A use-case analysis of Clinical Data Interchange Standards Consortium/Study Data Tabulation Model in academia in an investigator-initiated clinical trial.

Submitting data compliant with the Clinical Data Interchange Standards Consortium (CDISC) standards is mandatory for new drug applications (NDAs). The standards set by CDISC are widely adopted in the pharmaceutical business world. Introduction of CDISC standards in academia can be necessary to reduce labor, resolve the shortage of data managers in academia, and gain new knowledge through standardized data accumulation. However, the introduction of CDISC standards has not progressed in communities within the academia that do not apply for NDAs. Therefore, herein, we created study data tabulation model (SDTM)-compliant datasets within the academia, without outsourcing, to reduce costs associated with investigator-initiated clinical trials. First, we input data from paper case report forms (CRFs) into an electronic data capture system with minimal function for paper CRFs, "Ptosh," which is compatible with SDTM. Then, we developed a generic program to convert data exported from Ptosh into fully SDTM-compliant datasets. The consistency was then verified with an SDTM validator, Pinnacle21 Community V3.0.1 (P21C). This resulted in generation of SDTM datasets, resolving all "Rejects" in P21C, thereby achieving the required quality level. Although Ptosh directly exports data in SDTM format, manual mapping of items on CRFs to SDTM variables prepared in Ptosh is necessary. SDTM mapping requires extensive knowledge and skills, and it was assumed that mapping is challenging for the staff without in-depth knowledge of CDISC standards and datasets. Therefore, for CDISC dissemination in academia, it is crucial to secure the staff, time, and funding to acquire the knowledge.

Clinical and genetic diagnosis of thirteen Japanese patients with hereditary spherocytosis.

Hereditary spherocytosis is the most frequent cause of hereditary hemolytic anemia and is classified into five subtypes (SPH1-5) according to OMIM. Because the clinical and laboratory features of patients with SPH1-5 are variable, it is difficult to classify these patients into the five subtypes based only on these features. We performed target capture sequencing in 51 patients with hemolytic anemia associated with/without morphological abnormalities in red blood cells. Thirteen variants were identified in five hereditary spherocytosis-related genes (six in ANK1 [SPH1]; four in SPTB [SPH2]; and one in each of SPTA1 [SPH3], SLC4A1 [SPH4], and EPB42 [SPH5]). Among these variants, seven were novel. The distribution pattern of the variants was different from that reported previously in Japan but similar to those reported in other Asian countries. Comprehensive genomic analysis would be useful and recommended, especially for patients without a detailed family history and those receiving frequent blood transfusions due to chronic hemolytic anemia.

Identification of stomatal-regulating molecules from de novo arylamine collection through aromatic C-H amination.

Stomata-small pores generally found on the leaves of plants-control gas exchange between plant and the atmosphere. Elucidating the mechanism that underlies such control through the regulation of stomatal opening/closing is important to understand how plants regulate photosynthesis and tolerate against drought. However, up-to-date, molecular components and their function involved in stomatal regulation are not fully understood. We challenged such problem through a chemical genetic approach by isolating and characterizing synthetic molecules that influence stomatal movement. Here, we describe that a small chemical collection, prepared during the development of C-H amination reactions, lead to the discovery of a Stomata Influencing Molecule (SIM); namely, a sulfonimidated oxazole that inhibits stomatal opening. The starting molecule SIM1 was initially isolated from screening of compounds that inhibit light induced opening of dayflower stomata. A range of SIM molecules were rapidly accessed using our state-of-the-art C-H amination technologies. This enabled an efficient structure-activity relationship (SAR) study, culminating in the discovery of a sulfonamidated oxazole derivative (SIM*) having higher activity and enhanced specificity against stomatal regulation. Biological assay results have shed some light on the mode of action of SIM molecules within the cell, which may ultimately lead to drought tolerance-conferring agrochemicals through the control of stomatal movement.

Free moment induced by oblique transverse tarsal joint: investigation by constructive approach.

The human foot provides numerous functions that let humans deal with various environments. Recently, study of the structure of the human foot and adjustment of an appropriate reaction force and vertical free moment during bipedal locomotion has gained attention. However, little is known about the mechanical (morphological) contribution of the foot structure to the reaction force and free moment. It is difficult to conduct a comparative experiment to investigate the contribution systematically by using conventional methods with human and cadaver foot experiments. This study focuses on the oblique transverse tarsal joint (TTJ) of the human foot, whose mechanical structure can generate appropriate free moments. We conduct comparative experiments with a rigid foot, a non-oblique joint foot (i.e. mimicking only the flexion/extension of the midfoot), and an oblique joint foot. Axial loading and walking experiments were conducted with these feet. The axial loading experiment demonstrated that the oblique foot generated free moment in the direction of internal rotation, as observed in the human foot. The walking experiment showed that the magnitude of the free moment generated with the oblique foot is significantly lower than that with the rigid foot during the stance phase. Using this constructive approach, the present study demonstrated that the oblique axis of the TTJ can mechanically generate free moments. This capacity might affect the transverse motion of bipedal walking.

Phase 1/2 study of alectinib in RET-rearranged previously-treated non-small cell lung cancer (ALL-RET).

BACKGROUND: Rearranged during transfection (RET) rearrangements occur in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib administered at doses of 300 mg and 600 mg twice daily (BID) is approved for. ALK: rearranged NSCLC in Japan and other countries, respectively. Since alectinib has activity against RET, we conducted a phase (P) 1/2 study of alectinib to determine its activity in Japanese patients with. RET: rearranged NSCLC. METHODS: This study was a single-arm, open-label, multi-institutional P1/2 trial. Previously treated patients with RET-rearranged NSCLC, screened by nation-wide network (LC-SCRUM-Japan), were recruited. In P1, alectinib (600 or 450 mg BID) was administered following a 3+3 design and its safety was assessed. During P2, alectinib was administered at the recommended dose (RD) determined in P1. The primary endpoint was the objective response rate (ORR) in RET inhibitor-naïve patients treated with the RD of alectinib. RESULTS: Thirty-four patients were administered alectinib. In cohort 1 (600 mg BID) of P1, we observed 5 dose-limiting toxicities (DLTs), including grade 3 rash and thromboembolic event, in 3 of 6 patients. In cohort 2 (450 mg BID), we observed no DLTs in 3 patients. Pharmacokinetic analysis revealed that AUC0-10 to 600 mg BID was higher than that previously reported in global trials. We determined 450 mg BID as the RD for P2. In 25 RET inhibitor-naïve patients, one achieved an objective response (4%) and 13 achieved disease control at 8 weeks (52%). The median progression-free survival (PFS) was 3.4 months (95% CI, 2.0-5.4), while the median overall survival was 19.0 months (5.4-NE). We observed grade 3 adverse events (AEs) (4%) including pneumonitis in P2. CONCLUSIONS: Alectinib exerts limited activity against RET-rearranged NSCLC. Further investigation to elucidate the mechanisms underlying sensitivity and resistance of RET inhibitors is required to improve outcomes for these patients.

Development of microstructured fish scale collagen scaffolds to manufacture a tissue-engineered oral mucosa equivalent.

The present study aimed to develop a more biomimetic tissue-engineered oral mucosa equivalent comprising 1% type I tilapia scale collagen scaffold having microstructures mimicking the dermal-epidermal junction of oral mucosa and oral keratinocytes as graft materials for human use. We designed four micropattern prototypes mimicking the dermal-epidermal junction. Using a semiconductor process and soft lithography, negative molds were fabricated to develop microstructures using both polydimethylsiloxane and silicon substrates. Micropattern configurations of dermal-epidermal junctions manufactured from fish collagen consisting of a fibril network using our micropatterning system were well preserved, although the internal fibril network of the pillar pattern was sparse. Mixing 1% chondroitin sulfate with the collagen matrix minimized tissue-engineered oral mucosa equivalent contraction. Histologic examinations showed a flattening of the vertical dimensions of all microstructures and expansion of their pitches, indicating changes in the originally designed configurations. Nonetheless, histologic examinations revealed that a fully differentiated and stratified epithelial layer was developed on all scaffolds, suggesting that the microstructured fish scale collagen scaffolds have potential in the manufacturing of tissue-engineered oral mucosa equivalents for clinical use; however, enhancement of the mechanical properties of micropatterns is required. Our micropatterning technology can also apply to the development of oral mucosa in vitro models.

Phase I study of vorinostat with gefitinib in BIM deletion polymorphism/epidermal growth factor receptor mutation double-positive lung cancer.

Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) harboring BIM deletion polymorphism (BIM deletion) have poor responses to EGFR TKI. Mechanistically, the BIM deletion induces preferential splicing of the non-functional exon 3-containing isoform over the functional exon 4-containing isoform, impairing TKI-induced, BIM-dependent apoptosis. Histone deacetylase inhibitor, vorinostat, resensitizes BIM deletion-containing NSCLC cells to EGFR-TKI. In the present study, we determined the safety of vorinostat-gefitinib combination and evaluated pharmacodynamic biomarkers of vorinostat activity. Patients with EGFR-mutated NSCLC with the BIM deletion, pretreated with EGFR-TKI and chemotherapy, were recruited. Vorinostat (200, 300, 400 mg) was given daily on days 1-7, and gefitinib 250 mg was given daily on days 1-14. Vorinostat doses were escalated based on a conventional 3 + 3 design. Pharmacodynamic markers were measured using PBMC collected at baseline and 4 hours after vorinostat dose on day 2 in cycle 1. No dose-limiting toxicities (DLT) were observed in 12 patients. We determined 400 mg vorinostat as the recommended phase II dose (RP2D). Median progression-free survival was 5.2 months (95% CI: 1.4-15.7). Disease control rate at 6 weeks was 83.3% (10/12). Vorinostat preferentially induced BIM mRNA-containing exon 4 over mRNA-containing exon 3, acetylated histone H3 protein, and proapoptotic BIMEL protein in 11/11, 10/11, and 5/11 patients, respectively. These data indicate that RP2D was 400 mg vorinostat combined with gefitinib in BIM deletion/EGFR mutation double-positive NSCLC. BIM mRNA exon 3/exon 4 ratio in PBMC may be a useful pharmacodynamic marker for treatment.

Abundant a proliferation-inducing ligand (APRIL)-producing macrophages contribute to plasma cell accumulation in immunoglobulin G4-related disease.

BACKGROUND: This study aimed to investigate the contribution of a proliferation-inducing ligand (APRIL), a member of the tumor necrosis factor (TNF) superfamily implicated in plasma cell survival, to the development of plasma cell-rich lesions in immunoglobulin G4-related disease (IgG4-RD). METHODS: We performed immunohistochemical staining for APRIL with Stalk-1 and Aprily-8 antibodies specifically recognizing APRIL-producing cells and secreted APRIL, respectively, in renal and submandibular lesions of IgG4-RD in comparison with those of Sjögren's syndrome and sialolithiasis. RESULTS: Numerous Stalk-1-positive APRIL-producing cells were detectable in lesions of IgG4-RD. These cells, identified as CD163-positive M2 macrophages, secreted APRIL that distributed close to and even on infiltrating plasma cells. In contrast, APRIL-producing cells and the secreted form of APRIL were rarely detectable in lesions of Sjögren's syndrome or sialolithiasis. Notably, APRIL expression decreased concomitantly with the level of plasma cell infiltration after successful glucocorticoid treatment. CONCLUSIONS: Abundant infiltration into tissue lesions of APRIL-producing M2 macrophages and retention of secreted APRIL in plasma-cell-rich areas support a role for APRIL in the pathogenesis of plasma cell-rich lesions in IgG4-RD.

Phase I/II study of alectinib in lung cancer with RET fusion gene: study protocol.

BACKGROUND: The rearranged during transfection (RET) fusion gene was discovered as a driver oncogene in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib is an approved anaplastic lymphoma kinase (ALK) inhibitor that may also be effective for RET fusion-positive NSCLC. METHODS/DESIGN: RET fusion-positive NSCLC patients treated with at least one regimen of chemotherapy are being recruited. In step 1, alectinib (600 or 450 mg, twice daily) will be administered following a 3+3 design. The primary endpoint is safety. In step 2, alectinib will be administered at the recommended dose (RD) defined by step 1. The primary endpoint is the response rate of RET inhibitor treatment-naïve patients. CONCLUSION: This is the first study to investigate the safety and preliminary efficacy of alectinib in RET fusion-positive NSCLC patients. If successful, alectinib treatment may lead to substantial and important changes in the management of NSCLC with RET fusion genes. J. Med. Invest. 64: 317-320, August, 2017.

Cu-Catalyzed aromatic C-H imidation with N-fluorobenzenesulfonimide: mechanistic details and predictive models.

The LCuBr-catalyzed C-H imidation of arenes by N-fluorobenzenesulfonimide (NFSI), previously reported by us, utilizes an inexpensive catalyst and is applicable to a broad scope of complex arenes. The computational and experimental study reported here shows that the mechanism of the reaction is comprised of two parts: (1) generation of the active dinuclear CuII-CuII catalyst; and (2) the catalytic cycle for the C-H bond imidation of arenes. Computations show that the LCuIBr complex used in experiments is not an active catalyst. Instead, upon reacting with NFSI it converts to an active dinuclear CuII-CuII catalyst that is detected using HRMS techniques. The catalytic cycle starting from the CuII-CuII dinuclear complex proceeds via (a) one-electron oxidation of the active catalyst by NFSI to generate an imidyl radical and dinuclear CuII-CuIII intermediate, (b) turnover-limiting single-electron-transfer (SET1) from the arene to the imidyl radical, (c) fast C-N bond formation with an imidyl anion and an aryl radical cation, (d) reduction of the CuII-CuIII dinuclear intermediate by the aryl radical to regenerate the active catalyst and produce an aryl-cation intermediate, and (e) deprotonation and rearomatization of the arene ring to form the imidated product. The calculated KIE for the turnover-limiting SET1 step reproduces its experimentally observed value. A simple predictive tool was developed and experimentally validated to determine the regiochemical outcome for a given substrate. We demonstrated that the pre-reaction LCuX complexes, where X = Cl, Br and I, show a similar reactivity pattern as these complexes convert to the same catalytically active dinuclear CuII-CuII species.

Supplemental feeding of a gut microbial metabolite of linoleic acid, 10-hydroxy-cis-12-octadecenoic acid, alleviates spontaneous atopic dermatitis and modulates intestinal microbiota in NC/nga mice.

The present study investigated the antiallergic and anti-inflammatory effects of 10-hydroxy-cis-12-octadecenoic acid (HYA), a novel gut microbial metabolite of linoleic acid, in NC/Nga mice, a model of atopic dermatitis (AD). Feeding HYA decreased the plasma immunoglobulin E level and skin infiltration of mast cells with a concomitant decrease in dermatitis score. HYA feeding decreased TNF-α and increased claudin-1, a tight junction protein, levels in the mouse skin. Cytokine expression levels in the skin and intestinal Peyer's patches cells suggested that HYA improved the Th1/Th2 balance in mice. Immunoglobulin A concentration in the feces of the HYA-fed mice was approximately four times higher than that in the control mice. Finally, denaturing gradient gel electrophoresis of the PCR-amplified 16 S rRNA gene of fecal microbes indicated the modification of microbiota by HYA. Taken together, the alterations in the intestinal microbiota might be, at least in part, associated with the antiallergic effect of HYA.

Hints to the diagnosis of uromodulin kidney disease.

BACKGROUND: Uromodulin kidney disease (UKD) is an inherited kidney disease caused by a uromodulin (UMOD) gene mutation. The UMOD gene encodes the Tamm-Horsfall protein (THP), which is the most abundant protein in healthy human urine. Because of its rarity, the incidence of UKD has not been fully elucidated. The purpose of the present study is to clarify the frequency of UKD among patients who underwent renal biopsy. METHODS: Immunostaining for THP was performed for patients <50 years of age with renal insufficiency and hyperuricemia without overt urinalysis abnormality from renal biopsy databases. Serum and urinary THP concentrations were evaluated in available individuals. RESULTS: Fifteen patients were selected for immunostaining from a total of 3787 patients. In three independent patients, abnormal THP accumulation in renal tubular cells was observed. A novel missense A247P UMOD mutation was detected in two of the three patients, including one having a typical family history of familial juvenile hyperuricemic nephropathy. Serum and urinary THP concentrations of all available patients with UMOD A247P mutation were significantly lower than those of controls. CONCLUSIONS: In the present study, UKD was detected in <1 in 1000 subjects who underwent renal biopsies. However, in subjects meeting all of the above criteria, abnormal THP accumulation was detected in 20% (3/15), suggesting that renal biopsy with immunostaining for THP is a good tool for diagnosing UKD. Also, low serum THP concentration detected in the present subjects might be a good diagnostic marker or important in understanding the pathogenesis of UKD.

Catalytic C-H imidation of aromatic cores of functional molecules: ligand-accelerated Cu catalysis and application to materials- and biology-oriented aromatics.

Versatile imidation of aromatic C-H bonds was accomplished. In the presence of copper bromide and 6,6'-dimethyl-2,2'-bipyridyl, a range of aromatics, such as polycyclic aromatic hydrocarbons, aromatic bowls, porphyrins, heteroaromatics, and natural products, can be imidated by N-fluorobenzenesulfonimide. A dramatic ligand-accelerated copper catalysis and an interesting kinetic profile were uncovered.

Therapeutic potential of SOX2 inhibition for embryonal carcinoma.

PURPOSE: Some nonseminomatous germ cell tumors are resistant to any type of chemotherapy. Control of embryonal carcinoma cells is crucial to manage nonseminomatous germ cell tumors. We established SOX2 targeting therapy in an embryonal carcinoma model. MATERIALS AND METHODS: SOX2 expression was evaluated in a series of testicular germ cell tumor tissue samples. The antitumor effect of SOX2 knockdown was analyzed in vitro and in vivo using an embryonal carcinoma model. RESULTS: In testicular germ cell tumor tissue SOX2 was expressed in the foci of embryonal carcinoma but negative in seminoma and yolk sac tumors. In an embryonal carcinoma model SOX2-siRNA induced apoptotic cell death in vitro and significant growth suppression in vivo. CONCLUSIONS: This study shows the therapeutic potential of SOX2 silencing for embryonal carcinoma. However, further improvements are needed in SOX2-siRNA delivery to the tumor.

Methylation profile of DNA repetitive elements in human testicular germ cell tumor.

Testicular germ cell tumors (TGCTs) have a unique epigenetic profile distinct from that of other types of cancer. To further evaluate epigenetics of TGCTs, this study examines DNA methylation patterns of DNA repetitive elements in TGCTs. Bisulfite genomic sequencing and combined bisulfite restriction analysis (COBRA) were used to analyze the methylation patterns of DNA repetitive elements (LINE1 and Alu repeats) in embryonal carcinoma (EC) derived cell lines, primary TGCT tissues, noncancerous testicular tissues adjacent to TGCTs and cancer cells derived from somatic tissues (testicular malignant lymphoma tissues and renal cell carcinoma cell lines). Through both bisulfite genomic sequencing and COBRA, LINE1 was extensively hypomethylated in both seminomatous and nonseminomatous TGCT tissues as well as EC cell lines. We studied two Alu repeats locating in the 5' end of E-cadherin and XIST by bisulfite genomic sequencing. These two Alu elements were extensively hypomethylated in seminomatous TGCTs, but methylated in nonseminomatous TGCTs, including two EC derived cell lines. This increased unmethylated profile in seminomatous TGCTs was observed also by COBRA for Alu repeats. Although partial demethylation of DNA repetitive elements was observed in cancer cells of somatic tissue origin, the degree of demethylation was more pronounced in TGCTs than in cancer cells of somatic tissue origin. We observed abnormal demethylation of DNA repetitive elements in some of the tissues adjacent to TGCTs. The results indicate that the underlying mechanisms to undergo or maintain demethylation of DNA repetitive sequences differ between TGCTs and cancer cells of somatic tissue origin.

Changes in the brain activation balance in motor-related areas after constraint-induced movement therapy; a longitudinal fMRI study.

PRIMARY OBJECTIVE: This study investigated the longitudinal changes in brain activation balance in motor-related areas after Constraint-Induced Movement Therapy (CIMT). METHODS AND PROCEDURES: The subjects included seven ischemic stroke patients with mild right hemiparesis. Eight normal subjects were also included. The patients underwent functional MRI and motor function tests (Fugl-Meyer Assessment; FMA, modified Wolf Motor Function Test; mWMFT) both before and immediately after CIMT and also after a 3-month follow-up. RESULTS: The motor function test scores improved immediately after CIMT; moreover, these scores were either maintained or improved even at the 3-month follow-up. In a comparison of the chronological data of the contralaterality index of the affected hand movement, the cerebellar activity changed significantly to ipsilateral activation immediately after CIMT and thereafter the cerebellar activity further changed to ipsilateral activation at the 3-month follow-up. A correlation was observed among the contralateral activation, FMA and mWMFT scores in SM1 and the ipsilateral activation and in the mWMFT scores in the cerebellum at the 3-month follow-up examinations. CONCLUSION: The participation of the contralateral SM1 and the ipsilateral cerebellum is thus considered to play an important role in the satisfactory recovery of the motor function after CIMT intervention.

Chemistry of anthracene-acetylene oligomers. XVII. Synthesis, structure, and dynamic behavior of 1,8-anthrylene pentamers and hexamers with acetylene linkers.

Three types of cyclic oligomers consisting of five or six 1,8-anthrylene units with acetylene linkers were synthesized by macrocyclization of the corresponding acyclic precursors with coupling reactions. DFT calculations at the M05/3-21G level revealed that the pentamers had a relatively rigid structure with strained alkyne carbons. Meanwhile, out of several possible conformers the hexamers preferred to take parallelogram-prism structures due to transannular π···π interactions, and conformational interconversions via rotation about the acetylene axes took place rapidly at room temperature. NMR spectra and electronic spectra are discussed on the basis of molecular structures. The enantiomers of the chiral hexamer with one diacetylene linker were resolved by chiral HPLC, and showed optical activity.

DNMT3L is a novel marker and is essential for the growth of human embryonal carcinoma.

PURPOSE: Testicular germ cell tumors (TGCT) have a unique epigenetic profile distinct from that of other types of cancer. Elucidation of these properties has a potential to identify novel markers for TGCTs. EXPERIMENTAL DESIGN: We conducted comprehensive analysis of DNA methyltransferase (DNMT) gene expression in TGCTs. Based on the expression profiles of DNMT genes in TGCTs, we generated a rabbit polyclonal anti-human DNMT3L antibody. We then studied the role of DNMT3L in TGCTs by the treatment of two embryonal carcinoma (EC) cell lines with a small interfering RNA system. Finally, we evaluated the immunohistochemical detection of DNMT3L in TGCT tissues. We also compared the patterns of DNMT3L immunohistochemistry with those of CD30 and SOX2. RESULTS: Among the DNMT genes, we found that mRNA for DNMT3L was specifically expressed in TGCTs, but neither in normal testicular tissues nor in cancer cells of somatic tissue origin. DNMT3L protein was strongly expressed in two EC cell lines, but not in the cell lines of somatic tissue origin. Transfection of small interfering RNA for DNMT3L significantly reduced DNMT3L expression and resulted in growth suppression and apoptosis in EC cells. Immunohistochemical analysis showed that DNMT3L protein was present only in EC cells, but not in the other types of TGCT components and cancer cells of somatic tissue origin. DNMT3L staining was more prominent and specific than CD30 or SOX2 staining for detecting EC cells. CONCLUSION: DNMT3L is a novel marker and is essential for the growth of human embryonal carcinoma.

Identification of stemonamide synthetic intermediates as a novel potent anticancer drug with an apoptosis-inducing ability.

We previously demonstrated that Pim-3, a protooncogene with serine/threonine kinase activity, was aberrantly expressed in malignant lesions but not in normal tissues of endoderm-derived organs, including pancreas, liver, colon and stomach. Moreover, aberrantly expressed Pim-3 can prevent tumor cell apoptosis by inactivating a proapoptotic molecule, Bad, and enhancing the expression of an antiapoptotic molecule, Bcl-X(L). These observations prompted us to speculate that a chemical targeting Pim-3 kinase may be a good candidate for a novel type of anticancer drug. Hence, we screened various low-molecule compounds by examining their capacity to inhibit Pim-3 kinase activity in vitro. We observed that some synthetic intermediates of stemonamide can inhibit in vitro activities of Pim-3 kinase and its related kinases, such as Pim-1 and Pim-2. Moreover, these compounds inhibit in vitro cell proliferation of various human pancreatic, hepatocellular and colon cancer cell lines. Furthermore, the compounds can induce apoptosis of human pancreatic cancer cell lines in vitro by reducing the amount of phospho-Ser(112)-Bad, but not total amounts of Bad and Pim-3. Finally, when the compound was administered to nude mice injected with a human pancreatic cancer cell line, it retarded tumor growth by increasing apoptotic cell numbers and decreasing proliferating cell numbers without causing serious adverse effects on blood counts. These observations indicate that the chemicals and its related compounds may be effective for the treatment of tumors of endoderm-derived organs, particularly the pancreas.

Epigenetic profile of testicular germ cell tumours.

DNA methylation is the best known and most thoroughly studied epigenetic mechanism. Hypermethylation of CpG islands associated with silencing of tumour suppressor genes or tumour-related genes is a common hallmark of human cancer. The list of tumour-related genes with aberrant hypermethylation in their CpG islands has been increasing. There is also the potential for using DNA methylation profile data as markers for various types of human cancer. In this paper, we review the methylation profile of testicular germ cell tumours (TGCTs). We show that TGCTs have distinctive DNA methylation profiles that differ from those of somatic tissue-derived cancers or somatic tissues. We also discuss the methylation profile of TGCTs in terms of the DNA reprogramming that occurs in primordial germ cells or pre-implantation embryos. Finally, we describe the potential clinical utility of this unique methylation phenotype in TGCTs with regard to developing a novel tumour marker. These data suggest that unmethylated DNA fragments in TGCTs may have diagnostic implications. Further elucidation of epigenetic profiles in TGCTs is expected to provide a new insight into the biology of this disease.