49 research outputs found
Extensive molecular profiling of squamous cell anal carcinoma in a phase 2 trial population: Translational analyses of the “CARACAS” study
Background: Molecular characteristics of squamous cell anal carcinoma (SCAC) are poorly explored. Immune checkpoint inhibitors showed limited activity in phase I/II trials, but predictive and prognostic biomarkers are lacking. Patients and methods: In the phase II randomised trial CARACAS (NCT03944252), avelumab alone (Arm A) or with cetuximab (Arm B) was tested in pre-treated advanced SCAC , with overall response rate being the primary end-point. On pre-treatment tumour tissue samples, we assessed Human papillomavirus status, programmed-death ligand 1 (PD-L1) expression, mismatch repair proteins expression, tumour mutational burden (TMB) and comprehensive genomic profiling by FoundationOne CDx. Tumour-infiltrating lymphocytes were characterised on haematoxylin-eosine-stained samples. Primary objective was to describe response to immunotherapy in the CARACAS trial population according to molecular and histological characteristics. Secondary objectives were to assess progression-free survival (PFS) and overall survival (OS) according to molecular biomarkers. Results: High PD-L1 (>40 with combined positive score) was significantly more frequent in patients with disease control (p = 0.0109). High TMB (>10 mutations per megabase) was related to better OS (hazard ratio (HR) = 0.09; 95%confidence interval (CI) 0.01-0.68; p = 0.019) and PFS (HR = 0.44; 95%CI = 0.15-1.27; p = 0.129). High expression of PD-L1 conferred longer OS (HR = 0.46; 95%CI = 0.19-1.08; p = 0.075) and PFS (HR = 0.42; 95%CI = 0.20-0.92; p = 0.03). Neither OS (HR = 1.30; 95%CI = 0.72-2.36; p = 0.39) or PFS (HR = 1.31; 95%CI = 0.74-2.31; p = 0.357) was affected by high (>1.2) Tumour-infiltrating lymphocytes count. High TMB and PD-L1identified patients were with significantly better OS (HR = 0.33; 95%CI = 0.13-0.81; p = 0.015) and PFS (HR = 0.48; 95%CI = 0.23-1.00; p = 0.015). Conclusions: To our knowledge, TranslaCARACAS is the first study to document prognostic role of TMB and PD-L1 in advanced SCAC patients treated with immune checkpoint inhibitors
Activation of mGlu3 Receptors Stimulates the Production of GDNF in Striatal Neurons
Metabotropic glutamate (mGlu) receptors have been considered potential targets
for the therapy of experimental parkinsonism. One hypothetical advantage
associated with the use of mGlu receptor ligands is the lack of the adverse
effects typically induced by ionotropic glutamate receptor antagonists, such as
sedation, ataxia, and severe learning impairment. Low doses of the mGlu2/3
metabotropic glutamate receptor agonist, LY379268 (0.25–3 mg/kg, i.p.)
increased glial cell line-derived neurotrophic factor (GDNF) mRNA and protein
levels in the mouse brain, as assessed by in situ
hybridization, real-time PCR, immunoblotting, and immunohistochemistry. This
increase was prominent in the striatum, but was also observed in the cerebral
cortex. GDNF mRNA levels peaked at 3 h and declined afterwards, whereas GDNF
protein levels progressively increased from 24 to 72 h following LY379268
injection. The action of LY379268 was abrogated by the mGlu2/3 receptor
antagonist, LY341495 (1 mg/kg, i.p.), and was lost in mGlu3 receptor knockout
mice, but not in mGlu2 receptor knockout mice. In pure cultures of striatal
neurons, the increase in GDNF induced by LY379268 required the activation of the
mitogen-activated protein kinase and phosphatidylinositol-3-kinase pathways, as
shown by the use of specific inhibitors of the two pathways. Both in
vivo and in vitro studies led to the conclusion
that neurons were the only source of GDNF in response to mGlu3 receptor
activation. Remarkably, acute or repeated injections of LY379268 at doses that
enhanced striatal GDNF levels (0.25 or 3 mg/kg, i.p.) were highly protective
against nigro-striatal damage induced by
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice, as assessed by
stereological counting of tyrosine hydroxylase-positive neurons in the pars
compacta of the substantia nigra. We speculate that selective mGlu3 receptor
agonists or enhancers are potential candidates as neuroprotective agents in
Parkinson's disease, and their use might circumvent the limitations
associated with the administration of exogenous GDNF
Understanding Factors Associated With Psychomotor Subtypes of Delirium in Older Inpatients With Dementia
Redox cycling metals: Pedaling their roles in metabolism and their use in the development of novel therapeutics
Essential metals, such as iron and copper, play a critical role in a plethora of cellular processes including cell growth and proliferation. However, concomitantly, excess of these metal ions in the body can have deleterious effects due to their ability to generate cytotoxic reactive oxygen species (ROS). Thus, the human body has evolved a very well-orchestrated metabolic system that keeps tight control on the levels of these metal ions. Considering their very high proliferation rate, cancer cells require a high abundance of these metals compared to their normal counterparts. Interestingly, new anti-cancer agents that take advantage of the sensitivity of cancer cells to metal sequestration and their susceptibility to ROS have been developed. These ligands can avidly bind metal ions to form redox active metal complexes, which lead to generation of cytotoxic ROS. Furthermore, these agents also act as potent metastasis suppressors due to their ability to up-regulate the metastasis suppressor gene, N-myc downstream regulated gene 1. This review discusses the importance of iron and copper in the metabolism and progression of cancer, how they can be exploited to target tumors and the clinical translation of novel anti-cancer chemotherapeutics
Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both
Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population
Do MYO9B genetic variants predispose to coeliac disease? An association study in a cohort of South Italian children.
Background. Coeliac disease is a complex disorder influenced by environmental and genetic factors. A genome wide linkage study identified the myosin IXB (MYO9B) as a gene possibly associated with coeliac disease. Recently, a Dutch study reported a strong association of a single SNP, rs 2305764, of MYO9B with coeliac disease. However, two successive studies carried out on British and Swedish/Norwegian
cohorts reported lack of association of the MYO9B variant with coeliac disease.
Aims. The aim of the present study is to verify the effects of the MYO9B rs 2305764 polymorphism on disease risk in a Mediterranean population of coeliac children.
Patients and methods. To address this issue, an association study was performed in 223 (127 females) Italian coeliac children and adolescents and in 600 controls.
Results. The allelic frequencies of the MYO9B rs 2305764 polymorphism found in our patients and in the population control were not statistically different (P = 0.46).
Conclusion. The MYO9B gene rs 2305764 polymorphism is not associated to coeliac disease in coeliac children from Southern Italy. This is in accordance with the most recent reports. Ethnic differences or a false positive result might explain the discrepancy with the Dutch study
Do MY09B genetic variants predispone to coeliac disease? an association study in a cohort of south italian children
Vinorelbine and Alternating Cisplatin and Ifosfamide in the Treatment of Non-Small Cell Lung Cancer
Structure-activity studies on neuropeptide S - Identification of the amino acid residues crucial for receptor activation
Neuropeptide S (NPS) has been recently recognized as the
endogenous ligand for the previous orphan G-protein-coupled
receptor GPR154, now referred to as the NPS receptor
(NPSR). The NPS-NPSR receptor system regulates important
biological functions such as sleeping/wakening, locomotion,
anxiety, and food intake. To collect information on the mechanisms
of interaction between NPS and its receptor, a classical
structure-activity relationship study was performed.
Human (h) NPS derivatives obtained by Ala and D-scan and
N- and C-terminal truncation were assessed for their ability
to stimulate calcium release in HEK293 cells expressing the
human recombinant NPSR. The results of this study indicate
that (i) the effect of hNPS is mimicked by the fragment hNPS-
(1-10); (ii) Phe2, Arg3, and Asn4 are crucial for biological
activity; (iii) the sequence Thr8-Gly9-Met10 is important for
receptor activation, although with non-stringent chemical
requirements; and (iv) the sequence Val6-Gly7 acts as a hinge
region between the two above-mentioned domains. However,
the stimulatory effect of hNPS given intracerebroventricularly
on mouse locomotor activity was not fully mimicked by
hNPS-(1-10), suggesting that the C-terminal region of the
peptide maintains importance for in vivo activity. In conclusion,
this study identified the amino acid residues of this peptide
most important for receptor activation