• Rossen Moesgaard posted an update 6 months ago

    These insights have led to a new model for the disorder-to-order transition in IDPs termed ‘templated folding’, whereby the binding partner dictates distinct structural transitions en route to product, while ensuring a co-operative folding. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.The global incidence of the sexually transmitted disease gonorrhea is expected to rise due to the spread of Neisseria gonorrhoeae strains with decreased susceptibility to extended-spectrum cephalosporins (ESCs). ESC resistance is conferred by mosaic variants of penicillin-binding protein 2 (PBP2) that have diminished capacity to form acylated adducts with cephalosporins. To elucidate the molecular mechanisms of ESC resistance, we conducted a biochemical and high-resolution structural analysis of PBP2 variants derived from the decreased susceptibility N. gonorrhoeae strain 35/02 and ESC-resistant strain H041. Our data reveal that mutations both lower affinity of PBP2 for ceftriaxone and restrict conformational changes that normally accompany acylation. Specifically, we observe that a G545S substitution hinders rotation of the β3 strand necessary to form the oxyanion hole for acylation and also traps ceftriaxone in a non-canonical configuration. In addition, F504L and N512Y substitutions appear to prevent bending of the β3-β4 loop that is required to contact the R1 group of ceftriaxone in the active site. Other mutations also appear to act by reducing flexibility in the protein. Overall, our findings reveal that restriction of protein dynamics in PBP2 underpins the ESC resistance of N. gonorrhoeae. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.PURPOSE The standard treatment of patients with locally advanced rectal cancer consists of preoperative chemoradiotherapy (CRT) followed by surgery. However, the response of individual tumors to CRT is extremely diverse, presenting a clinical dilemma. This broad variability in treatment response is likely attributable to intratumor heterogeneity (ITH). EXPERIMENTAL DESIGN We addressed the impact of ITH on response to CRT by establishing single cell-derived cell lines (SCDCLs) from a treatment-naïve rectal cancer biopsy after xenografting. RESULTS Individual SCDCLs derived from the same tumor responded profoundly different to CRT in vitro Clonal reconstruction of the tumor and derived cell lines based on whole exome sequencing revealed 9 separate clusters with distinct proportions in the SCDCLs. Missense mutations in SV2A and ZWINT were clonal in the resistant SCDCL, but not detected in the sensitive SCDCL. Single cell genetic analysis by multiplex FISH revealed the expansion of a clone with a loss of PIK3CA in the resistant SCDCL. Gene expression profiling by total RNA-sequencing identified the activation of the Wnt-, Akt- and Hedgehog signaling pathways in the resistant SCDCLs. Wnt pathway activation in the resistant SCDCLs was confirmed using a reporter assay. CONCLUSIONS Our model system of patient-derived SCDCLs provides evidence for the critical role of ITH for treatment response in patients with rectal cancer and shows that distinct genetic aberration profiles are associated with treatment response. We identified specific pathways as the molecular basis of treatment response of individual clones, which could be targeted in resistant subclones of a heterogenous tumor. Copyright ©2020, American Association for Cancer Research.PURPOSE We assessed the predictive potential of PET/CT-based radiomics, lesion volume, and routine blood markers for early differentiation of pseudoprogression from true progression at 3 months. EXPERIMENTAL DESIGN 112 metastatic melanoma patients treated with immune checkpoint inhibition. Median follow-up 22 months. All 716 metastases were segmented individually on CT and FDG-PET imaging at 3 time-points baseline (TP0), 3 months (TP1), 6 months (TP2). Response was defined on a lesion-individual level (RECIST 1.1) and retrospectively correlated with FDG-PET/CT radiomic-features and the blood-markers LDH/S100. Seven multivariate prediction model-classes were generated. RESULTS 2-year (median) overall survival, progression-free survival and immune-progression-free survival were 69% (not reached), 24% (6 months) and 42% (16 months). At 3 months, 106 (16%) lesions had progressed, of which 30 (5%) were identified as pseudoprogression at 6 months. Patients with pseudoprogressive lesions and without true-progressiveor delayed treatment switch. Copyright ©2020, American Association for Cancer Research.PSMA radioligand therapy is a promising new class of therapy for prostate cancer. Heterogeneity of PSMA expression are important factors explaining variability in clinical results. The ability to visualise the target with theranostics provides unique mechanistic insights. Potential clinically-applicable strategies to improve patient selection and optimise therapeutic efficacy are discussed. Copyright ©2020, American Association for Cancer Research.Although the last two decades have seen a broad improvement in overall survival, colorectal cancer (CRC) is still the second leading cause of cancer deaths worldwide. Patient populations continue to face poor disease prognoses due to the challenges of early detection and the molecular subtypes driving their CRC. Consequently, many patients present with metastatic CRC, which often limits options and shifts treatment focus away from curative interventions. BRAFV600E mutations are present in approximately 10% of CRC tumors and are associated with uninhibited cell proliferation, reduced apoptosis and resistance to standard therapeutic options. In CRC, BRAFV600E mutations are associated with decreased overall survival, poor treatment responses, and different patterns of metastatic spread compared to tumors with wildtype BRAF. Success in treating other BRAFV600E-mutant cancers with BRAF inhibitors as monotherapy has not translated into efficacious treatment of metastatic CRC. Consequently, combination therapy with inhibitors of BRAF, MEK, and epidermal growth factor receptor, which overcomes the innate treatment-resistant characteristics of BRAFV600E-mutant CRC, is now recommended by treatment guidelines. read more Copyright ©2020, American Association for Cancer Research.

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