Synaptonemal complex protein 3 as a novel prognostic marker in early stage non-small cell lung cancer

Synaptonemal complex protein 3 is a marker for cell transformation that has prognostic significance in various cancers. However, the prognostic significance of synaptonemal complex protein 3 has not been studied in non-small cell lung cancer. To investigate the potential correlation between synaptonemal complex protein 3 and various clinicopathologic parameters, we assessed the expression of synaptonemal complex protein 3 in archival tumor tissues from 258 patients with non-small cell lung cancer by immunohistochemical staining. By immunofluorescence, synaptonemal complex protein 3 was detected in both the cytoplasmic and nuclear fractions of NCI-H1299 cell. In tumor samples, synaptonemal complex protein 3 is detected as cytoplasmic expression pattern and observed in 50 clinical samples (19.4%) by immunohistochemical staining. Synaptonemal complex protein 3 expression was correlated with T status (P = .008), lymph node metastasis (P = .010), tumor types (P = .019), and pleural invasion (P = .005). In multivariate analysis of patients with early stage disease, increased synaptonemal complex protein 3 expression predicted worse overall survival in early stage (stage I and II) with pT1 status (P = .041). These results suggest that positive synaptonemal complex protein 3 expression is a portent of poor outcome and may be a potential biomarker in the early stages of the non-small cell lung cancer for survival and may provide clues in the identification of patients for adjuvant therapy.ope

Prognostic implications of forkhead box protein O1 (FOXO1) and paired box 3 (PAX3) in epithelial ovarian cancer

BACKGROUND: Transcription factors forkhead box protein O1 (FOXO1) and paired box 3 (PAX3) have been reported to play important roles in various cancers. However, their role in epithelial ovarian cancer (EOC) has not been elucidated yet. Therefore, we evaluated the expression and clinical significance of FOXO1 and PAX3 in EOC. METHODS: Immunohistochemical analyses of FOXO1 and PAX3 in 212 EOCs, 57 borderline ovarian tumors, 153 benign epithelial ovarian tumors, and 79 nonadjacent normal epithelial tissues were performed using tissue microarray. Various clinicopathological variables, including the survival of EOC patients, were compared. In addition, the effect of FOXO1 on cell growth was assessed in EOC cell lines. RESULTS: FOXO1 and PAX3 protein expression levels were significantly higher in EOC tissues than in nonadjacent normal epithelial tissues, benign tissues, and borderline tumors (all p < 0.001). In EOC tissues, FOXO1 expression was positively correlated with PAX3 expression (Spearman's rho = 0.118, p = 0.149). Multivariate survival analysis revealed that high FOXO1 expression (hazard ratio = 2.77 [95% CI, 1.48-5.18], p = 0.001) could be an independent prognostic factor for overall survival. Most importantly, high expression of both FOXO1 and PAX3 showed a high hazard ratio (4.60 [95% CI, 2.00-10.55], p < 0.001) for overall survival. Also in vitro results demonstrated that knockdown of FOXO1 was associated with decreased cell viability, migration, and colony formation. CONCLUSIONS: This study revealed that high expression of FOXO1/PAX3 is an indicator of poor prognosis in EOC. Our results suggest the promising potential of FOXO1 and PAX3 as prognostic and therapeutic markers. The possible link between biological functions of FOXO1 and PAX3 in EOC warrants further studies.ope

Investigation of Amygdalar Structural Characteristics According to Gender and Empathizing Tendency

학위논문 (박사)-- 서울대학교 대학원 : 협동과정뇌과학전공, 2014. 8. 최석우.서론: 공감(empathy)은 타인의 감정, 생각을 이해하는 능력이며 일상적인 사회생활 유지에 필수적이다. 공감 경향의 정도는 남성과 여성 간의 차이가 있으며 이는 뇌 내 신경학적 수준의 성별 차이에서 기인하는 것으로 제시되어 왔다. 뇌 내 편도체의 경우 공감과 관련한 주요한 역할을 수행하는 것으로 연구되어 왔으나 공감 경향과 편도체의 세부핵 수준에서의 구조적 관계를 밝히고자 하는 연구는 없었다. 이에 편도체 표면 기반 형태 분석을 이용하여 뇌 내 생물학적 성별 차이를 고려한 편도체의 세부핵 내의 구조적 특성과 공감 경향 간의 관계를 연구하였다. 방법: 만 20-60세의 정상 성인 97명(남성 50명, 여성 47명)을 대상으로 인구학적, 임상적 정보를 얻고 고해상도의 뇌 자기공명영상 자료를 획득하였다. 획득한 뇌 자기공명영상 자료 중 T1 강조영상(T1-weighted image)에서 편도체를 자동 구획하고 편도체 표면 기반 형태 분석 방법론을 이용하여 평균 3차원 편도체 모형 기준의 피험자 개별의 편도체를 조정 후 편도체의 반경을 구하고 형태 분석을 수행하였다. 편도체 세부핵은 확률맵으로 구획하여 세부핵 별 구조적 비율을 계산하였다. 연구 대상자에게 공감지수 척도와 체계화지수 척도의 한국어 번안 질문지를 제공하여 검사를 수행하였고 체계화지수 변환값에서 공감지수 변환값을 뺀 D 점수를 계산하여, 편도체 형태와의 관계를 분석하였다. 해당 분석은 남성 군, 여성 군으로 성별을 나누어 수행하였다. 결과: 여성 군 내에서 D 점수와 우측 편도체 내 측기저핵 영역의 클러스터에서 유의미한 부적 상관관계가 나타났다(corrected P < 0.05, cluster size = 28). 남성 군 내에서는 D 점수와 양측 편도체 내의 유의미한 상관관계를 갖는 클러스터 영역은 나타나지 않았다. 우측 편도체 측기저핵 영역 일부에서 연구 대상자 전체의 성별과 D 점수 간의 유의미한 부적 상호작용이 있는 것으로 나타났다(corrected P < 0.05, cluster size = 46). 결론: 여성 군 내의 우측 편도체 측기저핵 영역의 클러스터 반경과 공감 경향이 정적 상관관계를 보였고 남성 군 내에서는 유의미한 결과가 없었다. 또한 해당 부위는 성별과 공감 경향 정도 간의 상호작용이 있었다. 성 공감 경향과 연계된 편도체 측기저핵의 구조적 특성은 성 호르몬 등의 성 특이성의 영향을 받음을 시사한다. 편도체 표면 기반 형태 분석을 통한 본 연구 결과는 공감 경향 관련 편도체 세부핵 단위의 분석이 구조적, 기능적 연구에서의 활용이 의미가 있음을 시사하며, 성별 차이를 고려한 뇌 자기공명영상 연구의 필요를 강조하였다.Introduction: Empathy is defined as the ability to understand another persons emotions and thoughts, and it is essential in maintaining ordinary social life. Men and women differ in the extent of the empathizing tendency, which has been suggested to be due to sex differences in the brain at a neurological level. Although there have been many studies indicating the crucial role of the amygdala in empathy, no studies have been conducted thus far on the structural relationship between the subregions of the amygdala and the empathizing tendency. Thus, the present study examined the structural properties of the amygdalar subregions and their relationship with the empathizing tendency, by using amygdalar surface-based shape analysis in consideration of sex differences. Methods: Demographic and clinical information as well as high-resolution brain magnetic resonance (MR) images were collected from 97 healthy adults (50 men, 47 women) aged between 20 and 60 years. Using the obtained T1-weighted MR images, the amygdala was automatically segmented. Amygdalar surface-based shape analysis was performed to adjust each participant's amygdala based on the average three-dimensional amygdala model. Subsequently, the radii of each participant's amygdala were measured. The amygdalar subregions were segmented by the probabilistic map and the ratio of each amygdalar nuclear compartment was calculated. The association between the radii of the amygdala and the D scores, which were obtained by subtracting the conversion values of the Empathy Quotient (EQ) scores from those of the Systemizing Quotient (SQ) scores, was assessed to analyze the relationship between the shape of the amygdala and the D scores. The analyses for men and women were performed separately. Results: In women, a significant negative correlation was found between the D scores and the cluster located at the basolateral subregion of the amygdala (corrected P < 0.05, cluster size = 28). However, in men, no such correlation was observed between the D scores and the clusters in the amygdala. Moreover, there were significant negative interactions between sex and D scores in some of the basolateral subregion of the right amygdala (corrected P < 0.05, cluster size = 46). Conclusion: There was a positive correlation in women between the radius of the cluster at the basolateral subregion of the right amygdala and the empathizing tendency, whereas no such correlation was found in men. Also, significant interactions of sex and the empathizing tendency were observed in the identified region. The structural properties of the amygdalar basolateral subregion associated with the sex-related empathizing tendency may be the result of sex-specific factors such as sex hormones. The present results from the amygdalar surface-based shape analysis suggests that the analysis of the amygdala at a subregional level in relation to the empathizing tendency may be useful in structural and functional brain research, and that there is a need for future brain imaging studies on the sex-specific differences of the brain.목 차 연구 배경 및 필요성 ----------------------------------------------------------------------- 1 1. 공감, 체계화의 정의와 측정 ------------------------------------------------- 1 2. 공감, 체계화의 성별 간 차이 ----------------------------------------------- 4 3. 편도체의 공감 관련 역할 ------------------------------------------------------ 6 4. 편도체의 세부 구조와 기능 -------------------------------------------------- 8 5. 편도체의 구조와 공감 관련 기능의 성별 차이--------------------- 11 6. 연구 목적 및 가설 ----------------------------------------------------------------- 20 연구 대상 및 방법 -------------------------------------------------------------------------- 23 1. 연구 대상자 ---------------------------------------------------------------------------- 23 2. 뇌 자기공명영상 자료 획득 -------------------------------------------------- 24 3. 전처리(preprocessing) ------------------------------------------------------------ 25 4. 편도체 자동 구획(automatic segmentation) -------------------------- 26 5. 편도체 표면 기반 형태 분석 (amygdalar surface-based shape analysis) ----------------------------- 27 6. 편도체 세부핵 구획 및 분석 ------------------------------------------------ 29 7. 편도체의 편측화 분석 ----------------------------------------------------------- 32 8. 임상적 검사도구: 공감지수, 체계화지수 측정 및 D 점수 계산 --------------------------------------------------------------------------- 33 9. 임상적 검사도구: 공감지수 척도 내 요인분석 -------------------- 36 10. 대뇌피질 두께 분석(cortical thickness analysis) ------------------- 37 11. 통계 분석 ------------------------------------------------------------------------------- 38 결과 -------------------------------------------------------------------------------------------------- 41 1. 인구학적 특성 및 임상적 평가 -------------------------------------------- 41 2. D 점수에 따른 편도체의 세부 구조 형태의 특성 ------------ 46 3. 편도체 세부핵 구조 분석 결과 --------------------------------------------- 47 4. 공감지수 척도의 요인분석 ---------------------------------------------------- 65 5. 편도체의 편측화 분석 결과 -------------------------------------------------- 71 6. 여성 군 내에서 D 점수와 유의미한 관계를 가지는 편도체 세부핵 영역과 대뇌피질 간 구조적 연결-------------- 72 7. 민감도 분석(sensitivity analysis) -------------------------------------------- 76 고찰 -------------------------------------------------------------------------------------------------- 78 1. 연구 결과 요약 및 고찰 -------------------------------------------------------- 78 2. 본 연구의 장점 및 의의 -------------------------------------------------------- 88 3. 본 연구의 한계점 및 후속 연구 방향 ---------------------------------- 90 참고 문헌 ----------------------------------------------------------------------------------------- 94Docto

The paraffin-embedded RNA metric (PERM) for RNA isolated from formalin-fixed, paraffin-embedded tissue

RNA isolated from formalin-fixed, paraffin-embedded (FFPE) tissue is commonly evaluated in both investigative and diagnostic pathology. However, the quality of the data is directly impacted by RNA quality. The RNA integrity number (RIN), an algorithm based on a combination of electrophoretic features, is widely applied to RNA isolated from paraffin-embedded tissue, but it is a poor indicator of the quality of that RNA. Here we describe the novel paraffin-embedded RNA metric (PERM) for quantifying the quality of RNA from FFPE tissue. The PERM is based on a formula that approximates a weighted area-under-the-curve analysis of an electropherogram of the extracted RNA. Using biochemically degraded RNAs prepared from experimentally fixed mouse kidney specimens, we demonstrate that PERM values correlate with mRNA transcript measurements determined using the QuantiGene system. Furthermore, PERM values correlate with real-time PCR data. Our results demonstrate that the PERM can be used to qualify RNA for different end-point studies and may be a valuable tool for molecular studies using RNA extracted from FFPE tissue.ope

TOM40 Inhibits Ovarian Cancer Cell Growth by Modulating Mitochondrial Function Including Intracellular ATP and ROS Levels

TOM40 is a channel-forming subunit of translocase, which is essential for the movement of proteins into the mitochondria. We found that TOM40 was highly expressed in epithelial ovarian cancer (EOC) cells at both the transcriptional and translational levels; its expression increased significantly during the transformation from normal ovarian epithelial cells to EOC (p < 0.001), and TOM40 expression negatively correlated with disease-free survival (Hazard ratio = 1.79, 95% Confidence inerval 1.16-2.78, p = 0.009). TOM40 knockdown decreased proliferation in several EOC cell lines and reduced tumor burden in an in vivo xenograft mouse model. TOM40 expression positively correlated with intracellular adenosine triphosphate (ATP) levels. The low ATP and high reactive oxygen species (ROS) levels increased the activity of AMP-activated protein kinase (AMPK) in TOM40 knockdown EOC cells. However, AMPK activity did not correlate with declined cell growth in TOM40 knockdown EOC cells. We found that metformin, first-line therapy for type 2 diabetes, effectively inhibited the growth of EOC cell lines in an AMPK-independent manner by inhibiting mitochondria complex I. In conclusion, TOM40 positively correlated with mitochondrial activities, and its association enhances the proliferation of ovarian cancer. Also, metformin is an effective therapeutic option in TOM40 overexpressed ovarian cancer than normal ovarian epithelium.ope

Practice guidelines for management of uterine corpus cancer in Korea: a Korean Society of Gynecologic Oncology Consensus Statement

Clinical practice guidelines for gynecologic cancers have been developed by many organizations. Although these guidelines have much in common in terms of the practice of standard of care for uterine corpus cancer, practice guidelines that reflect the characteristics of patients and healthcare and insurance systems are needed for each country. The Korean Society of Gynecologic Oncology (KSGO) published the first edition of practice guidelines for gynecologic cancer treatment in late 2006; the second edition was released in July 2010 as an evidence-based recommendation. The Guidelines Revision Committee was established in 2015 and decided to produce the third edition of the guidelines as an advanced form based on evidence-based medicine, considering up-to-date clinical trials and abundant qualified Korean data. These guidelines cover screening, surgery, adjuvant treatment, and advanced and recurrent disease with respect to endometrial carcinoma and uterine sarcoma. The committee members and many gynecologic oncologists derived key questions from the discussion, and a number of relevant scientific literatures were reviewed in advance. Recommendations for each specific question were developed by the consensus conference, and they are summarized here, together with other details. The objective of these practice guidelines is to establish standard policies on issues in clinical areas related to the management of uterine corpus cancer based on the findings in published papers to date and the consensus of experts as a KSGO Consensus Statement.ope

Assessment of a panel of tumor markers for the differential diagnosis of benign and malignant effusions by well-based reverse phase protein array

BACKGROUND: The differential diagnosis of benign and malignant effusion is often hampered by low cell content or insufficiently preserved tumor cells. In this study, we evaluated the combined diagnostic value of six tumor markers measured by well-based reverse-phase protein array (RPPA) for diagnosis of malignant effusion. METHODS: A total of 114 patients (46 with malignant effusions, 32 with probable malignant effusions, and 36 with benign effusions) were enrolled. Expressional levels of MUC1, EMA, Pan-CK, HSP90, TGF-β and CA125 were determined by well-based RPPA. RESULTS: Median relative expression of MUC1, Pan-CK and EMA were significantly higher in malignant effusion than those in probable malignant or benign (p < 0.001, p = 0.003, p < 0.001, respectively), whereas the level of TGF-β in malignant effusions were significantly lower than that in the other groups (p = 0.005). For predicting malignancy, EMA presented the best areas under the curve of 0.728 followed by MUC1 of 0.701. The sensitivity of 52.0% for MUC1 and 48.0% for EMA were not better than cytology. However, sensitivity, negative predictive value, and accuracy of the tumor marker panel were better than cytology by 14.7%, 7.5%, and 6.1%, respectively. CONCLUSIONS: Tumor marker panel measured by well-based RPPA showed values in the differential diagnosis between benign and malignant effusions. Further large scale studies need to be performed to evaluate the utility of this panel of markers. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1433424467160224.ope

REP1 inhibits FOXO3-mediated apoptosis to promote cancer cell survival

Rab escort protein 1 (REP1) is a component of Rab geranyl-geranyl transferase 2 complex. Mutations in REP1 cause a disease called choroideremia (CHM), which is an X-linked eye disease. Although it is postulated that REP1 has functions in cell survival or death of various tissues in addition to the eye, how REP1 functions in normal and cancer cells remains to be elucidated. Here, we demonstrated that REP1 is required for the survival of intestinal cells in addition to eyes or a variety of cells in zebrafish, and also has important roles in tumorigenesis. Notably, REP1 is highly expressed in colon cancer tissues and cell lines, and silencing of REP1 sensitizes colon cancer cells to serum starvation- and 5-FU-induced apoptosis. In an effort to elucidate the molecular mechanisms underlying REP1-mediated cell survival under those stress conditions, we identified FOXO3 as a binding partner of REP1 using a yeast two-hybrid (Y2H) assay system, and we demonstrated that REP1 blocked the nuclear trans-localization of FOXO3 through physically interacting with FOXO3, thereby suppressing FOXO3-mediated apoptosis. Importantly, the inhibition of REP1 combined with 5-FU treatment could lead to significant retarded tumor growth in a xenograft tumor model of human cancer cells. Thus, our results suggest that REP1 could be a new therapeutic target in combination treatment for colon cancer patients.ope

Modulated electro-hyperthermia with weekly paclitaxel or cisplatin in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal carcinoma: The KGOG 3030 trial

The present study (KGOG 3030) aimed to evaluate the safety of modulated electro-hyperthermia (mEHT) therapy with weekly administration of paclitaxel or cisplatin in female patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal carcinoma. A total of 12 patients were randomized into the paclitaxel or cisplatin arm at a 1:1 ratio. Patients received weekly administration of paclitaxel (70 mg/m2) or cisplatin (40 mg/m2) intravenously on days 1, 8 and 15, and underwent mEHT therapy for 1 h on days 1, 4, 8, 11, 15, 18, 21 and 24 for each 4-week cycle. The primary endpoint was the occurrence of dose-limiting toxicity (DLT). The secondary endpoints were treatment-emergent adverse events (TEAEs), objective response rate, carbohydrate antigen 125 (CA125) response rate, progression-free survival (PFS) and overall survival (OS). In total, 16 patients were recruited, but four patients dropped out. None of the 12 remaining patients (6 each in the two arms) experienced DLT. Overall, 0 and 4 grade 3 TEAEs (anemia, nausea, neutrophil count decreased and platelet count decreased) occurred in the paclitaxel and cisplatin arm, respectively. Furthermore, one confirmed partial response and two CA125 responses were observed in the cisplatin arm. The median PFS time in the paclitaxel and cisplatin arms was 3.0 months (range, 1.7-4.6 months) and 6.8 months (range, 3.9-11.8 months), respectively, while the median OS time was 11.5 months (range, 8.4-28.8+ months) and not reached (range, 3.9-38.5+ months), respectively. In conclusion, mEHT therapy with weekly paclitaxel or cisplatin appeared safe and warrants further investigation. The present trial was registered with www.clinicaltrials.gov on January 22, 2015 (trial registration no. NCT02344095).ope

NANOG confers resistance to complement-dependent cytotoxicity in immune-edited tumor cells through up-regulating CD59

Cancer immunoediting drives the adaptation of tumor cells to host immune surveillance. Previously, we have demonstrated that immunoediting driven by cytotoxic T lymphocytes (CTLs) enriches NANOG+ tumor cells with immune-refractory properties. Here, we found that CTL-mediated immune pressure triggered cross-resistance of tumor cells to the complement system, a part of the innate immune system. In this process, NANOG upregulated the membrane-bound complement regulatory protein (mCRP) CD59 through promoter occupancy, thereby contributing to the resistance of tumor cells against complement-dependent cytotoxicity (CDC). Notably, targeting of NANOG sensitized the immune-refractory tumor cells to trastuzumab-mediated CDC. Collectively, our results revealed a possible mechanism through which selection imposed by T-cell based immunotherapy triggered complement-resistant phenotypes in the tumor microenvironment (TME), by establishing a firm molecular link between NANOG and CD59 in immune-edited tumor cells. We believe these results hold important implications for the clinical application of CDC-mediated therapeutic antibody.ope