No abstract

Phagocytosis of apoptotic cells by myeloid cells has been implicated in the maintenance of immune homeostasis. In this study, we found that T cell immunoglobulin- and mucin domain-containing molecule-4 (TIM-4) repressed tumor-specific immunity triggered by chemotherapy-induced tumor cell death. TIM-4 was found to be highly expressed on tumor-associated myeloid cells such as macrophages (TAMs) and dendritic cells (TADCs) and danger-associated molecular patterns (DAMPs) released from chemotherapy-damaged tumor cells induced TIM-4 on tumor-associated myeloid cells recruited from bone marrow-derived precursors. TIM-4 directly interacted with AMPKα1 and activated autophagy-mediated degradation of ingested tumors, leading to reduced antigen presentation and impaired CTL responses. Consistently, blockade of the TIM-4-AMPKα1-autophagy pathway augmented the antitumor effect of chemotherapeutics by enhancing tumor-specific CTL responses. Our finding provides insight into the immune tolerance mediated by phagocytosis of dying cells, and targeting of the TIM-4-AMPKα1 interaction constitutes a unique strategy for augmenting antitumor immunity and improving cancer chemotherapy.

The molecular mechanism by which sperm triggers Ca 2C oscillation, oocyte activation, and early embryonic development has not been clarified. Recently, oocyte activation has been shown to be induced by sperm-specific phospholipase Cz (PLCz). The ability of PLCz to induce oocyte activation is highly conserved across vertebrates. In the present study, porcine PLCz cDNA was identified and the nucleotide sequence was determined. The expression pattern of porcine PLCz mRNA during the period of postnatal testicular development was shown to be similar to that of mouse PLCz. PLCz mRNA expression in the pig and mouse was detected only in the testes when the elongated spermatids had differentiated, and was detected from day 96 after birth in the pig. Histological examination of porcine testis during the period of postnatal development revealed the presence of spermatozoa from day 110 after birth. These findings suggest that the synthesis of PLCz mRNA starts when spermiogenesis is initiated. Microinjection of porcine PLCz complementary RNA into porcine oocytes demonstrated that porcine PLCz has the ability to trigger repetitive Ca 2C transients in porcine oocytes similar to that observed during fertilization. It was also found that porcine PLCz cRNA has the potential to induce oocyte activation and initiate embryonic development up to the blastocyst stage.

Summary:A 5-year-old boy received CD34-positive HLA haploidentical bone marrow transplantation from his father as treatment for refractory advanced neuroblastoma. He had residual disease in the para-aortic lymph nodes and multiple bones after the transplant. However, all of his residual disease had disappeared completely 3 years later. He developed grade I acute graft-versus-host disease (GVHD) but had no symptoms of chronic GVHD or any other complications. This case demonstrates the possibility of a graft-versus-tumor effect against neuroblastoma by HLA-mismatched allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplantation (2003) 32, 103-106. doi:10.1038/sj.bmt.1704070 Keywords: neuroblastoma; CD34; graft-versus-tumorThe therapeutic effect of donor lymphocyte infusion (DLI) for relapsed CML after allogeneic bone marrow transplantation (BMT) has been established, 1 and the immunotherapeutic aspect of allogeneic hematopoietic stem cell transplantation (HSCT) has recently been emphasized, especially since the introduction of a reduced-intensity preparative regimen followed by allogeneic HSCT. Successful nonmyeloablative allogeneic PBSCT for metastatic renal cell carcinoma was reported by Childs et al. 2Although similar trials have been ongoing for many kinds of solid tumors, 3 a graft-versus-tumor (GVT) effect against neuroblastoma (NBL) has not been reported. We describe a patient with refractory advanced NBL who showed tumor regression over 3 years after allogeneic SCT, despite persistent metastatic lesions after SCT. This is the first case suggesting a GVT effect in neuroblastoma. Case reportA 4-year-old boy was diagnosed with stage 4 NBL (INSS: international neuroblastoma staging system) involving his right adrenal gland, multiple para-aortic lymph nodes, bone marrow and multiple bones in April 1997. Tumor markers were abnormally elevated at the diagnosis. Urinary vanillymandelic acid (VMA) and homovanillic acid (HVA) were 313.6 (upper limit 16.0) and 251.0 (upper limit 35.0) mg/mg creatinine, respectively. Serum neuron-specific enolase (NSE) was beyond the range of measurement (41000 ng/ml, upper limit 10.0). The response for induction chemotherapy (modified A1: 4 vincristine, cyclophosphamide, pirarubicin and cisplatin, CPT-11) was partial and double megatherapy was performed (Figure 1) according to our strategy. The first megatherapy, consisting of ifosfamide (12.5 g/m 2 ) and LPAM (210 mg/m 2 ) followed by autologous CD34-positive BM cell rescue, was given in November 1997. CD34-positive cells were collected by the Isolex system (NEXELL, Deerfield, IL, USA) and cryopreserved during repeated first-line chemotherapy aimed at purging of tumor cells. Extirpation of the primary tumor with ipsilateral nephrectomy and biopsy of the para-aortic lymph nodes and a bone marrow were carried out after the first megatherapy in December 1997. Viable NBL cells were found histologically in the resected tumor, sampled lymph nodes and a bone specimen. Prognostic evaluations of the resected tumors were as ...

Background: Vesicoureteric reflux (VUR) is the retrograde flow of urine from the bladder into the ureters. It is the most common urological anomaly in children, and a major cause of end-stage renal failure and hypertension in both children and adults. VUR is seen in approximately 1-2% of Caucasian newborns and is frequently familial. Objective and methods: In order to search for genetic loci involved in VUR, we performed a genome-wide linkage scan using 4710 single-nucleotide polymorphisms (SNPs) in 609 individuals from 129 Irish families with .1 affected member. Results: Nonparametric linkage (NPL) analysis of the dataset yielded moderately suggestive linkage at chromosome 2q37 (NPL max = 2.67, p,0.001). Analysis of a subset without any additional features, such as duplex kidneys, yielded a maximum NPL score of 4.1 (p = 0.001), reaching levels of genome-wide statistical significance. Suggestive linkage was also seen at 10q26 and 6q27, and there were several smaller peaks. Conclusion: Our results confirm the previous conclusion that VUR is genetically heterogeneous, and support the identification of several disease-associated regions indicated by smaller studies, as well as indicating new regions of interest for investigation.

The administration of rikkunshito resulted in symptomatic relief and improved gastric emptying in profoundly handicapped patients with delayed gastric emptying.

Resistance to anticancer therapeutics greatly affects the phenotypic and functional properties of tumor cells, but how chemoresistance contributes to the tumorigenic activities of cancer stem-like cells remains unclear. In this study, we found that a characteristic of cancer stem-like cells from chemoresistant tumors (CSC-R) is the ability to produce a variety of proinflammatory cytokines and to generate M2-like immunoregulatory myeloid cells from CD14 þ monocytes. Furthermore, we identified the IFN-regulated transcription factor IRF5 as a CSC-Rspecific factor critical for promoting M-CSF production and generating tumorigenic myeloid cells. Importantly, myeloid cells primed with IRF5 þ CSC-R facilitate the tumorigenic and stem cell activities of bulk tumors.Importantly, the activation of IRF5/M-CSF pathways in tumor cells were correlated with the number of tumorassociated CSF1 receptor þ M2 macrophages in patients with non-small lung cancer. Collectively, our findings show how chemoresistance affects the properties of CSCs in their niche microenvironments. Cancer Res; 74(10); 2698-709. Ó2014 AACR.

No abstract