Association of Loss of Heterozygosity at the p53 Locus with Chemoresistance in Osteosarcomas

Although the osteosarcoma is considered to be among the most chemosensitive malignancies and preoperative chemotherapy is commonly applied, an appreciable proportion of cases are in fact quite insensitive. Predictive markers for chemosensitivity are therefore desirable in order to develop effective treatment strategies. Thirty-two cases of conventional osteosarcomas treated at the Cancer Institute Hospital, Tokyo, were analyzed. The sensitivity to preoperative chemotherapy was investigated with reference to loss of heterozygosity (LOH) at the 17p13 ( p 53) and 13q14 ( Rb ) loci and expression of the cell-cycle associated proteins, p53, Rb, p21/Waf-1, mdm-2 and Ki-67, as detected immunohistochemically. LOH was detected by analyzing polymerase chain reaction products at marker microsatellite loci. The efficacy of chemotherapy was evaluated both radiologically and histologically. LOH at p 53 or Rb loci was seen in 54% (13/24) and 58% (14/24) of cases, respectively. Only 15% of osteosarcomas with LOH at the p 53 locus were sensitive to preoperative chemotherapy, as compared to 64% of tumors without such loss ( P <0.05). A similar but much less distinct tendency was observed with LOH at the Rb locus. No relationship was evident between chemosensitivity and immunohistochemical staining patterns for p53, Rb, p21/Waf-1, mdm-2 or Ki-67. The results suggest that p 53 gene deletion, but not the other parameters investigated, may be useful for predicting chemoresistance of osteosarcomas.     

Profiling of proteins phosphorylated or dephosphorylated during hyperactivation via activation on hamster spermatozoa

Background and Aims  It has been widely accepted that sperm hyperactivation is regulated by protein phosphorylations. But, the sperm hyperactivation phosphorylation pathway is not well understood yet because several different proteins have been detected in other studies. In order to understand the phosphorylation pathway that regulates hyperactivation, we established how to extract sperm protein completely and detected proteins that were phosphorylated during hyperactivation. Methods  Protein phosphorylation of hamster spermatozoa was detected by western blotting using antiphospho-amino acid monoclonal antibodies or the SELDI ProteinChip system with IMAC-Ga(III). Results  We detected 75 protein/peptide phosphoryations using the method established in the present study. Tyrosine phosphorylations occurred during hyperactivation. Serine or threonine phosphorylations occurred for 30 min. Furthermore, four of the serine or threonine phosphorations were phosphorylated by A-kinase. As for peptides, 15 peptides were dephosphorylated for 30 min. Other peptides were phosphorylated during hyperactivation. Conclusions  Because most of the proteins detected in the present study have been described previously, we could detect comprehensive protein phosphorylations. Moreover, we also detected many novel phosphopeptides. Although we did not understand the role of peptide, it was likely that motility was basically regulated by serine/threonine phosphorylations and hyperactivation was mainly regulated by tyrosine phosphorylations. (Reprod Med Biol 2006; 5: 123–135)     

Gender-specific gene expression in post-mortem human brain: localization to sex chromosomes.

Gender differences in brain development and in the prevalence of neuropsychiatric disorders such as depression have been reported. Gender differences in human brain might be related to patterns of gene expression. Microarray technology is one useful method for investigation of gene expression in brain. We investigated gene expression, cell types, and regional expression patterns of differentially expressed sex chromosome genes in brain. We profiled gene expression in male and female dorsolateral prefrontal cortex, anterior cingulate cortex, and cerebellum using the Affymetrix oligonucleotide microarray platform. Differentially expressed genes between males and females on the Y chromosome (DBY, SMCY, UTY, RPS4Y, and USP9Y) and X chromosome (XIST) were confirmed using real-time PCR measurements. In situ hybridization confirmed the differential expression of gender-specific genes and neuronal expression of XIST, RPS4Y, SMCY, and UTY in three brain regions examined. The XIST gene, which silences gene expression on regions of the X chromosome, is expressed in a subset of neurons. Since a subset of neurons express gender-specific genes, neural subpopulations may exhibit a subtle sexual dimorphism at the level of differences in gene regulation and function. The distinctive pattern of neuronal expression of XIST, RPS4Y, SMCY, and UTY and other sex chromosome genes in neuronal subpopulations may possibly contribute to gender differences in prevalence noted for some neuropsychiatric disorders. Studies of the protein expression of these sex-chromosome-linked genes in brain tissue are required to address the functional consequences of the observed gene expression differences.     

Three-Dimensional Evaluation of Innominate Bone Rotation in Female Patients with Developmental Dysplasia of the Hip

BackgroundPatients with developmental dysplasia of the hip (DDH) are known to have abnormal pelvic morphologies; however, rotation of innominate bone features remains unclear. Thus, we investigated innominate bone rotation in patients with DDH by measuring the associated angles and distances using three-dimensional (3D) computed tomography.MethodsWe defined four straight lines in pelvic 3D models: from the anterior superior iliac spine to the posterior superior iliac spine, from the anterior inferior iliac spine to the posterior inferior iliac spine, from the pubic tubercle to the ischial spine, and from the pubic tubercle to the ischial tuberosity. Similarly, we measured the angles formed by these lines using the vertical axis of the anterior pelvic plane on the horizontal plane and the horizontal axis on the sagittal plane. Additionally, we measured the distances between the femoral head centers and the acetabular centers in the coronal plane.ResultsThe difference in internal rotation angle between the superior and inferior parts of the iliac bone was significantly lower, by approximately 1.7°, in the DDH group than in the control group (p = 0.007); the difference between the inferior and superior parts of the ischiopubic bone was significantly higher, by approximately 1.5°, in the DDH group (p < 0.001). In the sagittal plane, the sum of the superior aspect of the iliac bone and the inferior aspect of the ischium was significantly lower in the DDH group (p = 0.001) than in the control group. The distances between the femoral heads and the acetabula were significantly greater in the DDH group than in the control group (p = 0.03, p < 0.01, respectively).ConclusionsPatients with DDH had a more internally rotated ilium and ischiopubic bone than normal individuals; however, it should be emphasized that internal rotation was reduced near the acetabulum, and the acetabulum was shifted laterally. Similarly, it was shown that patients with DDH had different rotations of the ilium and ischiopubic bone in the sagittal plane.     

Colorectal Cancer Screening Program in Songjiang district,Shanghai between 2015 and 2017: Evaluation of participation rate and the associated factor

Little is known about the participation rate of newly implemented colorectal cancer (CRC) screening programs in China. Our goals were to identify factors associated with nonparticipation for CRC screening in Songjiang District, Shanghai.We analyzed individuals included in an observational cohort study from 4 towns (Xin Qiao, She Shan, Mao Gang, and Zhong Shan) in Songjiang District. The participation rate was calculated for the CRC screening program based on a fecal immunochemical test and a risk assessment questionnaire between 2015 and 2017 inclusive.Of the 27,130 individuals eligible for inclusion in this study, 20,863 (76.9%) participated in CRC screening at least once during 2015 and 2017. The factors linked with nonparticipation were; being male (odds ratio [OR] 0.87, 95% confidence interval [CI] 0.82–0.93, P < .01), unmarried (OR 0.71, 95% CI 0.64–0.80, P < .01), having a high education level (middle school, OR 0.82, 95% CI 0.74–0.90, P < .01, high school or above, OR 0.64, 95% CI 0.57–0.73, P < .01), absence of chronic disease (OR 0.90, 95% CI 0.85–0.96, P < .01), and living in 2 out of the 4 towns covered (Xin Qiao, OR 0.72, 95% CI 0.66–0.78, P < .01, Zhong Shan, OR 0.29, 95% CI 0.26–0.31, P < .01).The current study revealed several associated factors with nonparticipation for the CRC screening in Songjiang district. These findings will help identify target populations that require an individualized approach to increase the participation rate.     

A dose-finding study of glycosylated G-CSF (Lenograstim) combined with CHOP therapy for stem cell mobilization in patients with non-Hodgkin's lymphoma

BACKGROUND: Peripheral blood stem cell (PBSC) reinfusion has been widely used for hematopoietic reconstitution after high-dose chemotherapy. However, the optimal dose of granulocyte colony-stimulating factor (G-CSF) for PBSC mobilization in combination with chemotherapy for autograft remains unknown. METHODS: To find the optimal dose of glycosylated G-CSF (lenograstim) for PBSC mobilization in combination with chemotherapy for aggressive non-Hodgkin's lymphoma (NHL), we conducted a dose-finding study on 43 newly diagnosed patients who had unfavorable prognostic factors. They received four to six courses of cyclophosphamide, doxorubicin, vincristine and prednisolone combined with lenograstim every 2 weeks (biweekly CHOP therapy). PBSC apheresis was started after the third course of biweekly CHOP therapy. Lenograstim was given daily from day 3 until the day of the last apheresis. The optimum dose of lenograstim was assessed based on mobilization efficacy and safety profiles at a daily single dose of 2, 5 and 10 microg/kg for eight patients in each level. RESULTS: The collected number of CD34+ cells in the first apheresis products was higher in the 5 microg/kg group than in the 2 microg/kg group (median, 4.22 x 10(6) vs 2.49 x 10(6) CD34+ cells/kg, P = 0.051). The highest dose of 10 microg/kg (median, 2.99 x 10(6) CD34+ cells/kg) failed to show a dose dependence in PBSC mobilization. The efficacy and safety of the 5 microg/kg dose were further confirmed in an additional 19 patients. CONCLUSIONS: The present study suggests that the recommended dose of lenograstim for PBSC mobilization with CHOP therapy in untreated NHL is 5 microg/kg.     

Two single nucleotide polymorphisms in <Emphasis Type="Italic">PRDM9</Emphasis> (<Emphasis Type="Italic">MEISETZ</Emphasis>) gene may be a genetic risk factor for Japanese patients with azoospermia by meiotic arrest

Purpose

To investigate whether defects in human PRDM9, CDK2 and PSMC3IP are associated with azoospermia Mutational analysis was performed in Japanese patients with azoospermia caused by meiotic arrest.

Methods

Mutational screening of the coding regions of human PRDM9, CDK2 and PSMC3IP was done by direct sequencing using genomic DNA from 18 Japanese patients. Statistical analysis of the detected coding single nucleotide polymorphisms (cSNPs) in patients and normal control men was then carried out.

Results

One cSNP was detected in CDK2 and PSMC3IP. There were no significant differences in genotype distribution and allele frequencies between the patient and control groups in these two genes. However, three novel cSNPs were detected in the PRDM9. The genotype and allele frequencies of heterozygotes in SNP2 and SNP3 of PRDM9 were significantly higher in the patient group than in the control group.

Conclusion

We found a possible association between PRDM9 and azoospermia by meiotic arrest.

     

The Simultaneous Onset of Pancreatitis and Colitis as Immune-related Adverse Events in a Patient Receiving Nivolumab Treatment for Renal Cell Carcinoma

Immune checkpoint inhibitors (ICIs), which have anti-tumor effects, are currently approved for treatment of several kinds of advanced malignancies. However, with their increasing use, a variety of immune-related adverse events (irAEs) in administered patients have been reported. We herein report a rare case of the simultaneous onset of acute pancreatitis and colitis as irAEs during nivolumab treatment given to a patient with renal cell carcinoma, who then shown marked improvement with corticosteroid therapy.     

Total syntheses of ent-hypocoprin A and ent-hypocoprin B

This study reports the stereoselective total syntheses of the antipodes of the unique 3/10 bicyclic skeletal sesquiterpenoids, namely, hypocoprin A and hypocoprin B. The synthesis involved conjugate addition accelerated by trimethylsilyl chloride, construction of the ten-membered ring via the intramolecular S_N2 reaction promoted by 1,8-diazabicyclo[5.4.0]undec-7-ene, and osmium-mediated π-facial selective dihydroxylation to functionalize the 1,1-disubstituted alkene.

This study reports the stereoselective total syntheses of the antipodes of the unique 3/10 bicyclic skeletal sesquiterpenoids, namely, hypocoprin A and hypocoprin B.