Tubo-ovarian abscess caused by Clostridioides difficile after eight months of surgery: Case report and review of extraintestinal abdominal abscess cases.

We present a case of tubo-ovarian abscess (TOA) caused by Clostridioides difficile (CD) in a 43-year-old female. Despite lacking a history of sexually transmitted diseases, the patient had undergone paraovarian cystectomy nine months before admission. Transvaginal ultrasonography performed eight months post-surgery revealed left ovarian enlargement, accompanied by subsequent lower abdominal pain and fever exceeding 38 °C. As oral antibiotic treatment was ineffective, the patient was admitted to our hospital. Computed tomography upon admission revealed a massive TOA. Surgical drainage of the abscess was performed, and CD was identified in the culture from the pus. The TOA was treated with a three-month course of metronidazole and oral amoxicillin/clavulanic acid. While CD is commonly associated with colitis, extraintestinal manifestations are exceptionally rare. This case represents the inaugural report of TOA resulting from CD. A literature review on abdominal and pelvic CD abscesses found that patients undergoing surgical drainage had a favorable prognosis. Therefore, surgical intervention plays an important role in the management of CD abscesses.

Proposal for individual treatment by tubal occlusion factor based on the results of salpingoscopic salpingoplasty.

AIM: As a treatment for tubal infertility, falloposcopic tuboplasty (FT) is one of the options for patients who wish to conceive naturally. Based on the results of FT, we propose an appropriate time of transitioning to assisted reproductive technology (ART) for tubal infertility. OBJECTS AND METHODS: We examined the outcomes of cases of tubal infertility during the period from June 1999 through March 2021 who were performed tuboplasty at our hospital using the FT catheter system under laparoscopy. RESULTS: The number of treated cases was 828. There were 243 cases of endometriosis and 119 cases of genital chlamydial infection. By FT, 712 cases (86.0%) were successfully recanalized. Of the 712 cases, 189 conceived naturally (26.5%) and miscarriages were 23 cases (12.2%), ectopic pregnancies were 8 cases (4.2%). The mean duration from FT to pregnancy was 6.5 months in natural pregnancy group, 90% of them were pregnant within 14 months. In endometriosis cases, the pregnancy rate after FT did not change significantly among clinical stage. CONCLUSIONS: Even when the fallopian tube was recanalized by FT, if the couple is unable to conceive naturally, they had better to consider switching to ART at about 14 months. When the couples with endometriosis consider switching to ART, we suggest deciding without considering the rASRM stage.

The role of transperineal ultrasonography for perinatal management: A review.

BACKGROUND: Transperineal ultrasound (TPUS) has become an increasingly popular tool in obstetrics due to its objective, non-invasive, and real-time imaging capabilities. AIM: This review aims to describe the basic approaches, current utilization, and potential future applications of TPUS. MATERIALS & METHOD: A comprehensive literature review on TPUS was conducted. In addition, discussions at academic meetings and congress focused on TPUS were also considered. RESULTS: TPUS was initially used in prostate biopsies and is currently applied to evaluating fetal head descent in labor, with the angle of progression being the most widely used parameter. It is more tolerated than conventional invasive or expensive methods, such as digital vaginal examinations or MRIs. Additionally, TPUS can assess the internal rotation of the fetal head in the birth canal. DISCUSSION: Compared to other imaging modalities like MRI and CT scans, TPUS is easier to perform and more cost-effective. It also provides real-time imaging, allowing for quick and accurate assessments. It also help clinicians make critical decisions regarding the mode of delivery and identify patients at high risk for fecal incontinence postpartum. With its many benefits, TPUS has the potential to become a standard tool in urogynecology and obstetrics. CONCLUSIONS: Transperineal ultrasound is a non-invasive imaging modality that is well-tolerated and easy to understand for patients and their family and help medical staff support the patients. Transperineal ultrasound can be applied in real-time monitoring of labor progress, helping predict the possibility of vaginal delivery during labor, and further research in this area is warranted.

Intrauterine adhesion after hysteroscopic myomectomy of submucous myomas.

PURPOSE: To evaluate the frequency of intrauterine adhesion (IUA) after hysteroscopic myomectomy, and to analyze the association of IUA and the location of submucous myomas and the use of postoperative barrier (POB). METHODS: Hysteroscopic myomectomy was performed in 217 patients with submucous myomas. The retrospective investigation was performed, and the cases were divided into three groups: cases with solitary submucous myoma (SSM; group 1), cases with apposing submucous myomas (ASMs; group 2) and cases with submucous myomas that were far from each other or not in apposition to one another (not apposing submucous myomas: NASMs; group 3). As POB, intrauterine device with oxidized regenerated cellulose and silicon sheet was inserted immediately after surgery. RESULTS: IUA formation after hysteroscopic myomectomy was more frequent in group 2 than groups 1 and 3 (p = 0.03 and 0.01, respectively), despite the higher rates of POB use (p = 0.02). There was no significant difference in IUA formation in cases with POB between each group (p = 0.06 and 0.21, respectively). But in cases without POB, group 2 showed higher rates of IUA formation than group 1 (p = 0.04) and group 3 (p = 0.03). Multivariable analysis for IUA formation demonstrated that ASMs were a risk factor of IUA (hazard ratio [HR] = 27.9, p < 0.01), and the use of POB was a prognostic factor for reduction of IUA formation (HR = 0.08, p < 0.01). CONCLUSION: ASMs appear to be a risk factor for IUA formation. The use of POB may be associated with preventing IUA formation after hysteroscopic myomectomy.

The TGF-ß/UCHL5/Smad2 Axis Contributes to the Pathogenesis of Placenta Accreta.

Placenta accreta is a high-risk condition causing obstetric crisis and hemorrhage; however, its pathogenesis remains unknown. We aimed to identify the factors contributing to trophoblast invasiveness and angiogenic potential, which in turn drive the pathogenesis of placenta accreta. We focused on the transforming growth factor (TGF)-ß1-Smad pathway and investigated the intrinsic relationship between the time- and dose-dependent inhibition of the ubiquitinating enzyme UCHL5 using bAP15, a deubiquitinase inhibitor, after TGF-ß1 stimulation and the invasive and angiogenic potential of two cell lines, gestational choriocarcinoma cell line JEG-3 and trophoblast cell line HTR-8/SVneo. UCHL5 inhibition negatively regulated TGF-ß1-induced Smad2 activation, decreasing extravillous trophoblast invasiveness. Smad1/5/9 and extracellular signal-regulated kinase (ERK) were simultaneously activated, and vascular endothelial growth factor was secreted into the trophoblast medium. However, extravillous trophoblast culture supernatant severely impaired the vasculogenic potential of human umbilical vein endothelial cells. These results suggest that the downstream ERK pathway and Smad1/5/9 potentially regulate the TGF-ß1-Smad pathway in extravillous trophoblasts, whereas Smad2 contributes to their invasiveness. The abnormal invasive and angiogenic capacities of extravillous cells, likely driven by the interaction between TGF-ß1-Smad and ERK pathways, underlie the pathogenesis of placenta accreta.

A case of adenomyosis with leiomyoma that was effectively treated with relugolix and kamishoyosan add-on therapy.

BACKGROUND: Recently, relugolix, an oral gonadotropin-releasing hormone receptor antagonist, has been considered an effective therapy for leiomyoma based on a phase 3 study in Japanese women. Leiomyoma combined with severe adenomyosis occasionally occurs in perimenopausal women; however, little information on the effectiveness of relugolix against severe adenomyosis exists. CASE PRESENTATION: A 49-year-old woman was referred to our hospital with acute lower abdominal pain and abnormal uterine bleeding. Magnetic resonance imaging revealed multiple leiomyomas with diffuse adenomyosis. Left hydrosalpinx was also observed. The patient refused surgical treatment and preferred oral relugolix. Since she experienced a hot flush and headache induced by relugolix, a traditional Japanese Kampo, kamishoyosan, was added to improve the side effects of relugolix. The patient was asymptomatic at the time of this report and experienced a significant shrinkage in uterine volume. Ultimately, she avoided hysterectomy as desired. CONCLUSIONS: To our knowledge, this is the first report of co-occurring adenomyosis and leiomyoma, which was effectively treated with relugolix. Although the management of adverse side effects, including hot flush and headache by relugolix, has recently attracted attention and controversy, relugolix add-on therapy with kamishoyosan may help treat menopausal symptoms.

Effect of murine double-minute 2 inhibitors in preclinical models of advanced clear cell carcinomas originating from ovaries and kidneys.

Advanced clear cell carcinomas originating from both ovaries and kidneys with cancerous peritonitis have poor prognoses. Murine double-minute 2 (MDM2) is a potential therapeutic target for clear cell ovarian carcinomas with WT TP53. Herein, we characterized the antiangiogenic and antitumor effects of the MDM2 inhibitors DS-3032b and DS-5272 in 6 clear cell ovarian carcinoma cell lines and 2 clear cell renal carcinoma cell lines, as well as in clear cell ovarian carcinomas s.c. xenograft and ID8 (murine ovarian cancer cells with WT TP53) cancer peritonitis mouse models. In clear cell ovarian carcinoma s.c. xenograft mouse models, DS-3032b significantly reduced WT TP53 clear cell ovarian carcinoma- and clear cell renal carcinoma-derived tumor volumes. In ID8 mouse models, DS-5272 significantly inhibited ascites production, reduced body weight, and significantly improved overall survival. Additionally, DS-5272 reduced the tumor burden of peritoneal dissemination and decreased CD31+ cells in a dose-dependent manner. Furthermore, DS-5272 significantly decreased vascular endothelial growth factor concentrations in both sera and ascites. Combined therapy with MDM2 inhibitors and everolimus showed synergistic, and dose-reduction potential, for clear cell carcinoma treatment. Our findings suggest that MDM2 inhibitors represent promising molecular targeted therapy for clear cell carcinomas, thereby warranting further studies to evaluate the efficacy and safety of dual MDM2/mTOR inhibitors in clear cell carcinoma patients.

Rikkunshito attenuates induction of epithelial-mesenchymal switch via activation of Sirtuin1 in ovarian cancer cells.

Rikkunshito, a traditional Japanese herbal medicine, improves appetite via activation of gastrointestinal hormone ghrelin pathway. The function of ghrelin is mediated by growth hormone secretagogue receptor (GHSR1a), and ghrelin has been known to possess diverse physiological functions including growth suppression of some cancer cells. Considering that increased ghrelin signaling by Rikkunshito could enhance sirtuin1 (SIRT1) activity in nervous system, we aimed to investigate the effect of Rikkunshito in ovarian cancer cells. Ovarian cancer cell lines were treated with Rikkunshito, and cellular viability, gene expressions and epithelial-mesenchymal transition (EMT) status were investigated. To investigate the involvement of SIRT1 by Rikkunshito in SKOV3 cancer cells, endogenous expression of SIRT1 was depleted using small interfering RNA (siRNA). Treatment with Rikkunshito elevated ghrelin, GHSR1a and SIRT1, while cellular viability was decreased. The treatment of Rikkunshito also inhibited cellular migration and invasion status in a dose-dependent manner, and these effects were translated to the enhanced EMT status, although the role of SIRT1 was not determined. Our study revealed a novel function of Rikkunshito in enhancing EMT status of ovarian cancer cells. Therefore, we would like to propose that Rikkunshito may be used as a novel adjunctive therapy in chemotherapy of ovarian cancer because platinum-based chemotherapy frequently used for the treatment of ovarian cancer inevitably impairs appetite.

Histone methyltransferase SMYD2 selective inhibitor LLY-507 in combination with poly ADP ribose polymerase inhibitor has therapeutic potential against high-grade serous ovarian carcinomas.

Dysfunction of histone methylation is known to be related to cancer progression. The histone methyltransferase SMYD2 methylates histone protein H3 and non-histone proteins, including poly ADP ribose polymerase 1 (PARP1). There have been reports of SMYD2 overexpression in several types of cancers. However, there are no reports regarding its role in high-grade serous ovarian carcinomas (HGSOCs). Therefore, we investigated the expression profile and conducted functional analysis on SMYD2 in HGSOC cells. In addition, we verified whether SMYD2 inhibition increases the susceptibility of HGSOC cells to PARP inhibitors. We analyzed the expression of histone methyltransferase SMYD2 by quantitative real-time polymerase chain reaction and immunohistochemistry using HGSOC clinical tissues (n = 35). We performed functional analyses, including cell proliferation assay, cell cycle analysis, and immunoblotting, after treatment with SMYD2 siRNAs and SMYD2 selective inhibitor LLY-507 in HGSOC cells. We also performed colony-formation assay after combination treatment with LLY-507 and PARP inhibitor olaparib in HGSOC cells. The expression profiles of SMYD2 showed significant overexpression of SMYD2 in HGSOC clinical tissues. The knockdown or inhibition of SMYD2 by siRNAs or LLY-507, respectively, suppressed cell growth by increasing the proportion of apoptotic cells. LLY-507 showed additive effect with olaparib in the colony-formation assay. These findings suggest that LLY-507 can be used alone or in combination with a PARP inhibitor for the treatment of patients with HGSOC.

The histone methyltransferase WHSC1 is regulated by EZH2 and is important for ovarian clear cell carcinoma cell proliferation.

BACKGROUND: Wolf-Hirschhorn syndrome candidate gene-1 (WHSC1), a histone methyltransferase, has been found to be upregulated and its expression to be correlated with expression of enhancer of zeste homolog 2 (EZH2) in several cancers. In this study, we evaluated the role of WHSC1 and its therapeutic significance in ovarian clear cell carcinoma (OCCC). METHODS: First, we analyzed WHSC1 expression by quantitative PCR and immunohistochemistry using 23 clinical OCCC specimens. Second, the involvement of WHSC1 in OCCC cell proliferation was evaluated by MTT assays after siRNA-mediated WHSC1 knockdown. We also performed flow cytometry (FACS) to address the effect of WHSC1 on cell cycle. To examine the functional relationship between EZH2 and WHSC1, we knocked down EZH2 using siRNAs and checked the expression levels of WHSC1 and its histone mark H3K36m2 in OCCC cell lines. Finally, we checked WHSC1 expression after treatment with the selective inhibitor, GSK126. RESULTS: Both quantitative PCR and immunohistochemical analysis revealed that WHSC1 was significantly overexpressed in OCCC tissues compared with that in normal ovarian tissues. MTT assay revealed that knockdown of WHSC1 suppressed cell proliferation, and H3K36me2 levels were found to be decreased in immunoblotting. FACS revealed that WHSC1 knockdown affected the cell cycle. We also confirmed that WHSC1 expression was suppressed by EZH2 knockdown or inhibition, indicating that EZH2 is upstream of WHSC1 in OCCC cells. CONCLUSIONS: WHSC1 overexpression induced cell growth and its expression is, at least in part, regulated by EZH2. Further functional analysis will reveal whether WHSC1 is a promising therapeutic target for OCCC.

Array comparative genomic hybridization analysis discloses chromosome copy number alterations as indicators of patient outcome in lymph node-negative breast cancer.

BACKGROUND: Patients with lymph node metastasis-negative (pN0) invasive breast cancer have favorable outcomes following initial treatment. However, false negatives which occur during routine histologic examination of lymph nodes are reported to underestimate the clinical stage of disease. To identify a high-risk group in pN0 invasive breast cancer, we examined copy number alterations (CNAs) of 800 cancer-related genes. METHODS: Using array-based comparative genomic hybridization (CGH) in 51 pN0 cases (19 relapsed and 32 non-relapsed cases), the positivities of specific gene CNAs in the relapsed and non-relapsed groups were compared. An unsupervised hierarchical cluster analysis was then performed to identify case groups that were correlated with patient outcomes. RESULTS: The cluster analysis identified three distinct clusters of cases: groups 1, 2, and 3. The major component was triple-negative cases (69%, 9 of 13) in group 1, luminal B-like (57%, 13 of 23) and HER2-overexpressing (26%, 6 of 23) subtypes in group 2, and luminal A-like subtype (60%, 9 of 15) in group 3. Among all 51 cases, those in group 1 showed significantly worse overall survival (OS) than group 2 (p = 0.014), and 5q15 loss was correlated with worse OS (p = 0.017). Among 19 relapsed cases, both OS and relapse-free survival (RFS) rates were significantly lower in group 1 than in group 2 (p = 0.0083 and 0.0018, respectively), and 5q15 loss, 12p13.31 gain, and absence of 16p13.3 gain were significantly correlated with worse OS and RFS (p = 0.019 and 0.0027, respectively). CONCLUSIONS: As the target genes in these loci, NR2F1 (5q15), TNFRSF1A (12p13.31), and ABCA3 (16p13.3) were examined. 5q15 loss, 12p13.31 gain, and absence of 16q13.3 gain were potential indicators of high-risk recurrence and aggressive clinical behavior of pN0 invasive breast cancers.

Detection of HPV RNA molecules in stratified mucin-producing intraepithelial lesion (SMILE) with concurrent cervical intraepithelial lesion: a case report.

BACKGROUND: Stratified mucin-producing intraepithelial lesion (SMILE) is a rare precursor lesion in the uterine cervix that is considered a variant of adenocarcinoma in situ (AIS). Although human papillomavirus (HPV) is thought to be related to the development of SMILE, there is little information available on the detection of HPV integrated into the lesion. CASE PRESENTATION: A 30-year-old female underwent a routine uterine cervical cancer screening, and her Pap smear indicated the possible existence of atypical glandular cells. A cervical biopsy with endocervical curettage was performed. The histopathological analysis showed that she had SMILE and high-grade squamous intraepithelial lesion (HSIL) on her cervix. The lesion was found to be positive for HPV genotypes 52 and 68 by multiplex PCR. In situ hybridization with HPV RNA probes revealed that these HPV types were involved in the onset of HSIL and SMILE, respectively. CONCLUSIONS: Rare, high-risk HPV genotypes may contribute to the development of SMILE, and their detection can be useful for preventing the progression to carcinoma and ensuring adequate patient management.

Anti-tumor activity of dual inhibition of phosphatidylinositol 3-kinase and MDM2 against clear cell ovarian carcinoma.

INTRODUCTION: PI3K pathway signaling has received attention as a molecular target in clear cell ovarian carcinoma (CCOC). MDM2 is one of the AKT effectors in the PI3K pathway, which binds to and degrades p53. In this study, we aimed to clarify the prognostic significance of PIK3CA and MDM2 expression, and potential therapeutic effect of a dual inhibition of the PI3K pathway and MDM2. MATERIALS AND METHODS: cDNA expression was evaluated by using microarray data using 75 samples of CCOC. DS-7423 (dual inhibitor of pan-PI3K and mTOR) and RG7112 (MDM2 inhibitor) were used on CCOC cell lines to evaluate cell proliferation, expression level of MDM2 related proteins, and apoptosis by MTT assay, western blotting, and flow cytometry. DS-7423 (3 mg/kg) and/or RG7112 (50 mg/kg) were orally administrated every day for three weeks, and the anti-tumor effect was evaluated using tumor xenografts, along with immunohistochemistry. RESULTS: Tumors with high expression of both PIK3CA and MDM2 showed significantly worse prognosis in expression array of 71 CCOCs (P = 0.013). Dual inhibition of the PI3K pathway by DS-7423 and MDM2 by RG7112 showed synergistic anti-proliferative effect in 4 CCOC cell lines without TP53 mutations. The combination therapy more robustly induced pro-apoptotic proteins (PUMA and cleaved PARP) with increase of sub G1 population and apoptotic cells, compared with either single agent alone. The combination therapy significantly reduced tumor volume in mice (P < 0.001 in OVISE, and P = 0.038 in RMG-I) without severe body weight loss. Immunohistochemistry from the xenograft tumors showed that the combination treatment significantly reduced vascularity and cell proliferation, with an increase of apoptotic cell death. CONCLUSION: A combination therapy targeting the PI3K pathway and MDM2 might be a promising therapeutic strategy in CCOC.

Usefulness of cell-free and concentrated ascites reinfusion therapy in the therapeutic management of advanced ovarian cancer patients with massive ascites.

BACKGROUND: The management of refractory ascites in advanced ovarian cancer (AOC) is vital for patients with abdominal distention, respiratory distress, and anorexia due to massive ascites with cancer peritonitis. We analyzed the benefits of concentrated ascites reinfusion therapy (CART) in the management of AOC. METHODS: We reviewed records of AOC patients who underwent CART between January 2011 and March 2017. We retrospectively analyzed patients' backgrounds and physiological changes, including body weight, abdominal girth, urine volume, blood component values, blood pressure, heart rate, and body temperature before and after CART. We investigated the clinicopathological significance of CART by measuring the mean number of ascites tumor cell (ATC) clusters before CART. RESULTS: A retrospective analysis was performed on 29 cases of AOC with massive ascites involving 47 CART sessions. The patients' mean age was 56.6 ± 12.8 years, and the mean number of sessions was 1.7 ± 1.2. The mean volume of the processed ascites was 2,937 ± 820 mL, which was concentrated to 272 ± 84 mL containing 85.0 ± 33.2 g protein on average. Significant reductions in abdominal girth (- 5.30 ± 0.65 cm; p < 0.0001) and body weight (- 2.97 ± 0.26 kg; p = 0.0011), increased urine volume (+ 824.29 ± 145.21 mL; p < 0.0001), and improved serum albumin levels (+ 0.18 ± 0.34; p < 0.0001) were observed after CART. Analysis of variance revealed significant elevations in body temperature after CART in 11 patients with a small number of ATC clusters. CONCLUSIONS: CART is useful for the therapeutic management of AOC patients with refractory massive ascites. Elevations of body temperature after CART may be avoided by the investigation of patients' peritoneal cytology before CART.

Expression of the glucagon-like peptide-1 receptor and its role in regulating autophagy in endometrial cancer.

BACKGROUND: A previous report showed that a glucagon-like peptide-1 receptor (GLP-1R) agonist (exenatide) induced apoptosis in endometrial cancer cells. However, the pathophysiological role of GLP-1R in endometrial cancer has not been fully elucidated. Here, we investigated the effects of the GLP-1R agonist liraglutide in endometrial cancer cells and examined the association between GLP-1R expression and clinicopathological characteristics in endometrial cancer patients. METHODS: Human Ishikawa endometrial cancer cells were treated with different concentrations of liraglutide. To assess the effects of liraglutide, cell viability, colony formation, flow cytometry, Western blotting, and immunofluorescence assays were performed. Autophagy induction was examined by analyzing LC3 and p62 expression and autophagosome accumulation. Moreover, using a tissue microarray, we analyzed GLP-1R expression in 154 endometrial cancer tissue samples by immunohistochemistry. RESULTS: In accordance with the previous report, liraglutide inhibited Ishikawa cell growth in a dose-dependent manner. Liraglutide significantly induced autophagy, and phosphorylated AMPK expression was elevated. Immunohistochemical analysis revealed that GLP-1R expression was associated with positive estrogen receptor and progesterone receptor status, and higher GLP-1R expression was significantly correlated with better progression-free survival. CONCLUSIONS: The use of liraglutide to target autophagy in endometrial cancer cells may be a novel potential treatment for endometrial cancer. Furthermore, higher GLP-1R expression may be associated with better prognosis in endometrial cancer patients.

Blood Vessel Invasion Is a Strong Predictor of Postoperative Recurrence in Endometrial Cancer.

OBJECTIVES: Although lymphovascular space invasion is a prognostic factor for the recurrence of resectable endometrial cancer, the differential impacts of lymphatic vessel invasion (LVI) and blood vessel invasion (BVI) on the recurrence of endometrial cancer are poorly described. We investigated the prognostic significance of LVI and BVI on the recurrence of endometrial cancer and their association with patterns of recurrence. METHODS: We retrospectively reviewed 376 patients with stage I to III endometrial cancer who underwent surgery with curative intent at our institution between 2007 and 2015. The associations of the presence of lymphovascular space invasion or LVI and BVI with recurrence-free survival and patterns of recurrence were evaluated. RESULTS: Lymphovascular space invasion positivity was an independent prognostic factor for recurrence-free survival (hazards ratio [HR], 3.070; 95% confidence interval [CI], 1.404-6.824; P = 0.0048). However, when categorized by LVI versus BVI, the latter was a strong independent prognostic factor (HR, 2.697; CI, 1.288-5.798; P = 0.0081), whereas the former was not (HR, 1.740; CI, 0.795-3.721; P = 0.1637). Hematogenous metastasis was the most prevalent form of recurrence in endometrial cancer (24 [50%] of all 48 recurrent cases). Notably, 17 (19.5%) of 87 patients with BVI developed hematogenous metastases, compared with 7 (2.4%) of 289 without BVI (χ test, P < 0.0001). CONCLUSIONS: Blood vessel invasion rather than LVI was a strong predictor of postoperative recurrence in stage I to III endometrial cancer, probably due to its predisposition to hematogenous metastases.

Enhanced efficacy against cervical carcinomas through polymeric micelles physically incorporating the proteasome inhibitor MG132.

Treatment of recurrent or advanced cervical cancer is still limited, and new therapeutic choices are needed for improving prognosis and quality of life of patients. Because human papilloma virus (HPV) infection is critical in cervical carcinogenesis, with the E6 and E7 oncogenes of HPV degrading tumor suppressor proteins through the ubiquitin proteasome system, the inhibition of the ubiquitin proteasome system appears to be an ideal target to suppress the growth of cervical tumors. Herein, we focused on the ubiquitin proteasome inhibitor MG132 (carbobenzoxy-Leu-Leu-leucinal) as an anticancer agent against cervical cancer cells, and physically incorporated it into micellar nanomedicines for achieving selective delivery to solid tumors and improving its in vivo efficacy. These MG132-loaded polymeric micelles (MG132/m) showed strong tumor inhibitory in vivo effect against HPV-positive tumors from HeLa and CaSki cells, and even in HPV-negative tumors from C33A cells. Repeated injection of MG132/m showed no significant toxicity to mice under analysis by weight change or histopathology. Moreover, the tumors treated with MG132/m showed higher levels of tumor suppressing proteins, hScrib and p53, as well as apoptotic degree, than tumors treated with free MG132. This enhanced efficacy of MG132/m was attributed to their prolonged circulation in the bloodstream, which allowed their gradual extravasation and penetration within the tumor tissue, as determined by intravital microscopy. These results support the use of MG132 incorporated into polymeric micelles as a safe and effective therapeutic strategy against cervical tumors.

Characterization of novel transcripts of human papillomavirus type 16 using cap analysis gene expression technology.

We have performed cap-analysis gene expression (CAGE) sequencing to identify the regulatory networks that orchestrate genome-wide transcription in human papillomavirus type 16 (HPV16)-positive cervical cell lines of different grades: W12E, SiHa, and CaSki. Additionally, a cervical intraepithelial neoplasia grade 1 (CIN1) lesion was assessed for identifying the transcriptome expression profile. Here we have precisely identified a novel antisense noncoding viral transcript in HPV16. In conclusion, CAGE sequencing should pave the way for understanding a diversity of viral transcript expression.

A case of lymphangioleiomyomatosis associated with endometrial cancer and severe systemic lupus erythematosus.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare idiopathic disorder that occurs in women of childbearing age, and consists of a diffuse proliferation of abnormal smooth muscle cells along the thoracic and abdominal lymphogenous route. CASE PRESENTATION: We experienced a case of a 47-yo woman with recent history of systemic lupus erythematosus (SLE) diagnosed with endometrial cancer, initially suspected to have metastasized to pelvic and para-aortic lymph nodes based on preoperative diagnostic imaging. Subsequent pathological diagnosis revealed stage IB endometrial cancer without evidence of lymph node involvement. Instead, enlarged pelvic and para-aortic lymph nodes were found to be due to extrapulmonary LAM, from a primary lesion found inside the uterine myometrium. SLE improved after surgery. CONCLUSION: This is the first reported case of comorbid endometrial cancer, SLE, and aggressive LAM metastasizing to regional lymph nodes, and strengthens the clinical evidence for a common role of mTOR pathway hyperactivity and estrogen responsiveness in the pathophysiology of metastasizing lesions of the genital tract.

Expression of Par3 polarity protein correlates with poor prognosis in ovarian cancer.

BACKGROUND: Previous studies have shown that the cell polarity protein partitioning defective 3 (Par3) plays an essential role in the formation of tight junctions and definition of apical-basal polarity. Aberrant function of this protein has been reported to be involved in epithelial-mesenchymal transition (EMT) and cancer invasion. The aim of this study was to examine the functional mechanism of Par3 in ovarian cancer. METHODS: First, we investigated the association between Par3 expression level and survival of 50 ovarian cancer patients. Next, we conducted an in vitro analysis of ovarian cancer cell lines, focusing on the cell line JHOC5, to investigate Par3 function. To investigate the function of Par3 in invasion, the IL-6/STAT3 pathway was analyzed upon Par3 knockdown with siRNA. The effect of siRNA treatment was assessed by qPCR, ELISA, and western blotting. Invasiveness and cell proliferation following treatment with siRNA against Par3 were investigated using Matrigel chamber, wound healing, and cell proliferation assays. RESULTS: Expression array data for ovarian cancer patient samples revealed low Par3 expression was significantly associated with good prognosis. Univariate analysis of clinicopathological factors revealed significant association between high Par3 levels and peritoneal dissemination at the time of diagnosis. Knockdown of Par3 in JHOC5 cells suppressed cell invasiveness, migration, and cell proliferation with deregulation of IL-6/STAT3 activity. CONCLUSION: Taken together, these results suggest that Par3 expression is likely involved in ovarian cancer progression, especially in peritoneal metastasis. The underlying mechanism may be that Par3 modulates IL-6 /STAT3 signaling. Here, we propose that the expression of Par3 in ovarian cancer may control disease outcome.