Analyzing Optimal Wearable Motion Sensor Placement for Accurate Classification of Fall Directions.

Falls represent a significant risk factor, necessitating accurate classification methods. This study aims to identify the optimal placement of wearable sensors-specifically accelerometers, gyroscopes, and magnetometers-for effective fall-direction classification. Although previous research identified optimal sensor locations for distinguishing falls from non-falls, limited attention has been given to the classification of fall direction across different body regions. This study assesses inertial measurement unit (IMU) sensors placed at 12 distinct body locations to determine the most effective positions for capturing fall-related data. The research was conducted in three phases: first, comparing classifiers across all sensor locations to identify the most effective; second, evaluating performance differences between sensors placed on the left and right sides of the body; and third, exploring the efficacy of combining sensors from the upper and lower body regions. Statistical analyses of the results for the most effective classifier model demonstrate that the support vector machine (SVM) is more effective than other classifiers across all sensor locations, with statistically significant differences in performance. At the same time, the comparison between the left and right sensor locations shows no significant performance differences within the same anatomical areas. Regarding optimal sensor placement, the findings indicate that sensors positioned on the pelvis and upper legs in the lower body, as well as on the shoulder and head in the upper body, were the most effective results for accurate fall-direction classification. The study concludes that the optimal sensor configuration for fall-direction classification involves strategically combining sensors placed on the pelvis, upper legs, and lower legs.

Circulating Exosomal miR-1290 for Diagnosis of Epithelial Ovarian Cancer.

The aim of the study was to develop a new diagnostic biomarker for identifying serum exosomal miRNAs specific to epithelial ovarian cancer (EOC) and to find out target gene of the miRNA for exploring the molecular mechanisms in EOC. A total of 84 cases of ovarian masses and sera were enrolled, comprising EOC (n = 71), benign ovarian neoplasms (n = 13). We detected expression of candidate miRNAs in the serum and tissue of both benign ovarian neoplasm group and EOC group using real-time polymerase chain reaction. Immunohistochemistry were constructed using formalin fixed paraffin embedded (FFPE) tissue to detect expression level of suppressor of cytokine signaling 4 (SOCS4). In the EOC group, miRNA-1290 was significantly overexpressed in serum exosomes and tissues as compared to benign ovarian neoplasm group (fold change ≥ 2, p < 0.05). We observed area under the receiver operating characteristic curve (AUC) for miR-1290, using a cut-off of 0.73, the exosomal miR-1290 from serum had AUC, sensitivity, and specificity values of 0.794, 69.2 and 87.3, respectively. In immunohistochemical study, expression of SOCS4 in EOC was lower than that in benign ovarian neoplasm. Serum exosomal miR-1290 could be considered as a biomarker for differential diagnosis of EOC from benign ovarian neoplasm and SOCS4 might be potential target gene of miR-1290 in EOC.

Vogt-Koyanagi-Harada syndrome-like uveitis after nivolumab administration as a treatment for ovarian cancer.

PURPOSE: To report a case of Vogt-Koyanagi-Harada (VKH) syndrome-like posterior uveitis after nivolumab administration to treat an ovarian cancer with an electrophysiological finding. A 61-year-old woman with ovarian cancer (stage 3A) and salpingo-oophorectomy surgery history visited the clinic complaining of blurred vision in both eyes. She had been enrolled a clinical trial using nivolumab in patients with ovarian cancer. She received four cycles of nivolumab administration and experienced blurred vision one week before the initial visit. There was no remarkable finding in the anterior segment and the vitreous body. Multiple subretinal fluid accumulations and serous retinal detachment were identified on the posterior pole. Subretinal fluid with choroidal folding was noted in optical coherence tomography, and multiple leakage points were also observed in wide-field fundus fluorescein angiography. Therefore, intravenous high-dose steroid pulse therapy was applied under the diagnosis of VKH syndrome-like posterior uveitis induced by an immunotherapy agent. After steroid therapy, the subretinal fluid was absorbed completely, and the patient's visual acuity was recovered to the normal range. The amplitudes in the multifocal electroretinogram were also restored after the treatment. CONCLUSION: Nivolumab is a human IgG4 monoclonal antibody and an immune checkpoint inhibitor. It is associated with the upregulation of T-cell activity by interfering with the interaction between the programmed death-1 (PD-1) receptor and the PD-ligand. Targeted therapy using immunotherapy agents has been widely used for malignant melanoma, lung cancer, renal cell carcinoma, and other cancers. However, immunotherapy agents such as nivolumab can induce autoimmune-related adverse events including uveitis. This report suggests that VKH syndrome-like posterior uveitis could be induced by nivolumab administration for an ovarian cancer treatment, which was resolved by steroid pulse therapy.

Prognostic Value of Fluorine-18 Fluorodeoxyglucose Uptake of Bone Marrow on Positron Emission Tomography/Computed Tomography for Prediction of Disease Progression in Cervical Cancer.

OBJECTIVE: This study aimed to evaluate the prognostic value of fluorine-18 fluorodeoxyglucose (FDG) uptake of bone marrow (BM) on positron emission tomography (PET)/computed tomography in patients with uterine cervical cancer. METHODS: One hundred forty-five patients with cervical cancer who underwent staging FDG PET/computed tomography and subsequent surgical resection or chemoradiotherapy were retrospectively enrolled in the study. Mean BM FDG uptake (BM standardized uptake value [SUV]) and BM-to-liver uptake ratio of FDG uptake (BLR) were measured. Relationships of BM SUV and BLR with hematologic and inflammatory markers were evaluated. Prognostic values of PET parameters for predicting disease progression-free survival and distant recurrence-free survival (DRFS) were assessed with a Cox proportional hazards regression model. RESULTS: Bone marrow SUV and BLR were significantly correlated with white blood cell count and neutrophil-to-lymphocyte ratio. In the multivariate Cox regression analysis, International Federation of Gynecology and Obstetrics stage (P = 0.048), neutrophil-to-lymphocyte ratio (P = 0.028), platelet-to-lymphocyte ratio (PLR; P = 0.004), maximum SUV of cervical cancer (P = 0.030), and BLR (P = 0.031) were significantly associated with progression-free survival, whereas lymph node metastasis (P = 0.041), PLR (P = 0.002), and BLR (P = 0.025) were significantly associated with DRFS. In a patient subgroup with chemoradiotherapy, BLR (P = 0.044) was still an independent prognostic factor for predicting DRFS in multivariate analysis along with PLR (P = 0.004). CONCLUSIONS: In patients with cervical cancer, BLR is associated with an increased risk of disease progression and distant recurrence.

Management of Endometrial Hyperplasia With a Levonorgestrel-Releasing Intrauterine System: A Korean Gynecologic-Oncology Group Study.

OBJECTIVE: The aim of the study was to evaluate the efficacy of the levonorgestrel intrauterine system (LNG-IUS) for treatment of endometrial hyperplasia (EH). METHODS: A prospective multicenter study was conducted from November 2010 to March 2014. Patients with histologically confirmed EH were treated with LNG-IUS. At 3, 6, and 9 months after LNG-IUS insertion, follow-up endometrial aspiration biopsies with the LNG-IUS in the uterus were undertaken. At the 12th month of follow-up, endometrial tissues were obtained via 2 methods: endometrial aspiration biopsy with the LNG-IUS in the uterus, followed by dilatation and curettage (D&C) after LNG-IUS removal. The primary outcome was the regression rate at 12 months after LNG-IUS insertion, and the secondary outcome was the consistency of the results between the endometrial aspiration biopsy and the D&C. RESULTS: The study population comprised 75 patients, including 37 with simple hyperplasia without atypia; 3 with atypical simple hyperplasia; 23 with complex hyperplasia without atypia, and 12 with atypical complex hyperplasia. Of these patients treated with the LNG-IUS, 38 (50.7%) were followed up at 12 months after LNG-IUS insertion. The complete regression rate at 12 months was 94.7% (36/38): 100% (6/6) of patients with atypical EH and 93.7% (30/32) with EH without atypia. In all of the cases (100%, 36/36), patients achieved complete regression within 3 months of LNG-IUS insertion. A comparison of the pathologic results from endometrial aspiration biopsy and D&C was carried out for 15 patients. In the histologic results by endometrial aspiration biopsy, 14 patients were diagnosed as "normal endometrium" and 1 as "insufficient tissue for pathologic evaluation." Among the 14 cases of normal endometrium by endometrial aspiration biopsy, 1 was diagnosed as "residual EH" by D&C, and the 1 case with insufficient tissue was diagnosed as normal endometrium by D&C. CONCLUSIONS: Levonorgestrel intrauterine system is an effective and favorable method for treatment of EH.

Management of Endometrial Hyperplasia: A Survey of Members of the Korean Gynecologic Oncology Group.

OBJECTIVES: This study aimed to investigate the current management of endometrial hyperplasia (EH) in Korea. MATERIALS AND METHODS: This was an electronic survey, which included 40 questions, that was distributed to the members of the Korean Gynecologic Oncology Group in 2014. RESULTS: In total, 50 (69%) of 72 members responded to the survey. The oral progestogens were the most popular choices for managing EH without atypia (simple hyperplasia(SH), 64%; complex hyperplasia (CH), 52%). In the case of CH with atypia, most of the gynecologist respondents would perform hysterectomy (95.9%). For fertility preservation, the oral progestogens were the most popular choices (SH, 75.5%; CH, 56.3%), followed by the levonorgestrel-releasing intrauterine system (LNG-IUS). More than 70% of the respondents reported use of dilatation and curettage as a follow-up method. CONCLUSIONS: Our survey results show that most of Korean gynecologic oncologists still prefer oral progestogens for conservative management of EH, notwithstanding the many successful reports on the LNG-IUS. As a follow-up evaluation method, dilatation and curettage is mostly used. To identify the optimum therapy, a randomized controlled trial comparing the LNG-IUS with continuous oral progestogens is required. Furthermore, a large-scale prospective study to confirm the most reliable technique for follow-up evaluation is necessary.

Clinical significance of a negative loop electrosurgical excision procedure biopsy in patients with biopsy-confirmed high-grade cervical intraepithelial neoplasia.

OBJECTIVE: We sought to determine which clinical factors can predict this phenomenon and to better understand the clinical significance of negative loop electrosurgical excision procedure (LEEP) findings through long-term follow-up. METHODS: We identified 559 patients with biopsy-confirmed cervical intraepithelial neoplasia grade 2 or 3 (CIN 2, 3) who were treated by LEEP between February 2001 and December 2010. Preconization clinical characteristics, as well as high-risk human papillomavirus (hrHPV) status, were analyzed as possible predictors of an absence of a lesion in the specimen. The clinical significance of an absence of a lesion in the specimen, as well as other factors, was evaluated by Cox hazard regression analysis in terms of recurrence. RESULTS: No lesion on the LEEP specimen was found in 102 (18.2%) of 559 patients with CIN 2,3 on punch biopsy. Punch biopsy status of CIN 2, low HPV viral load (<100 relative light units [RLU]), and negative or positive HPV infection other than type 16 were significantly related to no lesion in the LEEP specimen. Postoperative HPV persistence (≥10 RLU) and same-type HPV detection were significantly related to recurrent disease of CIN 2+ (p < .001). The recurrence of patients with no lesion in LEEP did not statistically differ from that of patients with a lesion in the LEEP specimen (p = .390). CONCLUSIONS: The absence of a lesion in the LEEP specimen is very common. A negative LEEP is associated with a persistence/recurrence rate similar to that of positive LEEP. We recommend that the follow-up for patients with no lesion in the LEEP specimen should be the same as that for patients with a lesion.

1p36.22 region containing PGD gene is frequently gained in human cervical cancer.

AIM: To identify commonly occurring DNA copy number alterations in Korean cervical cancers. METHODS: DNA copy number alteration was screened by whole-genome array comparative genomic hybridization (CGH) analysis. For the array CGH discovery, genomic DNA from five cervical cancers and 10 normal cervical tissues were examined. For the independent validation of the most significant chromosomal alteration (1p36.22, PGD gene), 40 formalin-fixed paraffin-embedded cervical tissue samples were collected; 10 of them were used for quantitative polymerase chain reaction and the other 30 samples were used for immunohistochemical analysis. Chromosomal segments differently distributed between cancers and normal controls were determined to be recurrently altered regions (RAR). RESULTS: A total of 13 RAR (11 RAR losses and two RAR gains) were defined in this study. Of the 13 cervical cancer-specific RAR, RAR gain in the 1p36.22 locus where the PGD gene is located was the most commonly detected in cancers (P = 0.004). In the quantitative polymerase chain reaction replication, copy number gain of the PGD gene was consistently identified in cervical cancers but not in the normal tissues (P = 0.02). In immunohistochemical analysis, PGD expression was significantly higher in cervical cancers than normal tissues (P = 0.02). CONCLUSION: Our results will be helpful to understand cervical carcinogenesis, and the PGD gene can be a useful biomarker of cervical cancer.

Development and validation of artificial intelligence-based analysis software to support screening system of cervical intraepithelial neoplasia.

Cervical cancer, the fourth most common cancer among women worldwide, often proves fatal and stems from precursor lesions caused by high-risk human papillomavirus (HR-HPV) infection. Accurate and early diagnosis is crucial for effective treatment. Current screening methods, such as the Pap test, liquid-based cytology (LBC), visual inspection with acetic acid (VIA), and HPV DNA testing, have limitations, requiring confirmation through colposcopy. This study introduces CerviCARE AI, an artificial intelligence (AI) analysis software, to address colposcopy challenges. It automatically analyzes Tele-cervicography images, distinguishing between low-grade and high-grade lesions. In a multicenter retrospective study, CerviCARE AI achieved a remarkable sensitivity of 98% for high-risk groups (P2, P3, HSIL or higher, CIN2 or higher) and a specificity of 95.5%. These findings underscore CerviCARE AI's potential as a valuable diagnostic tool for highly accurate identification of cervical precancerous lesions. While further prospective research is needed to validate its clinical utility, this AI system holds promise for improving cervical cancer screening and lessening the burden of this deadly disease.

Tumor-homing peptide iRGD-conjugate enhances tumor accumulation of camptothecin for colon cancer therapy.

Poor intracellular uptake of therapeutics in the tumor parenchyma is a key issue in cancer therapy. We describe a novel approach to enhance tumor targeting and achieve targeted delivery of camptothecin (CPT) based on a tumor-homing internalizing RGD peptide (iRGD). We synthesized an iRGD-camptothecin conjugate (iRGD-CPT) covalently coupled by a heterobifunctional linker and evaluated its in vitro and in vivo activity in human colon cancer cells. In vitro studies revealed that iRGD-CPT penetrated cells efficiently and reduced colon cancer cell viability to a significantly greater extent at micromolar concentrations than did the parent drug. Furthermore, iRGD-CPT showed high distribution toward tumor tissue, effectively suppressed tumor progression, and showed enhanced antitumor effects relative to the parent drug in a mouse model, demonstrating that iRGD-CPT is effective in vivo cancer treatment. These results suggest that intracellular delivery of CPT via the iRGD peptide is a promising drug delivery strategy that will facilitate the development of CPT derivatives and prodrugs with improved efficacy.

From the Beginning of the Korean Gynecologic Oncology Group to the Present and Next Steps.

The Korean Gynecologic Oncology Group (KGOG) was established in 2002 and is the only organization in Korea conducting multi-center clinical trials for gynecologic cancers. Since its re-establishment as a non-profit organization in 2021, KGOG has grown significantly, now including 207 gynecologic oncology specialists from 76 hospitals. This growth is a testament to the dedication and hard work of all those involved in the organization. KGOG is committed to maximizing the activation of multi-center clinical research through policies that support patients with rare diseases and gynecologic cancer research, focusing on strengthening institutional capacity, equalizing participation opportunities, and enhancing information sharing. A significant milestone for KGOG was becoming a member of the US Gynecologic Oncology Group (GOG) in 2005, allowing participation in GOG clinical trials. KGOG later joined the Gynecologic Cancer InterGroup (GCIG) and strengthened its capabilities by hosting the first Endometrial Cancer Consensus Conference-Clinical Research (ECCC-CR) in 2023. KGOG holds biannual meetings and symposia, as well as 224 operating committee meetings annually to review the discussions of the Tumor Site Committee. KGOG has conducted 156 investigator-initiated trial (IIT) or sponsor-initiated trial (SIT) studies as KGOG-led or participated in research. Currently, 18 studies are registered, and 10 are in preparation. To date, 68 papers have been published. KGOG conducts six national projects and collaborates with external organizations such as the NRG Oncology Foundation, Gynecologic Oncology Group Partners (GOG-P), GCIG, East Asian Gynecologic Oncology Trial group (EAGOT), and the Japanese Gynecologic Oncology Group (JGOG). Through collaboration with renowned international research institutions, KGOG has significantly expanded the scope of its research, achieving noteworthy clinical outcomes. This report not only introduces the history and recent status of KGOG but also presents the exciting future direction of the organization, filled with potential breakthroughs and advancements in gynecologic oncology research.

Therapeutic effects of surgical debulking of metastatic lymph nodes in cervical cancer IIICr: a trial protocol for a phase III, multicenter, randomized controlled study (KGOG1047/DEBULK trial).

BACKGROUND: Bulky or multiple lymph node (LN) metastases are associated with poor prognosis in cervical cancer, and the size or number of LN metastases is not yet reflected in the staging system and therapeutic strategy. Although the therapeutic effects of surgical resection of bulky LNs before standard treatment have been reported in several retrospective studies, well-planned randomized clinical studies are lacking. Therefore, the aim of the Korean Gynecologic Oncology Group (KGOG) 1047/DEBULK trial is to investigate whether the debulking surgery of bulky or multiple LNs prior to concurrent chemoradiation therapy (CCRT) improves the survival rate of patients with cervical cancer IIICr diagnosed by imaging tests. METHODS: The KGOG 1047/DEBULK trial is a phase III, multicenter, randomized clinical trial involving patients with bulky or multiple LN metastases in cervical cancer IIICr. This study will include patients with a short-axis diameter of a pelvic or para-aortic LN ≥2 cm or ≥3 LNs with a short-axis diameter ≥1 cm and for whom CCRT is planned. The treatment arms will be randomly allocated in a 1:1 ratio to either receive CCRT (control arm) or undergo surgical debulking of bulky or multiple LNs before CCRT (experimental arm). CCRT consists of extended-field external beam radiotherapy/pelvic radiotherapy, brachytherapy and LN boost, and weekly chemotherapy with cisplatin (40 mg/m²), 4-6 times administered intravenously. The primary endpoint will be 3-year progression-free survival rate. The secondary endpoints will be 3-year overall survival rate, treatment-related complications, and accuracy of radiological diagnosis of bulky or multiple LNs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05421650; Clinical Research Information Service Identifier: KCT0007137.

Human papillomavirus type 16 causes larger colposcopic lesions than other HPV types in patients with grade 3 cervical intraepithelial neoplasia.

OBJECTIVE: Recent studies have shown that human papillomavirus (HPV) type 16 causes more definite visual abnormalities on cervigram than other HPV types and is thus easier to evaluate colposcopically. We examined factors, including HPV-16, related to colposcopic lesions in patients with grade 3 cervical intraepithelial neoplasia (CIN 3). METHODS: A retrospective chart review included 108 women with CIN 3 who underwent the loop electrosurgical excision procedure (LEEP). Lesions were assessed according to the number of cervical quadrant(s) involved by colposcopy, dichotomized as 2 or fewer or 3 or more quadrants involved. The Hybrid Capture 2 (HC2) test and HPV DNA chip assay (MyGene Co, Seoul, Korea) were used to detect HPV before punch biopsy or loop electrosurgical excision procedure. The type of HPV was dichotomized as HPV-16 or other (including negative cases). The HC2 viral load cutoff was 300 relative light units. Cytology was dichotomized as (1) low grade, less than, or equal to low-grade squamous lesions; or (2) high-grade, with high-grade squamous lesions or worse. Age and menopausal status were also assessed. RESULTS: The mean (SD) age of the 108 women was 41.9 (10.7) years (range = 22-76 y). Seventy-one (65.7%) had lesions involving 2 quadrants or fewer and 37 (34.3%) had lesions involving 3 quadrants or more. Multiple logistic regression revealed that larger lesions (≥3 quadrants involved) were significantly associated with HPV-16 (p = .032, odds ratio [OR] = 2.552, 95% confidence interval = 1.085-6.000) but not with age, menopausal status, cytologic grade, or HPV HC2 viral load. CONCLUSIONS: Our data suggest that colposcopic lesions differ according to HPV type and that HPV-16 is associated with larger lesions, facilitating lesion detection by colposcopy.

A Flexible and Transparent PtNP/SWCNT/PET Electrochemical Sensor for Nonenzymatic Detection of Hydrogen Peroxide Released from Living Cells with Real-Time Monitoring Capability.

We developed a transparent and flexible electrochemical sensor using a platform based on a network of single-walled carbon nanotubes (SWCNTs) for the non-enzymatic detection of hydrogen peroxide (H2O2) released from living cells. We decorated the SWCNT network on a poly(ethylene terephthalate) (PET) substrate with platinum nanoparticles (PtNPs) using a potentiodynamic method. The PtNP/SWCNT/PET sensor synergized the advantages of a flexible PET substrate, a conducting SWCNT network, and a catalytic PtNP and demonstrated good biocompatibility and flexibility, enabling cell adhesion. The PtNP/SWCNT/PET-based sensor demonstrated enhanced electrocatalytic activity towards H2O2, as well as excellent selectivity, stability, and reproducibility. The sensor exhibited a wide dynamic range of 500 nM to 1 M, with a low detection limit of 228 nM. Furthermore, the PtNP/SWCNT/PET sensor remained operationally stable, even after bending at various angles (15°, 30°, 60°, and 90°), with no noticeable loss of current signal. These outstanding characteristics enabled the PtNP/SWCNT/PET sensor to be practically applied for the direct culture of HeLa cells and the real-time monitoring of H2O2 release by the HeLa cells under drug stimulation.

Upregulation of programmed death ligand-1 in tumor-associated macrophages affects chemotherapeutic response in ovarian cancer cells.

To better understand the mechanism of chemoresistance in ovarian cancer cells, we aimed to investigate the influence of macrophages on the tumor cell response to carboplatin and identify the genes associated with chemoresistance. We mimicked the tumor microenvironment (TME) using a co-culture technique and compared the proliferation of ovarian cells with and without macrophages. We also examined M1 and M2 marker expression and the expression of key TME genes. Post the co-culture, we treated ovarian cancer cells with carboplatin and elucidated the function of programmed death-ligand 1 (PD-L1) in carboplatin chemoresistance. We investigated CD68 and PD-L1 expression in normal and cancerous ovarian tissues using immunohistochemistry (IHC). Finally, we analyzed the association between CD68 or PD-L1 expression and survival outcomes. Inducible nitric oxide synthase (iNOS) was downregulated, while the gene expression of M2 macrophage markers was increased in ovarian cancer cells. PD-L1, vascular endothelial growth factor (VEGF), Interleukin (IL)-6, IL-10, IL-12, signal transducer and activator of transcription 3 (STAT3), B-cell lymphoma 2 (BCL2), multidrug resistance 1 (MDR1), and colony stimulating factor 1 (CSF-1) were upregulated. Notably, PD-L1 was upregulated in both the ovarian cancer cells and macrophages. Ovarian cancer cells co-cultured with macrophages exhibited statistically significant carboplatin resistance compared to single-cultured ovarian cancer cells. PD-L1 silencing induced chemosensitivity in both types of co-cultured ovarian cancer cells. However, IHC results revealed no correlation between PD-L1 expression and patient survival or cancer stage. CD68 expression was significantly increased in cancer cells compared to normal or benign ovarian tumor cells, but it was not associated with the survival outcomes of ovarian cancer patients. Our study demonstrated that ovarian cancer cells interact with macrophages to induce the M2 phenotype. We also established that PD-L1 upregulation in both ovarian cancer cells and macrophages is a key factor for carboplatin chemoresistance.

Mitochondria targeting molecular transporters: synthesis, lipophilic effect, and ionic complex.

As mitochondria are potential therapeutic targeting sites for the treatment of human diseases, delivering cytotoxic drugs, antioxidants, and imaging molecules to mitochondria can provide new therapeutic opportunities. In an attempt to develop a new mitochondria-targeting vector, we synthesized sorbitol-based molecular transporters with multiple guanidines, measured their partition coefficients, compared their targeting efficiency using fluorescent images and Pearson's correlation coefficients, and studied cellular uptake mechanisms. To increase the targeting ability of these molecular transporters to mitochondria, alanine-naphthalene as a lipophilic group was attached to the molecular transporter, which improved translocation across cellular membranes and led to higher accumulation in mitochondria. The molecular transporter was able to form an ionic complex with antibiotics, resulting in low cell viability. These data demonstrate that the molecular transporter with a lipophilic group could be utilized as a potential drug delivery vector for treating mitochondrial dysfunction.

Anticancer, Antibacterial, Antioxidant, and DNA-Binding Study of Metal-Phenalenyl Complexes.

Phenalenyl (PLY)-based metal complexes are a new addition to the metal complex family. Various applications of metal-based phenalenyl complexes (metal-PLY) have been reported, such as catalyst, quantum spin simulators, spin electronic devices, and molecular conductors, but the biological significance of metal-PLY (metal = Co(II), Mn(III), Ni(II), Fe(III), and Al(III)) systems has yet to be explored. In this study, the anticancer properties of such complexes were investigated in ovarian cancer cells (SKOV3 and HEY A8), and the cytotoxicity was comparable to that of other platinum-based drugs. Antibacterial activity of the metal-PLY complexes against both gram-negative (E. coli) and gram-positive (S. aureus) bacteria was studied using a disk diffusion test and minimum inhibitory concentration (MIC) methods. All five metal-PLY complexes showed significant antibacterial activity against both bacterial strains. The antioxidant properties of metal-PLY complexes were evaluated following the 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging method and were acceptable. The DNA-binding properties of these metal-PLY complexes were investigated using absorption spectroscopy, fluorescence spectroscopy, viscosity measurements, and thermal denaturation methods. Experimental evidence revealed that the complexes bind to DNA through intercalation, and the molecular docking study supported this conclusion.

Intracellular delivery of oxaliplatin conjugate via cell penetrating peptide for the treatment of colorectal carcinoma in vitro and in vivo.

Pt-based drugs are one of the main active agents in colorectal cancer treatment. However, drug resistance and dose-dependent side effects are the main barriers that restrict their clinical applications. As an alternative approach to these issues, we designed and synthesized a cell penetrating peptide (CPP) octaarginine-oxaliplatin conjugate that quickly and successfully delivered oxaliplatin into colon cancer cells. The CPP octaarginine is a well-studied cationic peptide that can play a role as a drug delivery vector. In this work, an octaarginine CPP (RRRRRRRR) was conjugated with oxaliplatin via a specific heterobifunctional linker. The in vitro studies showed the conjugate had affinity toward mitochondria inside cells and the MTT assay confirmed that conjugate is active in low micromolar range against colon cancer cells, requiring much lower concentrations than the oxaliplatin alone to reach IC50. More importantly, in the in vivo mouse study, the conjugate effectively inhibited tumor growth and showed considerably high antitumor activity, demonstrating the conjugate can perform well in vivo. This strategy may offer a new approach for designing oxaliplatin derivatives or prodrugs with remarkable therapeutic capabilities.

The anti-aging gene KLOTHO is a novel target for epigenetic silencing in human cervical carcinoma.

BACKGROUND: Klotho was originally characterized as an anti-aging gene that predisposed Klotho-deficient mice to a premature aging-like syndrome. Recently, KLOTHO was reported to function as a secreted Wnt antagonist and as a tumor suppressor. Epigenetic gene silencing of secreted Wnt antagonists is considered a common event in a wide range of human malignancies. Abnormal activation of the canonical Wnt pathway due to epigenetic deregulation of Wnt antagonists is thought to play a crucial role in cervical tumorigenesis. In this study, we examined epigenetic silencing of KLOTHO in human cervical carcinoma. RESULTS: Loss of KLOTHO mRNA was observed in several cervical cancer cell lines and in invasive carcinoma samples, but not during the early, preinvasive phase of primary cervical tumorigenesis. KLOTHO mRNA was restored after treatment with either the DNA demethylating agent 2'-deoxy-5-azacytidine or histone deacetylase inhibitor trichostatin A. Methylation-specific PCR and bisulfite genomic sequencing analysis of the promoter region of KLOTHO revealed CpG hypermethylation in non-KLOTHO-expressing cervical cancer cell lines and in 41% (9/22) of invasive carcinoma cases. Histone deacetylation was also found to be the major epigenetic silencing mechanism for KLOTHO in the SiHa cell line. Ectopic expression of the secreted form of KLOTHO restored anti-Wnt signaling and anti-clonogenic activity in the CaSki cell line including decreased active beta-catenin levels, suppression of T-cell factor/beta-catenin target genes, such as c-MYC and CCND1, and inhibition of colony growth. CONCLUSIONS: Epigenetic silencing of KLOTHO may occur during the late phase of cervical tumorigenesis, and consequent functional loss of KLOTHO as the secreted Wnt antagonist may contribute to aberrant activation of the canonical Wnt pathway in cervical carcinoma.

Random biopsy after colposcopy-directed biopsy improves the diagnosis of cervical intraepithelial neoplasia grade 2 or worse.

OBJECTIVES: To evaluate the usefulness of additional random biopsies in the diagnosis of cervical intraepithelial neoplasia grade 2 (CIN 2) or worse (CIN 2+) after colposcopy-directed biopsy. MATERIALS AND METHODS: A retrospective chart review was performed in 107 women with satisfactory colposcopy results after colposcopy-directed biopsy with random biopsy for abnormal cervical cytological evaluation at Soonchunhyang University Hospital between April 2008 and November 2009. Random biopsies were performed at the cervical squamocolumnar junction in lesion-free quadrants of the cervix. Loop electrosurgical excision procedure conizations were performed in 59 women. Age, referral cytology, lesion size, human papilloma virus (HPV) viral load, and HPV type were analyzed as possible indicators of lesion severity detected using random biopsy. RESULTS: The mean age was 39.3 years (range = 21-72 y), and 96 (89.7%) women were premenopausal. Sixty-three women had CIN 2+; of those, 8 (12.7%) were diagnosed using random biopsies: 6 had high-grade squamous intraepithelial lesions; 1 had low-grade squamous intraepithelial lesions; and 1 had atypical squamous cells of undetermined significance. Lesions diagnosed as CIN 2+ using random biopsies were significantly correlated with high-grade cytology (p <.001) and lesion size (p <.001) but not age (cutoff = 40 years), HPV viral load (cutoff = 300 relative light units; Hybrid Capture 2), or HPV genotype. Of 59 patients who underwent loop electrosurgical excision procedure conization, the disease severity of 9 (15.3%) cases was upgraded 1 or more grades, compared with the punch biopsy results. CONCLUSIONS: The detection of CIN 2+, particularly high-grade cytological abnormalities and large lesion size, can be increased by additional random biopsies after satisfactory colposcopy. Loop electrosurgical excision procedure conization can detect lesions not detected by punch biopsy.