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sProper dendrite morphogenesis and neuronal migration are crucial for cerebral cortex development and neural circuit formation. In this study, we sought to determine if the histone deacetylase HDAC6 plays a role in dendrite development and neuronal migration of pyramidal neurons during cerebral cortex development. It was observed that knockdown of HDAC6 leads to defective dendrite morphogenesis and abnormal Golgi polarization in vitro, and the expression of wild type cortactin or deacetyl-mimetic cortactin 9KR rescued the defective phenotypes of the HDAC6 knockdown neurons. This suggests that HDAC6 promotes dendritic growth and Golgi polarization through cortactin deacetylation in vitro. We also demonstrated that ectopic expression of SIRT2, a cytoplasmic NAD+ − dependent deacetylase, suppresses the defects of HDAC6 knockdown neurons. These results indicate that HDAC6 and SIRT2 may be functionally redundant during dendrite development. Neurons transfected with both HDAC6 and SIRT2 shRNA or acetyl-mimetic cortactin 9KQ showed slow radial migration compared to the control cells during cerebral cortex development. Furthermore, a large portion of cortactin 9KQ-expressing pyramidal neurons at layer II/III in the cerebral cortex failed to form an apical dendrite toward the pial surface and had an increased number of primary dendrites, and the percentage of neurons with dendritic Golgi decreased in cortactin 9KQ-expressing cells, compared to control neurons. Taken together, this study suggests that HDAC6 and SIRT2 regulate neuronal migration and dendrite development through cortactin deacetylation in vivo.

Background: Lymphopenia is frequently observed in advanced cancer patients even before initiation of systemic anti-cancer treatment. The aim of this study is to investigate the pre-treatment lymphopenia as a prognostic factor for breast cancer specific survival (BCSS), distant recurrence free survival (DRFS) in patients with early breast cancer (EBC) and overall survival (OS), OS2 (from diagnosis with stage IV to death) with metastatic breast cancer (MBC) in large-scaled early and metastatic breast cancer database cohort. Methods: We reviewed demographic, clinical, pathologic, and survival data from Yonsei Breast Cancer Center Registry. In large scaled database, 5252 patients who underwent surgery with stage I-III EBC at the Yonsei Cancer Center between 2006 and 2015 were included and 1481 patients who were newly diagnosed de novo or recurrent MBC were included. The pre-treatment lymphocyte count was obtained from complete blood count (CBC) assay before the initiation of any treatment. Lymphopenia was defined as an absolute lymphocyte count (ALC) < 1000/mm3. Clinicopathologic factors, such as human epidermal growth factor 2 (HER2) receptor, hormone receptor (HR) status and metastatic site, were reviewed. To evaluate the prognostic factors, Kaplan-Meier, log-rank, and Cox regression analysis were performed. Results: Of 5211 eligible EBC patients, 2690 (51.6%) stage I and 1857 (35.6%) stage II patients was included. De novo and recurrent MBC patients were 260 (31.0%) and 576 (69.0%). The incidences of pre-treatment lymphopenia were 3.0% (154/5211) in EBC and 14.5% (121/836) in MBC: 10 (3.9%) in de novo stage IV and 117 (19.3%) in recurrent stage IV. There was no difference in pre-treatment lymphopenia incidence among histologic subtypes in EBC cohort, but it was significantly higher in triple negative breast cancer (TNBC) in MBC. EBC patients with HBsAg positive showed higher incidence of pre-treatment lymphopenia than HBV negative patients (7.3% vs. 2.9%, p=0.003). In MBC cohort, patients with early distant recurrent (less than 2 year) disease (35.8%, p Conclusions: In this large-scaled and retrospectively analyzed a dataset, we showed highest incidence of pre-treatment lymphopenia in recurrent MBC, not affected by previous chemotherapy exposure. Pre-treatment lymphopenia was a significant poor prognostic factor in recurrent stage IV MBC, but not in EBC or de novo stage IV MBC. Citation Format: Jee Hung Kim, Min Hwan Kim, Gun Min Kim, Byeong-Woo Park, Young Up Cho, Seung Il Kim, Seho Park, Hyung Seok Park, Ji Ye Kim, Hyun Cheol Chung, Soonmyung Paik, Joohyuk Sohn. Comprehensive analysis of lymphopenia in large-scaled early and metastatic breast cancer database cohort [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-43.

Background The antibody-drug conjugate targeting HER2, DS8201 has shown clinical activity against breast cancer with low-level HER2 expression in early clinical trial. In this study, we investigated the clinical implication and prognostic impact of intermediate HER2 expression in the prospectively collected ER (+) early breast cancer (EBC) and metastatic breast cancer (MBC) cohorts. Methods We analyzed the prospectively collected database of EBC and MBC cohort patients in Yonsei Cancer Center. We defined patients with HER2 immunohistochemistry (IHC) 0~1+ as HER2-negative group, and IHC 2+ and in situ hybridization (ISH) negative as HER2-intermediate group. Only ER (+) patients with complete HER2 IHC and ISH status were selected, excluding HER2 IHC 3+ or ISH+ patients. A total of 2,657 early breast cancer and 535 metastatic breast cancer patients were finally analyzed. The clinical and pathological characteristics and survival outcome of the patients were compared between HER2-negative and HER2-intermediate group in each cohort. Results The 654 (24.6%) EBC patients and 166 (31.0%) MBC patients were classified as HER2-intermediate group. The HER2-intermediate patients were more common in PR negative (30.4% versus 22.6%, p< 0.001) and higher nuclear grade (grade 2 or 3) patients (25.7% versus 17.4%, p = 0.001) in EBC cohort and in age ≥ 55 patients (36.7% versus 27.4%, p = 0.001) in MBC cohort. Other characteristics were not different between two groups in both cohorts. The HER2-intermediate patients showed significantly poorer recurrence-free survival (RFS) than HER2-negative patients in EBC patients (p = 0.044), although the prognostic impact was not significant in the multivariate analysis. Of note, intermediate HER2 expression was associated with significantly poorer RFS in EBC patients (p = 0.007) of age ≥ 55, but did not affect the RFS in patients of age < 55. The intermediate HER2 expression independently predicted poorer RFS of EBC patients of age ≥ 55 (Hazard ratio [HR], 1.95; 95% Confidence interval [CI], 1.03-3.73; p = 0.042) in multivariate Cox regression analysis with adjustment of other prognostic factors, T stage, N stage, PR status, and histologic grade. In line with result of EBC cohort, intermediate HER2 expression was associated with poorer overall survival (OS) in MBC patients of age ≥ 55 (p = 0.037), not affecting OS in MBC patients of age < 55. Intermediate HER2 expression predicted significantly poorer OS in MBC patients of age ≥ 55 (HR, 1.45; 95% CI, 1.01-2.07; p = 0.044) independent from PR status, disease status (recurrent versus de novo stage IV), and visceral metastasis. Conclusion Our analysis demonstrates intermediate HER2 expression as an independent poor prognostic factor for ER (+) breast cancer patients with age ≥ 55 in both EBC and MBC cohorts. The clinical efficacy of new HER2-targeting antibody-drug conjugates needs to be validated in this high-risk subset of ER (+) breast cancer patients. Citation Format: Min Hwan Kim, Gun Min Kim, Jee Hung Kim, Ji Ye Kim, Hyung Seok Park, Seho Park, Young Up Cho, Byeong Woo Park, Seung Il Kim, Joo-Hyuk Sohn. Intermediate HER2 expression predicts poor prognosis in ER (+) breast cancer patients aged 55 and older [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-33.

Pyogenic granuloma is a benign vascular tumor of the skin or mucous membrane. One-third of pyogenic granulomas have been reported in the head and neck, but it is rarely present in the external auditory canal. Pyogenic granuloma mostly presents as a solitary granuloma, and only a few cases of multiple forms have been reported. This report describes a rare case of multiple pyogenic granulomas in the external auditory canal of a 36-year-old man along with a review of the literatures. Although it is very rare for PGs to occur in the EAC, it can be suspected in conditions such as after acute and/or chronic trauma, hormonal changes or systemic drug administration, rapid growth, and easy bleeding tendency with a friable surface. Some PGs may spontaneously resolve, but when they cause symptoms, excision is recommended for treatment and diagnosis. In the case of excision, the tumor should be excised down to the perichondrium level to prevent recurrence. Although PG mainly occurs in a solitary form, the present case shows a new clinical variation where multiple PGs were present in the EAC.

BackgroundThe trastuzumab biosimilar CT-P6 has demonstrated equivalent efficacy and comparable safety to reference trastuzumab (RTZ) in clinical trials of human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC). Here, we present the first real-world comparison of CT-P6 versus RTZ with dual HER2-targeted therapy for the neoadjuvant and palliative first-line treatment with HER2-positive EBC and metastatic breast cancer (MBC) patients in two tertiary hospitals in Korea.MethodsWe retrospectively investigated medical records in the Severance Breast Cancer Registry in Korea. We identified patients with HER2-positive EBC (n=254) who had received neoadjuvant chemotherapy with RTZ or CT-P6, plus pertuzumab, carboplatin and docetaxel (TCHP) and untreated stage IV MBC (n=103) who had received palliative first-line treatment with RTZ or CT-P6, plus pertuzumab and docetaxel (THP) between May 2014 and December 2019. The primary endpoints were pathologic complete response (pCR) in the EBC and progression-free survival (PFS) in the MBC cohort. Overall survival (OS), overall response rate (ORR), disease control rate (DCR), and cardiac safety were secondary endpoints.ResultsA similar percentage of EBC patients achieved a pCR with CT-P6 versus RTZ (74.4% [93/125]) vs 69.8% [90/129], p=0.411). For patients with MBC, median follow-up duration was 23.0 and 41.0 months for CT-P6 and RTZ groups, respectively; median PFS did not differ significantly between two groups (13.0 vs 18.0 months, 95% confidence intervals (CIs) 0.0-26.6 vs 11.3-24.7, p=0.976). The ORR, DCR, and cardiac safety profiles did not also show significant difference efficacy outcomes between two groups.ConclusionsThese real-world data suggest that biosimilar trastuzumab CT-P6 has similar effectiveness and cardiac safety to RTZ in HER2-positive EBC and MBC patients, when administered as part of dual HER2-targeted therapy with pertuzumab plus chemotherapy in the neoadjuvant or palliative setting.

Diffuse involvement of colorectal lymphoma masquerading as colitis is a very rare presentation of primary colorectal lymphoma. Detecting occult lymphoma is difficult in the setting of diffuse colonic involvement with no definite mass and inflammatory mucosal changes. We encountered a case of diffuse-type primary colorectal lymphoma simulating ulcerative colitis in a previously healthy 31-year-old woman. Despite multiple mucosal biopsies, the biopsy diagnosis was not made due to unawareness of atypical lymphocytes admixed with dense lymphoplasmacytic infiltration. The present case emphasizes the importance of being aware of this rare presentation of primary colorectal lymphoma in order to avoid misdiagnosis.

Extreme responders to anticancer therapy are rare among advanced breast cancer patients. Researchers, however, have yet to investigate treatment responses therein on the whole exome level. We performed whole exome analysis to characterize the genomic landscape of extreme responders among metastatic breast cancer patients. Clinical samples were obtained from breast cancer patients who showed exceptional responses to anti-HER2 therapy or hormonal therapy and from those who did not. Matched breast tumor tissue (somatic DNA) and blood samples (germline DNA) were collected from a total of 30 responders and 15 non-responders. Whole exome sequencing using Illumina HiSeq2500 was performed for all 45 patients (90 samples). Somatic single nucleotide variants (SNVs), indels, and copy number variants (CNVs) were identified for the genomes of each patient. Group-specific somatic variants and mutational burden were statistically analyzed. Sequencing of cancer exomes for all patients revealed 1839 somatic SNVs (1661 missense, 120 nonsense, 43 splice-site, 15 start/stop-lost) and 368 insertions/deletions (273 frameshift, 95 in-frame), with a median of 0.7 mutations per megabase (range, 0.08 to 4.2 mutations per megabase). Responders harbored a significantly lower nonsynonymous mutational burden (median, 26 vs. 59, P = 0.02) and fewer CNVs (median 13.6 vs. 97.7, P = 0.05) than non-responders. Multivariate analyses of factors influencing progression-free survival showed that a high mutational burden and visceral metastases were significantly related with disease progression. Extreme responders to treatment for metastatic breast cancer are characterized by fewer nonsynonymous mutations and CNVs., Lim, Kim and Jung et al. report a whole-exome sequence analysis of 30 Korean patients showing extreme treatment responses for metastatic breast cancer. They find that compared to non-responders, extreme responders have fewer nonsynonymous mutations and copy number variants.

Cancer chemotherapy resistance is one of the most critical obstacles in cancer therapy. One of the well-known mechanisms of chemotherapy resistance is the change in the mitochondrial death pathways which occur when cells are under stressful situations, such as chemotherapy. Mitophagy, or mitochondrial selective autophagy, is critical for cell quality control because it can efficiently break down, remove, and recycle defective or damaged mitochondria. As cancer cells use mitophagy to rapidly sweep away damaged mitochondria in order to mediate their own drug resistance, it influences the efficacy of tumor chemotherapy as well as the degree of drug resistance. Yet despite the importance of mitochondria and mitophagy in chemotherapy resistance, little is known about the precise mechanisms involved. As a consequence, identifying potential therapeutic targets by analyzing the signal pathways that govern mitophagy has become a vital research goal. In this paper, we review recent advances in mitochondrial research, mitophagy control mechanisms, and their implications for our understanding of chemotherapy resistance.

Hypothalamic neurons including proopiomelanocortin (POMC)-producing neurons regulate body weights. The non-motile primary cilium is a critical sensory organelle on the cell surface. An association between ciliary defects and obesity has been suggested, but the underlying mechanisms are not fully understood. Here we show that inhibition of ciliogenesis in POMC-expressing developing hypothalamic neurons, by depleting ciliogenic genes IFT88 and KIF3A, leads to adulthood obesity in mice. In contrast, adult-onset ciliary dysgenesis in POMC neurons causes no significant change in adiposity. In developing POMC neurons, abnormal cilia formation disrupts axonal projections through impaired lysosomal protein degradation. Notably, maternal nutrition and postnatal leptin surge have a profound impact on ciliogenesis in the hypothalamus of neonatal mice; through these effects they critically modulate the organization of hypothalamic feeding circuits. Our findings reveal a mechanism of early life programming of adult adiposity, which is mediated by primary cilia in developing hypothalamic neurons., Ciliary defects and obesity has been associated, but the underlying mechanism is unclear. Here, the authors show that inhibition of ciliogenesis in POMC neurons during development results in lysosomal protein degradation-dependent axonal disruption and adult obesity in mice.

Although Ki67 labeling index is a potential predictive marker for chemotherapy benefit, its clinical utility has been limited by the lack of a standard scoring method resulting in poor interobserver reproducibility. Especially, there is no consensus on the use of average versus hotspot score for reporting. In order to determine the best method for Ki67 scoring and validate manual scoring method proposed by the International Ki67 Working Group (IKWG), we systematically compared average versus hotspot score in 240 cases with a public domain image analysis program QuPath. We used OncotypeDx Recurrence Score (RS) as a benchmark to compare the potential clinical utility of each scoring methods. Both average and hotspot scores showed statistically significant but only modest correlation with OncotypeDx RS. Only hotspot score could meaningfully distinguish RS low-risk versus high-risk patients. However, hotspot score was less reproducible limiting its clinical utility. In summary, our data demonstrate that utility of the Ki67 labeling index is influenced by the choice of scoring method.

Foot-and-mouth disease (FMD) is considered one of the highly contagious viral infections affecting livestock. In Korea, an FMD vaccination policy has been implemented nationwide since 2010 for the prevention and control of FMD. Since the vaccines are imported from various countries, standardized quality control measures are critical. In this study, we aimed to validate a high-performance liquid chromatography (HPLC) device in the Animal and Plant Quarantine Agency lab and identify an appropriate FMD vaccine pretreatment method for HPLC&mdash, a simple, reliable, and practical method to measure antigen content. Based on the analyses of specificity, linearity, accuracy, repeatability, intermediate precision, limits of detection, and limits of quantification using FMD standard samples, we validated the method using a standard material. Overall, we confirmed that the HPLC technique is effective for the quantitative assessment of the FMD virus 146S antigen in Korea. Using commercial FMD vaccines, we evaluated three separation methods and identified the method using n-pentanol and trichloroethylene as optimal for HPLC analysis. Our HPLC method was effective for the analytical detection of the antigen content in FMD vaccine, and it may be useful as a reference method for national lot-release testing.

Objective Kallikrein 5 (KLK5), which is frequently observed in normal cervico-vaginal fluid, is known to be related to prognosis in several solid tumors. We investigated the prognostic significance of KLK5 in uterine cervical cancer using tumor tissue microarray and immunohistochemistry staining. Methods We analyzed samples of 165 patients with uterine cervical cancer who received definitive radiation therapy between 2004 and 2012. We divided patients into two groups stratified by their KLK5 activity by immunohistochemistry staining: negative/weak (0–1+) (n=120 patients) and moderate/strong (2–3+) group (n=45 patients). Patient and tumor characteristics, patterns of failure, and survival outcomes were compared. Univariable and multivariable analyses were performed to identify prognostic factors. Results Patients with KLK5 2–3+ were younger (median: 52 vs. 60 years) and had frequent paraaortic lymph node involvement (40.0% vs. 18.3%) than those with KLK5 0–1+. With a median follow-up of 60.8 (interquartile range, 47.5–77.9) months, patients with KLK5 2–3+ had inferior 5-year locoregional recurrence-free survival and distant metastasis-free survival of 61.7% (vs. 77.5% in KLK5 0–1+ group) and 59.4% (vs. 72.8% in the KLK5 0–1+ group), respectively (all p

Purpose Dose-dense chemotherapy (DD-CT) is a preferred (neo)adjuvant regimen in early breast cancer (BC). Although the results of reported randomized trials are conflicting, a recent metaanalysis showed improved overall and disease-free survival with DD-CT compared to conventional schedules. However, no DD-CT safety data for Korean BC patients are available. This phase II study was conducted to evaluate the safety and efficacy of pegteograstim in Korean BC patients receiving DD-CT. Materials and methods Patients with operable (stage I-III), histologically confirmed BC received four cycles of intravenous doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) on day 1 every 2 weeks as neoadjuvant or adjuvant therapy. Pegteograstim (6.0 mg) was administered subcutaneously on day 2 of each cycle. The primary endpoint was the incidence of febrile neutropenia (FN). The secondary endpoints were safety and tolerability. Results Of 63 patients, one (1.6%) developed FN during all cycles of DD-CT. Dose delay was observed in four patients (6.3%) and dose reduction in two (3.2%) during DD-CT. Frequent adverse events (AEs) were nausea, alopecia, generalized muscle weakness, myalgia, mucositis, anorexia, dyspepsia, and diarrhea; most AEs were related to chemotherapy. Grade 3-4 AEs were reported in five of 63 patients (7.9%), and all grade 3 and 4 AEs were related to chemotherapy. Adverse drug reactions possibly linked to pegteograstim were abdominal pain, bone pain, myalgia, generalized muscle weakness, and headache in five of 63 patients (7.9%). Conclusion Dose-dense AC (doxorubicin/cyclophosphamide) chemotherapywith pegteograstim support is a tolerable and safe regimen in Korean early BC patients.

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTCL) is a rare type of lymphoma that accounts for only 5%–18% of all cases of non-Hodgkin lymphoma (NHL). In published series, 60%–90% of NK/T-cell lymphomas are localized to the nasal and upper airway. We describe a 55-year man who presented with cough, sputum, dyspnea on exertion, and a chest computed tomography scan shows diffuse ground glass opacities (GGOs), suggestive of an interstitial lung disease. He was treated with a corticosteroid and his symptoms improved. However, when the corticosteroid was tapered, his symptoms recurred. The patient underwent a surgical lung biopsy and ENKTCL was diagnosed. We present this case because ENKTCL involving only the lung is very rare but very informative. To our knowledge, our patient is the first case that primary pulmonary ENKTCL is presented with GGOs., Graphical Abstract

A better understanding of tumor biology is important in the identification of molecules that are downregulated in malignancy and in determining their role in tumor suppression. B-cell translocation gene 1 (BTG1) has been shown to act as a tumor suppressor in several types of human malignancy. In this study, we analyzed BTG1 expression in ovarian carcinoma cell lines, and we investigated the mechanism underlying the observed alterations. The methylation status of the BTG1 promoter region was determined by methylation-specific polymerase chain reaction, and the effect of demethylation on BTG1 expression was analyzed. BTG1 protein expression in ovarian high-grade serous carcinoma tissue samples was evaluated using immunohistochemistry. BTG1 mRNA and protein expression were reduced in ovarian carcinoma cells. In BTG1-silenced ovarian cancer cells, the BTG1 promoter was highly methylated. Treatment with 5-aza-deoxycytidine significantly elevated BTG1 mRNA and protein expression. Immunostaining demonstrated that BTG1 expression was significantly lower in ovarian carcinoma tissue samples than nonpathological ovaries and fallopian tubes. We demonstrated that BTG1 silencing in ovarian carcinoma occurs through epigenetic repression and is involved in the ovarian carcinogenesis. Our data suggest that BTG1 is a potential therapeutic target for patients with ovarian carcinoma.

An attention guided convolutional neural network (CNN) for the classification of breast cancer histopathology images is proposed. Neural networks are generally applied as black box models and often the network’s decisions are difficult to interpret. Making the decision process transparent, and hence reliable is important for a computer-assisted diagnosis (CAD) system. Moreover, it is crucial that the network’s decision be based on histopathological features that are in agreement with a human expert. To this end, we propose to use additional region-level supervision for the classification of breast cancer histopathology images using CNN, where the regions of interest (RoI) are localized and used to guide the attention of the classification network simultaneously. The proposed supervised attention mechanism specifically activates neurons in diagnostically relevant regions while suppressing activations in irrelevant and noisy areas. The class activation maps generated by the proposed method correlate well with the expectations of an expert pathologist. Moreover, the proposed method surpasses the state-of-the-art on the BACH microscopy test dataset (part A) with a significant margin.

Mild mitochondrial stress in POMC neurons promotes thermogenesis in inguinal white adipose tissues and prevents diet-induced obesity. Normal mitochondrial dynamics and functions in hypothalamic neurons are pivotal in the maintenance of systemic energy homeostasis. CRIF1 has been identified as a mito-ribosomal protein which critically mediates incorporation of mitochondrial DNA (mtDNA)-encoded oxidative phosphorylation (OXPHOS) polypeptides into the inner mitochondrial membrane. Complete loss of CRIF1 in neurons causes severe OXPHOS dysfunction and leads to a neuronal death. To study the impact of mitochondrial stress in hypothalamic proopiomelanocortin (POMC) neurons, we generated a mice model lacking CRIF1 expression specifically in the POMC neurons using cre-lox system. Both male and female POMC-cre; CRIF1f/f mice developed obesity since the 10-15 weeks of age due to a gradual loss of POMC neurons. Unexpectedly, energy expenditure and thermogenesis were enhanced in POMC-cre; CRIF1+/f mice compared to their wild littermates. Moreover, they were resistance to diet-induced obesity when exposed to a high fat diet (HFD) before the 10 weeks of age. For the mechanism of enhanced thermogenesis, we found increased UCP1 expression and brown adipocyte-like cells in the inguinal subcutaneous white adipose tissue (ingWAT), so called "browning of subcutaneous fat depot." More strikingly, the expression of mitochondrial unfolded protein response (UPRmt) markers was significantly increased in the ingWAT of POMC-cre; CRIF1+/f mice. These findings strongly suggest that mild mitochondrial stress in POMC neurons causes mitochondrial stress response in the remote organ (ingWAT) via unidentified cell-non-autonomous mechanisms, leading to increased thermogenic activity in this fat depot. Disclosure S. Kim: None. S. Min: None. G. Kang: None. J. Kim: None. J. Choi: None. M. Kim: None. Funding National Research Foundation of Korea (NRF-2013M3C7A1056024)

Constitutive Proopiomelanocortin (POMC)-expressing cells are mainly found in the hypothalamic arcuate nucleus, brainstem solitary tract nucleus, and pituitary gland. The cAMP-dependent protein kinase A (PKA) critically transduces signaling pathways of many important hormones and neurotransmitters including glucagon, GLP-1, α-MSH, dopamine and catecholamine. We generated the mice deleting PKA regulatory subunit R1A (Prkar1a) in POMC-expressing cells to induce constitutive activation of PKA signaling in POMC cells. These mice exhibited interesting phenotypes similar to human Cushing's syndrome; thin skin, hair loss, increased fat mass but reduced muscle and bone mass, female infertility, retarded linear growth, hump and insulin resistance. Moreover, they had increased corticosterone levels both in urine and plasma along with adrenal cortical hypertrophy. Interestingly, despite severe insulin resistance and obesity, plasma glucose concentrations were significantly lower in both fasting and post-glucose loading conditions. These mice showed enhanced insulin-independent glucose disposal. FDG-PET scanning and 2DG uptake tests revealed increased glucose uptake in the brain and the kidney. Normalization of corticosteroid levels by bilateral adrenalectomy and corticosteroid replacement could not normalize blood glucose. Collectively, our hypothesis is that abnormal activation of PKA signaling in pituitary POMC cells causes human Cushing’s syndrome-like phenotype whereas unusual activation of PKA signaling in hypothalamic POMC neurons enhances glucose disposal in the brain and the kidney. Disclosure J. Choi: None. S. Min: None. G. Kang: None. J. Kim: None. M. Kim: None. Funding National Research Foundation of Korea

This study investigated the distribution of HPV types in Korean women and evaluated the carcinogenic risk of individual HPV types and the potential effects of HPV vaccines. A total of 4,081 HPV-positive samples between 2014 and 2017 were included. The most prevalent genotypes were HPV 16, 58, 68, and 56. Among them, HPV 16 was significantly higher in high-grade squamous intraepithelial neoplasia or worse (HSIL+ ) group. In cytologically evaluating the risk for HSIL+ by individual HPV types, HPV 16 was associated with the highest risk of HSIL+ (OR = 10.82; 95% CI: 7.93–14.77), followed by HPV 33, 31, 52, 18, 58, 51, and 35, in descending order (OR = 3.50 [type 33] to 2.62 [type 35]). Among those types, HPV 16, 18, 31, 33, and 58 were also significantly associated with HSIL+ on histologic evaluation. The analysis of the HPV subgroups covered by the different vaccines revealed that the HPV types covered by the 9-valent vaccine had a high association with HSIL+ (OR = 4.09; 95% CI: 3.02–5.54). Our findings highlight the different carcinogenic risks posed by the high risk HPV genotypes and the positive potential effects of the 9-valent HPV vaccine in reducing HPV-associated cervical cancer in Korea.

Background/aim Previous studies have documented that osteoprotegerin (OPG) is involved in the development and progression of several human malignancies. However, OPG has also been shown to act as a tumor suppressor. The aim of this study was to examine the expression status of OPG in ovarian carcinoma cells and investigate the underlying mechanism responsible for alterations in OPG expression. Materials and methods The expression levels of OPG mRNA and protein were assessed in human ovarian carcinoma cell lines. The methylation status of the OPG promoter region was determined using the bisulfite pyrosequencing technique. The effects of demethylation on OPG expression were also analyzed. Results The human ovarian carcinoma cell lines, SW 626, OVCAR-3, ES-2, TOV-112D, and TOV-21G, expressed significantly lower levels of OPG mRNA and protein than the normal human ovarian epithelial cell line, HS823.Tc. Moreover, three CpG sites in the OPG promoter region were highly methylated in the SW 626, OVCAR-3, ES-2, and TOV-112D ovarian carcinoma cell lines compared to normal control cells. Furthermore, in all the examined ovarian carcinoma cell lines, treatment with the demethylating agent, 5-aza-2-deoxycytidine, resulted in significantly increased expression levels of OPG mRNA and protein compared to the respective pre-treatment levels. Conclusion OPG expression was down-regulated in the studied ovarian carcinoma cells compared to the normal control cells, while demethylation significantly restored OPG expression in the OPG-down-regulated cell lines. Our results suggest that OPG down-regulation in ovarian carcinoma occurs, at least partly, through epigenetic repression, suggesting its involvement in ovarian carcinogenesis.

Poly (ADP-ribose) polymerase 1 inhibitors (PARPi) are used to treat recurrent ovarian cancer (OC) patients due to greater survival benefits and minimal side effects, especially in those patients with complete or partial response to platinum-based chemotherapy. However, acquired resistance of platinum-based chemotherapy leads to the limited efficacy of PARPi monotherapy in most patients. Twist is recognized as a possible oncogene and contributes to acquired cisplatin resistance in OC cells. In this study, we show how Twist knockdown cisplatin-resistant (CisR) OC cells blocked DNA damage response (DDR) to sensitize these cells to a concurrent treatment of cisplatin as a platinum-based chemotherapy agent and niraparib as a PARPi on in vitro two-dimensional (2D) and three-dimensional (3D) cell culture. To investigate the lethality of PARPi and cisplatin on Twist knockdown CisR OC cells, two CisR cell lines (OV90 and SKOV3) were established using step-wise dose escalation method. In addition, in vitro 3D spheroidal cell model was generated using modified hanging drop and hydrogel scaffolds techniques on poly-2-hydroxylethly methacrylate (poly-HEMA) coated plates. Twist expression was strongly correlated with the expression of DDR proteins, PARP1 and XRCC1 and overexpression of both proteins was associated with cisplatin resistance in OC cells. Moreover, combination of cisplatin (Cis) and niraparib (Nira) produced lethality on Twist-knockdown CisR OC cells, according to combination index (CI). We found that Cis alone, Nira alone, or a combination of Cis+Nira therapy increased cell death by suppressing DDR proteins in 2D monolayer cell culture. Notably, the combination of Nira and Cis was considerably effective against 3D-cultures of Twist knockdown CisR OC cells in which Endoplasmic reticulum (ER) stress is upregulated, leading to initiation of mitochondrial-mediated cell death. In addition, immunohistochemically, Cis alone, Nira alone or Cis+Nira showed lower ki-67 (cell proliferative marker) expression and higher cleaved caspase-3 (apoptotic marker) immuno-reactivity. Hence, lethality of PARPi with the combination of Cis on Twist knockdown CisR OC cells may provide an effective way to expand the therapeutic potential to overcome platinum-based chemotherapy resistance and PARPi cross resistance in OC.

Low-grade mitochondrial stress can promote health and longevity, a phenomenon termed mitohormesis. Here, we demonstrate the opposing metabolic effects of low-level and high-level mitochondrial ribosomal (mitoribosomal) stress in hypothalamic proopiomelanocortin (POMC) neurons. POMC neuron-specific severe mitoribosomal stress due to Crif1 homodeficiency causes obesity in mice. By contrast, mild mitoribosomal stress caused by Crif1 heterodeficiency in POMC neurons leads to high-turnover metabolism and resistance to obesity. These metabolic benefits are mediated by enhanced thermogenesis and mitochondrial unfolded protein responses (UPR(mt)) in distal adipose tissues. In POMC neurons, partial Crif1 deficiency increases the expression of β-endorphin (β-END) and mitochondrial DNA-encoded peptide MOTS-c. Central administration of MOTS-c or β-END recapitulates the adipose phenotype of Crif1 heterodeficient mice, suggesting these factors as potential mediators. Consistently, regular running exercise at moderate intensity stimulates hypothalamic MOTS-c/β-END expression and induces adipose tissue UPR(mt) and thermogenesis. Our findings indicate that POMC neuronal mitohormesis may underlie exercise-induced high-turnover metabolism.

// Gun Yoon 1, * , Chang Won Koh 2, * , Nara Yoon 3 , Ji-Ye Kim 4 , Hyun-Soo Kim 4 1 Shinsegae Women’s Hospital, Daegu, Republic of Korea 2 Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul, Republic of Korea 3 Department of Pathology, The Catholic University of Korea Incheon St. Mary’s Hospital, Incheon, Republic of Korea 4 Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea * These authors have contributed equally to this work Correspondence to: Hyun-Soo Kim, email: hyunsookim@yuhs.ac Keywords: p16, endometrium, peritumoral stroma, endometrioid carcinoma, serous carcinoma Received: October 07, 2016 Accepted: November 16, 2016 Published: November 25, 2016 ABSTRACT p16 is a negative regulator of cell proliferation and is considered a tumor suppressor protein. Alterations in p16 protein expression are associated with tumor development and progression. However, the p16 expression status in the peritumoral stroma has not been investigated in the endometrium. Therefore, we evaluated stromal p16 expression in different types of endometrial lesions using immunohistochemistry. Differences in the p16 expression status according to the degree of malignancy and histological type were analyzed. This study included 62, 26, and 36 cases of benign, precancerous, and malignant endometrial lesions, respectively. Most benign lesions showed negative or weak expression, whereas precancerous lesions showed a variable degree of staining proportion and intensity. Atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN) and serous endometrial intraepithelial carcinoma (SEIC) had significantly higher stromal p16 expression levels than benign lesions. Endometrioid carcinoma (EC), serous carcinoma (SC), and carcinosarcoma showed significantly elevated stromal p16 expression levels compared with benign and precancerous lesions. In addition, there were significant differences in stromal p16 expression between AH/EIN and SEIC and between EC and SC. In contrast, differences in stromal p16 expression among nonpathological endometrium, atrophic endometrium, endometrial polyp, and hyperplasia without atypia were not statistically significant. Our observations suggest that stromal p16 expression is involved in the development and progression of endometrial carcinoma, and raise the possibility that p16 overexpression in the peritumoral stroma is associated with aggressive oncogenic behavior of endometrial SC.

We performed a retrospective analysis of the clinical features and patient outcomes for advanced-stage glassy cell carcinoma of the uterine cervix. The study was restricted to cases in which the glassy cell features constituted at least 95% of the biopsied specimen. During the study period, 675 patients were diagnosed with primary cervical carcinoma. Five (0.7%) of the 675 patients had cervical glassy cell carcinoma; of these, three were premenopausal, and two were postmenopausal. Abnormal vaginal bleeding was the most frequent presenting symptom. Glassy cell carcinoma presented as a fungating, exophytic, or infiltrative mass. The greatest tumor dimension ranged from 3 to 9 cm. All patients had parametrial extension. Four patients had stage IIB tumors, and one had a stage IIIB tumor. All patients received concurrent chemoradiation therapy. The patient with a stage IIIB tumor died of hypovolemic shock caused by upper gastrointestinal bleeding during radiation therapy. Three patients with stage IIB tumors survived for more than 8 years without tumor recurrence or metastasis. One of these three patients died of pelvic recurrence 10 years after the initial diagnosis. Cervical glassy cell carcinoma has traditionally been considered an aggressive, highly malignant tumor with poor prognosis, but our data suggest that patient survival is not significantly decreased compared with other histological types of cervical carcinoma. It will be necessary to analyze patient outcomes using a larger number of cervical glassy cell carcinoma cases to confirm our findings.

Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, was first described by Rosai and Dorfman in 1969 [1]. A subtype of this disease shows overlapping features with IgG4-related disease [2]. Soft tissue involvement of RDD is very rare, and there has been no report of RDD associated with acute myeloid leukemia to date. Here, we describe a case of soft tissue RDD (STRDD) with features of IgG4-related disease in a patient with a history of acute myeloid leukemia.