Sensitization of spinal itch transmission neurons in a mouse model of chronic itch requires an astrocytic factor.

BACKGROUND: Chronic itch is a highly debilitating symptom among patients with inflammatory skin diseases. Recent studies have revealed that gastrin-releasing peptide (GRP) and its receptor (gastrin-releasing peptide receptor [GRPR]) in the spinal dorsal horn (SDH) play a central role in itch transmission. OBJECTIVE: We aimed to investigate whether GRP-GRPR signaling is altered in SDH neurons in a mouse model of chronic itch and to determine the potential mechanisms underlying these alterations. METHODS: Patch-clamp recordings from enhanced green fluorescent protein (EGFP)-expressing (GRPR+) SDH neurons were used to examine GRP-GRPR signaling in spinal cord slices obtained from Grpr-EGFP mice. Immunohistochemical, genetic (gene expression and editing through adeno-associated virus vectors), and behavioral approaches were also used for in vivo experiments. RESULTS: We observed potentiation of GRP-evoked excitation in the GRPR+ SDH neurons of mice with contact dermatitis, without concomitant changes in GRPR expression. Interestingly, increases in excitation were attenuated by suppressing the reactive state of SDH astrocytes, which are known to be reactive in patients with chronic itch conditions. Furthermore, CRISPR-Cas9-mediated astrocyte-selective in vivo editing of a gene encoding lipocalin-2 (LCN2), an astrocytic factor implicated in chronic itch, suppressed increases in GRP-induced excitation of GRPR+ neurons, repetitive scratching, and skin damage in mice with contact dermatitis. Moreover, LCN2 potentiated GRP-induced excitation of GRPR+ neurons in normal mice. CONCLUSION: Our findings indicate that, under chronic itch conditions, the GRP-induced excitability of GRPR+ SDH neurons is enhanced through a non-cell-autonomous mechanism involving LCN2 derived from reactive astrocytes.

[Disappearance of a gastric lesion following modified FOLFOX6 chemotherapy in a patient with metastatic colorectal cancer: a case report and literature review].

A 48-year-old man with colorectal cancer and right inguinal lymph node metastasis had previously undergone radiotherapy and chemotherapy (uracil/tegafur/leucovorin) after a colostomy in another hospital before being referred to us. Esophagogastroduodenoscopy (EGD) revealed the presence of a gastric metastatic lesion. After three courses of treatment with a modified regimen of leucovorin plus 5-fluorouracil plus oxaliplatin-6 (mFOLFOX6), EGD revealed that the gastric lesion had disappeared; computed tomography revealed that the size of the primary tumor and inguinal lymph node metastasis were markedly reduced. Subsequently, he underwent rectal resection of the primary tumor and continued treatment with mFOLFOX6 in combination with bevacizumab. We reviewed 29 similar cases from the literature, and determined that surgical resection of the tumor and appropriate chemotherapy can lead to long-term survival for patients with gastric metastases from colorectal cancer. Furthermore, positive CK20 and CDX2 expression and negative CK7 expression were useful adjuncts in the immunohistochemical diagnosis of gastric metastases from colorectal adenocarcinoma.

Cyclooxygenase-2 expression is increased in early intestinal-type gastric cancer and gastric mucosa with intestinal metaplasia.

OBJECTIVE: Cyclooxygenase-2 (COX-2) expression is increased in gastric cancer. We examined COX-2 expression in early stage gastric cancer and background mucosa to elucidate the role of COX-2 in gastric carcinogenesis. METHODS: Thirty-three early gastric cancers obtained from 30 patients infected with Helicobacter pylori were studied. Twenty-three patients had an intestinal, four patients had a diffuse, and three patients had both an intestinal and a diffuse type cancer. Expression of COX-2 protein was detected by immunohistochemistry by counting the number of positive staining cells per 100 cells. RESULTS: Mean COX-2 expression was 84.1 (SD 11.4) in 26 intestinal type cancers and was significantly higher than that in seven diffuse type cancers (23.1 +/- 9.7) (P < 0.001). In three patients who had both the intestinal and the diffuse type cancer, COX-2 expression was 92, 90 and 83 in the intestinal type cancer and only 25, 24 and 7 in the corresponding diffuse type cancer. In 18 patients who had intestinal metaplasia (15 had incomplete metaplasia), COX-2 expression was 60.2 (24.2) in the crypts with metaplasia while it was only 16.8 (10.7) in the crypts without metaplasia (P < 0.001). CONCLUSIONS: COX-2 expression may be associated with the carcinogenesis of the intestinal type gastric cancer and, speculatively, inhibition of COX-2 might have preventative effects on the intestinal type gastric cancer.