Prevention of vincristine-induced peripheral neuropathy by protecting the endothelial glycocalyx shedding.

Vincristine-induced peripheral neuropathy (VIPN) adversely affects the quality of life and treatment continuity of patients. The endothelial glycocalyx (eGCX) protects nerves from harmful substances released from the capillary vessels, but its role in peripheral neuropathy remains unclear. We investigated the impact of eGCX protection on VIPN. Using a murine model of VIPN, we administered nafamostat mesylate to protect the eGCX shedding, and analyzed the eGCX integrity and manifestation of peripheral neuropathy. Nafamostat treatment suppressed allodynia associated with neuropathy. Additionally, nafamostat administration resulted in the suppression of increased vascular permeability in capillaries of peripheral nerves, further indicating its positive influence on eGCX in VIPN model mice. This study provided the importance of eGCX in VIPN. With the potential for rapid clinical translation through drug repositioning, nafamostat may be a new promising treatment for the prevention of VIPN.

Exploring the Vital Link Between Glioma, Neuron, and Neural Activity in the Context of Invasion.

Because of their ability to infiltrate normal brain tissue, gliomas frequently evade microscopic surgical excision. The histologic infiltrative property of human glioma has been previously characterized as Scherer secondary structures, of which the perivascular satellitosis is a prospective target for anti-angiogenic treatment in high-grade gliomas. However, the mechanisms underlying perineuronal satellitosis remain unclear, and therapy remains lacking. Our knowledge of the mechanism underlying Scherer secondary structures has improved over time. New techniques, such as laser capture microdissection and optogenetic stimulation, have advanced our understanding of glioma invasion mechanisms. Although laser capture microdissection is a useful tool for studying gliomas that infiltrate the normal brain microenvironment, optogenetics and mouse xenograft glioma models have been extensively used in studies demonstrating the unique role of synaptogenesis in glioma proliferation and identification of potential therapeutic targets. Moreover, a rare glioma cell line is established that, when transplanted in the mouse brain, can replicate and recapitulate the human diffuse invasion phenotype. This review discusses the primary molecular causes of glioma, its histopathology-based invasive mechanisms, and the importance of neuronal activity and interactions between glioma cells and neurons in the brain microenvironment. It also explores current methods and models of gliomas.

Alterations in metabolites in the anterior cingulate cortex and thalamus and their associations with pain and empathy in patients with chronic mild pain: a preliminary study.

Proton magnetic resonance spectroscopy (1H-MRS) has shown inconsistent alterations in the brain metabolites of individuals with chronic pain. We used 3T 1H-MRS to investigate the brain metabolites in the anterior cingulate cortex and thalamus of 22 patients with chronic mild pain and no gait disturbance and 22 healthy controls. The chronic-pain group included patients with chronic low back pain and/or osteoarthritis but none suffering from hypersensitivity. There were no significant between group-differences in glutamate, glutamate plus glutamine (Glx), N-acetylaspartate, glycerophosphorylcholine (GPC), glutamine, creatine plus phosphocreatine, or myo-inositol in the anterior cingulate cortex, but the patients showed a significant decrease in GPC, but not other metabolites, in the thalamus compared to the controls. The GPC values in the patients' thalamus were significantly correlated with pain components on the Short-Form McGill Pain Questionnaire (SF-MPQ-2) and affective empathy components on the Questionnaire of Cognitive and Affective Empathy (QCAE). The GPC in the patients' anterior cingulate cortex showed significant correlations with cognitive empathy components on the QCAE. Myo-inositol in the controls' anterior cingulate cortex and Glx in the patients' thalamus each showed significant relationships with peripheral responsivity on the QCAE. These significances were not significant after Bonferroni corrections. These preliminary findings indicate important roles of GPC, myo-inositol, and Glx in the brain of patients with chronic mild pain.

Prognostic value of radiological T category using conventional MRI in patients with oral tongue cancer: comparison with pathological T category.

PURPOSE: This study aimed to compare the radiological tumor (T)-category using multiparametric MRI with the pathological T category in patients with oral tongue squamous cell carcinoma (OTSCC) and to examine which is a better predictor of prognosis. METHODS: This retrospective study included 110 consecutive patients with surgically resected primary OTSCC who underwent preoperative contrast-enhanced MRI. T categories determined by maximum diameter and depth of invasion were retrospectively assessed based on the pathological specimen and multiparametric MRI. The MRI assessment included the axial and coronal T1-weighted image (T1WI), axial T2-weighted image (T2WI), coronal fat-suppressed T2WI, and axial and coronal fat-suppressed contrast-enhanced T1WI (CET1WI). Axial and coronal CET1WI measurements were divided into two groups: measurements excluding peritumoral enhancement (MEP) and measurements including peritumoral enhancement. The prognostic values for recurrence and disease-specific survival after radiological and pathological T categorization of cases into T1/T2 and T3/T4 groups were compared. RESULTS: The T category of MEP on coronal CET1WI was the most relevant prognostic factor for recurrence [hazard ratio (HR) = 3.30, p = 0.001] and the HR was higher than the HR for pathological assessment (HR = 2.26, p = 0.026). The T category determined by MEP on coronal CET1WI was also the most relevant prognostic factor for disease-specific survival (HR = 3.12, p = 0.03), and the HR was higher than the HR for pathological assessment (HR = 2.02, p = 0.20). CONCLUSION: The T category determined by MEP on the coronal CET1WI was the best prognostic factor among all radiological and pathological T category measurements.

The phosphorylated retinoid X receptor-α promotes diethylnitrosamine-induced hepatocarcinogenesis in mice through the activation of ß-catenin signaling pathway.

Previous studies have shown that phosphorylation of the retinoid X receptor-α (RXRα) is associated with the development of hepatocellular carcinoma (HCC). However, these findings were revealed using HCC cell lines that express phosphorylated-RXRα (p-RXRα) proteins; therefore, it remains unclear whether p-RXRα affects hepatocarcinogenesis in vivo. Therefore, to investigate the biological function of p-RXRα in vivo, we developed a doxycycline-inducible ES cell line and transgenic mouse, both of which overexpress the phosphomimetic mutant form of RXRα, T82D/S260D, in a doxycycline-dependent manner. We found that the development of liver tumors, especially high-grade adenoma and HCC, was enhanced in diethylnitrosamine (DEN)-treated T82D/S260D-inducible mice. Moreover, the increased incidence of liver tumors in the transgenic mice was attributable to the promotion of cell cycle progression. Interestingly, the expression of ß-catenin protein and its target gene cyclin D1 was elevated in the liver tumors of DEN-treated T82D/S260D-inducible mice, concurrent with increased cytoplasmic and nuclear ß-catenin protein expression, indicating its stabilization and transcriptional activation. These results indicate that p-RXRα promotes DEN-induced hepatocarcinogenesis in mice through the activation of the ß-catenin signaling pathway, suggesting that p-RXRα may serve as a possible therapeutic target for HCC.

Induced genetic ablation of Rest leads to the alteration of stimulus-induced response of the vagal nerve.

Rest (RE1-silencing transcription factor, also called Nrsf) is involved in the maintenance of the undifferentiated state of neuronal stem/progenitor cells by preventing precocious expression of neuronal genes. In order to further investigate the function of Rest in neurons, we generated and examined mice evoking genetic ablation of Rest specifically in neural tissues by generating Rest conditional knockout mice. As the Rest knockout mice are embryonically lethal, we used a Sox1-Cre allele to excise the floxed Rest gene from the early stage of nerve cell differentiation including neural crest-derived nerve cells. Using this conditional Rest knockout Sox1-Cre; Restflox/flox mice, we have revealed the role of Rest in the parasympathetic nervous system in the stomach and heart.

Development of extrahepatic bile ducts and mechanisms of tumorigenesis: Lessons from mouse models.

The biliary system is a highly branched tubular network consisting of intrahepatic bile ducts (IHBDs) and extrahepatic bile ducts (EHBDs). IHBDs are derived from hepatic progenitor cells, while EHBDs originate directly from the endoderm through a separate branching morphogenetic process. Traits that are important for cancer are often found to overlap in developmental and other processes. Therefore, it has been suggested that intrahepatic cholangiocarcinomas (iCCAs) and extrahepatic cholangiocarcinomas (eCCAs) have different developmental mechanisms. While much evidence is being gathered on the mechanism of iCCAs, the evidence for eCCA is still very limited. The main reason for this is that there are very few appropriate animal models for eCCA. We can gain important insights from these animal models, particularly genetically engineered mouse models (GEMMs). GEMMs are immunocompetent and mimic human CCA subtypes with a specific mutational pattern, allowing the development of precancerous lesions, that is, biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB). This review provides a summary of the pathogenesis and mechanisms of eCCA that can be revealed by GEMMs. Furthermore, we discuss several clinical questions, such as whether BilIN and IPNB really become malignant, whether the peribiliary gland is the origin of eCCAs, and others.

Prediction of overall survival in patients with pancreatic ductal adenocarcinoma: histogram analysis of ADC value and correlation with pathological intratumoral necrosis.

BACKGROUND: To evaluate the utility of histogram analysis (HA) of apparent diffusion coefficient (ADC) values to predict the overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC) and to correlate with pathologically evaluated massive intratumoral necrosis (MITN). MATERIALS AND METHODS: Thirty-nine patients were included in this retrospective study with surgically resected PDAC who underwent preoperative magnetic resonance imaging. Twelve patients received neoadjuvant chemotherapy. HA on the ADC maps were performed to obtain the tumor HA parameters. Using Cox proportional regression analysis adjusted for age, time-dependent receiver-operating-characteristic (ROC) curve analysis, and Kaplan-Meier estimation, we evaluated the association between HA parameters and OS. The association between prognostic factors and pathologically confirmed MITN was assessed by logistic regression analysis. RESULTS: The median OS was 19.9 months. The kurtosis (P < 0.001), entropy (P = 0.013), and energy (P = 0.04) were significantly associated with OS. The kurtosis had the highest area under the ROC curve (AUC) for predicting 3-year survival (AUC 0.824) among these three parameters. Between the kurtosis and MITN, the logistic regression model revealed a positive correlation (P = 0.045). Lower survival rates occurred in patients with high kurtosis (cutoff value > 2.45) than those with low kurtosis (≤ 2.45) (P < 0.001: 1-year survival rate, 75.2% versus 100%: 3-year survival rate, 14.7% versus 100%). CONCLUSIONS: HA derived kurtosis obtained from tumor ADC maps might be a potential imaging biomarker for predicting the presence of MITN and OS in patients with PDAC.

Regulation of Mesothelial Cell Fate during Development and Human Diseases.

Mesothelial cells (MCs) play a classic role in maintaining homeostasis in pleural, peritoneal, and pericardial cavities. MCs work as lubricants to reduce friction between organs, as regulators of fluid transport, and as regulators of defense mechanisms in inflammation. MCs can differentiate into various cells, exhibiting epithelial and mesenchymal characteristics. MCs have a high potential for differentiation during the embryonic period when tissue development is active, and this potential decreases through adulthood. The expression of the Wilms' tumor suppressor gene (Wt1), one of the MC markers, decreased uniformly and significantly from the embryonic period to adulthood, suggesting that it plays a major role in the differentiation potential of MCs. Wt1 deletion from the embryonic period results in embryonic lethality in mice, and even Wt1 knockout in adulthood leads to death with rapid organ atrophy. These findings suggest that MCs expressing Wt1 have high differentiation potential and contribute to the formation and maintenance of various tissues from the embryonic period to adulthood. Because of these properties, MCs dynamically transform their characteristics in the tumor microenvironment as cancer-associated MCs. This review focuses on the relationship between the differentiation potential of MCs and Wt1, including recent reports using lineage tracing using the Cre-loxP system.

Vascular endothelial injury exacerbates coronavirus disease 2019: The role of endothelial glycocalyx protection.

The potential for a rapid increase in severity is among the most frightening aspects of severe acute respiratory syndrome coronavirus 2 infection. Evidence increasingly suggests that the symptoms of coronavirus disease-2019 (COVID-19)-related acute respiratory distress syndrome (ARDS) differ from those of classic ARDS. Recently, the severity of COVID-19 has been attributed to a systemic, thrombotic, and inflammatory disease that damages not only the lungs but also multiple organs, including the heart, brain, toes, and liver. This systemic form of COVID-19 may be due to inflammation and vascular endothelial cell injury. The vascular endothelial glycocalyx comprises glycoproteins and plays an important role in systemic capillary homeostasis maintenance. The glycocalyx covers the entire vascular endothelium, and its thickness varies among organs. The endothelial glycocalyx is very thin in the pulmonary capillaries, where it is affected by gaseous exchange with the alveoli and the low intravascular pressure in the pulmonary circulation. Despite the clearly important roles of the glycocalyx in vascular endothelial injury, thrombosis, vasculitis, and inflammation, the link between this structure and vascular endothelial cell dysfunction in COVID-19 remains unclear. In this prospective review, we summarize the importance of the glycocalyx and its potential as a therapeutic target in cases of systemic COVID-19.

Specific Deletion of p16INK4a with Retention of p19ARF Enhances the Development of Invasive Oral Squamous Cell Carcinoma.

The cyclin-dependent kinase inhibitor 2A (CDKN2A)/alternate reading frame (ARF) locus consists of two overlapping tumor suppressor genes, p16INK4a and p14ARF (p19ARF in mice), encoding two unrelated proteins in alternative reading frames. Previous reports suggest that p16INK4a and p14ARF alterations independently exhibit differential roles, and p16INK4a is more closely associated with a poor prognosis in oral cancer. However, the role of p16INK4a-specific loss in oral squamous cell carcinogenesis remains unclear. The authors assessed chemical carcinogen 4-nitroquinoline 1-oxide (4NQO)-induced multistep oral squamous cell carcinogenesis in mice carrying p16INK4a-specific loss with retention of the p19ARF gene (p16INK4a-/-). 4NQO-treated p16-/- mice exhibited a higher incidence and multiplicity of oral squamous cell carcinoma (OSCC) development relative to 4NQO-treated wild-type mice. 4NQO-treated p16INK4a-/- OSCC cells exhibited higher proliferation and up-regulation of Arf, transcription factor E2f1, tumor protein p63 (tp63), and oncogenic ΔNp63, an isoform p63, compared with observations in 4NQO-treated wild-type OSCC cells. Furthermore, the overexpression of oncogenic ΔNp63 was associated with human OSCC. In conclusion, these results in mice indicate the biological significance of p16INK4a-specific loss with retention of p19ARF in oral squamous cell carcinogenesis, and ΔNp63 may be a potential target for OSCC.

Characterization of aldo-keto reductase 1C subfamily members encoded in two rat genes (akr1c19 and RGD1564865). Relationship to 9-hydroxyprostaglandin dehydrogenase.

Rat genes, akr1c19 and RGD1564865, encode members (R1C19 and 20HSDL, respectively) of the aldo-keto reductase (AKR) 1C subfamily, whose functions, however, remain unknown. Here, we show that recombinant R1C19 and 20HSDL exhibit NAD+-dependent dehydrogenase activity for prostaglandins (PGs) with 9α-hydroxy group (PGF2α, its 13,14-dihydro- and 15-keto derivatives, 9α,11ß-PGF2 and PGD2). 20HSDL oxidized the PGs with much lower Km (0.3-14 µM) and higher kcat/Km values (0.064-2.6 min-1µM-1) than those of R1C19. They also differed in other properties: R1C19, but not 20HSDL, oxidized some 17ß-hydroxysteroids (5ß-androstane-3α,17ß-diol and 5ß-androstan-17ß-ol-3-one). 20HSDL was specifically inhibited by zomepirac, but not by R1C19-selective inhibitors (hexestrol, flavonoids, ibuprofen and flufenamic acid), although the two enzymes were sensitive to indomethacin and cis-unsaturated fatty acids. The mRNA for 20HSDL was expressed abundantly in rat kidney and at low levels in the liver, testis, brain, heart and colon, in contrast to ubiquitous expression of R1C19 mRNA. The comparison of enzymic features of R1C19 and 20HSDL with rat PG dehydrogenases and other AKRs suggests not only a close relationship of 20HSDL with 9-hydroxy-PG dehydrogenase in rat kidney, but also roles of R1C19 and rat AKRs (1C16 and 1C24) in the metabolism of PGF2α, PGD2 and 9α,11ß-PGF2 in other tissues.

Novel hepatitis B virus infection mouse model using herpes simplex virus type 1 thymidine kinase transgenic mice.

BACKGROUND AND AIM: The chronicity of hepatitis B virus (HBV) infection is the result of impaired HBV-specific immune responses that cannot eliminate or cure the infected hepatocytes efficiently. Previous studies have used immunodeficient mice such as herpes simplex virus type 1 thymidine kinase NOD/Scid/IL2Rrnull (HSV-TK-NOG) mice. However, it is difficult to analyze the immune response in the previous models. In the present study, we established a novel HBV infection model using herpes simplex virus type 1 thymidine kinase (HSV-TK) mice in which the host immune system was not impaired. METHODS: Herpes simplex virus type 1 thymidine kinase mice were injected intraperitoneally with ganciclovir (GCV). Seven days after GCV injection, GCV-treated mice were transplanted with 1 × 106 hepatocytes from HBV-transgenic (HBV-Tg) mice. RESULTS: Serum alanine aminotransferase levels in HSV-TK mice increased 1 and 2 weeks after GCV injection. The number and viability of hepatocytes from the whole liver of HBV-Tg mice significantly increased using digestion medium containing liberase. Hepatitis B surface antigen (HBsAg)-positive areas in the liver tissue were observed for at least 20 weeks after HBsAg-positive hepatocyte transplantation. In addition, we measured HBsAg in the serum after transplantation. HBsAg levels in HBV-Tg hepatocyte-replaced mice increased 4 weeks after transplantation. Furthermore, we examined the immune response in HSV-TK mice. The increase in hepatitis B surface antibody levels in replaced mice was maintained for 20 weeks. Also, interferon-γ-producing cells were increased in non-replaced mice. CONCLUSIONS: A novel HBV infection mouse model will help to understand the mechanisms of HBV tolerance similar to human chronic HBV-infected patients and can be used to develop a new strategy to treat chronic HBV infection.

Magnetic resonance imaging findings of extrauterine high-grade serous carcinoma based on new pathologic criteria for primary site assignment.

BACKGROUND: There has been no study that has reported magnetic resonance imaging (MRI) findings of extrauterine high-grade serous carcinomas (HGSCs) that have been histologically determined by the new criteria. PURPOSE: To assess MRI findings of extrauterine HGSCs based on new pathologic criteria. MATERIAL AND METHODS: Fifty patients with histopathologically proven extrauterine HGSCs, who underwent pretreatment gadolinium-enhanced MRI, were included in this study. After surgery, the primary sites were histopathologically determined based on new criteria for primary site assignment in extrauterine HGSCs as follows: fallopian tube (n = 34); ovary (n = 9); primary peritoneal HGSC (n = 1); and tubo-ovarian (n = 6). We retrospectively reviewed MR images and compared the MR findings between tubal and ovarian primaries. RESULTS: MRI patterns with tubal primaries were classified as ovarian cancer (62%), peritoneal cancer (35%), and fallopian tube cancer (3%). MRI patterns with ovarian primaries were classified as ovarian cancer (78%) and peritoneal cancer (22%). The frequency of the involvement of the fallopian tube, ovary, peritoneum, uterus, and lymph node was not significantly different between the two pathologies. There was no significant difference in the abnormal amount of ascites, hemorrhagic ascites, or characteristics of the ovarian lesions between the two pathologies. CONCLUSION: On MR images, tubal primaries almost always exhibited ovarian or peritoneal cancer pattern, but rarely exhibited fallopian tube cancer pattern. MR findings could not accurately differentiate between tubal and ovarian primaries; therefore, histopathologic investigation is essential for determination of the primary site of extrauterine HGSCs.

Dimeric dihydrodiol dehydrogenase is an efficient primate 1,5-anhydro-D-fructose reductase.

1,5-Anhydro-D-fructose (AF), a metabolite of the anhydrofructose pathway of glycogen metabolism, has recently been shown to react with intracellular proteins and form advanced glycation end-products. The reactive AF is metabolized to non-reactive 1,5-anhydro-D-glucitol by AF reductase in animal tissues and human cells. Pig and mouse AF reductases were characterized, but primate AF reductase remains unknown. Here, we examined the AF-reducing activity of eleven primate NADPH-dependent reductases with broad substrate specificity for carbonyl compounds. AF was reduced by monkey dimeric dihydrodiol dehydrogenase (DHDH), human aldehyde reductase (AKR1A1) and human dicarbonyl/L-xylulose reductase (DCXR). DHDH showed the lowest KM (21 µM) for AF, and its kcat/KM value (1208 s-1mM-1) was much higher than those of AKR1A1 (1.3 s-1mM-1), DCXR (1.1 s-1mM-1) and the pig and mouse AF reductases. AF is a novel substrate with higher affinity and catalytic efficiency than known substrates of DHDH. Docking simulation study suggested that Lys156 in the substrate-binding site of DHDH contributes to the high affinity for AF. Gene database searches identified DHDH homologues (with >95% amino acid sequence identity) in humans and apes. Thus, DHDH acts as an efficient AF reductase in primates.

Role of the DEK oncogene in the development of squamous cell carcinoma.

DEK is a highly conserved nuclear factor that plays an important role in the regulation of multiple cellular processes. DEK was discovered to be an oncogene as a fusion with NUP214 gene, which results in producing DEK-NUP214 proteins, in a subset of patients with acute myeloid leukemia. Subsequently, DEK overexpression was reported in many cancers, thus DEK itself is considered to be an oncoprotein. DEK has been reported to play important roles in the progression of early and late stage squamous cell carcinoma (SCC) and is useful for early diagnosis of the disease. These findings have made DEK an attractive therapeutic target, especially for human papillomavirus (HPV)-associated SCC. However, the mechanism of DEK in SCC remains unclear. In this review, we discuss human DEK oncogene-related SCC.

CT and MR imaging findings of solitary nevus lipomatosus cutaneous superficialis: radiological-pathological correlation.

OBJECTIVE: This study assessed the CT and MRI findings of solitary nevus lipomatosus cutaneous superficialis (NLCS). MATERIALS AND METHODS: Eleven patients with histopathologically and clinically confirmed solitary NLCS who underwent CT and/or MRI were enrolled. Radiological and histopathological findings of elevated lesions located above the level of the surrounding normal skin surface and coexisting subcutaneous lipoma-like lesions were assessed retrospectively. RESULTS: Elevated skin lesions were observed in all 11 patients; these lesions were pedunculated in 4 patients (36%) and broad-based in 7 (64%). The CT attenuation of elevated lesions was fat attenuation in 2 out of 7 patients (29%), slightly increased fat attenuation in 4 out of 7 (57%), and combined fat and soft-tissue attenuation in 1 out of 7 (14%). The MR signal intensity of elevated lesions on T1-weighted images was fat signal intensity in 2 out of 6 patients (33%), slightly decreased fat signal intensity in 3 out of 6 (50%), and combined fat signal intensity and hypointensity in 1 out of 6 (17%). Subcutaneous lipoma-like lesions with fat attenuation and/or fat signal intensity were observed in 6 out of 11 patients (55%). Histopathologically, various amounts of fatty tissue and collagenous fiber were observed within the elevated lesions in all 11 patients. CONCLUSION: The CT and MRI features of solitary NLCS were the broad-based or pedunculated elevated lesions, including fatty components. Additionally, subcutaneous lipoma-like lesions were frequently observed.

Exogenous Application of Proteoglycan to the Cell Surface Microenvironment Facilitates to Chondrogenic Differentiation and Maintenance.

Osteoarthritis (OA), a disease that greatly impacts quality of life, has increasing worldwide prevalence as the population ages. However, its pathogenic mechanisms have not been fully elucidated and current therapeutic treatment strategies are inadequate. In recent years, abnormal endochondral ossification in articular cartilage has received attention as a pathophysiological mechanism in OA. Cartilage is composed of abundant extracellular matrix components, which are involved in tissue maintenance and regeneration, but how these factors affect endochondral ossification is not clear. Here, we show that the application of aggrecan-type proteoglycan from salmon nasal cartilage (sPG) exhibited marked proliferative capacity through receptor tyrosine kinases in chondroprogenitor cells, and also exhibited differentiation and three-dimensional structure formation via phosphorylation of Insulin-like Growth Factor-1 Receptor and Growth Differentiation Factor 5 expression. Furthermore, sPG inhibited calcification via expression of Runx2 and Col10 (factors related to induction of calcification), while increasing Mgp, a mineralization inhibitory factor. As a result of analyzing the localization of sPG applied to the cells, it was localized on the surface of the cell membrane. In this study, we found that sPG, as a biomaterial, could regulate cell proliferation, differentiation and calcification inhibition by acting on the cell surface microenvironment. Therefore, sPG may be the foundation for a novel therapeutic approach for cartilage maintenance and for improved symptoms in OA.

Mouse Akr1cl gene product is a prostaglandin D2 11-ketoreductase with strict substrate specificity.

A mouse gene, Akr1cl, encodes a member of the aldo-keto reductase 1C subfamily (AKR1CL), whose function, however, remains unknown. Here, we show that the recombinant AKR1CL is an NADPH-dependent reductase of prostaglandin (PG) D2 (Km 3.2 µM, kcat 5.6 min-1) and oxidizes 9α,11ß-PGF2 (Km 30 µM, kcat 3.3 min-1) in the reverse reaction. In contrast, it did not exhibit oxidoreductase activity towards other PGs (E2, A1, B2 and F2α), steroids and nonsteroidal carbonyls and alcohols, which are substrates of other mammalian AKR1C subfamily enzymes. The enzyme activity was inhibited by estradiol, quercetin, benzbromarone, ethacrynic acid and flufenamic acid, of which estradiol was the most potent competitive inhibitor (Ki 3.2 µM). The mRNA for AKR1CL was expressed abundantly in mouse testis, ovary and adrenal gland, and at low levels in the brain, lung, small intestine and prostate. Thus, AKR1CL is the first PGD2 11-ketoreductase with strict substrate specificity in mammals. The site-directed mutagenesis of P85 in AKR1CL to the corresponding residue, W, in other mammalian AKR1C subfamily enzymes resulted in broad substrate specificity for nonsteroidal carbonyls and alcohols, suggesting that P85 plays a critical role in the strict specificity for PGD2 and 9α,11ß-PGF2.

A Comprehensive Review of Ovarian Serous Carcinoma.

Although ovarian serous carcinoma is a well-studied human gynecologic malignancy, this high-grade tumor remains fatal. The main purpose of this review is to summarize the accumulated evidence on serous malignant tumors and to clarify the unresolved issues. We discuss the 8 dichotomies of serous carcinoma: high grade versus low grade, ovarian versus extraovarian primary, extrauterine versus uterine primary, sporadic versus hereditary, orthodox versus alternative histology, p53 overexpression versus complete absence of immunophenotype, TP53-mutated versus intact precursor, and therapy responsive versus refractory. In addition, we summarize the molecular classification of high-grade serous carcinoma. This review would lead readers to rapid and parallel developments in understanding high-grade serous carcinoma.