In vivo studies on the effects of α1-adrenoceptor antagonists on pupil diameter and urethral tone in rabbits

α₁-Adrenoceptors mediate contraction of iris dilator smooth muscle and hence pupil dilatation. We compared the ability of i.v. bolus injections of alfuzosin, doxazosin, naftopidil, prazosin, tamsulosin and terazosin to antagonise phenylephrine-induced mydriasis relative to their potency for inhibiting phenylephrine-induced elevations of intraurethral pressure (IUP) in rabbits. Moreover, we compared the ability of these drugs to induce miosis in conscious rabbits in the absence of phenylephrine. All antagonists inhibited the effects of phenylephrine on pupil size and IUP, and the ratio of the respective ED₅₀ values was close to unity in all cases. The doses required to induce statistically significant miosis in the absence of phenylephrine were 30- to 100-fold higher than those inhibiting phenylephrine-induced mydriasis for all antagonists, except for naftopidil. Moreover, the miotic effects of all α₁-adrenoceptor antagonists were fully reversible within 8 h. We conclude that alfuzosin, doxazosin, naftopidil, prazosin, tamsulosin and terazosin inhibit phenylephrine-induced mydriasis in the same dose range as they inhibit elevations in IUP. Higher doses of all antagonists are required to induce miosis in the absence of an exogenous agonist, and such miosis is always reversible within hours.     

A tumor metastasis‐associated molecule TWIST1 is a favorable target for cancer immunotherapy due to its immunogenicity

Although neoantigens are one of the most favorable targets in cancer immunotherapy, it is less versatile and costly to apply neoantigen‐derived cancer vaccines to patients due to individual variation. It is, therefore, important to find highly immunogenic antigens between tumor‐specific or associated antigens that are shared among patients. Considering the cancer immunoediting theory, immunogenic tumor cells cannot survive in the early phase of tumor progression including two processes: elimination and equilibrium. We hypothesized that highly immunogenic molecules are allowed to be expressed in tumor cells after an immune suppressive tumor microenvironment was established, if these molecules contribute to tumor survival. In the current study, we focused on TWIST1 as a candidate for highly immunogenic antigens because it is upregulated in tumor cells under hypoxia and promotes tumor metastasis, which is observed in the late phase of tumor progression. We demonstrated that TWIST1 had an immunogenic peptide sequence TWIST1_140–162, which effectively activated TWIST1‐specific CD4⁺ T‐cells. In a short‐term culture system, we detected more TWIST1‐specific responses in breast cancer patients compared with in healthy donors. Vaccination with the TWIST1 peptide also showed efficient expansion of TWIST1‐reactive HTLs in humanized mice. These findings indicate that TWIST1 is a highly immunogenic shared antigen and a favorable target for cancer immunotherapy.     

The current status of perioperative chemotherapy for invasive bladder cancer: a multiinstitutional retrospective study in Japan

Background We conducted a multiinstitutional analysis to clarify the clinical significance of perioperative chemotherapy, in invasive bladder cancers in Japan, and to identify the patient subpopulations who could benefit from perioperative chemotherapy.Methods A total of 913 consecutive patients aged less than 80 years who underwent radical cystectomy for invasive bladder cancer from 1990 to 2000 at 32 Japanese hospitals were retrospectively analyzed. Median follow-up was 3.8 years (range, 0.1 to 11.8 years).Results In total, 341 patients (37.3%) were treated with perioperative chemotherapy, including neoadjuvant chemotherapy (n = 174), adjuvant chemotherapy (n = 114), or a combination of both chemotherapies (n = 53). With cisplatin-based combination chemotherapy, the MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) regimen was the one most frequently used for perioperative chemotherapy, but the average number of cycles was distinctly less than that in reported randomized trials. MEC (methotrexate, epirubicin, and cisplatin) chemotherapy had efficacy similar to that of the MVAC regimen. On analysis of patients stratified by stage, the overall survival of patients with adjuvant chemotherapy was significantly better than that of those without adjuvant chemotherapy, in patients with pT2b, pN0 or pT3, pN0 (P = 0.016 or 0.020, respectively), but adjuvant chemotherapy had no, or the opposite, effect on patients with pT2a, pN0, pT4, pN0, or pTany, pN+. On the other hand, neoadjuvant chemotherapy provided a statistically significant survival benefit only for patients with clinical T3N0 (P = 0.015). Of note, in the high-risk subgroup, the overall survival rate for patients with complete response (CR) after neoadjuvant chemotherapy was significantly better than that of patients with partial response (PR) or no change (NC)/progressive disease (PD) (P = 0.043).Conclusion In Japan, cisplatin-based combination chemotherapy has been the main modality adopted perioperatively for high-risk patients with radical cystectomy. This studys clinical results indicated that perioperative chemotherapy may improve survival in patients with T3N0 or pT2b/pT3, pN0 bladder cancer.     

Hypoxic status in ovarian serous and mucinous tumors: relationship between histological characteristics and HIF-1α/GLUT-1 expression

Material and methods We analyzed the expression of hypoxia inducible factor-1α (HIF-1α) and glucose transporter-1 (GLUT-1) by immunohistochemistry in ovarian serous and mucinous tumors from the point view of the histological characteristics and acquisition of malignancy. A total of 102 ovarian tumors were examined, composed of 31 adenomas (serous 17 and mucinous 14), 32 borderline tumors (serous 13 and mucinous 19), and 39 adenocarcinomas (serous 21 and mucinous 18). Results The overall positive ratios were as follows: HIF-1α, 74% of adenomas, 91% of borderline tumors, and 100% of adenocarcinomas; and GLUT-1, 68% of adenomas, 95% of borderline tumors, and 100% of adenocarcinomas. Comparing serous tumors and mucinous tumors, there was no significant difference in the positive ratios of HIF-1α and GLUT-1 of adenomas, borderline tumors, and adenocarcinomas. However, both markers were more strongly expressed in serous adenocarcinomas (HIF-1α, 3 + 100%; GLUT-1, 3 + 76%) than in mucinous adenocarcinomas (HIF-1α, 3 + 61%; GLUT-1, 3 + 28%). The results of immunoblotting and mRNA expression level analyses corresponded with those of immunohistochemical expression profiles. DNA binding assay also demonstrated that HIF-1 is more commonly activated in serous adenocarcinomas than in mucinous adenocarcinomas. Conclusion HIF-1α and GLUT-1 expressions seemed to be coordinated to adapt ovarian tumor cells into hypoxic conditions in close association with the acquisition of malignancy. We consider that the relatively strong expression of both markers in serous tumors compared with mucinous tumors is related to the difference in their histological characteristics.     

Detection of SYT-SSX fusion transcripts in paraffin-embedded tissues of syno vial sarcoma by reverse transcription-polymerase chain reaction

目的　探讨用逆转录 聚合酶链反应 (RT PCR)技术检测滑膜肉瘤石蜡包埋组织中SYT SSX融合基因的可行性。方法　我们采用RT PCR方法对 37例福尔马林固定、石蜡包埋的滑膜肉瘤组织中SYT SSX融合基因转录本进行了检测。为探讨SYT SSX融合基因对滑膜肉瘤的特异性 ,一系列非滑膜肉瘤的肿瘤标本作为阴性对照。融合基因检测结果用测序的方法进行了证实。结果　 37例滑膜肉瘤中 33例 (89 2 % )可检测出SYT SSX融合基因。 34例非滑膜肉瘤的肿瘤标本中均未显示SYT SSX融合基因产物扩增信号。此 34例标本中均可检测到PBGDmRNA表达。 33例SYT SSX阳性滑膜肉瘤中 ,SYT SSX1阳性 2 2例 ,SYT SSX2阳性 6例 ,其余 5例无法区分融合基因类型。融合基因类型与组织学亚型间存在相关性。所有 10例双相型滑膜肉瘤均为SYT SSX1型 ,而所有SYT SSX2阳性滑膜肉瘤均为单相型 (P <0 0 5 )。结论　我们的结果提示 ,RT PCR技术可以用于存档的福尔马林固定、石蜡包埋组织 ,作为滑膜肉瘤诊断和鉴别诊断敏感而且可靠的技术。SYT SSX融合基因类型与组织学亚型间存在相关性。SYT SSX2型仅见于单相型滑膜肉瘤。     

The Impact of Purple-Flesh Potato (Solanum tuberosum L.) cv. “Shadow Queen” on Minor Health Complaints in Healthy Adults: A Randomized,Double-Blind,Placebo-Controlled Study

The purple-flesh potato (Solanum tuberosum L.) cultivar “Shadow Queen” (SQ) naturally contains anthocyanins. This randomized, double-blind, placebo-controlled study determines whether ingesting purple potatoes increases the number of mesenchymal stem cells (MSC) and improves stress response, a minor health complaint in healthy adults (registration number: UMIN000038876). A total of 15 healthy subjects (ages: 50–70 years) with minor health complaints were randomly assigned to one of two groups. For 8 weeks, the placebo group received placebo potatoes cv. “Haruka” and the test group received test potato cv. SQ containing 45 mg anthocyanin. The MSC count and several stress responses were analyzed at weeks 0 and 8 of the intake periods. The ingestion of a SQ potato did not affect the MSC count but markedly improved psychological stress response, irritability, and depression as minor health complaints compared with “Haruka”. No adverse effects were noted. Hence, an 8-week intake of SQ could improve stress responses.     

The clinical relevance of unfolded protein response signaling in breast cancer

Protein homeostasis regulated by the Endoplasmic Reticulum (ER) is a recognized process involved in cancer progression. ER stress activates the Unfolded Protein Response (UPR) and has been implicated in a variety of cancers. Given the role of the UPR activation in carcinogenesis, we hypothesized that UPR activation could be associated with pathological progression, higher clinical stage, and worse survival in breast cancer. A total of 4,416 breast cancer patients from multiple independent cohorts were analyzed. We defined the UPR pathway score by the degree of enrichment by Gene Set Variant Analysis and median was used to divide high vs. low score groups in each cohort. High UPR breast cancer significantly enriched not only cell proliferation-related but also other pro-cancerous gene sets consistently in both METABIC and {"type":"entrez-geo","attrs":{"text":"GSE96058","term_id":"96058"}}GSE96058 cohort. Majority of UPR pathway score high cells in the bulk tumor were tumor cells compared to other cells, including stromal, T-, B-, and myeloid-cells (P<0.001). UPR score was significantly associated with advanced stage, high grade, and triple negative breast cancer (TNBC) (all P<0.001). High UPR breast cancer was associated with worse patient survival in both cohorts (all P<0.001). Among breast cancer subtype, ER-positive/HER2-negative breast cancer with high UPR was significantly associated with worse survival, but neither HER-positive nor TNBC. High UPR ER-positive/HER2-negative breast cancer was infiltrated with high level of Th1 and Th2 cells, M1 macrophage, and plasma cells. On the other hand, they were significantly infiltrated with high level of several types of stromal cells in tumor microenvironment (all P<0.001). Finally, high UPR metastatic breast cancer was also associated with worse patient survival (P=0.041). UPR signaling is associated with cancer aggressiveness, and worse survival, especially ER-positive/HER2-negative breast cancer subtype.     

Fatty liver with metabolic disorder,such as metabolic dysfunction‐associated fatty liver disease,indicates high risk for developing diabetes mellitus

IntroductionNonalcoholic fatty liver disease (NAFLD) is diagnosed after excluding other liver diseases. The pathogenesis of NAFLD when complicated by other liver diseases has not been established completely. Metabolic dysfunction‐associated fatty liver disease (MAFLD) involves more metabolic factors than NAFLD, regardless of complications with other diseases. This study aimed to clarify the effects of fatty liver occurring with metabolic disorders, such as MAFLD without diabetes mellitus (DM), on the development of DM.Materials and MethodsWe retrospectively assessed 9,459 participants who underwent two or more annual health check‐ups. The participants were divided into the MAFLD group (fatty liver disease with overweight/obesity or non‐overweight/obesity complicated by metabolic disorders), simple fatty liver group (fatty liver disease other than MAFLD group), metabolic disorder group (metabolic disorder without fatty liver disease), and normal group (all other participants).ResultsThe DM onset rates in the normal, simple fatty liver, metabolic disorder, and MAFLD groups were 0.51, 1.85, 2.52, and 7.36%, respectively. In the multivariate analysis, the MAFLD group showed a significantly higher risk of DM onset compared with other three groups (P < 0.01). Additionally, the risk of DM onset was significantly increased in fatty liver disease with overweight/obesity or pre‐diabetes (P < 0.01).ConclusionsFatty liver with metabolic disorders, such as MAFLD, can be used to identify patients with fatty liver disease who are at high risk of developing DM. Additionally, patients with fatty liver disease complicated with overweight/obesity or prediabetes are at an increased risk of DM onset and should receive more attention.     

Secondary arteriovenous malformation due to subclavian vein occlusion

An 80-year-old man underwent rectal resection and insertion of a central venous catheter through the left subclavian vein 16 years earlier. Following surgery, he developed edema of his left upper limb that became exacerbated and infected. Computed tomography showed occlusion of the subclavian vein and multiple arteriovenous shunts from the branches of the axillary artery to the venous sac of the axillary vein. Angiography confirmed numerous shunts between the branches of the axillary artery and vein and dilated collateral veins. Embolization of the venous sac was performed using coils, alcohol, and glue. Postprocedural angiography showed complete eradication of the nidus.     

SAMP8 mice as a neuropathological model of accelerated brain aging and dementia: Toshio Takeda's legacy and future directions

Senescence accelerated mice P8 (SAMP8) show significant age‐related deteriorations in memory and learning ability in accordance with early onset and rapid advancement of senescence. Brains of SAMP8 mice reveal an age‐associated increase of PAS‐positive granular structures in the hippocampal formation and astrogliosis in the brain stem and hippocampus. A spongy degeneration in the brain stem appears at 1 month of age and reaches a maximum at 4‐8 months. In addition, clusters of activated microglia also appear around the vacuoles in the brain stem. β/A4(Aβ) protein‐like immunoreactive granular structures are observed in various regions and increase in number markedly with age. Other age‐associated histological changes include cortical atrophy, neuronal cell loss in locus coeruleus and lateral tegmental nuclei, intraneuronal accumulation of lipopigments in Purkinje cells and eosinophilic inclusion bodies in thalamic neurons. A blood–brain barrier dysfunction and astrogliosis are also prominent with advancing age in the hippocampus. These changes are generally similar to the pathomorphology of aging human brains and characterized by their association with some specific glioneuronal reactions. As for the hallmarks of Alzheimer brains, tau morphology has not yet been confirmed regardless of the age‐related increase in phosphorylated tau in SAMP8 mice brains, but early age‐related Aβ deposition in the hippocampus has recently been published. SAMP8 mice are, therefore, not only a senescence‐accelerated model but also a promising model for Alzheimer's disease and other cognitive disorders.