11 research outputs found
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Strict Major Histocompatibility Complex Molecule Class-Specific Binding by Co-Receptors Enforces MHC-Restricted αβ TCR Recognition during T Lineage Subset Commitment
Since the discovery of co-receptor dependent αβTCR recognition, considerable effort has been spent on elucidating the basis of CD4 and CD8 lineage commitment in the thymus. The latter is responsible for generating mature CD4 helper and CD8αβ cytotoxic T cell subsets. Although CD4+ and CD8+ T cell recognition of peptide antigens is known to be MHC class II- and MHC class I-restricted, respectively, the mechanism of single positive (SP) thymocyte lineage commitment from bipotential double-positive (DP) progenitors is not fully elucidated. Classical models to explain thymic CD4 vs. CD8 fate determination have included a stochastic selection model or instructional models. The latter are based either on strength of signal or duration of signal impacting fate. More recently, differential co-receptor gene imprinting has been shown to be involved in expression of transcription factors impacting cytotoxic T cell development. Here, we address commitment from a structural perspective, focusing on the nature of co-receptor binding to MHC molecules. By surveying 58 MHC class II and 224 MHC class I crystal structures in the Protein Data Bank, it becomes clear that CD4 cannot bind to MHC I molecules, nor can CD8αβ or CD8αα bind to MHC II molecules. Given that the co-receptor delivers Lck to phosphorylate exposed CD3 ITAMs within a peptide/MHC (pMHC)-ligated TCR complex to initiate cell signaling, this strict co-receptor recognition fosters MHC class-restricted SP thymocyte lineage commitment at the DP stage even though both co-receptors are expressed on a single cell. In short, the binding preference of an αβTCR for a peptide complexed with an MHC molecule dictates which co-receptor subsequently binds, thereby supporting development of that subset lineage. How function within the lineage is linked further to biopotential fate determination is discussed
Purification, crystallization and preliminary X-ray analysis of Hsp33 from Saccharomyces cerevisiae
Heat-shock protein Hsp33 from S. cerevisiae was crystallized and diffraction data were collected to 2.7 Å resolution
Purification, crystallization and preliminary X-ray analysis of Hsp33 from Saccharomyces cerevisiae
Heat-shock protein Hsp33 from S. cerevisiae was crystallized and diffraction data were collected to 2.7 Å resolution
Hepatitis B virus and hepatocellular carcinoma at the miRNA level
AIM: To study Hepatitis B virus (HBV) infection and its association with hepatocellular carcinoma (HCC) at the miRNA level
Outcomes of post-immunotherapy durable responders of advanced hepatocellular carcinoma - with emphasis on locoregional therapy for oligoprogression
Introduction
The progression patterns, dispositions, and outcomes of patients with advanced hepatocellular carcinoma (HCC) who achieved durable responses with immunotherapy remain poorly characterized.
Methods
Patients with advanced HCC who received immune checkpoint inhibitor (ICI)-based immunotherapy and achieved durable responses were retrospectively included. A durable response was defined as partial response (PR) or stable disease (SD) per RECIST 1.1 for more than 8 months after initiation of immunotherapy. Oligoprogression and polyprogression were defined as progression at ≤ 3 and > 3 lesions, respectively.
Results
A total of 91 durable responders (63 PR and 28 SD) were identified. The majority had chronic viral hepatitis (n=69, 75.8%). Forty-seven (51.6%) and 44 (48.4%) patients received the index immunotherapy as first-line and second or beyond-line therapy, respectively. Fifty-four (59.3%) patients subsequently developed progression, with a predominant pattern of oligoprogression (66.7%). The median overall survival (OS) was 46.2 months (95% CI: 34.1–58.3). For patients with subsequent progression, employment of locoregional therapy (LRT) for progression was associated with prolonged OS (univariate analysis: hazard ratio [HR] 0.397, p=0.009; multivariate analysis: HR 0.363, p=0.050). Patients with oligoprogression who received LRT showed longer median OS than those who did not (48.4 vs. 20.5 months, p<0.001). In contrast, the median OS of patients with polyprogression who received LRT was not different from those without LRT (27.7 vs. 25.5 months, p=0.794).
Conclusion
Approximately 60% of the post-immunotherapy durable responders of HCC subsequently develop progression. Proactive LRT may further rescue patients who develop subsequent oligoprogression. Prospective studies are mandatory to clarify the proper management of durable responders with subsequent progression