Comprehensive analysis of indels in whole-genome microsatellite regions and microsatellite instability across 21 cancer types.

Microsatellites are repeats of 1- to 6-bp units, and approximately 10 million microsatellites have been identified across the human genome. Microsatellites are vulnerable to DNA mismatch errors and have thus been used to detect cancers with mismatch repair deficiency. To reveal the mutational landscape of microsatellite repeat regions at the genome level, we analyzed approximately 20.1 billion microsatellites in 2717 whole genomes of pan-cancer samples across 21 tissue types. First, we developed a new insertion and deletion caller (MIMcall) that takes into consideration the error patterns of different types of microsatellites. Among the 2717 pan-cancer samples, our analysis identified 31 samples, including colorectal, uterus, and stomach cancers, with a higher proportion of mutated microsatellite (≥0.03), which we defined as microsatellite instability (MSI) cancers of genome-wide level. Next, we found 20 highly mutated microsatellites that can be used to detect MSI cancers with high sensitivity. Third, we found that replication timing and DNA shape were significantly associated with mutation rates of microsatellites. Last, analysis of mutations in mismatch repair genes showed that somatic SNVs and short indels had larger functional impacts than germline mutations and structural variations. Our analysis provides a comprehensive picture of mutations in the microsatellite regions and reveals possible causes of mutations, as well as provides a useful marker set for MSI detection.

Ecological Dynamics of Broad- and Narrow-Host-Range Viruses Infecting the Bloom-Forming Toxic Cyanobacterium Microcystis aeruginosa.

Microcystis aeruginosa is predicted to interact and coexist with diverse broad- and narrow-host-range viruses within a bloom; however, little is known about their affects on Microcystis population dynamics. Here, we developed a real-time PCR assay for the quantification of these viruses that have different host ranges. During the sampling period, total Microcystis abundance showed two peaks in May and August with a temporary decrease in June. The Microcystis population is largely divided into three phylotypes based on internal transcribed sequences (ITS; ITS types I to III). ITS I was the dominant phylotype (66% to 88%) except in June. Although the ITS II and III phylotypes were mostly less abundant, these phylotypes temporarily increased to approximately equivalent abundances of the ITS I population in June. During the same sampling period, the abundances of the broad-host-range virus MVGF_NODE331 increased from April to May and from July to October with a temporary decrease in June, in which its dynamics were in proportion to the increase of total Microcystis abundances regardless of changes in host ITS population composition. In contrast, the narrow-host-range viruses MVG_NODE620 and Ma-LMM01 were considerably less abundant than the broad-host-range virus and generally did not fluctuate in the environment. Considering that M. aeruginosa could increase the abundance and sustain the bloom under the prevalence of the broad-host-range virus, host abundant and diverse antiviral mechanisms might contribute to coexistence with its viruses. IMPORTANCE The bloom-forming toxic cyanobacterium Microcystis aeruginosa interacts with diverse broad- and narrow-host-range viruses. However, the dynamics of the Microcystis population (at the intraspecies level) and viruses with different host ranges remain unknown. Our real-time PCR assays unveiled that the broad-host-range virus gradually increased in abundance over the sampling period, in proportion to the increase in total Microcystis abundance regardless of changes in genotypic composition. The narrow-host-range viruses were considerably less abundant than the broad-host-range virus and did not generally fluctuate in the environment. The expansion and maintenance of the Microcystis bloom even under the increased infection by the broad-host-range virus suggested that highly abundant and diverse antiviral mechanisms allowed them to coexist with viruses under selective pressure. This paper expands our knowledge about the ecological dynamics of Microcystis viruses and provides potential insights into their coexistence with their host.

Rac1 activation in oral squamous cell carcinoma as a predictive factor associated with lymph node metastasis.

OBJECTIVES: Secondary lymph node metastasis (SLNM) indicates a poor prognosis, and limiting it can improve the survival rate in early-stage tongue squamous cell carcinoma (TSCC). Many factors have been identified as predictors of SLNM; however, there is no unified view. Ras-related C3 botulinum toxin substrate 1 (Rac1) was found to be a promoter of the epithelial-mesenchymal transition (EMT) and is also attracting attention as a new therapeutic target. This study aims to investigate the role of Rac1 in metastasis and its relationship with pathological findings in early-stage TSCC. MATERIALS AND METHODS: Rac1 expression levels of 69 cases of stage I/II TSCC specimens and their association with clinicopathological characteristics were evaluated by immunohistochemical staining. The role of Rac1 in oral squamous cell carcinoma (OSCC) was examined after Rac1 in OSCC cell lines was silenced in vitro. RESULTS: High Rac1 expression was significantly associated with the depth of invasion (DOI), tumor budding (TB), vascular invasion, and SLNM (p < 0.05). Univariate analyses revealed that Rac1 expression, DOI, and TB were factors significantly associated with SLNM (p < 0.05). Moreover, our multivariate analysis suggested that Rac1 expression was the only independent determinant of SLNM. An in vitro study revealed that Rac1 downregulation tended to decrease cell migration and proliferation. CONCLUSION: Rac1 was suggested to be an important factor in the metastasis of OSCC, and it could be useful as a predictor of SLNM.

[Malignant Melanoma of a Male Breast That Was Difficult to Differentiate from Breast Cancer-A Case Report].

INTRODUCTION: Malignant melanoma in the male breast is extremely rare. Here we report a case of malignant melanoma in which a small cystic lesion in the male breast gradually increased during follow-up and was difficult to distinguish from breast cancer. CASE: A 65-year-old male was diagnosed with a tumor in the right breast and was referred to our department for further examination. At 42 years of age, he underwent tumor resection of a malignant melanoma of the abdominal skin. Mammary ultrasonography showed a 0.6 cm cystic mass in his right breast. Eight months later, the right breast mass had increased to 1.4 cm, and a core needle biopsy suggested breast cancer. Total mastectomy with axillary lymph node dissection was performed. HE staining of the resected tumor showed intranuclear inclusion bodies and some large nucleoli. On the basis of various immunostaining methods, malignant melanoma was diagnosed instead of breast cancer. After surgery, adjuvant chemotherapy with molecularly targeted drugs was administered. DISCUSSION: This might have been a case of male breast metastasis of malignant melanoma with very late recurrence.

Recurrent malignant peripheral nerve sheath tumor presenting as an asymptomatic intravenous thrombus extending to the heart: a case report.

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma mainly treated via surgical resection. Herein, we report a case of MPNST wherein a massive tumor thrombus extended to the major veins and heart. CASE PRESENTATION: A 39-year-old female with a history of neurofibromatosis type 1 developed MPNST from the right radial nerve. In addition to adjuvant chemotherapy, she underwent wide tumor resection and concomitant radial nerve resection, followed by postoperative radiotherapy. Histological evaluation revealed marked venous invasion. The 2-year follow-up CT revealed an asymptomatic recurrent tumor thrombus extending from the right subclavian vein to the heart. An urgent life-saving operation was performed to ligate the base of the right subclavian vein and remove the entire intravenous thrombus that extended to the right ventricle. The remaining tumor in the right subclavian vein increased in size 3 months after thrombectomy. After confirming the absence of any metastatic lesions, the patient underwent extended forequarter amputation to achieve surgical remission. One year later, a new metastasis to the right diaphragm was safely resected. The patient remains alive without any evidence of disease 2 years after the extended forequarter amputation. CONCLUSIONS: In cases of a previous history of microscopic venous invasion, recurrence can occur as a massive tumor thrombus that extends to the great vessels.

Methotrexate-associated lymphoproliferative disorder of the thoracic spine in a patient with rheumatoid arthritis receiving methotrexate: a case report.

Methotrexate-associated lymphoproliferative disorder is recognized as a lymphoma that occurs following methotrexate administration. The lesion of the spine is extremely rare, and only one case of lesion in the lumbar spine has been reported so far. Here, we present a case of methotrexate-associated lymphoproliferative disorder of the thoracic spine in a 54-year-old woman with rheumatoid arthritis. The lesion formed an extra-skeletal tumor mass from lateral to the vertebral body to the paravertebral muscle extending posterior to the epidural space without bone destruction. Magnetic resonance imaging showed low signal intensities on both T1- and T2-weighted images and high signal intensity with short-tau inversion recovery. These radiological findings were similar to those for primary spinal lymphoma. The lesion rapidly paralyzed the patient, forcing her to be treated with posterior spinal decompression. The lesion could not be resected because it adhered to the dura. Following the histopathological diagnosis as methotrexate-associated lymphoproliferative disorder, methotrexate administration was terminated. The remaining mass lesion showed complete regression within 6 months. Methotrexate-associated lymphoproliferative disorder, which could be cured by the discontinuation of methotrexate, should be considered a differential diagnosis in spinal lesion cases showing lymphoma-like appearance with methotrexate treatment to avoid unnecessary treatments.

[Two Cases of Hereditary Breast Cancer in Which Genetic Counseling Was Useful].

INTRODUCTION: The importance of genetic counseling has been noted for hereditary breast cancer. We report the cases of two 32-year-old woman, unmarried, BRCA mutation-positive patients. CASES: In Case 1, the chief complaint was awareness of a right breast mass. There was a family history of breast cancer(3 previous cases in the family). The BRCA2 mutation was positive during the BRACAnalysis test. Right breast mastectomy and axillary dissection were performed. Genetic counseling was performed postoperatively, and her eggs were cryopreserved. In Case 2, the chief complaint was calcification of the right breast. She also had a family history of breast cancer(3 previous cases in the family). The BRCA1 mutation was positive during the BRACAnalysis test. Nipple-sparing mastectomy and sentinel lymph node biopsy were performed, and the pathological diagnosis was DCIS. After genetic counseling, she did not desire the cryopreservation of her eggs. DISCUSSION: In these cases, the histological type, stage, subtype, BRCA mutation site, etc., were different from each other, and detailed support by genetic counseling was taken according to each medical condition such as surgery and postoperative adjuvant therapy.

Maternal high-fat diet induces sex-specific changes to glucocorticoid and inflammatory signaling in response to corticosterone and lipopolysaccharide challenge in adult rat offspring.

BACKGROUND: Maternal obesity as a result of high levels of saturated fat (HFD) consumption leads to significant negative health outcomes in both mother and exposed offspring. Offspring exposed to maternal HFD show sex-specific alterations in metabolic, behavioral, and endocrine function, as well as increased levels of basal neuroinflammation that persists into adulthood. There is evidence that psychosocial stress or exogenous administration of corticosterone (CORT) potentiate inflammatory gene expression; however, the response to acute CORT or immune challenge in adult offspring exposed to maternal HFD during perinatal life is unknown. We hypothesize that adult rat offspring exposed to maternal HFD would show enhanced pro-inflammatory gene expression in response to acute administration of CORT and lipopolysaccharide (LPS) compared to control animals, as a result of elevated basal pro-inflammatory gene expression. To test this, we examined the effects of acute CORT and/or LPS exposure on pro and anti-inflammatory neural gene expression in adult offspring (male and female) with perinatal exposure to a HFD or a control house-chow diet (CHD). METHODS: Rat dams consumed HFD or CHD for four weeks prior to mating, during gestation, and throughout lactation. All male and female offspring were weaned on to CHD. In adulthood, offspring were 'challenged' with administration of exogenous CORT and/or LPS, and quantitative PCR was used to measure transcript abundance of glucocorticoid receptors and downstream inflammatory markers in the amygdala, hippocampus, and prefrontal cortex. RESULTS: In response to CORT alone, male HFD offspring showed increased levels of anti-inflammatory transcripts, whereas in response to LPS alone, female HFD offspring showed increased levels of pro-inflammatory transcripts. In addition, male HFD offspring showed greater pro-inflammatory gene expression and female HFD offspring exhibited increased anti-inflammatory gene expression in response to simultaneous CORT and LPS administration. CONCLUSIONS: These findings suggest that exposure to maternal HFD leads to sex-specific changes that may alter inflammatory responses in the brain, possibly as an adaptive response to basal neuroinflammation.

IgG4-related pleural disease in a patient with pulmonary adenocarcinoma under durvalumab treatment: a case report.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are the standard treatment for non-small cell lung cancer. The unique adverse events that can arise after treatment with ICIs are known as immune-related adverse events (irAE). As the number of cases under treatment with ICIs increases, new types of characteristics of irAE have emerged. This case report suggests that IgG4-related pleural disease could occur as an irAE. CASE PRESENTATION: A 64-year-old man was diagnosed with pulmonary adenocarcinoma stage IIIB. Following concurrent chemoradiotherapy, durvalumab was administered every two weeks. The patient complained of dyspnea on effort 4 months after the initiation of durvalumab therapy. Chest CT scans showed mild bilateral pleural effusion 4 months after the initiation of durvalumab therapy, and the amount of pleural effusion increased further at 7 months. Durvalumab was thought to be a potential cause of pleural effusion and was withdrawn after 13 courses of administration over 7 months. The level of serum IgG4 was 2750 mg/dL. The levels of IgG4 of the pleural fluids were 2790 mg/dL on the right side and 2890 mg/dL on the left side at 7 months. Microscopic examination of the pleural biopsy revealed lymphoplasmacytic infiltration with storiform fibrosis. Immunohistochemical examinations showed that the number of IgG4-positive cells was > 20/high power field and the percentage of IgG4-positive to IgG-positive plasma cells was > 50%. Oral prednisolone at a dose of 30 mg/day was initiated, and remarkable clinical improvements were achieved. After 4 months of prednisolone therapy, the level of serum IgG4 decreased to 370 mg/dL and chest CT revealed the disappearance of bilateral pleural effusion. CONCLUSION: This was a case of IgG4-related pleural disease in a patient with pulmonary adenocarcinoma under durvalumab treatment. To our knowledge, this is the first case report of IgG4-related pleural disease as an irAE. It is important to consider the possibility of IgG4-related pleural disease in cases of pleural effusion during the treatment with ICIs.

[Chronic active Epstein-Barr virus infection with multiple vascular lesions successfully treated by cord blood transplantation].

An 18-year-old woman presented with fever and liver dysfunction. Computed tomography showed lymphadenopathy, hepatosplenomegaly, and vascular lesions such as aneurysms and irregularities at multiple arteries, including coronary arteries. Based on the high copy number of Epstein-Barr virus (EBV)-DNA in the peripheral blood, EBV-infected CD4+T cells, and the proliferation of EBER-positive cells in the bone marrow, chronic active EBV infection (CAEBV) was diagnosed. Although the fever and liver dysfunction improved as a result of the initial immunosuppressive therapy and multiagent chemotherapy, EBV-DNA remained high. Moreover, she experienced repeated episodes of angina pectoris due to coronary arterial lesions. Therefore, cord blood transplantation was performed after reduced-intensity conditioning. EBV-DNA decreased quickly after initiating the conditioning and became undetectable at day 7 after the transplant. Vascular lesions did not progress after the transplant, and the patient's angina pectoris resolved. At 2.5 years after the transplant, she is alive without disease recurrence. The prognosis of CAEBV with vascular lesions is especially poor. Although the indication for allogeneic hematopoietic stem cell transplantation (HSCT) is difficult to determine in such cases, the clinical course of our case suggests that allogenic HSCT could be safely performed under appropriate management and could successfully control not only CAEBV but also vascular lesions.

[Surgical Resection of Pulmonary Metastases from Gastric Cancer;Report of a Case].

Lung metastasis of gastric cancer often presents as multiple pulmonary metastases or cancerous lymphadenopathy, which is rarely indicated for surgery and has a poor prognosis. We report a case of solitary metastases that were surgically resected. The patient underwent distal gastrectomy for stomach cancer and then received chemotherapy for abdominal lymph node metastasis. However, he developed pulmonary metastases in the right S6 and S8, and thus underwent right S6 resection and partial resection 29 and 41 months after the gastrectomy, respectively. The pathological diagnosis was gastric cancer metastases. After undergoing surgery for resection of the metastases, he developed new metastases in abdominal lymph nodes and died 5 years after the 1st surgery.

Pseudomyogenic hemangioendothelioma of bone treated with denosumab: a case report.

BACKGROUND: Pseudomyogenic hemangioendothelioma (PMHE) is a rare endothelial neoplasm that involves the bones in only 14% of all cases. The optimal treatment strategy has not been established. We herein report a case of primary PMHE in which denosumab treatment showed activity in both imaging studies and the clinical outcome. CASE PRESENTATION: A 20-year-old woman presented with worsening pain in her left ankle. Imaging studies showed multifocal fluorodeoxyglucose (FDG)-avid [maximum standardized uptake value (SUVmax), 15.95] osteolytic lesions in the bones of her left lower extremity. While waiting for the definitive pathologic diagnosis of PMHE, denosumab, a human immunoglobulin G2 monoclonal antibody against RANKL, was initiated to treat progressive bone absorption after curettage of one of the lesions. Denosumab induced osteosclerosis around the lesions and pain relief and was discontinued 4 years after its initiation. Although all of the multifocal lesions remained, they all became less FDG-avid (SUVmax, 2.6), and the patient developed no signs of new lesions or distant metastasis. CONCLUSION: Denosumab plays a certain role in prevention of bone destruction by PMHE through suppression of osteoclast-like giant cells and would be an excellent treatment for bone absorption by PMHE of bone.

Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic.

Over 30 years ago Professor David Barker first proposed the theory that events in early life could explain an individual's risk of non-communicable disease in later life: the developmental origins of health and disease (DOHaD) hypothesis. During the 1990s the validity of the DOHaD hypothesis was extensively tested in a number of human populations and the mechanisms underpinning it characterised in a range of experimental animal models. Over the past decade, researchers have sought to use this mechanistic understanding of DOHaD to develop therapeutic interventions during pregnancy and early life to improve adult health. A variety of animal models have been used to develop and evaluate interventions, each with strengths and limitations. It is becoming apparent that effective translational research requires that the animal paradigm selected mirrors the tempo of human fetal growth and development as closely as possible so that the effect of a perinatal insult and/or therapeutic intervention can be fully assessed. The guinea pig is one such animal model that over the past two decades has demonstrated itself to be a very useful platform for these important reproductive studies. This review highlights similarities in the in utero development between humans and guinea pigs, the strengths and limitations of the guinea pig as an experimental model of DOHaD and the guinea pig's potential to enhance clinical therapeutic innovation to improve human health.

SOX4, an epithelial-mesenchymal transition inducer, transactivates ADAM28 gene expression and co-localizes with ADAM28 at the invasive front of human breast and lung carcinomas.

ADAM28 (a disintegrin and metalloproteinase 28) is abundantly expressed by carcinoma cells in the human breast and non-small cell lung carcinomas, and plays a role in carcinoma cell growth and metastasis. Although Src is an inducer of ADAM28 gene expression through the PI3K/AKT/mTOR and MEK/ERK pathways, direct transcriptional regulators for ADAM28 gene expression remain unknown. In this study, we performed the luciferase reporter assay and found that SOX4 (SRY-related HMG-box 4), an inducer of epithelial-mesenchymal transition (EMT), is a transcriptional activator for the ADAM28 gene. This activation required the SOX4-binding consensus sequence at the 5'-untranslated region of the mouse and human ADAM28 genes. Forced expression of SOX4 promoted the ADAM28 gene expression and migration in human breast and lung carcinoma cell lines. In the human breast and lung carcinoma tissues, ADAM28 and SOX4 were co-expressed at the invasive front of carcinoma cell nests. Our data demonstrate that SOX4 transactivates ADAM28 gene expression through direct binding to the ADAM28 promoter region and suggest the possibility that ADAM28 plays a role in invasion through SOX4-mediated EMT in the human breast and lung carcinomas.

A histological positive margin after surgery is correlated with high local re-recurrence rate in patients with recurrent myxofibrosarcoma.

OBJECTIVE: Myxofibrosarcoma has high frequency of local recurrence after surgery. To determine an optimal treatment for recurrent tumors, clinical features of recurrent cases should be characterized. METHODS: We performed a retrospective analysis of 30 patients with recurrent myxofibrosarcoma who underwent surgery between 1999 and 2008. RESULTS: A negative margin after surgery was achieved in only 12 patients (40.0%). The 5-year re-recurrence free-survival rate was 31.7%. The 5-year re-recurrence free survival for those with positive histological margin and those with negative margin were 9.8% and 62.3%, respectively, which indicated that a positive margin was the significant predictor of poor prognosis (P = 0.006). In 21 patients with recurrent myxofibrosarcoma in the extremities, 10 patients (47.6%) ultimately underwent amputation in the follow-up period and the 5-year amputation-free survival rate was 62.5%. The 5-year metastasis-free survival rates and the 5-year overall survival rates were 84.8% and 83.6%, respectively. CONCLUSIONS: In this study, the majority of recurrent cases could not achieve negative margins; notably, a positive margin is a significant poor prognostic indicator of local re-recurrence in patients with recurrent myxofibrosarcoma. To control local recurrence of myxofibrosarcoma was extremely difficult and amputation is often needed in the extremity cases.

Clinicopathological study of 5 cases of renal cell carcinoma with t(6;11)(p21;q12).

Renal cell carcinoma (RCC) with t(6;11)(p21;q12) has been incorporated into the recent WHO classification. We performed a clinicopathological study of 5 cases with such a tumor. The patients consisted of 4 males and 1 female. The age of patients ranged from 17 to 57 years with a mean age of 38.6 years. Tumor sizes ranged from 2.8 to 11 cm with a mean value of 6.5 cm. Despite immunotherapy and molecular-targeted therapy, one patient died of the disease 28 months after the surgery. Grossly, the cut surface of this tumor showed grayish white color in at least the focal area of all tumors. Furthermore, hemorrhage, daughter nodules and cystic changes were observed in two, three, and two tumors, respectively. Morphologically, all the tumors consisted of two components of large cells and small cells, and the latter surrounded basement membrane-like materials, forming rosette-like structures. Immunohistochemically, nuclei of tumor cells in all cases were positive for TFEB. Fluorescence in situ hybridization study confirmed the TFEB gene break in two tumors. Finally, urologists and pathologists should bear in mind that this tumor may occur in young adults to adults and might behave in an aggressive fashion. Break-apart FISH is useful for the definite diagnosis.

Induction of the UDP-Glucuronosyltransferase 1A1 during the Perinatal Period Can Cause Neurodevelopmental Toxicity.

Anticonvulsants can increase the risk of developing neurotoxicity in infants; however, the underlying mechanism has not been elucidated to date. Thyroxine [3,5,3',5'-l-tetraiodothyronine (T4)] plays crucial roles in the development of the central nervous system. In this study, we hypothesized that induction of UDP-glucuronosyltransferase 1A1 (UGT1A1)-an enzyme involved in the metabolism of T4-by anticonvulsants would reduce serum T4 levels and cause neurodevelopmental toxicity. Exposure of mice to phenytoin during both the prenatal and postnatal periods significantly induced UGT1A1 and decreased serum T4 levels on postnatal day 14. In the phenytoin-treated mice, the mRNA levels of synaptophysin and synapsin I in the hippocampus were lower than those in the control mice. The thickness of the external granule cell layer was greater in phenytoin-treated mice, indicating that induction of UGT1A1 during the perinatal period caused neurodevelopmental disorders. Exposure to phenytoin during only the postnatal period also caused these neurodevelopmental disorders. A T4 replacement attenuated the increase in thickness of the external granule cell layer, indicating that the reduced T4 was specifically associated with the phenytoin-induced neurodevelopmental disorder. In addition, these neurodevelopmental disorders were also found in the carbamazepine- and pregnenolone-16-α-carbonitrile-treated mice. Our study is the first to indicate that UGT1A1 can control neurodevelopment by regulating serum T4 levels.

Quality of Life in Physical and Psychological Health and Social Environment at Posthospitalization Period in Patients with Stroke.

BACKGROUND: Interaction of quality of life (QOL) in physical and psychological health and social environment has not been tested in stroke during a posthospitalization period, and a better understanding of the components of QOL would lead to a more integrated and person-centered approach to health management and outcome optimization. We investigated how QOL emerges from the sequelae of stroke and interacts with each other during the posthospitalization period. METHODS: We performed a cross-sectional study in 53 outpatients of stroke survivors (39 men and 14 women with a mean age of 66 years, 46 infarctions, and 7 hemorrhages). RESULTS: Eight QOL domains of psychological health were scored by interview, and 2 of them ("desire to distend what they can do" or "desire to do rehabilitation") were associated with the improvement of physical health during the posthospitalization period (P < .05 and P = .08, respectively). These patients were characterized by the items like "I need to succeed for health improvement, to go home, to go back to work, and to see grandchildren" as goals to achieve their desire (P < .05). In interaction of QOL in psychological health and social environment, another psychological domain "to gain satisfaction from the experience" was closely related to the presence of hobby or work before stroke attack (P < .05). CONCLUSION: During the posthospitalization period, QOL of psychological health may support that of physical health, being associated with the presence of hobby or work before stroke attack.

Difference in mesothelin-binding ability of serum CA125 between patients with endometriosis and epithelial ovarian cancer.

The epithelial ovarian carcinoma (EOC) is an aggressive malignant tumor, and is currently the leading cause of gynecologic cancer death. CA125 is the most commonly used serum marker for EOC, but shows a high-false-positive rate for several benign diseases such as endometriosis. The purpose of our study is therefore to identify a useful biochemical tool for detecting qualitative differences between CA125 from patients with endometriosis and EOC, and to facilitate differential diagnosis of these diseases. In our study, using two different CA125-binding molecules, i.e., recombinant mesothelin and an anti-CA125 monoclonal antibody, a novel sandwich ELISA for determining the serum levels of CA125 with mesothelin-binding ability (CA125(meso) ) was developed, and tested for patients with endometriosis (n = 59) and EOC (n = 36). We found that both the serum CA125(meso) level and the ratio of the serum CA125(meso) to CA125 levels (CA125(meso) /CA125) were significantly higher in patients with EOC than in patients with endometriosis (p < 0.00005 and p < 0.000001, respectively). Furthermore, receiver operating characteristic analysis showed that the CA125(meso) assay was superior to the conventional antibody-based CA125 assay in discriminating endometriosis from EOC. Thus, mesothelin-binding ability may be a useful indicator for qualitatively evaluating CA125 in patients with endometriosis and EOC.

Conserved epigenetic sensitivity to early life experience in the rat and human hippocampus.

Early life experience is associated with long-term effects on behavior and epigenetic programming of the NR3C1 (GLUCOCORTICOID RECEPTOR) gene in the hippocampus of both rats and humans. However, it is unlikely that such effects completely capture the evolutionarily conserved epigenetic mechanisms of early adaptation to environment. Here we present DNA methylation profiles spanning 6.5 million base pairs centered at the NR3C1 gene in the hippocampus of humans who experienced abuse as children and nonabused controls. We compare these profiles to corresponding DNA methylation profiles in rats that received differential levels of maternal care. The profiles of both species reveal hundreds of DNA methylation differences associated with early life experience distributed across the entire region in nonrandom patterns. For instance, methylation differences tend to cluster by genomic location, forming clusters covering as many as 1 million bases. Even more surprisingly, these differences seem to specifically target regulatory regions such as gene promoters, particularly those of the protocadherin α, ß, and γ gene families. Beyond these high-level similarities, more detailed analyses reveal methylation differences likely stemming from the significant biological and environmental differences between species. These results provide support for an analogous cross-species epigenetic regulatory response at the level of the genomic region to early life experience.