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Second-order spinal cord excitatory neurons play a key role in spinal processing and transmission of pain signals to the brain. Exogenously induced change in developmentally imprinted excitatory neurotransmitter phenotypes of these neurons to inhibitory has not yet been achieved. Here, we use a subpial dorsal horn-targeted delivery of AAV (adeno-associated virus) vector(s) encoding GABA (gamma-aminobutyric acid) synthesizing-releasing inhibitory machinery in mice with neuropathic pain. Treated animals showed a progressive and complete reversal of neuropathic pain (tactile and brush-evoked pain behavior) that persisted for a minimum of 2.5 months post-treatment. The mechanism of this treatment effect results from the switch of excitatory to preferential inhibitory neurotransmitter phenotype in dorsal horn nociceptive neurons and a resulting increase in inhibitory activity in regional spinal circuitry after peripheral nociceptive stimulation. No detectable side effects (e.g., sedation, motor weakness, loss of normal sensation) were seen between 2 and 13 months post-treatment in naive adult mice, pigs, and non-human primates. The use of this treatment approach may represent a potent and safe treatment modality in patients suffering from spinal cord or peripheral nerve injury-induced neuropathic pain.

Aims: This study investigated the relationship between the differentiation of tumour cells into crypts, which is determined by cell differentiation into Paneth and neuroendocrine cells, and tumour infiltration in gastric dysplasia. Methods and results: The lesions were endoscopically biopsied low‐grade dysplasia (LGD), endoscopically resected high‐grade dysplasia (HGD) or cancer with submucosal invasion. LGD (n = 32) displayed crypt differentiation across the entire width of the tumour in all cases. Crypt differentiation was identified as a characteristic of tumours with low biological malignancy. HGD (n = 40) included tumours with a mixture of areas with and without crypt differentiation (n = 25) and tumours with crypt differentiation throughout the entire width (n = 15). Of the cancers with submucosal invasion (n = 30), the morphological progression of the HGD area with crypt differentiation, the HGD area without crypt differentiation and invasive cancer without crypt differentiation was confirmed for 23 samples. In two lesions, invasive cancer without crypt differentiation developed from HGD without crypt differentiation throughout the tumour width. In five samples, well‐differentiated tubular adenocarcinoma with crypt differentiation developed from HGD with crypt differentiation and invaded with lamina propria‐like stroma. Conclusions: Loss of crypt differentiation could be an objective indicator of infiltration in the progression of HGD to invasive cancer. The invasive potential of dysplasia depends upon the presence or absence of crypt differentiation. [ABSTRACT FROM AUTHOR]

Benedikt syndrome is caused by a rare type of brain damage to the red nucleus and nearby locations. Clinically, it presents as ipsilateral oculomotor palsy and specific contralateral involuntary movement. These involuntary movements may affect activities of daily living(ADLs)in affected patients. We treated a case of Benedikt syndrome associated with neck clipping of a ruptured basilar-superior cerebellar artery aneurysm. A 66-year-old female patient was admitted to our department with headache. Initial computed tomography imaging and angiography showed subarachnoid hemorrhage and left basilar-superior cerebellar artery aneurysm. We performed neck clipping of the aneurysm. Immediately after the surgery, left oculomotor nerve palsy occurred. Right involuntary movement gradually developed from the fifth day after the surgery. Postoperative magnetic resonance imaging(MRI)showed an infarction around the left red nucleus. This specific involuntary movement significantly impaired the ADLs of the patient and persisted for two months. From three months after the surgery, it gradually improved. One and a half years after the surgery, the ADLs of the patient improved notably. It is important to preserve perforators in the treatment of distal basilar artery aneurysm. However, while ischemia of the red nucleus(e.g., due to perforator damage)may cause specific involuntary movements, they could recover spontaneously after a period of months.

We report a case of a 59-year-old woman who was forced to undergo mastectomy of the right breast (Rt Bt) plus axillary lymph node (Ax) dissection for right breast cancer at another hospital. The pathological diagnosis was invasive ductal carcinoma( scirrhou[s sci], pT2N2M0, Stage IIIA, estrogen recepto[r ER[]+], progesterone recepto[r PgR[]+], human epidermal growth factor receptor-2[HER2][2+]). Although no recurrence was observed after postoperative adjuvant chemotherapy and endocrine therapy, skin metastasis on the left back and pleuritis carcinomatosa were detected at our hospital 9 years and 6 months after the operation. Thereafter, bone metastasis, contralateral lymph node metastasis, and frequent occurrence of hepatic metastasis were sequentially detected. The patient was treated with chemotherapy (a total of 4 regimens) and endocrine therapy in addition to radiation therapy for lymph node metastasis over a period of approximately 2 years and 3 months; however, disease control was poor. Therefore, combined chemotherapy with paclitaxel and bevacizumab was initiated from February 2012. Soon after the initiation of combination therapy, the serum carcinoembryonic antigen (CEA) level gradually reduced and computed tomography (CT) revealed that the multiple-organ metastases had remarkably reduced in size. The response was classified as a clinical partial response (cPR). Although adverse events such as peripheral neuropathy, nose bleeding, and high blood pressure were observed, these were all of lesser that Grade 2 severity. The efficacy of chemotherapy was noted for 11 months.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands inhibit the growth of PPAR-gamma expressing cancer cells through terminal differentiation. However, there are few studies examining the effect of a PPAR-gamma ligand on metastatic potential of cancer cells in an animal model and the underlying molecular mechanisms. We have recently developed a rectal cancer xenograft animal model in which anti-tumor and anti-metastatic efficacy of agents can be evaluated. This study was designed to examine whether a representative PPAR-gamma ligand, thiazolidinedione (TZD), could inhibit growth and metastasis of PPAR-gamma positive HT-29 human colon cancer cells through the induction of terminal differentiation. TZD caused G1 arrest in association with a marked increase in p21Waf-1, Drg-1, and E-cadherin expression. In untreated cancer cells, fluorescence immunostaining demonstrated beta-catenin in the nucleus and/or cytoplasm; in TZD-treated cancer cells, beta-catenin localization shifted to the plasma membrane, in association with increased E-cadherin at this site and reduced tyrosine phosphorylation of beta-catenin. In addition, TZD completely inhibited lymph node and lung metastases in the xenograft animal model, and TZD inhibited growth of primary xenografts by 40%. These results suggest that TZD can function as a cytostatic anti-cancer agent to inhibit growth and metastasis of HT-29 colon cancer cells through differentiation-promoting effects. These effects involve not only modulation of the E-cadherin/beta-catenin system, but also up-regulation of Drg-1 gene expression.