Biology subjects

Houtman, J. C. D.

Publications and source records attributed to Houtman, J. C. D..

2 recordsLinked to original sources

bioRxiv2024

Targeting CXCR4 with -Pentixather Significantly Increases Overall Survival in Small Cell Lung Cancer

IntroductionSmall cell lung cancer (SCLC) has a 7% 5-year overall survival. C-X-C chemokine receptor 4 (CXCR4), an attractive target for theranostic agents, is highly expressed in SCLCs, and can be targeted with pentixather using the theranostic pair 212Pb/203Pb. The hypothesis that [212Pb/203Pb]-pentixather can be used safely and effectively for imaging and therapy in SCLC in xenograft models was tested. ResultsSPECT/CT imaging and biodistribution studies of tumor bearing mice injected with [203Pb]-pentixather demonstrated CXCR4-dependent uptake in tumors and accumulation of radioligand in kidneys and livers. Dosimetry calculations estimated [212Pb]-pentixather uptake in tumor and normal tissue. [212Pb]-pentixather treatment (37-111 kBq/g) of SCLC xenografts (DMS273 and H69AR) significantly prolonged survival and delayed tumor growth. When NSG mice grafted with human hCD34+ bone marrow were treated with [212Pb]-pentixather (37-111 kBq/g), significant cytopenias were observed in peripheral blood complete blood counts (CBCs) at 13-18 days post treatment which resolved by day 28-31. Flow cytometry of bone marrow hematopeotic stem cells in these animals at day 28-31 demonstrated a significantly reduced frequency of the human hematopoietic marker CD45 (hCD45+) and reconstitution of the bone marrow with murine CD45+ (mCD45+) lineages. Conclusions[203Pb]-pentixather can be used to image CXCR4 expressing SCLC xenografts and treatment with alpha emitter [212Pb]-pentixather significantly prolongs SCLC xenograft median overall survival. Significantly greater mCD45+ bone marrow repopulation was detected in NSG mice engrafted with human bone marrow 28-31 days following [212Pb]-pentixather treatment, relative to hCD45+ bone marrow.

cancer biology↗

bioRxiv2022

Comparative study of bacterial SPOR domains identifies functionally important differences in glycan binding affinity

Bacterial SPOR domains target proteins to the divisome by binding septal peptidoglycan (PG) at sites where cell wall amidases have removed stem peptides. These PG structures are referred to as denuded glycans. Although all characterized SPOR domains bind denuded glycans, whether there are differences in affinity is not known. Here we use isothermal titration calorimetry (ITC) to determine the relative PG glycan binding affinity (Kd) of four Escherichia coli SPOR domains and one Cytophaga hutchinsonii SPOR domain. We found that the Kd values ranged from approximately 1 {micro}M for E. coli DamXSPOR and C. hutchinsonii CHU2221SPOR to about 10 {micro}M for E. coli FtsNSPOR. To ask whether these differences in PG binding affinity are important for SPOR domain protein function, we constructed and characterized a set of DamX and FtsN "swap" proteins. As expected, all SPOR domain swap proteins localized to the division site, and in the case of FtsN all of the heterologous SPOR domains supported cell division. But for DamX only the high-affinity SPOR domain from CHU2221 supported normal function in cell division. In summary, different SPOR domains bind denuded PG glycans with different affinity, which appears to be very important for the function of some SPOR domain proteins (e.g., DamX) but not others (e.g., FtsN). ImportanceSPOR domain proteins are prominent components of the cell division apparatus in a wide variety of bacteria. The primary function of SPOR domains is to target proteins to the division site, which they accomplish by binding to septal peptidoglycan. But whether SPOR domains have any functions beyond septal targeting is unknown. Here we show that SPOR domains vary in their PG binding affinities and, at least in the case of the E. coli cell division protein DamX, having a high-affinity SPOR domain contributes to proper function.

microbiology↗