Feasibility of a self‐assembling peptide hydrogel scaffold for meniscal defect: An in vivo study in a rabbit model

The inner avascular zone of the meniscus has limited healing capacity as the area is poorly vascularized. Although peptide hydrogels have been reported to regenerate bone and cartilage, their effect on meniscus regeneration remains unknown. We tested whether the self‐assembling peptide hydrogel scaffold KI24RGDS stays in the meniscal lesion and facilitates meniscal repair and regeneration in an induced rabbit meniscal defect model. Full‐thickness (2.0 mm diameter) cylindrical defects were introduced into the inner avascular zones of the anterior portions of the medial menisci of rabbit knees (n = 40). Right knee defects were left empty (control group) while the left knee defects were transplanted with peptide hydrogel (KI24RGDS group). Macroscopic meniscus scores were significantly higher in the KI24RGDS group than in the control group at 2, 4, and 8 weeks after surgery. Histological examinations including quantitative and qualitative scores indicated that compared with the control group, the reparative tissue in the meniscus was significantly enhanced in the KI24RGDS group at 2, 4, 8, and 12 weeks after surgery. Immunohistochemical staining showed that the reparative tissue induced by KI24RGDS at 12 weeks postimplantation was positive for Type I and II collagen. KI24RGDS is highly biocompatible and biodegradable, with strong stiffness, and a three dimensional structure mimicking native extracellular matrix and RGDS sequences that enhance cell adhesion and proliferation. This in vivo study demonstrated that KI24RGDS remained in the meniscal lesion and facilitated the repair and regeneration in a rabbit meniscal defect model.     

Potential predictors of the onset of focal intestinal perforation in extremely low birth weight infants based on an analysis of coagulation and fibrinolysis markers at birth: A case-control study based on ten years of experience at a single institution

Purpose: We aimed to investigate potential predictors of focal intestinal perforation (FIP) in extremely low birth weight infants (ELBWIs) among coagulation and fibrinolysis markers at birth.Methods: We reviewed the medical records of FIP patients and their coagulation and fibrinolysis markers at birth between 2010 and 2019, and matched patients according to gestational age. FIP was diagnosed based on macroscopic intestinal perforation with a punched-out lesion without necrosis. Patient characteristics and blood test results, including coagulation and fibrinolysis marker levels, were compared between the groups.Results: Two hundred forty ELBWIs were enrolled in this study (FIP, n = 18; controls, n = 222). In the FIP group, the gestational age at birth was significantly younger (p = 0.023) and the birth weight was significantly lower (p = 0.007) in comparison to the control group. Furthermore, the FIP group showed significantly lower levels of fibrinogen (p = 0.027) and factor XIII (F-XIII) (p = 0.007). The receiver operating characteristics curves for fibrinogen and F-XIII revealed that the 95% confidence intervals of fibrinogen and F-XIII were 0.530–0.783 (p = 0.027), and 0.574–0.822 (p = 0.007), respectively.Conclusions: This is the first report focusing on coagulation and fibrinolysis markers in FIP patients at birth. The fibrinogen and F-XIII values at birth are potential predictors of FIP in ELBWIs.Type of Study: Study of Diagnostic Test (Case Control Study)Level of Evidence: Level IV     

Treatment results of radiotherapy to both the prostate and metastatic sites in patients with bone metastatic prostate cancer

Although systemic therapy is the standard treatment for metastatic prostate cancer, a randomized controlled trial showed radiotherapy to the prostate improved overall survival of metastatic prostate cancer patients with the low metastatic burden. Additionally, a randomized phase II trial showed that metastasis-directed therapy for oligo-recurrent prostate cancer improved androgen-deprivation therapy (ADT)-free survival. Therefore, administering radiotherapy to both prostate and metastatic regions might result in better outcomes. Thus, we report the treatment results of radiotherapy to both prostate and metastatic regions. Our institutional database was searched for patients who received radiotherapy to the prostate and metastatic regions. We summarized patient characteristics and treatment efficacy and performed statistical analysis to find possible prognostic factors. A total of 35 patients were included in this study. The median age was 66 years, and the median initial prostate-specific antigen (PSA) level was 32 ng/ml. The Gleason score was 7 in 10 patients, 8 in 13 patients, and 9 in 12 patients. The median radiotherapy dose was 72 Gy to the prostate and 50 Gy to the metastatic bone region. The 8-year overall survival, cause-specific survival, progression-free survival, and freedom from biochemical failure rate were 81, 85, 53, and 57%. Among the 35 patients, 12 were disease-free even after ADT was discontinued. In selected patients with metastatic prostate cancer, ADT and radiotherapy to the prostate and metastatic sites were effective. Patients with good response to ADT may benefit from radiotherapy to both prostate and metastatic regions.     

VAMP2 is expressed in myogenic cells during rat development

Vesicle-associated membrane protein 2 (VAMP2) is a member of the SNARE family of proteins that regulate the intracellular vesicle fusion process. This study investigated the developmental expression of VAMP2 in the rat embryo. In the trunk, VAMP2 was primarily found in the heart on embryonic day (E) 10. On E12.5, VAMP2 expression was found in nerve fibers, somites, and heart. In somites, epithelial cells in the dorsomedial lip, and elongated myoblasts in myotome were positive for VAMP2. On E16.5, VAMP2 was expressed in the heart, nerve fibers, and skeletal muscles. In skeletal muscles, multinuclear myotubes were positive for VAMP2. In the head, where muscles are derived both from somitic and non-somitic origin, VAMP2 was found in myotubes of the extrinsic ocular muscles and masseter muscle on E16.5. These findings suggest the involvement of VAMP2 in the development of skeletal muscles of somitic and non-somitic origins.     

GM-CSF-producing CCR2+CCR6+ Th17 cells are pathogenic in dextran sodium sulfate-induced colitis model in mice

Although excessive immune responses by Th17 cells, a helper T cell subset, are implicated in the pathogenesis of inflammatory bowel disease (IBD), the mechanism by which its localization in an inflamed colon is regulated remains unclear. Chemokines and their receptors are involved in the pathogenesis of IBD, however, the relative significance of each receptor on Th17 cells remains unknown. We generated C–C motif chemokine receptor 2 (CCR2) knockout (KO) and CCR6 KO mice in the syngeneic background using the CRISPR/Cas9 system and found that the phenotypes of experimental colitis worsened in both mutant mice. Surprisingly, the phenotype of colitis in CCR2/CCR6-double knockout (CCR2/6 DKO) mice was opposite to that of the single-deficient mice, with significantly milder experimental colitis (p < .05). The same was true for the symptoms in CCR6 KO mice, but not in wild type mice treated with a CCR2 inhibitor, propagermanium. Colonic CCR2⁺CCR6⁺ Th17 cells produced a potentially pathogenic cytokine GM-CSF whose levels in the gut were significantly reduced in CCR2/6 DKO mice (p < .05). These results suggest that GM-CSF-producing CCR2⁺CCR6⁺ Th17 cells are pathogenic and are attracted to the inflamed colon by either CCR2 or CCR6 gradient, which subsequently exacerbates experimental colitis in mice.     

A combination therapy with mitomycin c, etoposide, doxifluridine and medroxyprogesterone acetate as second line therapy for advanced breast cancer refractory to combination chemotherapy of cyclophosphamide, doxorubicin and 5 fluorouracil

Thirty-two patients with advanced breast cancer refractory to combination chemotherapy with cyclophosphamide (CPA), doxorubicin (ADR) and 5-fluorouracil (5-FU) (CAF) were treated with the combination of mitomycin C, etoposide, doxifluridine and medroxyprogesterone acetate as second line therapy. Observed responses included 6 patients (18.7%) with complete response (CR) and 7 (21.9%) with partial response (PR). Two (50%) out of 4 patients who had bone pain due to bone metastasis noted pain relief. CR or PR were obtained in 4 out of 12 patients who had not responded to the previous CAF therapy. While grade III myelosuppression was observed in 3 patients, other adverse effects were minimal. It is suggested that this combination therapy may be recommended for advanced breast cancer patients as a second therapy.     

Further analysis of the relationship between the epidemiological and hormonal aspects of 6 human neoplasias with special emphasis on the presentation of the topological features of oncogene activation tumor suppressor gene inactivation of individual neoplasias

The purpose of this study was to test the validity of the steroid carcinogenesis hypothesis by comparatively investigating the endocrinological and epidemiological aspects of cancers of the breast, uterine cervix, endometrium, stomach, esophagus and ovary. The emphasis of this study was placed on the extraction of the information on the topological feature of oncogene activation-tumor suppressor gene inactivation for each of 6 neoplasias using the data stock of the age-adjusted incidence rates (AAIRs) of 19 neoplasias from 47 population units of the world. Our investigation was started on the basis of the recognition that the world statistics data of cancer risk should include information on the interaction of oncogene activation-tumor suppressor gene inactivation for each human neoplasia, and that the sophisticated application of statistical analysis technics may allow us to assess separately the implications of oncogene activation and tumor suppressor gene inactivation in the genesis of a given neoplasia. In designing mathematical strategies, we had in mind the premise that oncogene activation and tumor suppressor gene inactivation represent 2 distinct entities in the world of chemistry, and that they should have each their own equilibrium models with 2 distinct equilibrium points. The details of the mathematical principles and procedures are presented in the text. The results were as follows: i) There was a good agreement of results between the observed value and the expected value of thermodynamics as regards the location of the equilibrium point in both instances - a finding to support the validity of our mathematical strategies. ii) One of our mathematical strategies (the use of the original coordinates and its variant coordinates in parallel) was found to be useful for assessing separately the implication of oncogene activation (the original coordinates) and that of tumor suppressor gene inactivation (the variant coordinates). iii) The correlation study of the endocrinological data with the epidemiological data in breast cancer strongly suggests the possibility that sex steroid may play a cardinal role in the oncogene activation at the initiation step of breast carcinogenesis. iv) Evidence is available to indicate that glucocorticoid under certain circumstances may play a crucial role in the process of tumor suppressor gene inactivation at the promotion step of breast carcinogenesis. v) The philosophical distinction between the steroid carcinogenesis theory and the random mutation criminal theory of carcinogenesis is discussed in the light of recent information on chemical carcinogenesis.     

Accumulation of L-[2-(F-18)]fluorophenylalanine in peri-infarct area in a patient with acute cerebral infarction

We studied the brain uptake of amino acid in a patient with acute cerebral infarction with L-[2-(F-18)] fluorophenylalanine and positron emission tomography. The increased accumulation of the ligand was specifically found in the peri-infarct area where oxygen metabolism was still maintained but decreased later in the 72-day follow-up period. The kinetic analysis revealed that increased accumulation was not due to increased transport from the blood to the brain but to delayed washout from the brain to the blood. Although the mechanism is still unknown, abnormally high accumulation of L-[F-18]fluorophenylalanine may predict delayed neuronal changes after ischemic insults of the brain.     

Mos positively regulates Xe-Wee1 to lengthen the first mitotic cell cycle of Xenopus

Several key developmental events occur in the first mitotic cell cycle of Xenopus; consequently this cycle has two gap phases and is approximately 60-75 min in length. In contrast, embryonic cycles 2-12 consist only of S and M phases and are 30 min in length. Xe-Wee1 and Mos are translated and degraded in a developmentally regulated manner. Significantly, both proteins are present in the first cell cycle. We showed previously that the expression of nondegradable Mos, during early interphase, delays the onset of M phase in the early embryonic cell cycles. Here we report that Xe-Wee1 is required for the Mos-mediated M-phase delay. We find that Xe-Wee1 tyrosine autophosphorylation positively regulates Xe-Wee1 and is only detected in the first 30 min of the first cell cycle. The level and duration of Xe-Wee1 tyrosine phosphorylation is elevated significantly when the first cell cycle is elongated with nondegradable Mos. Importantly, we show that the tyrosine phosphorylation of Xe-Wee1 is required for the Mos-mediated M-phase delay. These findings indicate that Mos positively regulates Xe-Wee1 to generate the G2 phase in the first cell cycle and establish a direct link between the MAPK signal transduction pathway and Wee1 in vertebrates.