Summary of baseline patient characteristics (n = 131).

<p>Summary of baseline patient characteristics (n = 131).</p

Representative PDAC cases with different EGFR/CXCR4 expression profiles: EGFR-/CXCR4− (A), EGFR+/CXCR4− (B), EGFR-/CXCR4+ (C), and EGFR+/CXCR4+ (D). Magnification x 100.

<p>Representative PDAC cases with different EGFR/CXCR4 expression profiles: EGFR-/CXCR4− (A), EGFR+/CXCR4− (B), EGFR-/CXCR4+ (C), and EGFR+/CXCR4+ (D). Magnification x 100.</p

Representative PDAC cases with different EGFR/CXCR4 expression profiles: EGFR-/CXCR4− (A), EGFR+/CXCR4− (B), EGFR-/CXCR4+ (C), and EGFR+/CXCR4+ (D). Magnification x 100.

<p>Representative PDAC cases with different EGFR/CXCR4 expression profiles: EGFR-/CXCR4− (A), EGFR+/CXCR4− (B), EGFR-/CXCR4+ (C), and EGFR+/CXCR4+ (D). Magnification x 100.</p

Univariate analysis for disease-free survival and overall survival.

<p>Univariate analysis for disease-free survival and overall survival.</p

Multivariate analysis for disease-free survival and overall survival.

<p>Multivariate analysis for disease-free survival and overall survival.</p

Table_1_Case Report: Life-threatening hypercalcemia associated with MMR-deficient endometrial carcinoma secreting parathyroid hormone.docx

Ectopic secretion of parathyroid hormone (PTH) is a rare cause of hypercalcemia in malignancy patients. A 56-year-old woman with life-threatening hypercalcemia was caused by poorly-differentiated endometrial carcinoma secreting PTH with concomitant nodular goiter mimic parathyroid tumors. The elevated level of PTH and calcium decreased immediately after cytoreductive surgery (CRS). The pathology confirmed mismatch repair (MMR)-deficient endometrial carcinoma with PTH expression. The patient received four-course chemotherapy and one-course immunotherapy after CRS. The disease progression led to multiple organ failure and death about five months after CRS. To our knowledge, this is the first case of hypercalcemia caused by MMR-deficient endometrial carcinoma with ectopic PTH secreting and the first report of malignancy associated hypercalcemia complicated with nodular goiter.</p

C/EBPδ Deficiency Sensitizes Mice to Ionizing Radiation-Induced Hematopoietic and Intestinal Injury

<div><p>Knowledge of the mechanisms involved in the radiation response is critical for developing interventions to mitigate radiation-induced injury to normal tissues. Exposure to radiation leads to increased oxidative stress, DNA-damage, genomic instability and inflammation. The transcription factor CCAAT/enhancer binding protein delta (<i>Cebpd</i>; C/EBPδ is implicated in regulation of these same processes, but its role in radiation response is not known. We investigated the role of C/EBPδ in radiation-induced hematopoietic and intestinal injury using a <i>Cebpd</i> knockout mouse model. <i>Cebpd</i>−/− mice showed increased lethality at 7.4 and 8.5 Gy total-body irradiation (TBI), compared to <i>Cebpd</i>+/+ mice. Two weeks after a 6 Gy dose of TBI, <i>Cebpd</i>−/− mice showed decreased recovery of white blood cells, neutrophils, platelets, myeloid cells and bone marrow mononuclear cells, decreased colony-forming ability of bone marrow progenitor cells, and increased apoptosis of hematopoietic progenitor and stem cells compared to <i>Cebpd+/+</i> controls. <i>Cebpd</i>−/− mice exhibited a significant dose-dependent decrease in intestinal crypt survival and in plasma citrulline levels compared to <i>Cebpd+/+</i> mice after exposure to radiation. This was accompanied by significantly decreased expression of γ-H2AX in <i>Cebpd</i>−/− intestinal crypts and villi at 1 h post-TBI, increased mitotic index at 24 h post-TBI, and increase in apoptosis in intestinal crypts and stromal cells of <i>Cebpd</i>−/− compared to <i>Cebpd+/+</i> mice at 4 h post-irradiation. This study uncovers a novel biological function for C/EBPδ in promoting the response to radiation-induced DNA-damage and in protecting hematopoietic and intestinal tissues from radiation-induced injury.</p></div

<i>Cebpd−/−</i> mice showed increased radiosensitivity to TBI.

<p>Thirty-day survival of <i>Cebpd−/−</i> mice and <i>Cebpd+/+</i> control mice exposed to 7.4 Gy (n = 7 per genotype) or 8.5 Gy (n = 12 mice per genotype) of TBI. <i>P = 0.02</i> for 7.4 Gy; <i>P</i><0.0001 for 8.5 Gy, as calculated by Logrank (Mantel-Cox) test. The numbers in parentheses indicate the number of animals that survived.</p

<i>Cebpd−/−</i> deficiency enhanced radiation-induced myelosuppression.

<p>Peripheral blood B cells, T cells, and myeloid cells from unirradiated (No IR) and irradiated (IR) <i>Cebpd+/+</i> and <i>Cebpd</i>−/− mice (n = 3/genotype) were enumerated 14 days after exposure to 6 Gy TBI by phenotyping (A, C, E) and expressed as percent of total WBCs (B, D, F). All data are represented as mean ± SEM.</p

<i>Cebpd−/−</i> mice had increased apoptosis and mitotic index and decreased levels of γ-H2AX in intestinal crypts, post-TBI.

<p>(A) Representative images of radiation-induced DNA fragmentation (TUNEL, green staining), DNA-damage marker γ -H2AX (red staining), and cellular nuclei (DAPI, blue staining) of proximal jejunums harvested from <i>Cebpd +/+</i> and <i>Cebpd</i>−/− mice at indicated times after exposure to 7.4 Gy TBI (magnification 10X). (B, C) Quantification of TUNEL-positive cells in intestinal crypts and stromal cells of the villi at indicated time-points after exposure to IR. (D, E) Quantification of γ-H2AX expression levels in intestinal crypts and villi at indicated time-points after exposure to IR. Values are presented as mean ± SEM, n = 4 per genotype per group. (F) Proximal jejunums of <i>Cebpd+/+</i> and <i>Cebpd</i>−/− mice were harvested at 0 h (No IR) and 24 h (IR) after exposure to 7.4 Gy TBI; representative images of immunohistochemical staining of phospho-histone H3 (Ser28) taken at 40× magnification. (G) Phospho-histone H3 (Ser28)-positive cells across approximately 100 intestinal crypts from unirradiated (No IR) and irradiated (IR) <i>Cebpd +/+</i> and <i>Cebpd</i>−/− mice were scored and represented as mean ± SEM, n = 4 per group.</p