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Vitamin D binding protein-macrophage activating factor (DBP-maf) is a potent inhibitor of tumor growth. Its activity, however, has been attributed to indirect mechanisms such as boosting the immune response by activating macrophages and inhibiting the blood vessel growth necessary for the growth of tumors. In this study we show for the first time that DBP-maf exhibits a direct and potent effect on prostate tumor cells in the absence of macrophages. DBP-maf demonstrated inhibitory activity in proliferation studies of both LNCaP and PC3 prostate cancer cell lines as well as metastatic clones of these cells. Flow cytometry studies with annexin V and propidium iodide showed that this inhibitory activity is not due to apoptosis or cell death. DBP-maf also had the ability to inhibit migration of prostate cancer cells in vitro. Finally, DBP-maf was shown to cause a reduction in urokinase plasminogen activator receptor (uPAR) expression in prostate tumor cells. There is evidence that activation of this receptor correlates with tumor metastasis. These studies show strong inhibitory activity of DBP-maf on prostate tumor cells independent of its macrophage activation.

Limited data exist on the specific association between gastroduodenal Crohn's disease (GDCD) and NOD2/CARD15 gene polymorphisms. The aim of this study was to assess the association between NOD2 polymorphisms and GDCD, and to assess the specific association between each of the 3 major allelic variants G908R, L1007P, and R702W and the clinical features of Crohn's disease. We retrospectively reviewed the records of 202 patients with confirmed Crohn's disease and complete data was performed. Seventy-one patients (35%) had at least 1 allelic variant: 55 had 1 variant, 4 were homozygous for L1007fs, 2 homozygous for R702W, and 10 were compound heterozygous. Eighteen patients with confirmed GDCD were identified; 10 (56%) had wild type, 4 (22%) had 1 variant, and 4 (22%) had 2 allelic variants (2 were L1007P homozygous and 2 compound heterozygous). Compared to patients without gastroduodenal involvement, those with GDCD were more likely to have 2 allelic variants (22% vs. 6%; odds ratio [OR] 2.7; 95% confidence interval [CI] 1.6-7.3) and to be homozygous for L1007P (11% vs. 1%; OR 5.2; 95% CI 2.5-9.4). G908R heterozygosity was associated with ileal involvement (OR 1.4; 95% CI 1.1-2.9) and smoking habits (OR 2.4; 95% CI 1.2-3.8), whereas L1007P homozygosity was associated with GDCD (OR 5.8; 95% CI 2.6-10.8). L1007P variation was associated with younger age at diagnosis as well. There was no specific association between R702W homo- or heterozygosity and any of the characteristics examined. In conclusion, GDCD is associated with double dose of the NOD2/CARD15 gene variants, particularly L1007P homozygosity. There is evidence of specific variant-phenotype associations. G908R heterozygosity is associated with ileal involvement and smoking, whereas L1007P homozygosity is strongly associated with GDCD and younger age at diagnosis.

Limited data exist on the specific association between gastroduodenal Crohn's disease (GDCD) and NOD2/CARD15gene polymorphisms. The aim of this study was to assess the association between NOD2polymorphisms and GDCD, and to assess the specific association between each of the 3 major allelic variants G908R, L1007P, and R702Wand the clinical features of Crohn's disease. We retrospectively reviewed the records of 202 patients with confirmed Crohn's disease and complete data was performed. Seventy-one patients (35%) had at least 1 allelic variant: 55 had 1 variant, 4 were homozygous for L1007fs, 2 homozygous for R702W, and 10 were compound heterozygous. Eighteen patients with confirmed GDCD were identified; 10 (56%) had wild type, 4 (22%) had 1 variant, and 4 (22%) had 2 allelic variants (2 were L1007Phomozygous and 2 compound heterozygous). Compared to patients without gastroduodenal involvement, those with GDCD were more likely to have 2 allelic variants (22% vs. 6%; odds ratio [OR] 2.7; 95% confidence interval [CI] 1.6-7.3) and to be homozygous for L1007P(11% vs. 1%; OR 5.2; 95% CI 2.5-9.4). G908Rheterozygosity was associated with ileal involvement (OR 1.4; 95% CI 1.1-2.9) and smoking habits (OR 2.4; 95% CI 1.2-3.8), whereas L1007Phomozygosity was associated with GDCD (OR 5.8; 95% CI 2.6-10.8). L1007Pvariation was associated with younger age at diagnosis as well. There was no specific association between R702Whomo- or heterozygosity and any of the characteristics examined. In conclusion, GDCD is associated with double dose of the NOD2/CARD15gene variants, particularly L1007Phomozygosity. There is evidence of specific variant-phenotype associations. G908Rheterozygosity is associated with ileal involvement and smoking, whereas L1007Phomozygosity is strongly associated with GDCD and younger age at diagnosis.

The use of binding peptides and binding proteins in the construction of ligand-enzyme conjugates for binding assays and for the affinity-based immobilization of enzymes and bacterial cells has been investigated. To this end, a genetically engineered peptide-enzyme conjugate was developed, consisting of the streptavidin binding peptide Strep-tag II and bacterial alkaline phosphatase as the marker enzyme. The peptide-enzyme conjugate was used to detect biotin, biocytin, and desthiobiotin. Though the detection limits were high relative to other methods, due to the low binding affinity of the peptide relative to biotin and its analogues, the dose-response curves obtained clearly show that peptide mimics can be used to detect non-peptide analytes. The reversible calcium-dependent binding of calmodulin was used to develop a reversible binding scheme for the enzyme organophophorous hydrolase (OPH). In order to utilize this reversible binding to immobilize OPH, the gene coding for vu-1 calmodulin was fused to the N-terminus of the opd gene, which codes for OPH. The resulting calodulin-OPH fusion protein was immobilized on a cellulose membrane functionalized with the phenothiazine derivative TAPP. The enzyme fusion, once immobilized, retained a significant amount of its specific activity, and could be repeatedly loaded, unloaded, and reloaded onto the membrane. Calmodulin was also used as an affinity tail for the immobilization of the thermostable phenol hydroxylase of Geobacillus stearothermophilus BR 219. It was proposed that the thermostable properties of calmodulin might allow it to be used in an affinity-based immobilization scheme for thermostable enzymes. Calmodulin was therefore genetically fused to the N-terminus of the phenol hydroxylase, and the enzyme fusion was successfully immobilized on TAPP-cellulose. Calmodulin was able to remain bound to the membrane at the optimum temperature of the phenol hydroxylase (55°C). Finally, a method for immobilizing bacterial cells on surfaces through the binding interaction of the antimicrobial peptide cecropin-P1 was developed. The antimicrobial peptide cecropin-P1 was covalently attached to microplate well surfaces, and used to immobilized E. coli 0157:H7 and K-12 cells, which were subsequently detected by an anti- E. coli-HRP conjugate. The data clearly demonstrated that the measured signals were dependent upon both the concentration of viable cells and the amount of cecropin-P1 coupled to the surface.

Background Direct KRASG12C inhibitors are approved for patients with non-small cell lung cancers (NSCLC) in the second-line setting. The standard-of-care for initial treatment remains immune checkpoint inhibitors, commonly in combination with platinum-doublet chemotherapy (chemo-immunotherapy). Outcomes to chemo-immunotherapy in this subgroup have not been well described. Our goal was to define the clinical outcomes to chemo-immunotherapy in patients with NSCLC with KRASG12C mutations. Patients and Methods Through next-generation sequencing, we identified patients with advanced NSCLC with KRAS mutations treated with chemo-immunotherapy at 2 institutions. The primary objective was to determine outcomes and determinants of response to first-line chemo-immunotherapy among patients with KRASG12C by evaluating objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). We assessed the impact of coalterations in STK11/KEAP1 on outcomes. As an exploratory objective, we compared the outcomes to chemo-immunotherapy in KRASG12C versus non-G12C groups. Results One hundred and thirty eight patients with KRASG12C treated with first-line chemo-immunotherapy were included. ORR was 41% (95% confidence interval (CI), 32-41), median PFS was 6.8 months (95%CI, 5.5-10), and median OS was 15 months (95%CI, 11-28). In a multivariable model for PFS, older age (P = .042), squamous cell histology (P = .008), poor ECOG performance status (PS) (P < .001), and comutations in KEAP1 and STK11 (KEAP1MUT/STK11MUT) (P = .015) were associated with worse PFS. In a multivariable model for OS, poor ECOG PS (P = .004) and KEAP1MUT/STK11MUT (P = .009) were associated with worse OS. Patients with KRASG12C (N = 138) experienced similar outcomes to chemo-immunotherapy compared to patients with non-KRASG12C (N = 185) for both PFS (P = .2) and OS (P = .053). Conclusions We define the outcomes to first-line chemo-immunotherapy in patients with KRASG12C, which provides a real-world benchmark for clinical trial design involving patients with KRASG12C mutations. Outcomes are poor in patients with specific molecular coalterations, highlighting the need to develop more effective frontline therapies. This study aimed to define the clinical outcomes of first-line chemo-immunotherapy in patients with non-small cell lung cancer with KRASG12C mutations and to examine the significance of PD-L1 tumor proportion score and comutation status (KEAP1 and STK11) on outcomes.

Background: Direct [KRAS.sup.G12C] inhibitors are approved for patients with non-small cell lung cancers (NSCLC) In the second-line setting. The standard-of-care for initial treatment remains immune checkpoint inhibitors, commonly in combination with platinum-doublet chemotherapy (chemo-immunotherapy). Outcomes to chemo-immunotherapy in this subgroup have not been well described. Our goal was to define the clinical outcomes to chemo-immunotherapy in patients with NSCLC with [KRAS.sup.G12C] mutations. Patients and Methods: Through next-generation sequencing, we identified patients with advanced NSCLC with KRAS mutations treated with chemo-immunotherapy at 2 institutions. The primary objective was to determine outcomes and determinants of response to first-line chemo-immunotherapy among patients with [KRAS.sup.G12C] by evaluating objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). We assessed the impact of coalterations in STK11/KEAP1 on outcomes. As an exploratory objective, we compared the outcomes to chemo-immunotherapy in [KRAS.sup.G12C] versus non-G12C groups. Results: One hundred and thirty eight patients with [KRAS.sup.G12C] treated with first-line chemo-immunotherapy were included. ORR was 41% (95% confidence interval (CI), 32-41), median PFS was 6.8 months (95%CI, 5.5-10), and median OS was 15 months (95%CI, 11-28). In a multivariable model for PFS, older age (P = .042), squamous cell histology (P = .008), poor ECOG performance status (PS) (P < .001), and comutations in KEAP1 and STK11 ([KEAP.sup.1MUT]/[STK11.sup.MUT]) (P = .015) were associated with worse PFS. In a multivariable model for OS, poor ECOG PS (P = .004) and [KEAP.sup.1MUT]/[STK11.sup.MUT] (P = .009) were associated with worse OS. Patients with [KRAS.sup.G12C] (N = 138) experienced similar outcomes to chemoimmunotherapy compared to patients with non-[KRAS.sup.G12C] (N = 185) for both PFS (P = .2) and OS (P = .053). Conclusions: We define the outcomes to first-line chemo-immunotherapy in patients with [KRAS.sup.G12C], which provides a real-world benchmark for clinical trial design involving patients with [KRAS.sup.G12C] mutations. Outcomes are poor in patients with specific molecular coalterations, highlighting the need to develop more effective frontline therapies. Key words: non-small cell lung cancer; [KRAS.sup.G12C]; combination therapy; chemotherapy; immunotherapy.