ΔNp63-restricted viral mimicry response impedes cancer cell viability and remodels tumor microenvironment in esophageal squamous cell carcinoma.

Tumor protein p63 isoform ΔNp63 plays roles in the squamous epithelium and squamous cell carcinomas (SCCs), including esophageal SCC (ESCC). By integrating data from cell lines and our latest patient-derived organoid cultures, derived xenograft models, and clinical sample transcriptomic analyses, we identified a novel and robust oncogenic role of ΔNp63 in ESCC. We showed that ΔNp63 maintains the repression of cancer cell endogenous retrotransposon expression and cellular double-stranded RNA sensing. These subsequently lead to a restricted cancer cell viral mimicry response and suppressed induction of tumor-suppressive type I interferon (IFN-I) signaling through the regulations of Signal transducer and activator of transcription 1, Interferon regulatory factor 1, and cGAS-STING pathway. The cancer cell ΔNp63/IFN-I signaling axis affects both the cancer cell and tumor-infiltrating immune cell (TIIC) compartments. In cancer cells, depletion of ΔNp63 resulted in reduced cell viability. ΔNp63 expression is negatively associated with the anticancer responses to viral mimicry booster treatments targeting cancer cells. In the tumor microenvironment, cancer cell TP63 expression negatively correlates with multiple TIIC signatures in ESCC clinical samples. ΔNp63 depletion leads to increased cancer cell antigen presentation molecule expression and enhanced recruitment and reprogramming of tumor-infiltrating myeloid cells. Similar IFN-I signaling and TIIC signature association with ΔNp63 were also observed in lung SCC. These results support the potential application of ΔNp63 as a therapeutic target and a biomarker to guide candidate anticancer treatments exploring viral mimicry responses.

Does preoperative 25-hydroxyvitamin D status significantly affect the calcium kinetics after total thyroidectomy?

BACKGROUND: Although previous studies have suggested that low preoperative 25-hydroxyvitamin D (25-OHD) is a risk factor for hypocalcemia after total thyroidectomy, the impact of preoperative 25-OHD on calcium (Ca)/parathyroid hormone (PTH) kinetics in the immediate postoperative period remains unclear. The study compared the postoperative Ca/PTH kinetics between different preoperative 25-OHD levels. PATIENTS: A total of 281 patients who underwent a total thyroidectomy were analyzed. Serum Ca was measured preoperatively within 1 h after surgery (Ca-D0) and on the following morning (Ca-D1). Preoperative 25-OHD was also measured after overnight fasting while postoperative PTH was checked at skin closure on day 0 (PTH-D0) and on the following morning on day 1 (PTH-D1). The Ca/PTH kinetics were compared between three groups (group I: preoperative 25-OHD < 10 ng/mL; group II: 25-OHD = 10-20 ng/mL; group III: 25-OHD > 20 ng/mL). RESULTS: Group I had significantly lower preoperative Ca (p = 0.016) and Ca-D0 (p = 0.036) but higher PTH-D1 (p = 0.015) than groups II and III. PTH-D0, Ca-D1, and the rate of clinically significant hypocalcemia were similar in the three groups. Group I had a significantly smaller Ca drop (-0.02 vs. 0.01 and 0.02 mmol/L, p = 0.011) and a tendency for a significantly smaller PTH drop (0.4 vs. 0.5 and 1.0 pmol/L, p = 0.073) than groups II and III. PTH-D1 (OR = 1.550) and 25-OHD (OR = 0.958) were independent factors for Ca drop from day 0 to day 1. CONCLUSIONS: Although group I began with lower serum Ca, those patients tended to have a greater PTH response to Ca drop and so preoperative 25-OHD did not significantly affect the overall Ca kinetics from preoperative to day 1.

Do low preoperative vitamin D levels reduce the accuracy of quick parathyroid hormone in predicting postthyroidectomy hypocalcemia?

BACKGROUND: Although some studies have suggested that low preoperative 25-hydroxyvitamin D (25-OHD) levels may increase the risk of hypocalcemia and decrease the accuracy of single quick parathyroid hormone in predicting hypocalcemia after total thyroidectomy, the literature remains scarce and inconsistent. Our study aimed to address these issues. METHODS: Of the 281 consecutive patients who underwent a total/completion total thyroidectomy, 244 (86.8%) did not require any oral calcium and/or calcitriol supplements (group 1), while 37 (13.2%) did (group 2) at hospital discharge. 25-OHD level was checked 1 day before surgery, and postoperative quick parathyroid hormone (PTH) was checked at skin closure (PTH-SC). Postoperative serum calcium was checked regularly. Hypocalcemia was defined by the presence of symptoms or adjusted calcium of <1.90 mmol/L. Significant factors for hypocalcemia were determined by univariate and multivariate analyses. The accuracy of PTH-SC in predicting hypocalcemia was measured by area under a receiver operating characteristic curve (AUC), and the AUC of PTH-SC was compared between patients with preoperative 25-OHD <15 and ≥15 ng/mL via bootstrapping. RESULTS: Preoperative 25-OHD level was not significantly different between groups 1 and 2 (13.1 vs. 12.5 ng/mL, p = 0.175). After adjusting for other significant factors, PTH-SC (odds ratio 2.49, 95% confidence interval 1.52-4.07, p < 0.001) and parathyroid autotransplantation (odds ratio 3.23, 95% confidence interval 1.22-8.60, p = 0.019) were the two independent factors for hypocalcemia. The AUC of PTH-SC was similar between those with 25-OHD <15 and ≥15 ng/mL (0.880 vs. 0.850, p = 0.61) CONCLUSIONS: Low 25-OHD was not a significant factor for hypocalcemia and did not lower the accuracy of quick PTH in predicting postthyroidectomy hypocalcemia.