230 research outputs found
Abstract 3845: Establishment and characterization of patient-derived xenografts of clear cell carcinoma of the ovary
No full textAbstract
Background; The patient-derived xenograft (PDX) model is likely to reflect original human cancer biology compared to cultured cell lines, since tumor tissues are directly implanted into animals. PDX models of ovarian cancer have been developed, but were not fully characterized at the molecular level, especially for clear cell carcinoma (CCC), which is more prevalent in Japan than western countries, exhibits chemoresistant phenotype and poor survival. The development of new treatment strategies and the better understanding of biology of CCC both depend on clinically relevant animal models. In particular, molecular annotated PDX models are useful for the preclinical investigation of anticancer drugs and individualized anticancer therapy. Methods; We transplanted 19 parent (primary or metastatic) tumors directly into NOG mice. The histologic characteristics were compared between parental tumors and PDX ones. Among CCC pairs, gene expression analysis, gene mutation analysis were conducted on parental tumors and corresponding PDX tumors. Response to chemotherapeutic agents was analyzed using PDX tumors of CCC, and correlated with clinical outcome. Results; Six of nineteen (31.6%) transplanted tumors could be passaged. Gene expression profiles revealed that engrafted tumors expressed more proliferation-related genes than those of non-englafted ones. Among six PDX models established, two were found to be CCC. Two PDX tumors of CCC maintained the histologic characteristics of parental CCC tumors. Gene expression profile revealed similar results between primary CCC and PDX tumors of CCC except that PDXs lost expression of immune-related genes.. Gene mutational analysis showed similar pattern between primary CCC and PDX of CCC. Drug-sensitivity test showed resistance to carboplatin in two PDX tumors of CCC, which is consistent with their clinical outcomes. Conclusions. PDXs of CCC were established and found to retain histologic and clinical features of original tumors, and can be utilized to screen new target drugs for platinum-resistant CCC.
Citation Format: Hidemichi Watari, Daisuke Endo, Kouhei Honda, Mihoko Kunitomo, Toshiyuki Nomura, Noriaki Sakuragi. Establishment and characterization of patient-derived xenografts of clear cell carcinoma of the ovary [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3845. doi:10.1158/1538-7445.AM2017-3845</jats:p
Abstract LB-323: Comparative miRNA microarray profiling indicates miR-363 promotes chemoresistance in ovarian cancer cells by targeting the Hippo member, LATS2
No full textAbstract
Ovarian cancer is the most aggressive female reproductive tract tumours. Taxane (TX) is widely used for ovarian cancer treatment. However, ovarian cancer often acquire chemoresistance. MicroRNAs (miR) have been reported to regulate many tumours’ chemoresistance. Here, we investigated the comparative microRNA expression profile between the ovarian cancer cells and their taxane-resistant counterpart, KF-TX to get novel markers for taxane resistance in ovarian cancer. The array data revealed that miR-486, miR143,miR145 and miR363 are the most upregulated miRNAs in association with TX resistance. However, miR-155, miR-100, miR-31 and miR-629 are the most significantly downregulated miRNAs after resistance development. We then focused on the role of miR-363 in chemoresistance of the ovarian cancer. qRT-PCR indicated that miR-363 was upregulated in KF-TX cells, confirming the array data, and introduction of miR-363 into sensitive ovarian cancer cells confers TX-resistance and significantly inhibited the expression of the Hippo member, LATS2, as indicated by viability, clonogenic assays and expression analysis. Furthermore, we validated the role of LATS2 in the TX-response by sh-based silencing, which also confers TX-resistance in the responsive ovarian cancer cells. On the other hand, specific inhibitor against miR-363 restored the response to TX. In addition, miR-363 was found to bind to the 3′-UTR of LATS2 mRNA, confirming that miR-363 directly targets LATS2 as indicated by dual luciferase assay. RT-PCR-based evaluation of miR-363 in a panel of human ovarian tumours revealed its upregulation in most of the tumour tissues identified as resistant while downregulation of the same gene in most of the tissues identified as sensitive ones. Moreover, higher levels of miR-363 in human ovarian cancer specimens were significantly correlated with TX chemoresistance and poor prognosis. Taken together, our study reveals the involvement of miR-363 in chemoresistance by targeting LATS2 in ovarian cancers, raising the possibility that combination therapy with a miR-363 inhibitor and TX may increase TX efficacy and reduce the chance of TX-resistance.
Note: This abstract was not presented at the meeting.
Citation Format: Noriaki Sakuragi, Mohamed Kamel Farah, Zeinab Mohamed, Safwat Okasha, Hidemichi Watari, Takashi Mitamura, sherif El Khamisy, Yusuke Ohba. Comparative miRNA microarray profiling indicates miR-363 promotes chemoresistance in ovarian cancer cells by targeting the Hippo member, LATS2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-323. doi:10.1158/1538-7445.AM2017-LB-323</jats:p
Changes of cerebral oxygenation indices measured by near infrared time‐resolved spectroscopy during spinal anesthesia for cesarean section: Simultaneous measurement with cerebral blood flow
No full textAim To measure the changes in cerebral oxygenation indices by near infrared time-resolved spectroscopy and the cerebral blood flow simultaneously after spinal anesthesia for cesarean section. Methods This prospective observational study was conducted for 25 pregnant women scheduled for elective cesarean section under spinal anesthesia. During a period of 15 min after spinal anesthesia, cerebral oxygenation (ScO2), and the total cerebral hemoglobin concentration (tHb) were measured using near infrared time-resolved spectroscopy and mean cerebral blood flow velocity (Vm) was measured using transcranial Doppler ultrasonography. Next, in the women who had nausea during the observed period, we compared these values when nausea was detected with those when it was not. Results Mean arterial pressure (MAP) decreased to around 60 mmHg (by 25% compared to the control) 6 min after spinal anesthesia. Compared to the control, ScO2 decreased by about 3% after 6 min and then gradually increased. The tHb, which reflects cerebral blood volume started to decrease just after spinal anesthesia and this continued until 12 min (the decrease was about 12%). Vm decreased by about 7%. In the 14 women who had nausea, MAP, Vm, and ScO2 values when nausea was detected were significantly lower than when it was not. Conclusion The changes in cerebral hemodynamics may be small after spinal anesthesia in ordinary cesarean section compared to the reduction of systemic arterial blood pressure. There might be greater decreases in cerebral blood flow and oxygenation when nausea occurred in the pregnant women who experienced it after spinal anesthesia
Intracellular clusterin negatively regulates ovarian chemoresistance: compromised expression sensitizes ovarian cancer cells to paclitaxel
No full textUnderstanding the molecular events that lead to
paclitaxel (TX) resistance is necessary to identify effective
means to prevent chemoresistance. Previously, results from
our lab revealed that secretory clusterin (CLU) form
positively mediates TX response in ovarian cancer cells.
Thus, we had interest to study the role of another nonsecreted
form (intracellular clusterin (i-CLU)) in chemoresponse.
Here, we provide evidences that i-CLU form
localizes mainly in the nucleus and differentially expressed
in the TX-responsive KF cells, versus TX-resistant, KF-TX,
ovarian cancer cells and negatively regulate cellular chemoresponse.
I-CLU was cloned, by deleting the secretionleading
signaling peptide from full-length CLU cDNA, and
transiently over-expressed in OVK-18 cells. Forced expression
of truncated i-CLU was mainly detectable in the nuclei
and significantly reduced cellular growth, accumulating
cells in G1 phase which finally died through apoptosis.
Importantly, compromised expression of i-CLU under an
inducible promoter was tolerated and did not induce
apoptosis but sensitized ovarian cancer cells to TX. We
then demonstrated that this sensitization mechanism was
cell cycle independent and relied on i-CLU/Ku70 binding
probably due to controlling the free amount of Ku70
available for DNA repair in the nucleus. Results from CLU
immunehistochemistry in ovarian tumor tissues verified the
retardation of nuclear CLU staining in the recurrent tumor
even though their primary counterparts showed nuclear
CLU staining. Thus, the controversial data on CLU
function in chemo-response/resistance may be explained
by a shift in the pattern of CLU expression and intracellular
localization as well when tumor acquires chemoresistance
Tailoring lymphadenectomy according to the risk of lymph node metastasis in endometrial cancer
No full textIt has been strongly suggested that patients with endometrial cancer with low risk of lymph node metastasis do not benefit from lymphadenectomy and that intermediate-risk/high-risk endometrial cancer patients benefit from complete pelvic and para-aortic lymphadenectomy. This hypothesis needs to be validated by prospective studies. For randomized controlled trials (RCT), heterogeneity of intervention compromises internal validity and non-participation of experienced doctors compromises external validity. As these situations easily occur in randomized surgical trials (RST) intended for high-risk patients, the effects of complicated surgery, such as full lymphadenectomy, might be underestimated in RST. In a famous RST, data for all eligible patients implied that survival outcome for the non-randomized group was significantly better than that for the randomized group. One plausible explanation is that physicians' judgment and experience produce better treatment decisions than do random choices. Although two RCT from European countries showed negative results of lymphadenectomy on prognosis, valuing the care of individual patients may be more important than uncritically adopting the results of RCT. In endometrial cancer, lymphadenectomy must be tailored to maximize the therapeutic effect of surgery and minimize its invasiveness and adverse effects. Two strategies are: (i) to remove lymph nodes most likely to harbor disease while sparing lymph nodes that are unlikely to be affected; and (ii) to perform full lymphadenectomies only on patients who can potentially benefit from them. Here, we focus on the second strategy. Preoperative risk assessments used in Japan and Korea to select low-risk patients who would not benefit from lymphadenectomy are discussed
Human papillomavirus 16-positive uterine cervical squamous cell carcinoma with coinfection with human papillomavirus 34 has a lower incidence in lymph node metastasis than that without coinfection with human papillomavirus 34
No full textOur earlier study demonstrated high prevalence of multiple human papillomavirus (HPV) infection in patients with invasive uterine cervical cancer, including squamous cell carcinoma (SCC). HPV 16 is the most predominant genotype related to SCC of the uterine cervix. The aim of this study was to reveal the biological significance of multiple HPV infection concerning the tumor progression of invasive uterine cervical SCC. In the present study, the effects of coinfection with genotypes other than HPV 16 on tumor growth and lymph node metastasis of invasive uterine cervical SCC with HPV 16 infection were examined. Although coinfection with most genotypes did not influence tumor progression, the clinical stage of patients coinfected with HPV 16 and HPV 34 was significantly lower than that of those without HPV 34 coinfection (p = 0.0038). Moreover, no patient coinfected with HPV 16 and HPV 34 manifested lymph node metastasis, but about half of the patient population without HPV 34 coinfection did (p = 0.0299). These findings suggested that coinfection with HPV 34 could prevent the tumor progression of invasive uterine cervical SCC with HPV 16 infection. Copyright (C) 2013 S. Karger AG, Base
Relationship between out‐of‐facility deliveries and distance and travel time to delivery facilities in Hokkaido, Japan: An ecological study
No full textAim: This study aimed to investigate the relationship between the distance and travel time from each municipality to the nearest delivery facilities in the other municipalities and the frequency of out-of-facility deliveries in Hokkaido. Methods: Vital statistics from 2016 to 2020 were used. For municipalities without delivery facilities, the distance and travel time from the town office of each municipality to the nearest delivery facility was measured using Google maps. Negative binomial regression with an offset term was used to calculate the relative risks (RRs) and 95% confidence intervals (CIs) of out-of-facility delivery for distance (= 60 km), and travel time by car (= 60 min) from the town office to the nearest delivery facility compared with the presence of delivery facilities. Results: The overall rate of out-of-facility deliveries in Hokkaido was 2.1 parts per thousand; in municipalities with delivery facilities, 1.8 parts per thousand, and in municipalities without delivery facilities, 3.1 parts per thousand. The adjusted RRs (95% CIs) for out-of-facility deliveries were significantly higher in municipalities with less than 30 km and travel time of less than 30 min to delivery facilities, 2.63 (1.34-5.17) and 2.76 (1.36-5.58), respectively, compared to municipalities with delivery facilities. However, the adjusted RR of out-of-facility delivery for municipalities >= 30 km was higher, although the difference was not significant. Conclusions: Even in municipalities with a distance to delivery facilities of less than 30 km or travel time of less than 30 min, we should keep in mind the occurrence of out-of-facility deliveries
The difficulty to diagnose cervical cancer developing in the perinatal period with the first‐trimester cytology: A retrospective study
No full textAim Cytological cervical cancer screening for pregnant women is routinely performed and still plays an essential role in Japan because of the considerably low rate of human pappillomavirus (HPV) vaccination. Though almost all pregnant women undergo cytological screening at their first trimester, we experienced invasive cervical cancers (ICC) diagnosed during pregnancy or postpartum period. We investigated the characteristics of perinatally diagnosed ICCs to clarify the difficulty in diagnosis during the pregnancy. Methods We retrospectively reviewed the clinical data on ICC diagnosed during pregnancy or within 1 year after delivery from 2010 to 2018 at Hokkaido University Hospital. Results We identified 18 ICC patients, and the median follow-up period was 46.5 months. Among eight patients with negative for intraepithelial lesion or malignancy (NILM), the mean duration to reach ICC diagnosis was 10.7 months, seven had stage IB1 or worse, and one was dead. On the other hand, among 10 women with abnormal cytology, the mean duration for diagnosis was 1.4 months, and 6 had stage IB1 or worse, and 1was dead. In terms of the timing of the final diagnosis, 8 were during pregnancy and 10 in the postpartum periods. Among eight pregnant patients, three resulted in a preterm delivery (33, 34, and 35 gestational weeks), and four terminated their pregnancies. One decided to continue the pregnancy until the term period. We performed conization in one patient and hysterectomy in seven. Conclusion A part of cytological examinations of pregnant women may result in presumed false-negative or underestimation, which keeps them away from the additional examination to find ICC
Lipopolysaccharide Induces Expression of Genes Encoding Pro-Inflammatory Cytokines and the Elastin-Degrading Enzyme, Cathepsin S, in Human Cervical Smooth-Muscle Cells
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