Introduction: Glomerulopathy is a group of diseases that affect mainly young adults between the ages of 20 and 40 years. Recently, it has been demonstrated that syndecan-1, a biomarker of endothelial glycocalyx damage, is increased in nephrotic patients with near-normal renal function and it is important to endothelial dysfunction in these patients. Angiopoietin-2 (AGPT2) is an endothelial growth factor that promotes cell derangement. Here we evaluated AGPT2 levels in patients with nephrotic syndrome, near-normal renal function and the possible interaction of AGPT2 with endothelial glycocalyx derangement. Methods: This was a cross-sectional study performed from January through November 2017. Adult patients (age > 18 years) with nephrotic syndrome and without immunosuppression were included. Blood samples were drawn after a 12 h fast for later measurement of syndecan-1 and AGPT2. Mediation analyses were performed to assess the hypothesized associations of nephrotic syndrome features and AGPT2 with syndecan-1. Results: We included 65 patients, 37 (56.9%) of them female, with primary glomerular disease. Syndecan-1 in nephrotic patients was higher than in control individuals (102.8 ± 36.2 vs. 28.2 ± 9.8 ng/mL, p < 0.001). Correlation of syndecan-1 with the main features of nephrotic syndrome after adjustment for age and estmmated glomerular filtration rate (eGFR) demonstrated that syndecan-1 was significantly associated with 24-h urinary protein excretion, total cholesterol, LDL (low density lipoprotein)-cholesterol, HDL (high-density lipoprotein)-cholesterol, and triglycerides. Angiopoietin-2 was independently associated with serum albumin, 24 h urinary protein excretion, total cholesterol, and LDL-cholesterol, in addition to being strongly associated with syndecan-1 (0.461, p < 0.001). The results of the mediation analyses showed that the direct association between LDL-cholesterol and syndecan-1 was no longer significant after AGPT-2 was included in the mediation analysis. AGPT2 explained 56% of the total observed association between LDL-cholesterol and syndecan-1. Conclusion: The association between LDL-cholesterol and glycocalyx derangement in nephrotic patients is possibly mediated by AGPT2.

BACKGROUND: Advanced metastatic colorectal cancer (mCRC) has a 14% 5-year survival rate with little progress made for microsatellite stable tumors. KRAS mutations occur in about 40-50% of mCRC and are associated with more aggressive drug resistance and lack of response to anti-EGFR therapies. Recent advances have led to small molecules targeting KRAS G12C that have been undergoing clinical testing in lung, mCRC, and other tumor types. ONC212 is a fluorinated imipridone with strong anti-cancer activity in nM range and preclinical efficacy against pancreatic and other malignancies. Through extensive structure-based drug design, MRTX1133 was identified as a noncovalent, potent, and selective inhibitor of KRASG12D. MRTX1133 suppresses KRASG12D signaling in cells and in vivo, MRTX1133 binds to the switch II pocket and inhibits the protein-protein interactions necessary for activation of the KRAS pathway. MATERIALS & METHODS: We investigated cell viability and drug synergies of 5-FU or ONC212 plus KRAS G12D inhibitor MRTX1133 in 6 human CRC and 4 human pancreatic cancer cell lines at 72 hours. Experiments evaluated drug effects on pERK using western blot at 6 and 24 hours. We evaluated changes at 48 hours in cytokine profiles in treated cells using a custom panel of 62 cytokines, chemokines, and growth factors associated with tumor growth, immune stimulation or immune suppression. RESULTS: Colorectal and pancreatic cancer cell lines had IC50 sensitivities ranging from 7 to 12 microM for 5-FU 0.2-0.8 microM for ONC212, &gt;100 nM to &gt;5,000 nM for MRTX1133 (G12D N=4: LS513 &gt;100, HPAF-II &gt;1,000, SNUC2B &gt;5,000, PANC-1 &gt;5,000). For non-G12D, the range of IC50 for MRTX1133 was &gt;1,000 to &gt;5,000 nM for CRC lines with G12V, G13D, or WT KRAS (N=7). Synergies between MRTX1133 and either 5-FU or ONC212 were observed across cell lines regardless of the presence of KRAS G12D mutation with combination indices of &lt;0.5 indicating strong synergy. The observed synergy was greater with the combination of MRTX1133 and ONC212 compared to the synergy with 5-FU. Among the cytokine alterations, IL8/CXCL8, MICA, Angiopoietin 2, VEGF and TNF-alpha were reduced while IL-18/IL-1F4 increased with all treatments. CONCLUSIONS: Our ongoing studies reveal the potential activity of MRTX1133 against mCRC and pancreatic cancer cells regardless of KRAS G12D mutation and synergies were observed with 5-FU and ONC212 regardless of KRAS G12D mutation. Immune stimulatory cytokine profiles were observed with 5-FU, MRTX1133 and combination. The results suggest that KRAS G12D, KRAS G13D and WT KRAS should not be excluded from clinical trials especially with combination therapies involving MRTX1133 and standard-of-care 5-FU. Citation Format: Vida Tajiknia, Wafik El-Deiry, Maximilian Pinho Schwermann, Lanlan Zhou, Kelsey Huntington. Combination of 5-Fluorouracil or ONC212 plus KRAS G12D inhibitor MRTX1133 against colorectal and pancreatic cancer cells results in immune-stimulatory cytokine patterns and unexpected synergies independent of G12D mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1072.

Insulinoma is the most common pancreatic neuroendocrine tumor. The clinical manifestation is diverse, some of which may cause irreversible neurological deficits due to persistent hypoglycemia. This article reports a case of a 17-year-old patient who presented with visual scotoma, somnolence and loss of consciousness with blood glucose documentation of 15 mg / dL. He was admitted and underwent imaging tests. Tomography and Magnetic Resonance imaging did not clearly identify the pancreatic lesion, but tumor lesions were identified after arterial stimulation with calcium. Patient was submitted to surgical enucleation by laparotomy. In this context, there is still much discussion about the optimal sequence of exams for the exact tumor location. However, the use of less invasive exams such as arterial calcium stimulation is essential for adequate surgical resection.