Injury/ischemia-induced stem cells: up-to-date knowledge and future perspectives for neural regeneration

Brain injuries like ischemic stroke induce endogenous stem cell production. Although the precise traits of stem cells in pathological brains remain unclear, we previously demonstrated that injury/ischemia-induced stem cells(iSCs)are present in the post-stroke mouse(Nakagomi et al.,2009)and human brains(Beppu et al.,2019).

Neural regeneration by regionally induced stem cells within poststroke brains: Novel therapy perspectives for stroke patients

Ischemic stroke is a critical disease which causes serious neurological functional loss such as paresis. Hope for novel therapies is based on the increasing evidence of the presence of stem cell populations in the central nervous system (CNS) and the development of stem-cell-based therapies for stroke patients. Although mesenchymal stem cells (MSCs) represented initially a promising cell source, only a few transplanted MSCs were present near the injured areas of the CNS. Thus, regional stem cells that are present and/or induced in the CNS may be ideal when considering a treatment following ischemic stroke. In this context, we have recently showed that injury/ischemia-induced neural stem/progenitor cells (iNSPCs) and injury/ischemia-induced multipotent stem cells (iSCs) are present within post-stroke human brains and post-stroke mouse brains. This indicates that iNSPCs/iSCs could be developed for clinical applications treating patients with stroke. The present study introduces the traits of mouse and human iNSPCs, with a focus on the future perspective for CNS regenerative therapies using novel iNSPCs/iSCs.

A potential new tool to enhance translational success rate in stroke research by backcrossing techniques in transgenic mice

Ischemic stroke is a leading disease of the central nervous system,frequently coupled to severe damage and dysfunction in patients.Animal models mimicking human stroke provide useful tools for studying the pathomechanisms(e.g.,inflammation,neuroprotection,and neural regeneration),the treatment efficiency of various materials(e.g.,bioactive molecules or drugs),and transplantation usefulness by various cell types[e.g.,neural stem/progenitor cells(NSPCs),and mesenchymal or hematopoietic stem cells]under ischemic stroke.

Cyclooxygenase-2 expression after preoperative chemoradiotherapy correlates with more frequent esophageal cancer recurrence

AIM: To investigate the relationship between cycloo- xygenase-2 (COX-2), and vascular endothelial growth factor (VEGF), and to determine the clinical significance of this relationship in esophageal cancer patients undergoing chemoradiotherapy (CRT). METHODS: Immunohistochemical staining was used to evaluate COX-2 and VEGF expression in 40 patients with histologically-confirmed esophageal squamous carcinoma (ESCC) who were undergoing preoperative CRT. RESULTS: Fourteen out of 40 ESCC patients showed a pathological complete response (CR) after CRT. COX-2 and VEGF protein expressions were observed in the cytoplasm of 17 and 13 tumors, respectively, with null expression in 9 and 13 tumors, respectively. COX-2 expression was strongly correlated with VEGF expression (P < 0.05). There were also significant associations between COX-2 expression, tumor recurrence, and lymph-node involvement (P = 0.0277 and P = 0.0095, respectively). COX-2 expression and VEGF expression had significant prognostic value for disease-free survival (log-rank test; P = 0.0073 and P = 0.0341, respectively), but not for overall survival, as assessed by univariate analysis. CONCLUSION: Our results suggest that COX-2 expression correlates with VEGF expression and might be a useful prognostic factor for more frequent tumor recurrence in ESCC patients undergoing neoadjuvant CRT. These findings support the use of anti-angiogenic COX-2 inhibitors in the treatment of ESCC.

Persistent CXCR4 expression after preoperative chemoradiotherapy predicts early recurrence and poor prognosis in esophageal cancer

AIM: To study the effect of CXC chemokine receptor-4 (CXCR4) expression on disease progression and prognosis in esophageal cancer. METHODS: CXCR4 expression was evaluated in 37 patients with histologically confirmed esophageal squamous carcinomas (ESCC) undergoing preoperative chemoradiotherapy (CRT) by immunohistochemical staining. RESULTS: Eleven out of 37 ESCC patients showed a pathological complete response (CR) after CRT. CXCR4 protein expression was observed in cell cytoplasms of 13 tumors, and null expression was seen in 13 tumors. Distant recurrence was significantly more common in patients with positive CXCR4 expression (P = 0.0318). After a median follow-up time of 31.6 mo, 19 patients progressed (12 of 19 expressed positive CXCR4) and 11 died (10 of 11 expressed positive CXCR4). Overall survival was significantly correlated with lymph node metastasis (952.1 ± 53.8 d in negative group vs 475.1 ± 56.2 d in positive group, P = 0.023), distant metastasis (874.0 ± 60.4 d in negative group vs 434.9 ± 75.2 d in positive group, P = 0.014) and CRT (811.5 ± 51.2 d in responder group vs 459.6 ± 94.0 d in non-responder group, P = 0.00038) and further with an absence ofCXCR4 expression or no residual tumor (959.8 ± 51.0 d in null expression or no tumor group vs 412.0 ± 57.1 d in positive expression group, P = 0.0001). CONCLUSION: Persistent positive CXCR4 expression is implicated in tumor aggressiveness and poor prognosis in ESCC after CRT, and preoperative CRT may improve the prognosis of ESCC via CXCL12-CXCR4 signaling pathway.

Upregulation of macrophage migration inhibitory factor and calgizzarin by androgen in TM4 mouse Sertoli cells

Aim： To identify proteins induced by androgen in Sertoli cells during spermatogenesis. Methods： We analyzed protein profiles in TM4 Sertoli cells treated with dihydrotestosterone （DHT） using surface enhanced laser desorption ionization time-of-flight mass spectrometry （SELDI-TOF-MS）. Results： We found increases in the expression of a 5.0-kDa protein at 15 min, an 11.3-kDa protein at 24 h and 4.3 kDa, 5.7 kDa, 5.8 kDa, 9.95 kDa and 9.98 kDa proteins at 48 h after the treatment. In contrast, the expression of 6.3 kDa and 8.6 kDa proteins decreased at 30 min, and 4.9 kDa, 5.0 kDa, 12.4 kDa and 19.8 kDa proteins at 48 h after the treatment. The ll.3-kDa protein was identified as macrophage migration inhibitory factor （MIF） known to having various functions. The 9.98-kDa protein was identified as calgizzarin related to calcium channels. The timing of their expression suggests that MIF and calgizzarin are involved in late regulation of spermatogenesis in Sertoli cells by androgen. Conclusion： MIF and calgizzarin are two important androgen-responsive proteins produced by Sertoli cells and they might play a role in regulating spermatogenesis.

脑缺血后N-myc下游调控基因2保护血脑屏障完整性

脑缺血后血脑屏障(BBB)的破坏与外周细胞向脑内浸润、病孔损形成与进展、以及临床病程恶化密切相关。目前BBB完整性的调控机制,尤其是在永久性缺血后的调控机制尚未明确。本研究使用小鼠永久性脑缺血模型进行相关研究,结果显示,星形胶质细胞N-myc下游调控基因2(NDRG2)可能是缺血性脑卒中后BBB通透性的调控分子,该分子与分化和应激相关。免疫组化显示,在永久性大脑中动脉闭塞(MCAO)后,NDRG2在星形胶质细胞中的表达显著增加。敲除NDRG2基因,脑梗死体积增加,免疫细胞在缺血同侧大脑半球积聚增加。MCAO后,NDRG2基因敲除小鼠缺血侧皮质的缺血灶内及灶周血管周围区域内的血清蛋白(包括纤维蛋白原和免疫球蛋白)的外渗增强此之,MCAO后NDRG2基因敲除小鼠体内基质金属蛋白酶(MMPs)的表达也显著增加。在细胞培养中,NDRG2-/-星形胶质细胞中MMP-3的表达和分泌增加,这种增加可被腺病毒介导的NDRG2再表达所逆转。综上所述,脑缺血后,星形胶质细胞内的NDRG2可能通过调节MMP的表达,而在BBB通透性的调节和免疫细胞浸润中起到重要作用。

Anticipation phenomenon in familial adenomatous polyposis:an analysis of its origin

AIM To analyze the origin of the anticipationphenomenon,which means earlier death insuccessive generation in familial adenomatouspolyposis.METHODS The study subjects were 2161patients with familial adenomatous polyposisand their 7465 first-degree relatives who weremembers of 750 families registered at ourPolyposis Registry.The ages at death andcumulative mortality rates in the parent,theproband,and the child generations werecompared for both all subjects and the patientsalone.RESULTS In the patients over 5 years of age,the mean age at death was 50.9 years for theparent,42.3 years for the proband,and 33.3years for the child generations,respectively(P【0.001).The deceased rates in the threegenerations were 90.7%,51.3% and 23.1% ofthe patients,respectively,and this differencewas the main cause of the anticipation measuredby parent-child paring method.The cumulativemortality rates for all subjects failed to showanticipation,however the cumulative mortalityrates for the patients showed the anticipation.The anticipation phenomenon was shown by anyparent-child pairing methods for the deceasedpatients.Other important causes of theanticipation were different proportion of causesof death between generations(P【0.001),and alow proportion of detected or deceased patients (P【0.001)in the child generation.CONCLUSION Anticipation in familialadenomatous polyposis may be caused byparent-child paring methods as well as severalintergenerational biases.

ECA39 is a novel distant metastasis-related biomarker in colorectal cancer

AIM: To investigate the possible role of polysaccharide-K (PSK) -related markers in predicting distant metastasis and in the clinical outcome of colorectal cancer (CRC).METHODS: Firstly, we used protein microarrays to analyze the in vitro expression profiles of potential PSK-related markers in the human colorectal adenocarcinoma cell line SW480, which carries a mutant p53 gene. Then, we investigated the clinical implications of these markers in the prognosis of CRC patients. RESULTS: ECA39, a direct target of c-Myc, was identi-fied as a candidate protein affected by the anti-metastat-ic effects of PSK. Immunohistochemistry revealed that ECA39 was expressed at significantly higher levels in tumor tissues with distant metastases compared to those without (P < 0.00001). Positive ECA39 expression was shown to be highly reliable for the prediction of distant metastases (sensitivity: 86.7%, specificity: 90%, posi-tive predictive value: 86.7%, negative predictive value: 90%). A significantly higher cumulative 5-yr disease free survival rate was observed in the ECA39-negative patient group (77.3%) compared with the ECA39-positive patient group (25.8%) (P < 0.05). CONCLUSION: Our results suggest that ECA39 is a dominant predictive factor for distant metastasis in pa-tients with advanced CRC and that its suppression by PSK might represent a useful application of immuno-therapy as part of a program of integrated medicine.