EBioMedicine
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The anaplastic lymphoma kinase (ALK) fusion oncogene is observed in 3%-5% of non-small cell lung cancer (NSCLC). Crizotinib and ceritinib, a next-generation ALK tyrosine kinase inhibitor (TKI) active against crizotinib-refractory patients, are clinically available for the treatment of ALK-rearranged NSCLC patients, and multiple next-generation ALK-TKIs are currently under clinical evaluation. These ALK-TKIs exhibit robust clinical activity in ALK-rearranged NSCLC patients; however, the emergence of ALK-TKI resistance restricts the therapeutic effect. ⋯ Knockdown of ABCB1 or P-gp inhibitors sensitizes the patient-derived cancer cells to ceritinib, in vitro and in vivo. P-gp overexpression was identified in three out of 11 cases with in ALK-rearranged crizotinib or ceritinib resistant NSCLC patients. Our study suggests that alectinib, PF-06463922, or P-gp inhibitor with ceritinib could overcome the ceritinib or crizotinib resistance mediated by P-gp overexpression.
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Rheumatoid arthritis (RA) is characterized by chronic joint inflammation and associates with HLA-DRB1*04. The Collagen IIp261-273-specific T cell repertoire in the peripheral blood of DR4 + patients at the onset of the disease shows a restricted TCR-beta chain usage among which the most frequent is TRBV25. To define whether this group of DR4-restricted collagen-specific shared T cell could represent markers of active-severe disease and response to therapy, 90 subjects affected by early-RA were enrolled in the study; peripheral blood mononuclear cells were cultured with or without the human collagen II peptide p261-273 and were examined by immunoscope analysis for the usage of the previously identified shared TCR-beta chains. ⋯ HLA-DRB1* haplotypes 04-04, 04-01 and 04-11 were significantly associated with usage of TRBV25, higher disease activity at the onset of disease and poor response to DMARDs. Finally, the HLA-DRB1* haplotype appeared complementary with current serologic tools to predict good and poor responders in a treat to target strategy. The data reported here offer clues to predict the course of the disease and to foresee personalized treatments in RA patients.
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Sickle cell disease (SCD) in patients of HbSC genotype is considered similar, albeit milder, to that in homozygous HbSS individuals--but with little justification. In SCD, elevated red cell cation permeability is critical as increased solute loss causes dehydration and encourages sickling. Recently, we showed that the KCl cotransporter (KCC) activity in red cells from HbSC patients correlated significantly with disease severity, but that in HbSS patients did not. ⋯ Results suggest that KCC is likely to have greater involvement in red cell dehydration in HbSC patients, which could explain its association with disease severity in this genotype. This work supports the hypothesis that SCD in HbSC patients is a distinct disease entity to that in HbSS patients. Results suggest the possibility of designing specific treatments of particular benefit to HbSC patients and a rationale for the development of prognostic markers, to inform early treatment of children likely to develop more severe complications of the disease.
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Bipolar affective disorder has a high rate of comorbidity with a multitude of psychiatric disorders and medical conditions. Among all the potential comorbidities, co-existing anxiety disorders stand out due to their high prevalence. ⋯ Our results suggest a high rate of lifetime concurrent anxiety disorders in bipolar disorder. The diagnostic issues at the interface are particularly difficult because of the substantial symptom overlap. The treatment of co-existing conditions has clinically remained challenging.
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Neuropathic pain is defined as pain arising as a direct consequence of a lesion or a disease affecting the somatosensory system and it affects around 1 in 4 diabetic patients in the UK. The purpose of this genome-wide association study (GWAS) was to identify genetic contributors to this disorder. Cases of neuropathic pain were defined as diabetic patients with a multiple prescription history of at least one of five drugs specifically indicated for the treatment of neuropathic pain. ⋯ We found a cluster in the Chr1p35.1 (ZSCAN20-TLR12P) with a lowest P value of 2.74 × 10(- 7) at rs71647933 in females and a cluster in the Chr8p23.1, next to HMGB1P46 with a lowest P value of 8.02 × 10(- 7) at rs6986153 in males. Sex-specific narrow sense heritability was higher in males (30.0%) than in females (14.7%). This GWAS on diabetic neuropathic pain provides evidence for the sex-specific involvement of Chr1p35.1 (ZSCAN20-TLR12P) and Chr8p23.1 (HMGB1P46) with the disorder, indicating the need for further research.