SW480 and SW620 colon carcinoma cell lines derive from primary tumour and lymph-node metastasis of the same patient, respectively. For this reason, these cells represent an ideal system to analyse ...phenotypic variations associated with the metastatic process. In this study we analysed SW480 and SW620 cytoskeleton remodelling by measuring the cells' mechanics and morphological properties using different microscopic techniques. We observed that different specialized functions of cells, i.e. the capacity to metastasize of elongated cells inside the primary tumour and the ability to intravasate and resist shear forces of the stream of cells derived from lymph node metastasis, are reflected in their mechanical properties. We demonstrated that, together with stiffness and adhesion between the AFM tip and the cell surface, cell shape, actin organization and surface roughness are strictly related and are finely modulated by colorectal cancer cells to better accomplish their specific tasks in cancer growth and invasion.
Assessing the radon activity that exhales from building structures is crucial to identify the best strategies to prevent radon from entering a building or reducing its concentration in the inhabited ...spaces. The direct measurement is extremely difficult, so the common approach has consisted in developing models describing the radon migration and exhalation phenomena for building porous materials. However, due to the mathematical complexity of comprehensively modelling the radon transport phenomenon in buildings, simplified equations have been mostly adopted until now to assess the radon exhalation. A systematic analysis of the models applicable to radon transport has been carried out and it has resulted in four models differing in the migration mechanisms – only diffusive or diffusive and advective – and the presence of inner radon generation. The general solutions have been obtained for all the models. Moreover, three case-specific sets of boundary conditions have been formulated to account for all the actual scenarios occurring in buildings: both perimetral and partition walls and building structures in direct contact with soil or embankments. The corresponding case-specific solutions obtained serve as a key practical tool to improve the accuracy in assessing the contribution of building materials to indoor radon concentration according to the site-specific installation conditions in addition to the material inner properties.
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•Four mathematical models account for radon transport and generation mechanisms.•Case-specific boundary conditions represent the actual exhalation in buildings.•Analytical solutions are developed to assess the radon exhalation in all conditions.•The solutions provided serve as a tool to optimize the remedial action strategies.•The work output may help to achieve the circular economy goals in building industry.
There is the need to identify new prognostic markers to refine risk stratification for HER2-positive early breast cancer patients. The aim of this study was to evaluate the association of ...tumor-infiltrating lymphocytes (TILs) with distant disease-free survival (DDFS) in patients with HER2-positive early breast cancer enrolled in the ShortHER adjuvant trial which compared 9 weeks versus 1-year trastuzumab in addition to chemotherapy, and to test the interaction between TILs and treatment arm.
Stromal TILs were assessed for 866 cases on centralized hematoxylin and eosin-stained tumor slides. The association of TILs as 10% increments with DDFS was assessed with Cox models. Kaplan–Meier curves were estimated for patients with TILs ≥20% and TILs <20%. Median follow-up was 6.1 years.
Median TILs was 5% (Q1–Q3 1%–15%). Increased TILs were independently associated with better DDFS in multivariable model hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.59–0.89, P = 0.006, for each 10% TILs increment. Five years DDFS rates were 91.1% for patients with TILs <20% and 95.7% for patients with TILs ≥20% (P = 0.025). The association between 10% TILs increments and DDFS was significant for patients randomized to 9 weeks of trastuzumab (HR 0.60, 95% CI 0.41–0.88) but not for patients treated with 1 year of trastuzumab (HR 0.89, 95% CI 0.71–1.12; test for interaction P = 0.088). For patients with TILs <20%, the HR for the comparison between the short versus the long arm was 1.75 (95% CI 1.09–2.80, P=0.021); whereas, for patients with TILs ≥20% the HR for the comparison of short versus long arm was 0.23 (95% CI 0.05–1.09, P = 0.064), resulting in a significant interaction (P = 0.015).
TILs are an independent prognostic factor for HER2-positive early breast cancer patients treated with adjuvant chemotherapy and trastuzumab and may refine the ability to identify patients at low risk of relapse eligible for de-escalated adjuvant therapy.
Despite the recognised contribution of the stroma to breast cancer development and progression, the effective targeting of the tumor microenvironment remains a challenge to be addressed. We ...previously reported that normal fibroblasts (NFs) and, notably, breast cancer-associated fibroblasts (CAFs) induced epithelial-to-mesenchymal transition and increases in cell membrane fluidity and migration in well- (MCF-7) and poorly-differentiated (MDA-MB-231) breast cancer cells. This study was designed to better define the role played, especially by CAFs, in promoting breast tumor cell migration.
Fibroblast/breast cancer cell co-cultures were set up to investigate the influence of NFs and CAFs on gene and protein expression of Stearoyl-CoA desaturase 1 (SCD1), the main enzyme regulating membrane fluidity, as well as on the protein level and activity of its transcription factor, the sterol regulatory element-binding protein 1 (SREBP1), in MCF-7 and MDA-MB-231 cells. To assess the role of SREBP1 in the regulation of SCD1 expression, the desaturase levels were also determined in tumor cells treated with an SREBP1 inhibitor. Migration was evaluated by wound-healing assay in SCD1-inhibited (by small-interfering RNA (siRNA) or pharmacologically) cancer cells and the effect of CAF-conditioned medium was also assessed. To define the role of stroma-derived signals in cancer cell migration speed, cell-tracking analysis was performed in the presence of neutralising antibodies to hepatocyte growth factor, transforming growth factor-β or basic fibroblast growth factor.
A two to three fold increase in SCD1 mRNA and protein expression has been induced, particularly by CAFs, in the two cancer cell lines that appear to be dependent on SREBP1 activity in MCF-7 but not in MDA-MB-231 cells. Both siRNA-mediated and pharmacological inhibition of SCD1 impaired tumor cells migration, also when promoted by CAF-released soluble factors. Fibroblast-triggered increase in cancer cell migration speed was markedly reduced or abolished by neutralising the above growth factors.
These results provide further insights in understanding the role of CAFs in promoting tumor cell migration, which may help to design new stroma-based therapeutic strategies.
Objectives
Impulsivity is a vulnerability trait for poor self-regulation in substance use disorder (SUD). Working memory (WM) training improves impulsivity and self-regulation in psychiatric ...disorders. Here we test WM training in methamphetamine use disorder (MUD).
Methods
There are 15 MUD patients receiving inpatient treatment as usual (TAU) and 20 who additionally completed WM cognitive training (CT) and 25 healthy controls (HC). MANCOVA repeated measures analyses examined changes in impulsivity and self-regulation at baseline and after 4 weeks.
Results
Post hoc
t
tests confirmed that at baseline, feelings of self-control were significantly lower in the MUD (
t
= 2.001,
p
= 0.05) and depression was higher (
t
= 4.980,
p
= 0.001), as was BIS total impulsivity (
t
= 5.370,
p
= 0.001) compared to the HC group. Total self-regulation score was higher in HC than MUD patients (
t
= 5.370,
p
= 0.001). CT had a 35% learning rate (
R
2
= 0.3523,
p
< 0.05). Compared to follow-up TAU, follow-up CT group had higher self-reported mood scores (
t
= 2.784,
p
= 0.01) and higher compared to CT baseline (
t
= 2.386,
p
= 0.036). Feelings of self-control were higher in CT than TAU at follow-up (
t
= 2.736,
p
= 0.012) and also compared to CT baseline (
t
= 3.390,
p
= 0.006), lack of planning significantly improved in CT between baseline and follow-up (
t
= 2.219,
p
= 0.048), as did total impulsivity scores (
t
= 2.085,
p
= 0.048). Measures of self-regulation were improved in the CT group compared to TAU at follow-up, in total score (
t
= 2.442,
p
= 0.038), receiving score (
t
= 2.314,
p
= 0.029) and searching score (
t
= 2.362,
p
= 0.027). Implementing self-regulation was higher in the CT group compared to TAU (
t
= 2.373,
p
= 0.026).
Conclusions
WM training may improve control of impulsivity and self-regulation in people with MUD.
Few studies have been carried out to date that have addressed the epidemiology of extranodal marginal zone lymphomas (EN-MZLs).
We carried out a population-based study to investigate incidence rates ...(IRs) and time trends of EN-MZL diagnosed in the province of Modena (Italy) from 1997 to 2007.
One hundred and sixty-five cases were identified from the Modena Cancer Registry that corresponded to an age-standardized IR of 2.3 cases per 100000. A bimodal distribution of age was shown with the group of young patients mostly represented by males with cutaneous lymphoma. No time trends were observed for the IR; the incidence of gastric mucosa-associated lymphoid tissue (g-MALT) lymphomas (N = 51) markedly declined during the study period, dropping from 1.4 in 1997 to 0.2 in 2002 and then remaining stable until 2007; the calculated annual percent change for g-MALT was -17.0% (95% confidence interval -26.6% to -6.2%). We also observed a significant decrease in the rate of g-MALT associated with Helicobacter pylori (HP) infection from 61% to 17% of patients diagnosed before and after 2002 (P = 0.007; P for trend = 0.016).
This population-based study provides new insights into recent changes in the epidemiology of EN-MZL, mainly represented by the sharp reduced incidence of HP-positive g-MALT lymphomas.
Nivolumab is an anti-PD-1 antibody that restores the antitumour immune function of T cells, blocking the binding of PD-1 with its ligand PD-L1. PD-1 is expressed on T cells and interacts with PD-L1 ...on tumour cells. The PD-1-PD-L1 link inhibits T cell activation. In metastatic melanoma, PD-1-PD-L1 binding plays a critical role, and the advent of the immune checkpoint inhibitor nivolumab has delivered new and effective treatment options with proven clinical benefit. In the present study, we evaluated the efficacy of nivolumab in elderly patients with metastatic melanoma.
The study enrolled 55 elderly patients (75 years of age and older) with a diagnosis of metastatic melanoma. Primary endpoints of the study were progression-free survival (pfs) and the objective response rate; secondary endpoints were overall survival, reduction in serum lactate dehydrogenase (ldh) from before to after treatment, and tolerability.
Nivolumab was well tolerated and resulted in good disease control, with a manageable toxicity profile and significant clinical benefit. The duration of pfs was 5.1 months (95% confidence interval: 3.5 months to 6.8 months). A significant correlation was observed between reduction in serum ldh and pfs: 0.60 (95% confidence interval: 0.28 to 0.86;
= 0.002).
Nivolumab is an immunotherapy treatment that has proved to be an effective and well-tolerated therapeutic option in elderly patients with metastatic melanoma.
Purpose
Dienogest has recently been marketed as a medical treatment for endometriosis. Given the recent introduction on the market of Dienogest, little data are available regarding its effectiveness ...in routine clinical practice.
Methods
The study is an observational, single-center, cohort study. Eligible was women with a surgical diagnosis of endometriosis dating back <24 months or a clinical/instrumental diagnosis of endometriosis and endometriosis-associated pelvic pain score of at least 40 mm on a 100-mm visual analog scale (VAS) at start of treatment and who had been taking Dienogest 2 mg once daily treatment at the time of study entry for no more than 30 days, consecutively observed between September 2013 to September 2014. In accordance with routine practice, women came back for clinical assessment and evaluation of pain after 1 (V1), 3 (V2), and 12 (V3) months.
Results
A total of 132 women were enrolled in the study. A total of 21 of the enrolled patients were released from the study during follow-up due to adverse effects. The mean pelvic pain VAS score at baseline was 8.9 (SD 1.3). The corresponding values were 6.7 (SD 3.2) and 5.7 (SD 3.7) for dyspareunia and dyschezia. The mean VAS scores progressively and significantly decreased to 0.9 (SD 1.6) for pelvic pain, 1.4 (SD 2.1) for dyspareunia and 0.2 (SD 0.9) for dyschezia, respectively, 12 months after start of treatment.
Conclusion
This study confirms that in routine clinical practice, Dienogest 2 mg is an effective and well-tolerated treatment for endometriosis-related pain in women with endometriosis.
Hereditary tyrosinemia type 1 (HT1) is characterized by severe progressive liver disease and renal tubular dysfunction. NTBC therapy has revolutionized the management of HT1 but its effect on renal ...tubular function has so far been poorly investigated. The aim of this study was to describe the early effect of NTBC on renal tubular disease in patients with HT1.
Five HT1 patients (age between 5 and 53months) with different types of presentation were evaluated before and during the first 2weeks of therapy with NTBC in a retrospective case analysis for phosphate metabolism and renal tubular function.
Before starting NTBC therapy, all children manifested signs of renal dysfunction which included hypophosphatemia, acidosis, reduced phosphate reabsorption, aminoaciduria, glycosuria (Fanconi syndrome), and variable degree of proteinuria. Some patients also presented increased urinary calcium/creatinine ratio and raised fractional excretion of sodium. Starting of NTBC therapy resulted in the rapid normalization of plasma phosphate within one week from its initiation in majority of patients and in all patients during the second week of therapy. TmP/GFR normalized in 48h, while the other markers of renal dysfunction showed an improving trend over 2weeks.
NTBC is an efficient treatment for renal tubular dysfunction in HT1, allowing the return to normal function within a few weeks. Its early effect on renal tubular cells appeared to be very rapid, particularly in normalizing plasma phosphate and TmP/GFR. In our series of patients, the TmP/GFR resulted as the most reliable index of tubular function.
•NTBC allowed a rapid improvement of renal function in patients with HT1.•NTBC improved tubular reabsorption of phosphate, leading to normalization in plasma.•TmP/GFR resulted the most reliable index of tubular function.
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