proportion of energy to the diets of Italian adults while being one-quarter of the total energies in children/adolescents. UPF was associated with several psychosocial factors and eating behaviours. Increased adherence to Mediterranean diet would possibly result in lower UPF consumption

Functional and clinical implications of genetic structure in 1686 Italian exomes

To reconstruct the phenotypical and clinical implications of the Italian genetic structure, we thoroughly analyzed a whole-exome sequencing data set comprised of 1686 healthy Italian individuals. We found six previously unreported variants with remarkable frequency differences between Northern and Southern Italy in the HERC2, OR52R1, ADH1B, and THBS4 genes. We reported 36 clinically relevant variants (submitted as pathogenic, risk factors, or drug response in ClinVar) with significant frequency differences between Italy and Europe. We then explored putatively pathogenic variants in the Italian exome. On average, our Italian individuals carried 16.6 protein-truncating variants (PTVs), with 2.5% of the population having a PTV in one of the 59 American College of Medical Genetics (ACMG) actionable genes. Lastly, we looked for PTVs that are likely to cause Mendelian diseases. We found four heterozygous PTVs in haploinsufficient genes (KAT6A, PTCH1, and STXBP1) and three homozygous PTVs in genes causing recessive diseases (DPYD, FLG, and PYGM). Comparing frequencies from our data set to other public databases, like gnomAD, we showed the importance of population-specific databases for a more accurate assessment of variant pathogenicity. For this reason, we made aggregated frequencies from our data set publicly available as a tool for both clinicians and researchers (http://nigdb.cineca.it; NIG-ExIT)

778.1 nm distributed feedback lasers for Rb two-photon atomic systems with sub-4 kHz linewidths

A new epitaxial layer design with a double mode expander layer, high refractive index claddings, and an aluminum-free active area has been used to demonstrate distributed feedback lasers operating at 778.1 nm wavelength with reduced Lorentzian linewidth aimed at miniature atomic clock applications. The design also reduces the vertical beam divergence to improve the modal matching with optical fibers as well as maintain the high power output and reduce the emission linewidth. The lasers demonstrate single-mode operation with an over 35 dB side-mode suppression ratio, a power output ≤58 mW, a coupling efficiency to tapered fibers ≤40%, and a Lorentzian linewidth of 3.7 kHz. The performance allowed the free-running distributed feedback lasers to demonstrate spectroscopy of Rb vapor, which resolved the 85Rb and 87Rb two-photon transitions

Clinical and biological markers in gastric cancer: update and perspectives.

Gastric cancer is the second cause of death from cancer worldwide and the only chance to reach better outcomes lays on an early diagnosis. The need for non-invasive, low-cost tests is invoked also in countries in which imaging and endoscopic screening have already showed the ability to improve early diagnosis and overall survival. Genomic medicine could allow a better understanding of regulatory pathways driving the development and growth of gastric cancer and the characterization of specific molecular targets actually stimulate new drug developments. The knowledge of the role of Helicobacter pylori (HP) in gastric tumor pathogenesis has put new insides in the understanding of this peculiar disease and enriched the field of gastric biomarkers

Strong correlation between diet and development of colorectal cancer.

Multiple factors have been described among the causes of non-hereditary colorectal cancer. In Western countries, the most common risk factors include upper-middle socioeconomic status and dietary regimens rich in proteins and animal fats. High consumption of red meats, smoked foods, cold cuts, or canned foods is believed to contribute to carcinogenesis as they directly affect epithlial turnover and cause metabolism of biliary acids. Dietary fibers have protective effects in that they capture the fats and biliary acids, thereby inhibiting their activity. Tobacco smoking acts both locally and systemically on the colorectal mucosa through the production of carcinogenic agents. Finally, the action of alcohol, in association with nicotine addiction, also increases the risk of developing colorectal tumors. Knowledge of dietary and environmental factors is of paramount importance in implementing preventive strategies for colorectal cancer

Linear and nonlinear fractional hereditary constitutive laws of asphalt mixtures

The aim of this paper is to propose a fractional viscoelastic and viscoplastic model of asphalt mixtures using experimental data of several tests such as creep and creep recovery performed at different temperatures and at different stress levels. From a best fitting procedure it is shown that both the creep one and recovery curve follow a power law model. It is shown that the suitable model for asphalt mixtures is a dashpot and a fractional element arranged in series. The proposed model is also available outside of the linear domain but in this case the parameters of the model depend on the stress level

The Dietary Intake of Polyphenols Is Associated with a Lower Risk of Severe Lumbar Spinal Stenosis: A Case-Control Analysis from the PREFACE Study

Polyphenols are naturally occurring compounds endowed with antioxidant and anti-inflammatory properties. We sought to examine the association of dietary polyphenols with the risk of severe lumbar spinal stenosis (LSS), a condition possibly characterized by a high inflammatory component. A case-control study included 156 patients with LSS and indication to surgery and 312 controls, matched (1:2) for sex, age (±6 months), and physical activity. The polyphenol intake was calculated by matching food consumption data from a 188-item food frequency questionnaire with the Phenol-Explorer database regarding the polyphenol content of each reported food. In a multivariable-adjusted logistic regression analysis including lifestyles, sociodemographic factors, and the Mediterranean Diet Score, a 1-standard deviation (SD) increase in dietary polyphenols intake was associated with lower odds of LSS (Odds ratio [OR] = 0.65; 95% CI: 0.47–0.89). Analyses of different polyphenol classes showed that a per 1-SD in the consumption of flavonoids and stilbenes was related to lower LSS risk (OR = 0.57; 95% CI: 0.42–0.78; OR = 0.40; 95% CI: 0.27–0.61, respectively). Further adjustment for the total dietary antioxidant capacity did not modify the strength of these associations. A diet rich in polyphenols is independently associated with a lower risk of severe LSS, possibly through mechanisms that include the anti-inflammatory potential of these bioactive compounds