Acetylated tau exacerbates apoptosis by disturbing mitochondrial dynamics in HEK293 cells.

An increase in tau acetylation at K274 and K281 and abnormal mitochondrial dynamics have been observed in the brains of Alzheimer's disease (AD) patients. Here, we constructed three types of tau plasmids, TauKQ (acetylated tau mutant, by mutating its K274/K281 into glutamine to mimic disease-associated lysine acetylation), TauKR (non-acetylated tau mutant, by mutating its K274/K281 into arginine), and TauWT (wild-type human full-length tau). By transfecting these tau plasmids in HEK293 cells, we found that TauWT and TauKR induced mitochondrial fusion by increasing the level of mitochondrial fusion proteins. Conversely, TauKQ induced mitochondrial fission by reducing mitochondrial fusion proteins, exacerbating mitochondrial dysfunction and apoptosis. BGP-15 ameliorated TauKQ-induced mitochondrial dysfunction and apoptosis by improving mitochondrial dynamics. Our findings suggest that acetylation of K274/281 represents an important post-translational modification site regulating mitochondrial dynamics, and that BGP-15 holds potential as a therapeutic agent for mitochondria-associated diseases such as AD.

Propionate ameliorates diabetes-induced neurological dysfunction through regulating the PI3K/Akt/eNOS signaling pathway.

A large body of research has established diabetes-related cognitive deterioration, sometimes known as "diabetic encephalopathy". Current evidence supports that oxidative stress, neuronal apoptosis, and cerebral microcirculation weakness are associated with cognition deficits induced by diabetes. The present study explores the effect of propionate on neurological deficits, cerebral blood flow, and oxidative stress in diabetic mice. Propionate in different doses (37.5, 75 and 150 mg/kg) was orally administrated daily. Here, we show that propionate can markedly improve neurological function, which is correlated with its capabilities of stimulating nitrogen monoxide (NO) production, increasing cerebral microcirculation, suppressing oxidative stress, and reducing neuron loss in the hippocampus. In addition, the results of Western Blotting indicated that the brain-protective function of propionate in streptozocin (STZ)-induced type 1 diabetes mellitus (T1DM) mice is related to phosphoinositide 3-kinase (PI3K)/serine-threonine protein kinase (Akt)/endothelial nitrogen monoxide synthase (eNOS) signaling pathway. In a diabetic mouse model, propionate reduces cerebral microcirculation, hippocampus apoptosis, and neurological impairment. Thus, propionate, now employed as a food preservative, may also help slow diabetes-induced cognitive loss.

[Research Progress of Thalidomide and Its Derivatives in Treatment of Myelodysplastic Syndrome--Review].

Thalidomide and its derivatives have been used in the treatment of myelodysplastic syndrome (MDS) because of their anti-angiogenic and immunomodulatory effects. In recent years, some studies have found that thalidomide and its derivatives not only showed significant efficacy in lower-risk MDS patients with del (5q), but also showed advantages in non-del (5q) MDS patients. In addition, the discovery of its molecular targets and new substrates makes it possible to develop a new generation of immunomodulatory drugs (IMiDs) and to design IMiDs-based proteolysis-targeting chimeras. In this review, the new progress in mechanism and clinical application of thalidomide and its derivatives were summarized briefly, so as to provide a more scientific, reasonable and effective scheme to the treatment of MDS.

[Advances in the Action Mechanism of Classical Pathways IKKα and IKKß in Hematological Tumors and Drug Therapy Blocking Their Effect--Review].

In recent years, it is found that the classical IKKα and IKKß pathway were closely relates with hematological tumors, except the classical pathogenesis, moreover the classical IKKß pathway is deeply studied. The studies indicated that the IKKßis activated to phosphorylate the NF-κB through multiple cascades under the effect of extracellular IL-6, TNF-α and other stimulating factors. At the cellular level, the classical IKKßcan promote the tumor cell survival and proliferation, reduce the cell apoptosis, and promote the angiogenesis and cell transfer. Although the classical IKKα plays a role in regulating IKKß activity, but its role in non-classical pathway is more prominent. This review briefly summarizes the latest advance of researches on the pathogenesis of hematological malignancies in term of IKKα and IKKßpathway, so as to provide the theoretic basis for deeply understanding and studying the pathogenesis of hematologic tumors. At present, blocking the classical IKKα and IKKß pathway has become a new target for treatment of hematological tumors, moreover, some specific inhibitor for IKKα and IKKßpathway have been developed, for example, LY2409881, BMS 345541 and so on. Most of these drugs are in clinical trials and display some good anti-tumor effects.

An iPSC line (TYWHSTi002-A) derived from a patient with Pendred syndrome caused by compound heterozygous mutations in the SLC26A4 gene.

Pendred syndrome (PDS) is hereditary and is characterized by thyroid enlargement, cochlea abnormalities, and hearing impairment. In this study, we established an induced pluripotent stem cell line from a PDS patient with familial thyroid disorder, caused by compound heterozygous mutations in SLC26A4 (NM_000441.1; c.919-2A>G and c.1614 + 1G>A). Isolated peripheral blood mononuclear cells of the patient were reprogrammed using the transgene free Sendai viral vectors, encoding SOX2, OCT4, KLF4, and cMYC. The resulting iPSC line was verified based on morphology, pluripotency markers, and differentiation potential into all three germ layers, and demonstrated typical features in accordance with those of embryo stem cells.

Role of Chromatin Remodeling Genes and TETs in the Development of Human Midbrain Dopaminergic Neurons.

Understanding epigenetic regulation in the differentiation and maturation of dopaminergic neurons is critical to improve and develop new medications for Parkinson's disease (PD). To explore the role of ten-eleven translocation (TETs) family of dioxygenases and chromatin remodeling genes in the development of human midbrain dopaminergic (mDA) neurons, we globally analyze the epigenetic regulation of gene expression in human induced pluripotent stem cells (iPSCs) and iPSCs-derived mDA neurons. During the conversion of iPSCs into neuronal lineages of dopaminergic progenitors and mDA neurons, the expression patterns of epigenetic genes in multiple sets alter significantly. Vitamin C, an activator of TET enzymes, increases hydroxymethylcytosine (5hmC) level along with a higher yield of mDA neurons. Additionally, vitamin C treatment elevates gene expressions of TET2/3 and vitamin C transporters. Importantly, functional arrays indicate that vitamin C can promote neuronal maturation, synaptic activity, and dopamine release. Collectively, our study demonstrates that chromatin remodeling genes and the TET-5hmC pathway, which is regulated by vitamin C, are critical for the vital developmental stages of human mDA neurons.

Application of a combined model with seasonal autoregressive integrated moving average and support vector regression in forecasting hand-foot-mouth disease incidence in Wuhan, China.

Hand-foot-mouth disease (HFMD) is a serious public health problem with increasing cases and substantial financial burden in China, especially in Wuhan city. Hence, there is an urgent need to construct a model to predict the incidence of HFMD that could make the prevention and control of this disease more effective.The incidence data of HFMD of Wuhan city from January 2009 to December 2016 were used to fit a combined model with seasonal autoregressive integrated moving average (SARIMA) model and support vector regression (SVR) model. Then, the SARIMA-SVR hybrid model was constructed. Subsequently, the fitted SARIMA-SVR hybrid model was applied to obtain the fitted HFMD incidence from 2009 to 2016. Finally, the fitted SARIMA-SVR hybrid model was used to forecast the incidence of HFMD of the year 2017. To assess the validity of the model, the mean square error (MSE) and mean absolute percentage error (MAPE) between the actual values and predicted values of HFMD incidence (2017) were calculated.From 2009 to 2017, a total of 107636 HFMD cases were reported in Wuhan City, Hubei Province, and the male-to-female ratio is 1.60:1. The age group of 0 to 5 years old accounts for 95.06% of all reported cases and scattered children made up the large proportion (accounted for 56.65%). There were 2 epidemic peaks, from April to July and September to December, respectively, with an emphasis on the former. High-prevalence areas mainly emerge in Dongxihu District, Jiangxia District, and Hongshan District. SARIMA (1,0,1)(0,0,2)[12] is the optimal model given with a minimum Akaike information criterion (AIC) (700.71), then SVR model was constructed by using the optimum parameter (C = 100000, =0.00001, =0.01). The forecasted incidences of single SARIMA model and SARIMA-SVR hybrid model from January to December 2017 match the actual data well. The single SARIMA model shows poor performance with large MSE and MAPE values in comparison to SARIMA-SVR hybrid model.The SARIMA-SVR hybrid model in this study showed that accurate forecasting of the HFMD incidence is possible. It is a potential decision supportive tool for controlling HFMD in Wuhan, China.

The analysis of GM (1, 1) grey model to predict the incidence trend of typhoid and paratyphoid fevers in Wuhan City, China.

Typhoid and paratyphoid fevers (TPF), systemic emerging infectious diseases, is a serious health problem for society. If the incidence trend of TPF can be predicted, prevention and control measures can be taken in advance to reduce the harm to the people's health.Grey Model First Order One Variable [GM (1, 1)] was applied to predict the incidence trend of TPF with the incidence data of TPF in Wuhan City of China from 2004 to 2015. The original data were acquired from the national surveillance system.The GM (1, 1) model was established as y (t + 1) = 0.88 e + 0.15. The goodness-of-fit test indicated that the precision (degree 2) was qualified (C = 0.40, P = .91). We further compared actual values with predicted values in 2016 and found that GM (1, 1) model we built has excellent performance in incidence trend prediction.Our prediction shows that the TPF incidences in Wuhan City will be slowly decreasing in the next 3 years. It is, however, still necessary to strengthen the comprehensive prevention and control to reduce the incidence level of TPF.

Effectiveness of acupuncture in postpartum depression: a systematic review and meta-analysis.

OBJECTIVE: To assess the clinical effectiveness of acupuncture in the treatment of postpartum depression (PPD). METHODS: The following electronic databases were systematically searched: PubMed, Cochrane Library, SCI, Elsevier SDOL, China National Knowledge, Wan Fang database and Chinese Science and Technology Periodical Database. Only randomised controlled trials (RCTs) of acupuncture for PPD were considered. Primary outcomes were the Hamilton Rating Scale for Depression (HAMD) or the Edinburgh Postnatal Depression Scale (EPDS) scores and effective rate. Our secondary outcome was the level of oestradiol. The quality of all included trials was evaluated according to the Cochrane Collaboration. This protocol was registered in PROSPERO (CRD42016048528). RESULTS: Nine trials involving 653 women were selected. The result of this meta-analysis demonstrated that the acupuncture group had a significantly greater overall effective rate compared with the control group (seven trials, n=576, I2=24%; relative risk (RR) 1.15, 95% CI 1.06 to 1.24; P<0.001). Moreover, acupuncture significantly increased oestradiol levels compared with the control group (mean difference (MD) 36.92, 95% CI 23.14 to 50.71, P<0.001). Regarding the HAMD and EPDS scores, no difference was found between the two groups (five trials, n=276, I2=82%; MD-1.38, 95% CI -3.40 to 0.64; P=0.18; two trials, n=60, I2=16%; MD 1.08, 95% CI -1.09 to 3.26; P=0.33). CONCLUSIONS: Acupuncture appears to be effective for postpartum depression with respect to certain outcomes. However, the evidence thus far is inconclusive. Further high-quality RCTs following standardised guidelines with a low risk of bias are needed to confirm the effectiveness of acupuncture for postpartum depression.

Targeting H19 by lentivirus-mediated RNA interference increases A549 cell migration and invasion.

BACKGROUND: Lung cancer is one of the most common and a lethal malignancy in the world and non-small cell lung cancer (NSCLC) is the most usual type. H19 long non-coding RNA (lncRNA) plays essential roles in tumor development. But its role in tumor metastasis is still unclear. MATERIALS AND METHODS: MACC1 RNAi and Lentivirus-mediated H19-specific shRNA was used to establish H19 stable knocking-down A549 cells. Transwell assays were performed to examine the effect of H19 knocking-down on A549 cells migration and invasion. The downstream signaling proteins targeted by H19 were also examined by western blot. AG1478 and U0126 were used as the inhibitor of EGFR and ERK1/2, respectively. RESULTS: The knockdown of H19 increased the migration and invasion of A549 cells, and knockdown of metastasis-associated in colon cancer 1 (MACC1) decreased the migration and invasion of A549 cells. Furthermore, MACC1 protein targeted by H19 was upregulated as well as the downstream signaling proteins including epidermal growth factor receptor (EGFR), ß-catenin, extracellular-signal-regulated kinase 1/2 (ERK1/2). Inhibited the expression of EGFR or ERK1/2 significantly decreased the migration and invasion of tumor cells. CONCLUSION: Our findings showed that H19 functions as a suppressor of NSCLC and plays an important role in the migration and invasion of NSCLC. More importantly, H19 may regulate NSCLC metastasis through modulating cellular signaling pathway proteins related to cell proliferation and cell adhesion, including MACC1, EGFR, ß-catenin and ERK1/2. These results put forward our understanding of the detailed mechanism of H19 lncRNA regulating the process of NSCLC metastasis.

A novel small molecule agent displays potent anti-myeloma activity by inhibiting the JAK2-STAT3 signaling pathway.

The oncogenic STAT3 signaling pathway is emerging as a promising target for the treatment of multiple myeloma (MM). In the present study, we identified a novel STAT3 inhibitor SC99 in a target-based high throughput screen. SC99 inhibited JAK2-STAT3 activation but had no effects on other transcription factors such as NF-κB, and kinases such as AKT, ERK, and c-Src that are in association with STAT3 signaling pathway. Furthermore, SC99 downregulated the expression of STAT3-modulated genes, including Bcl-2, Bcl-xL, VEGF, cyclin D2, and E2F-1. By inhibiting the STAT3 signaling, SC99 induced MM cell apoptosis which could be partly abolished by the ectopic expression of STAT3. Furthermore, SC99 displayed potent anti-MM activity in two independent MM xenograft models in nude mice. Oral administration of SC99 led to marked decrease of tumor growth within 10 days at a daily dosage of 30 mg/kg, but did not raise toxic effects. Taken together, this study identified a novel oral JAK2/STAT3 inhibitor that could be developed as an anti-myeloma agent.

The ERK1/2 pathway participates in the upregulation of the expression of mesenteric artery α1 receptors by intravenous tail injections of mmLDL in mice.

Minimally modified low density lipoprotein (mmLDL) is a risk factor for cardiovascular diseases. However, no studies examining the effect of mmLDL on vascular smooth muscle receptors have been released. The current study investigated the effect of mmLDL on the mesenteric artery α1 adrenoceptor and the molecular mechanisms. Mice were divided into the normal saline (NS), mmLDL, and mmLDL+U0126 groups. In the mmLDL+U0126 group, the animals were subjected to an intravenous tail injection of mmLDL and an intraperitoneal injection of U0126. Vascular tension caused by noradrenaline (NA) in mesenteric arteries was measured with a sensitive myograph system. The serum levels of oxLDL, TNF-α, and IL-1ß were detected using enzyme-linked immunosorbent assays. The expressions of the α1 adrenoceptor, the α2 adrenoceptor, TNF-α, IL-1ß, and pERK1/2 were detected using real-time polymerase chain reactions and Western blot analysis. Compared with the NS group, the mmLDL group exhibited a noticeably enhanced NA shrinkage dose-response curve and a significantly increased Emax value (P<0.01). Prazosin (α1 adrenoceptor antagonist) caused a noticeable right shift of the dose-response curve. U0126 inhibited the increases in the serum levels and vessel wall expression of IL-1ß and TNF-α and enhanced the NA shrinkage dose-response curve caused by mmLDL, as observed by a significantly decreased Emax value (P<0.01). It inhibited the increased α1 adrenoceptor expression caused by mmLDL. The serum levels of IL-1ß and TNF-α demonstrated a positive correlation with the NA-induced maximum shrinkage percentage. U0126 inhibited the mmLDL-induced increase in the pERK1/2 protein level in the vessel wall. In conclusion, mmLDL increased the serum levels of IL-1ß and TNF-α in vivo by activating the ERK1/2 pathway, which resulted in α1 receptor-mediated vasoconstriction and an increase in the expression of α1 adrenoceptor. The results of this study may provide new ideas for the prevention and cure of cardiovascular diseases in the future.

Mitochondrial DNA hypomethylation in chrome plating workers.

A matched case-control study was conducted to examine the relationship between chromium (Cr) exposure and variation in mitochondrial (mt) DNA methylation. We enrolled 29 pairs of subjects in this study; Cr exposure was confirmed in the cases by detecting blood Cr and other metal ion concentrations. DNA damage caused by Cr exposure was determined in terms of binucleated micronucleus frequency (BNMN) and mtDNA copy number. Finally, a Sequenom MassARRAY platform was applied to inspect the DNA methylation levels of mitochondrially encoded tRNA phenylalanine (MT-TF), mitochondrially encoded 12S RNA (MT-RNR1), and long interspersed nucleotide element-1 (LINE-1) genes. The blood Cr ion concentration and micronucleus frequency of the Cr-exposed group were higher than those of the control group, whereas the mtDNA copy number remained unchanged. The methylation levels of MT-TF and MT-RNR1 but not LINE-1 were significantly lower in Cr-exposed workers. Pearson correlation analysis showed that workers with higher blood Cr ion concentrations exhibited lower MT-TF and MT-RNR1 gene methylation, and multiple linear regression analysis indicated that CpG sites 1 and 2 in MT-TF and CpG site 6 in MT-RNR1 were affected. These results suggested that methylation level of mtDNA has the possibility of acting as an alternative effect biomarker for Cr exposure.

Expression and DNA methylation status of the Rap2B gene in human bronchial epithelial cells treated by cigarette smoke condensate.

BACKGROUND: The relationship between lung cancer and smoking has been demonstrated. The Rap2B gene is usually overexpressed in lung cancers. This study was aimed to investigate the Rap2B gene expression and its promoter methylation in human bronchial epithelial cells (16HBE) treated by cigarette smoke condensate (CSC). METHODS: 16HBE cells were treated with CSC (1/8 IC50). Soft ager assay, tumorigenicity test, chromosome aberrations analysis were used to identify the transformed cells. The expression level of mRNA and protein of Rap2B was detected using real time PCR and Western blotting, respectively. The genome DNA methylation level was detected using combined bisulfite restriction analysis (COBRA) and the methylation status of the target fragment in Rap2B gene promoter was determined by bisulfite sequencing PCR (BSP). RESULTS: The 16HBE cells were successfully malignant transformed after the chronic exposure to CSC. The expression of Rap2B gradually increased in the process of malignant transformation. Meanwhile, global DNA was hypomethylated. However, no obvious change was observed in the methylation level of Rap2B gene promoter in transformed 16HBE cells. CONCLUSIONS: Rap2B gene may play an important role in the process of lung cancer and global DNA hypomethylation might be an early event in tumorigenesis.

Characterization of membrane occupation and recognition nexus repeat containing 3, meiosis expressed gene 1 binding partner, in mouse male germ cells.

Mammalian spermatogenesis is a well-organized process of cell development and differentiation. Meiosis expressed gene 1 (MEIG1) plays an essential role in the regulation of spermiogenesis. To explore potential mechanisms of MEIG1's action, a yeast two-hybrid screen was conducted, and several potential binding partners were identified; one of them was membrane occupation and recognition nexus repeat containing 3 (MORN3). MORN3 mRNA is only abundant in mouse testis. In the testis, Morn3 mRNA is highly expressed in the spermiogenesis stage. Specific anti-MORN3 polyclonal antibody was generated against N-terminus of the full-length MORN3 protein, and MORN3 expression and localization was examined in vitro and in vivo. In transfected Chinese hamster ovary cells, the antibody specifically crossed-reacted the full-length MORN3 protein, and immunofluorescence staining revealed that MORN3 was localized throughout the cytoplasm. Among multiple mouse tissues, about 25 kDa protein, was identified only in the testis. The protein was highly expressed after day 20 of birth. Immunofluorescence staining on mixed testicular cells isolated from adult wild-type mice demonstrated that MORN3 was expressed in the acrosome in germ cells throughout spermiogenesis. The protein was also present in the manchette of elongating spermatids. The total MORN3 expression and acrosome localization were not changed in the Meig 1-deficient mice. However, its expression in manchette was dramatically reduced in the mutant mice. Our studies suggest that MORN3 is another regulator for spermatogenesis, probably together with MEIG1.

Vitronectin silencing inhibits hepatocellular carcinoma in vitro and in vivo.

AIM: To explore if inhibition of vitronectin can be used for the treatment of hepatocellular carcinoma. MATERIALS & METHODS: RNAi technology was used to silence the expression of VTN in HepG2 and SMMC 7721 cells. Change of growth characteristics in these cells was evaluated. RESULTS: VTN silencing does not affect growth characteristics of cancer cells in monolayer cell culture, but could suppress the colonized growth of cells in soft agar. VTN-siRNA suppresses colony formation more than 80% compared with that of control in SMMC7721cells and leads to the inhibition of colony formation of over 70% in HepG2 cells. In addition, VTN silencing decreases the size of tumor xenografts in nude mice, particularly in male mice, with an inhibition rate of 46.6%. CONCLUSION: VTN plays a significant role in the malignant growth of tumor. Inhibition of VTN could potentially be applied for the treatment of hepatocellular carcinoma.

Interaction mechanisms between organic UV filters and bovine serum albumin as determined by comprehensive spectroscopy exploration and molecular docking.

Organic UV filters are a group of emerging PPCP (pharmaceuticals and personal care products) contaminants. Current information is insufficient to understand the in vivo processes and health risks of organic UV filters in humans. The interaction mechanism of UV filters with serum albumin provides critical information for the health risk assessment of these active ingredients in sunscreen products. This study investigates the interaction mechanisms of five commonly used UV filters (2-hydroxy-4-methoxybenzophenone, BP-3; 2-ethylhexyl 4-methoxycinnamate, EHMC; 4-methylbenzylidene camphor, 4-MBC; methoxydibenzoylmethane, BDM; homosalate, HMS) with bovine serum albumin (BSA) by spectroscopic measurements of fluorescence, circular dichroism (CD), competitive binding experiments and molecular docking. Our results indicated that the fluorescence of BSA was quenched by these UV filters through a static quenching mechanism. The values of the binding constant (Ka) ranged from (0.78±0.02)×10(3) to (1.29±0.01)×10(5) L mol(-1). Further exploration by synchronous fluorescence and CD showed that the conformation of BSA was demonstrably changed in the presence of these organic UV filters. It was confirmed that the UV filters can disrupt the α-helical stability of BSA. Moreover, the results of molecular docking revealed that the UV filter molecule is located in site II (sub-domain IIIA) of BSA, which was further confirmed by the results of competitive binding experiments. In addition, binding occurred mainly through hydrogen bonding and hydrophobic interaction. This study raises critical concerns regarding the transportation, distribution and toxicity effects of organic UV filters in human body.

Seasonal variation of newly notified pulmonary tuberculosis cases from 2004 to 2013 in Wuhan, China.

BACKGROUND: Although there was a report about the seasonal variation in Wuhan city, it only analyzed the prevalence data of pulmonary tuberculosis (TB) cases, and just studied the seasonality by subgroup of smear positive and negative from 2006 to 2010 by spectral analysis. In this study, we investigated the seasonality of the total newly notified pulmonary TB cases by subgroups such as time period, sex, age, occupation, district, and sputum smear result from 2004 to 2013 in Wuhan by a popular seasonal adjustment model (TRAMO-SEATS). METHODS: Monthly pulmonary TB cases from 2004 to 2013 in Wuhan were analyzed by the TRAMO-SEATS seasonal adjustment program. Seasonal amplitude was calculated and compared within the subgroups. RESULTS: From 2004 to 2013, there were 77.76 thousand newly notified pulmonary TB cases in Wuhan, China. There was a dominant peak spring peak (March) with seasonal amplitude of 56.81% and a second summer peak (September) of 43.40%, compared with the trough month (December). The spring seasonal amplitude in 2004-2008 was higher than that of 2009-2013(P<0.05). There were no statistical differences for spring seasonal amplitude within subgroups of gender, age, district, and sputum smear result (P>0.05). However, there were significant differences in spring seasonal amplitude by occupation, with amplitude ranging from 59.37% to 113.22% (P<0.05). The summer seasonal amplitude in 2004-2008 was higher than that of 2009-2013(P<0.05). There were no statistical differences in summer seasonal amplitude within subgroups of gender, district, sputum smear result(P>0.05). There were significant differences in summer seasonal amplitude by age, with amplitude ranging from 36.05% to 100.09% (P<0.05). Also, there were significant differences in summer seasonal amplitude by occupation, with amplitude ranging from 43.40% to 109.88% (P<0.05). CONCLUSIONS: There was an apparent seasonal variation in pulmonary TB cases in Wuhan. We speculated that spring peak in our study was most likely caused by the increased reactivation of the latent TB due to vitamin D deficiency and high PM2.5 concentration, while the summer peak was mainly resulted from the enhanced winter transmission due to indoor crowding in winter, overcrowding of public transportation over the period of the Spring Festival and health care seeking delay in winter.

Molecular alterations of PIK3CA in uterine carcinosarcoma, clear cell, and serous tumors.

OBJECTIVES: Type II endometrial carcinomas-uterine carcinosarcomas or uterine malignant mesodermal mixed tumors (UMMMTs), clear cell carcinomas (UCCs), and uterine serous carcinomas (USCs)-are aggressive malignancies that present with advanced disease and have high mortality rates. PIK3CA mutations are commonly found in endometrial cancers. The objective of the study was to characterize molecular alterations in the PIK3CA gene in these tumors. METHODS: A total of 84 cases (20 UMMMTs, 18 UCCs, and 46 USCs) were selected from the surgical pathology files of Weill Cornell Medical College and Johns Hopkins Hospital. The diagnoses were confirmed by gynecologic pathologists (L.H.E. and A.Y.). DNA was extracted from paraffin-embedded tissue. Polymerase chain reaction was performed for mutational analysis. All the studies were performed in accordance with approved Institutional Review Board protocols. RESULTS: Mutations in the PIK3CA gene were identified in 3 (15%) of 20 UMMMT, 3 (16.7%) of 18 UCC, and 10 (21.7%) of 46 USC cases. We report novel mutations in PIK3CA in uterine carcinosarcoma. CONCLUSIONS: A significant percentage of UMMMTs, UCCs, and USCs have mutations in PIK3CA. Further investigation is needed to develop targeted therapies for these aggressive uterine cancers.