Beta-galactoside-binding protein secreted by activated T cells inhibits antigen-induced proliferation of T cells.

We have used mRNA differential display PCR to search for genes induced in activated T cells and have found the LGALS1 (lectin, galactoside-binding, soluble) gene to be strongly up-regulated in effector T cells. The protein coded by the LGALS1 gene is a beta-galactoside-binding protein (betaGBP), which is released by cells as a monomeric negative growth factor but which can also associate into homodimers (galectin-1) with lectin properties. Northern blot analysis revealed that ex vivo isolated CD8+ effector T cells induced by a viral infection expressed high amounts of LGALS1 mRNA, whereas LGALS1 expression was almost absent in resting CD8+ T cells. LGALS1 expression could be induced in CD4+ and CD8+ T cells upon activation with the cognate peptide antigen and high levels of LGALS1 expression were found in concanavalin A-activated T cells but not in lipopolysaccharide-activated B cells. Gel filtration and Western blot analysis revealed that only monomeric betaGBP was released by activated CD8+ T cells and in vitro experiments further showed that recombinant betaGBP was able to inhibit antigen-induced proliferation of naive and antigen-experienced CD8+ T cells. Thus, these data indicate a role of betaGBP as an autocrine negative growth factor for CD8+ T cells

The economic impact of comorbidity in multiple sclerosis

Background Comorbid conditions are common in people with multiple sclerosis (pwMS). They can delay diagnosis and negatively impact the disease course, progression of disability, therapeutic management, and adherence to treatment.Objective To quantify the economic impact of comorbidity in multiple sclerosis (MS), based on cost-of-illness estimates made using a bottom-up approach.Methods A retrospective study was carried out in two northern Italian areas. The socio-demographic and clinical information, including comorbidities data, were collected through ad hoc anonymous self-assessment questionnaire while disease costs (direct and indirect costs of disease and loss of productivity) were estimated using a bottom-up approach. Costs were compared between pwMS with and without comorbidity. Adjusted incremental costs associated with comorbidity were reported using generalized linear models with log-link and gamma distributions or two-part models.Results 51.0% of pwMS had at least one comorbid condition. Hypertension (21.0%), depression (15.7%), and anxiety (11.7%) were the most prevalent. PwMS with comorbidity were more likely to use healthcare resources, such as hospitalizations (OR =1.21, p < 0.001), tests (OR =1.59, p < 0.001), and symptomatic drugs and supplements (OR = 1.89, p= 0.012), and to incur non-healthcare costs related to investment (OR =1.32, p < 0.001), transportation (OR = 1.33, p < 0.001), services (OR =1.33, p < 0.001), and informal care (OR =1.43, p= 0.16). Finally, they experienced greater productivity losses (OR =1.34, p< 0.001) than pwMS without comorbidity. The adjusted incremental annual cost per patient due to comorbidity was (sic)3,106.9 (13% of the overall costs) with MS disability found to exponentially affect annual costs.Conclusion Comorbidity has health, social, and economic consequences for pwMS

The economic impact of comorbidity in multiple sclerosis

Comorbid conditions are common in people with multiple sclerosis (pwMS). They can delay diagnosis and negatively impact the disease course, progression of disability, therapeutic management, and adherence to treatment.Objective: To quantify the economic impact of comorbidity in multiple sclerosis (MS), based on cost-of-illness estimates made using a bottom-up approach. Methods: A retrospective study was carried out in two northern Italian areas. The socio-demographic and clinical information, including comorbidities data, were collected through ad hoc anonymous self-assessment questionnaire while disease costs (direct and indirect costs of disease and loss of productivity) were estimated using a bottom-up approach. Costs were compared between pwMS with and without comorbidity. Adjusted incremental costs associated with comorbidity were reported using generalized linear models with log-link and gamma distributions or two-part models. Results: 51.0% of pwMS had at least one comorbid condition. Hypertension (21.0%), depression (15.7%), and anxiety (11.7%) were the most prevalent. PwMS with comorbidity were more likely to use healthcare resources, such as hospitalizations (OR = 1.21, p < 0.001), tests (OR = 1.59, p < 0.001), and symptomatic drugs and supplements (OR = 1.89, p = 0.012), and to incur non-healthcare costs related to investment (OR = 1.32, p < 0.001), transportation (OR = 1.33, p < 0.001), services (OR = 1.33, p < 0.001), and informal care (OR = 1.43, p = 0.16). Finally, they experienced greater productivity losses (OR = 1.34, p < 0.001) than pwMS without comorbidity. The adjusted incremental annual cost per patient due to comorbidity was €3,106.9 (13% of the overall costs) with MS disability found to exponentially affect annual costs. Conclusion: Comorbidity has health, social, and economic consequences for pwMS

Killing of Kras-Mutant Colon Cancer Cells via Rac-Independent Actin Remodeling by the beta GBP Cytokine, a Physiological PI3K Inhibitor Therapeutically Effective In Vivo

Activating mutations in Kras are the most frequent mutations in human cancer. They define a subset of patients who do not respond to current therapies and for whom prognosis is poor. Oncogenic Kras has been shown to deregulate numerous signalling pathways of which the most intensively studied are the Ras-ERK cascade and the PI3K-Akt cascade. However, to date there are no effective targeted therapies in the clinic against Kras-mutant cancers. Here we report that the βGBP cytokine, a physiological inhibitor of class I PI3Ks is a potent activator of apoptosis in Kras-mutant colorectal cancer cells, even when co-harboring mutant-activated PIK3CA. Our study unveils an elective route to intrinsic and extrinsic apoptosis which involves the cytoskeleton. Early events are inhibition of PI3K activity and Rac-independent actin rearrangement assignable to phosphoinositide changes at the plasma membrane. Cyclin E deregulation, arrest of DNA synthesis and Chk2 activation underscore events critical to the activation of an intrinsic apoptotic program. Clustering of CD95/Fas death receptors underscore events critical to the activation of extrinsic apoptosis. In nude mice we present the first evidence that xenograft tumor development is strongly inhibited by Hu-r-βGBP. Taken together our results open a new therapeutic opportunity against a subset of patients refractive to current treatments. This first demonstration of therapeutic efficacy against Kras-mutant colon cancer suggests that Hu-r-βGBP may also be therapeutically effective against other cancers harbouring activating Ras mutations as well as PIK3CA mutations

Description and preliminary experience with Virtual Visit Assessment (ViVA) during the COVID-19 pandemic, a structured virtual management protocol for patients with multiple sclerosis

In people with multiple sclerosis (PwMS), strict follow-up is essential. Telemedicine has the potential to overcome many of the difficulties in routine management. Herein, we present a structured protocol that can be used to remotely manage patients with MS, describing in detail the steps to be taken and exams needed at each stage. A working group was established which developed a tailored protocol that can be adapted to a variety of settings. The overall protocol consisted of 5 phases: enrolment, document sharing phase, pre-evaluation, virtual visit, and post-visit phase, which was divided into 14 individual steps. As of October 2020, 25 virtual visits have been carried out, all via Skype. The patient's caregiver was present during visits and had an active role. The average duration of the virtual visit was 24 min, and that of the pre-visit and post-visit were around 15 min each. Overall satisfaction as rated by physicians was considered high (8.0 +/- 0.5). Using the system usability scale (SUS), patients also favorably rated the virtual visit (96.6 +/- 6.1). In 20% of cases, the virtual visit was not sufficient to provide adequate information and an in-person clinical visit was recommended. The described protocol has the potential to provide benefits for the healthcare system as well as patients and their caregivers both during and beyond COVID-19 pandemic