Moiré synaptic transistor with room-temperature neuromorphic functionality.

Moiré quantum materials host exotic electronic phenomena through enhanced internal Coulomb interactions in twisted two-dimensional heterostructures1-4. When combined with the exceptionally high electrostatic control in atomically thin materials5-8, moiré heterostructures have the potential to enable next-generation electronic devices with unprecedented functionality. However, despite extensive exploration, moiré electronic phenomena have thus far been limited to impractically low cryogenic temperatures9-14, thus precluding real-world applications of moiré quantum materials. Here we report the experimental realization and room-temperature operation of a low-power (20 pW) moiré synaptic transistor based on an asymmetric bilayer graphene/hexagonal boron nitride moiré heterostructure. The asymmetric moiré potential gives rise to robust electronic ratchet states, which enable hysteretic, non-volatile injection of charge carriers that control the conductance of the device. The asymmetric gating in dual-gated moiré heterostructures realizes diverse biorealistic neuromorphic functionalities, such as reconfigurable synaptic responses, spatiotemporal-based tempotrons and Bienenstock-Cooper-Munro input-specific adaptation. In this manner, the moiré synaptic transistor enables efficient compute-in-memory designs and edge hardware accelerators for artificial intelligence and machine learning.

Impact of work type and APOE-e4 status on cognitive functioning in older women.

Prior research indicates that APOE-e4 allele(s) and working without compensation may be independently associated with risk for cognitive decline. This study investigated whether the interaction of type of work (paid versus unpaid) and presence of APOE-e4 allele(s) was associated with cognitive dysfunction in women in mid- and late-life. Participants included 340 females (mean age = 74.7 years) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. A two-way ANOVA to assess the simple main effects of type of work and APOE-e4 allele status on cognition as well as their interaction was performed. A two-way ANCOVA including age, education, and marital status as covariates was also conducted. The presence of one or two APOE-e4 allele(s) and unpaid work was associated with greater cognitive dysfunction. A significant interaction effect revealed engagement in paid work, regardless of the presence of APOE-e4 allele(s), was associated with better cognitive functioning. Consistent with prior literature, women who engage in unpaid forms of labor for the majority of their life may be at higher risk for cognitive decline, regardless of presence of APOE-e4 allele(s). Further research is needed to identify the factors related to unpaid labor that may increase risk for cognitive dysfunction.

Trifluoromethylation of 2D Transition Metal Dichalcogenides: A Mild Functionalization and Tunable p-Type Doping Method.

Chemical modification is a powerful strategy for tuning the electronic properties of 2D semiconductors. Here we report the electrophilic trifluoromethylation of 2D WSe2 and MoS2 under mild conditions using the reagent trifluoromethyl thianthrenium triflate (TTT). Chemical characterization and density functional theory calculations reveal that the trifluoromethyl groups bind covalently to surface chalcogen atoms as well as oxygen substitution sites. Trifluoromethylation induces p-type doping in the underlying 2D material, enabling the modulation of charge transport and optical emission properties in WSe2. This work introduces a versatile and efficient method for tailoring the optical and electronic properties of 2D transition metal dichalcogenides.

A System to Track Stent Location in the Human Body by Fusing Magnetometer and Accelerometer Measurements.

This paper will introduce a simple locating system to track a stent when it is deployed into a human artery. The stent is proposed to achieve hemostasis for bleeding soldiers on the battlefield, where common surgical imaging equipment such as fluoroscopy systems are not available. In the application of interest, the stent must be guided to the right location to avoid serious complications. The most important features are its relative accuracy and the ease by which it may be quickly set up and used in a trauma situation. The locating approach in this paper utilizes a magnet outside the human body as the reference and a magnetometer that will be deployed inside the artery with the stent. The sensor can detect its location in a coordinate system centered with the reference magnet. In practice, the main challenge is that the locating accuracy will be deteriorated by external magnetic interference, rotation of the sensor, and random noise. These causes of error are addressed in the paper to improve the locating accuracy and repeatability under various conditions. Finally, the system's locating performance will be validated in benchtop experiments, where the effects of the disturbance-eliminating procedures will be addressed.

Short Term Changes in Dietary Fat Content and Metformin Treatment During Lactation Impact Milk Composition and Mammary Gland Morphology.

Maternal health and diet can have important consequences for offspring nutrition and metabolic health. During lactation, signals are communicated from the mother to the infant through milk via macronutrients, hormones, and bioactive molecules. In this study we designed experiments to probe the mother-milk-infant triad in the condition of normal maternal health and upon exposure to high fat diet (HFD) with or without concurrent metformin exposure. We examined maternal characteristics, milk composition and offspring metabolic parameters on postnatal day 16, prior to offspring weaning. We found that lactational HFD increased maternal adipose tissue weight, mammary gland adipocyte size, and altered milk lipid composition causing a higher amount of omega-6 (n6) long chain fatty acids and lower omega-3 (n3). Offspring of HFD dams were heavier with more body fat during suckling. Metformin (Met) exposure decreased maternal blood glucose and several milk amino acids. Offspring of met dams were smaller during suckling. Gene expression in the lactating mammary glands was impacted to a greater extent by metformin than HFD, but both metformin and HFD altered genes related to muscle contraction, indicating that these genes may be more susceptible to lactational stressors. Our study demonstrates the impact of common maternal exposures during lactation on milk composition, mammary gland function and offspring growth with metformin having little capacity to rescue the offspring from the effects of a maternal HFD during lactation.

Reconfigurable MoS2 Memtransistors for Continuous Learning in Spiking Neural Networks.

Artificial intelligence and machine learning are growing computing paradigms, but current algorithms incur undesirable energy costs on conventional hardware platforms, thus motivating the exploration of more efficient neuromorphic architectures. Toward this end, we introduce here a memtransistor with gate-tunable dynamic learning behavior. By fabricating memtransistors from monolayer MoS2 grown on sapphire, the relative importance of the vertical field effect from the gate is enhanced, thereby heightening reconfigurability of the device response. Inspired by biological systems, gate pulses are used to modulate potentiation and depression, resulting in diverse learning curves and simplified spike-timing-dependent plasticity that facilitate unsupervised learning in simulated spiking neural networks. This capability also enables continuous learning, which is a previously underexplored cognitive concept in neuromorphic computing. Overall, this work demonstrates that the reconfigurability of memtransistors provides unique hardware accelerator opportunities for energy efficient artificial intelligence and machine learning.

Lanthanide-dependent coordination interactions in lanmodulin: a 2D IR and molecular dynamics simulations study.

The biological importance of lanthanides, and the early lanthanides (La3+-Nd3+) in particular, has only recently been recognized, and the structural principles underlying selective binding of lanthanide ions in biology are not yet well established. Lanmodulin (LanM) is a novel protein that displays unprecedented affinity and selectivity for lanthanides over most other metal ions, with an uncommon preference for the early lanthanides. Its utilization of EF-hand motifs to bind lanthanides, rather than the Ca2+ typically recognized by these motifs in other proteins, has led it to be used as a model system to understand selective lanthanide recognition. Two-dimensional infrared (2D IR) spectroscopy combined with molecular dynamics simulations were used to investigate LanM's selectivity mechanisms by characterizing local binding site geometries upon coordination of early and late lanthanides as well as calcium. These studies focused on the protein's uniquely conserved proline residues in the second position of each EF-hand binding loop. We found that these prolines constrain the EF-hands for strong coordination of early lanthanides. Substitution of this proline results in a more flexible binding site to accommodate a larger range of ions but also results in less compact coordination geometries and greater disorder within the binding site. Finally, we identify the conserved glycine in the sixth position of each EF-hand as a mediator of local binding site conformation and global secondary structure. Uncovering fundamental structure-function relationships in LanM informs the development of synthetic biology technologies targeting lanthanides in industrial applications.

Measuring Public Reaction to Violence Against Doctors in China: Interrupted Time Series Analysis of Media Reports.

BACKGROUND: Violence against doctors in China is a serious problem that has attracted attention from both domestic and international media. OBJECTIVE: This study investigates readers' responses to media reports on violence against doctors to identify attitudes toward perpetrators and physicians and examine if such trends are influenced by national policies. METHODS: We searched 17 Chinese violence against doctors reports in international media sources from 2011 to 2020. We then tracked back the original reports and web crawled the 19,220 comments in China. To ascertain the possible turning point of public opinion, we searched violence against doctors-related policies from Tsinghua University ipolicy database from 2011 to 2020, and found 19 policies enacted by the Chinese central government aimed at alleviating the intense patient-physician relationship. We then conducted a series of interrupted time series analyses to examine the influence of these policies on public sentiment toward violence against doctors over time. RESULTS: The interrupted time series analysis (ITSA) showed that the change in public sentiment toward violence against doctors reports was temporally associated with government interventions. The declarations of 10 of the public policies were followed by increases in the proportion of online public opinion in support of doctors (average slope changes of 0.010, P<.05). A decline in the proportion of online public opinion that blamed doctors (average level change of -0.784, P<.05) followed the declaration of 3 policies. CONCLUSIONS: The government's administrative interventions effectively shaped public opinion but only temporarily. Continued public policy interventions are needed to sustain the reduction of hostility toward medical doctors.

Attitudes Toward Human Papillomavirus Self-Sampling in Regularly Screened Women in Edmonton, Canada: A Cross-Sectional Study.

OBJECTIVE/PURPOSE: The aim of the study was to determine the level of interest in human papillomavirus (HPV) self-sampling as a method of cervical cancer screening in a population of women affiliated with a primary care clinic. MATERIALS AND METHODS: A survey was given to women (N = 182) between the ages of 25 and 69 years attending a family medicine clinic in Edmonton, Canada. Primary outcome measures include (1) the percentage of women who feel that HPV self-sampling should be available and (2) the percentage of women who would prefer HPV self-sampling to the Pap test. Secondary outcomes include the percentage of women aware of HPV self-sampling and factors associated with a preference for HPV self-sampling using logistic regression. RESULTS: Most women (84%) were up-to-date on Pap testing, and most (85%) had had postsecondary education (either completed or in progress). The percentage of the women who moderately or strongly felt that HPV self-sampling should be available was 60%; the percentage of the women who would prefer HPV self-sampling was 24%. Only 7% of the women reported being previously aware of HPV self-sampling. The factor associated with a preference for HPV self-sampling was the Pap comfort score, with an odds ratio of 1.51 (95% CI = 1.05-2.16, p = .026). CONCLUSIONS: In this population of well-educated women who were mostly up-to-date on cervical screening, there was a clear interest to have the option of HPV self-sampling. It is important for cancer screening programs to take this into account, given that women are the ultimate beneficiaries of these programs.

Primary HPV testing with cytology versus cytology alone in cervical screening-A prospective randomized controlled trial with two rounds of screening in a Chinese population.

We conducted a prospective randomized controlled trial with two screening rounds to evaluate the effectiveness of combining HPV testing with liquid-based cytology (LBC) as a co-test, compared to LBC only in cervical cancer screening of a Chinese population. First, 15,955 women aged 30-60 were randomized at a 1:1 ratio into an intervention group (Digene Hybrid Capture 2 HPV test with LBC) and a control group (LBC alone). Women in the intervention group would be referred for colposcopy and biopsy immediately if they were found to have high-risk HPV regardless of cytology results. The detection of cervical intraepithelial neoplasia grade 2 or above (CIN2+) lesions was significantly higher in the intervention group compared to the control (0.95% vs. 0.38%, OR 2.50, 95% CI 1.65-3.88). At the subsequent round of screening approximately 36 months later, CIN2+ detection was significantly lower in the intervention group (0.08% vs. 0.35%, OR 0.23, 95% CI 0.08-0.57). Over the two rounds of screening, the total detection of CIN2+ was higher in the intervention group (1.01% vs. 0.66%, OR 1.53, 95% CI 1.09-2.19). There was a fourfold increase (10.6% vs. 2.4%, p < 0.001) in the number of colposcopies performed in the intervention arm. Adding a high-risk HPV test to cytology for primary cervical screening led to earlier detection of clinically significant preinvasive lesions, resulting in a reduced detection of CIN2+ lesions in subsequent rounds and an increased rate of colposcopy.

Cytokine sensitivity screening highlights BMP4 pathway signaling as a therapeutic opportunity in ER+ breast cancer.

Despite the success of approved systemic therapies for estrogen receptor α (ER)-positive breast cancer, drug resistance remains common. We hypothesized that secreted factors from the human tumor microenvironment could modulate drug resistance. We previously screened a library of 297 recombinant-secreted microenvironmental proteins for the ability to confer resistance to the anti-estrogen fulvestrant in 2 ER+ breast cancer cell lines. Herein, we considered whether factors that enhanced drug sensitivity could be repurposed as therapeutics and provide leads for drug development. Screening data revealed bone morphogenic protein (BMP)4 as a factor that inhibited cell growth and synergized with approved anti-estrogens and cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). BMP4-mediated growth inhibition was dependent on type I receptor activin receptor-like kinase (ALK)3-dependent phosphorylation (P) of mothers against decapentaplegic homolog (SMAD/P-SMAD)1 and 5, which could be reversed by BMP receptor inhibitors and ALK3 knockdown. The primary effect of BMP4 on cell fate was cell-cycle arrest, in which RNA sequencing, immunoblot analysis, and RNA interference revealed to be dependent on p21WAF1/Cip1 upregulation. BMP4 also enhanced sensitivity to approved inhibitors of mammalian target of rapamycin complex 1 and CDK4/6 via ALK3-mediated P-SMAD1/5 and p21 upregulation in anti-estrogen-resistant cells. Patients bearing primary ER+ breast tumors, exhibiting a transcriptomic signature of BMP4 signaling, had improved disease outcome following adjuvant treatment with anti-estrogen therapy, independently of age, tumor grade, and tumor stage. Furthermore, a transcriptomic signature of BMP4 signaling was predictive of an improved biologic response to the CDK4/6i palbociclib, in combination with an aromatase inhibitor in primary tumors. These findings highlight BMP4 and its downstream pathway activation as a therapeutic opportunity in ER+ breast cancer.-Shee, K., Jiang, A., Varn, F. S., Liu, S., Traphagen, N. A., Owens, P., Ma, C. X., Hoog, J., Cheng, C., Golub, T. R., Straussman, R., Miller, T. W. Cytokine sensitivity screening highlights BMP4 pathway signaling as a therapeutic opportunity in ER+ breast cancer.

A case of neonatal pemphigus vulgaris with co-existing BP180 autoantibodies.

A male neonate was born with blisters on the trunk to a 37-year-old primigravid woman with a past medical history of recurrent, painful, topical steroid-responsive oral blisters. The diagnosis of neonatal pemphigus was made after the neonate and mother were found to have elevated desmoglein 3 (Dsg3) antibodies in conjunction with histopathologic features of pemphigus vulgaris. Interestingly, both neonate and mother also had elevated levels of BP180 antibodies, classically seen in bullous pemphigoid. This case is unique in that it portrays neonatal pemphigus, an already rare condition, complicated by the presence of BP180 antibodies.

A systematic review of dietary acids and habits on dental erosion in adolescents.

BACKGROUND: Dental erosion is the dissolution of dental hard tissues caused by acids of a non-bacterial origin. Dietary acids are considered the predominant and most controllable factor. AIM: To synthesise the literature on the effects of dietary acids and habits on dental erosion in the permanent dentition of 10- to 19-year-old adolescents. MATERIALS AND METHODS: An electronic literature search was undertaken in Cochrane, MEDLINE, CINAHL, Dentistry & Oral Sciences Source via EBSCOhost, and Embase with no restriction on the date of publication. RESULTS: The initial search identified 449 articles, and 338 remained after removal of duplicates. Seventy-seven articles remained after screening of titles and abstracts, and 52 were eligible for the full-text review. A considerable variety of beverages, food, and dietary habits were reported as risk factors for dental erosion. The most consistent findings implicated the erosive potential of carbonated beverages and the consumption of acidic drinks at bedtime. CONCLUSIONS: Although results were not consistent between cohort and cross-sectional studies, this review suggests certain dietary risk factors may contribute to dental erosion in adolescents. There is a need for more high-quality cohort studies to establish more conclusive evidence on the role of dietary acids and habits on dental erosion.

Mechanistic Assessment of Extrahepatic Contributions to Glucuronidation of Integrase Strand Transfer Inhibitors.

Integrase strand transfer inhibitor (INSTI)-based regimens dominate initial human immunodeficiency virus treatment. Most INSTIs are metabolized predominantly via UDP-glucuronosyltransferases (UGTs). For drugs predominantly metabolized by UGTs, including INSTIs, in vitro data recovered from human liver microsomes (HLMs) alone often underpredict human oral clearance. While several factors may contribute, extrahepatic glucuronidation may contribute to this underprediction. Thus, we comprehensively characterized the kinetics for the glucuronidation of INSTIs (cabotegravir, dolutegravir, and raltegravir) using pooled human microsomal preparations from liver (HLMs), intestine (HIMs), and kidney (HKMs) tissues; human embryonic kidney 293 cells expressing individual UGTs; and recombinant UGTs. In vitro glucuronidation of cabotegravir (HLMs≈HKMs>>>HIMs), dolutegravir (HLMs>HIMs>>HKMs), and raltegravir (HLMs>HKMs>> HIMs) occurred in hepatic and extrahepatic tissues. The kinetic data from expression systems suggested the major enzymes in each tissue: hepatic UGT1A9 > UGT1A1 (dolutegravir and raltegravir) and UGT1A1 (cabotegravir), intestinal UGT1A3 > UGT1A8 > UGT1A1 (dolutegravir) and UGT1A8 > UGT1A1 (raltegravir), and renal UGT1A9 (dolutegravir and raltegravir). Enzymes catalyzing cabotegravir glucuronidation in the kidney and intestine could not be identified unequivocally. Using data from dolutegravir glucuronidation as a prototype, a "bottom-up" physiologically based pharmacokinetic model was developed in a stepwise approach and predicted dolutegravir oral clearance within 4.5-fold (hepatic data only), 2-fold (hepatic and intestinal data), and 32% (hepatic, intestinal, and renal data). These results suggest clinically meaningful glucuronidation of dolutegravir in tissues other than the liver. Incorporation of additional novel mechanistic and physiologic underpinnings of dolutegravir metabolism along with in silico approaches appears to be a powerful tool to accurately predict the clearance of dolutegravir from in vitro data.

Autophagy promotes escape from phosphatidylinositol 3-kinase inhibition in estrogen receptor-positive breast cancer.

Hyperactivation of the PI3K pathway has been implicated in resistance to antiestrogen therapies in estrogen receptor α (ER)-positive breast cancer, prompting the development of therapeutic strategies to inhibit this pathway. Autophagy has tumor-promoting and -suppressing roles and has been broadly implicated in resistance to anticancer therapies, including antiestrogens. Chloroquine (CQ) is an antimalarial and amebicidal drug that inhibits autophagy in mammalian cells and human tumors. Herein, we observed that CQ inhibited proliferation and autophagy in ER+ breast cancer cells. PI3K inhibition with GDC-0941 (pictilisib) induced autophagy. Inhibition of autophagy using CQ or RNA interference potentiated PI3K inhibitor-induced apoptosis. Combined inhibition of PI3K and autophagy effectively induced mitochondrial membrane depolarization, which required the BH3-only proapoptotic proteins Bim and PUMA. Treatment with GDC-0941, CQ, or the combination, significantly suppressed the growth of ER+ breast cancer xenografts in mice. In an antiestrogen-resistant xenograft model, GDC-0941 synergized with CQ to provide partial, but durable, tumor regression. These findings warrant clinical evaluation of therapeutic strategies to target ER, PI3K, and autophagy for the treatment of ER+ breast cancer.-Yang, W., Hosford, S. R., Traphagen, N. A., Shee, K., Demidenko, E., Liu, S., Miller, T. W. Autophagy promotes escape from phosphatidylinositol 3-kinase inhibition in estrogen receptor-positive breast cancer.

Bromodomain and extraterminal inhibitors block the Epstein-Barr virus lytic cycle at two distinct steps.

Lytic infection by the Epstein-Barr virus (EBV) poses numerous health risks, such as infectious mononucleosis and lymphoproliferative disorder. Proteins in the bromodomain and extraterminal (BET) family regulate multiple stages of viral life cycles and provide promising intervention targets. Synthetic small molecules can bind to the bromodomains and disrupt function by preventing recognition of acetylated lysine substrates. We demonstrate that JQ1 and other BET inhibitors block two different steps in the sequential cascade of the EBV lytic cycle. BET inhibitors prevent expression of the viral immediate-early protein BZLF1. JQ1 alters transcription of genes controlled by the host protein BACH1, and BACH1 knockdown reduces BZLF1 expression. BET proteins also localize to the lytic origin of replication (OriLyt) genetic elements, and BET inhibitors prevent viral late gene expression. There JQ1 reduces BRD4 recruitment during reactivation to preclude replication initiation. This represents a rarely observed dual mode of action for drugs.

Giant aneurysmal benign fibrous histiocytoma (dermatofibroma).

Aneurysmal benign fibrous histiocytomas are variants of dermatofibromas. These benign blood-filled lesions can mimic malignancies due to their rapid and recurrent growth. Our patient is a 42-year-old Caucasian female with a past medical history of morbid obesity, diabetes, and hypertension, who presented with a mass on her left shoulder for 5 years' duration. The mass oozed occasionally and would appear to regress but then recur replaced with progressively larger masses. Upon inspection, the patient had a large pedunculated exophytic mass with vascularity. The mass was surgically removed under general anesthesia via wide local excision. Grossly, the excised skin was purple-tinged with an underlying fungating solid mass measuring 8.5 cm. Serial sections revealed a hemorrhagic, spongy, and granular cut surface. Histologically, the epidermis was hyperplastic, with underlying hyaline collagen bundles. The remainder of the mass was chronically inflamed and composed of spindled histiocytes, hemosiderin-laden macrophages, and blood-filled spaces lacking an endothelial lining. There was focal pleomorphism but no significant atypia. Immunohistochemical stains were strongly positive for vimentin and negative for CD31, CD34, and desmin. The overall architecture and immunophenotype are consistent with the diagnosis of aneurysmal benign fibrous histiocytoma.

Incidence, psychosocial burden, and economic impact of genital warts in Mexico.

OBJECTIVE: To estimate the burden of genital warts (GW)in Mexico. MATERIALS AND METHODS: We estimated the annual incidence of GW based on data reported by specialist physicians. We also assessed GW treatment practices, the average cost of treatment, and the psychosocial burden of GW among patients. RESULTS: The annual incidence of GW in Mexico was estimated to be 547 200 cases. Treatment procedures vary by specialist and patient gender. The estimated annual cost was $195 million USD. The psychosocial impact of GW was slightly greater in males than females. CONCLUSIONS: This is the first evaluation of the burden of GW in Mexico. Our data suggest that GW are common, with significant health-related costs and psychosocial impact.

OBJETIVO: Estimar la carga por verrugas genitales (VG) en México. MATERIAL Y MÉTODOS: Estimamos la incidencia anual de VG, con base en información proporcionada por médicos especialistas y el manejo de las VG, así como el costo promedio del tratamiento y la carga psicosocial de las VG. RESULTADOS: La incidencia anual de VG en México fue de 547 200 casos. Los tratamientos variaron según la especialidad y el sexo del paciente. El costo anual por VG fue de $195 millones de dólares estadounidenses. El impacto psicosocial de las VG es ligeramente mayor en hombres que en mujeres. CONCLUSIONES: Esta es la primera evaluación de la carga de VG en México. Los datos sugieren que las VG son frecuentes, tienen costos relacionados con salud e impactos psicosociales significativos.

MicroRNA-141 enhances anoikis resistance in metastatic progression of ovarian cancer through targeting KLF12/Sp1/survivin axis.

BACKGROUND: Cancer metastasis is determined by the formation of the metastatic niche and the ability of cancer cells to adapt to microenvironmental stresses. Anoikis resistance is a fundamental feature of metastatic cancer cell survival during metastatic cancer progression. However, the mechanisms underlying anoikis resistance in ovarian cancer are still unclear. METHODS: Expressions of miRNA-141 and its downstream targets were evaluated by qPCR, Western blotting, Immunohistochemical (IHC) and in situ hybridization (ISH) assays. The luciferase assays were used to prove KLF12 as the downstream target of miR-141. The cDNA microarray and apoptotic protein arrays were used to identify the targets of miR-141 and KLF12. The competition of KLF12 and Sp1 on survivin promoter was examined by ChIP assay. IHC analysis on ovarian cancer tissue array was used to evaluate the expressions of KLF12 and miR-141 and to show the clinical relevance. The functional studies were performed by in vitro and in vivo tumorigenic assays. RESULTS: Enforced expression of miR-141 promotes, while knockdown of miR-141 expression inhibits, cell proliferation, anchorage-independent capacity, anoikis resistance, tumor growth and peritoneal metastases of ovarian cancer cells. Bioinformatics and functional analysis identified that Kruppel-related zinc finger protein AP-2rep (KLF12) is directly targeted by miR-141. Consistent with this finding, knockdown of KLF12 phenocopied the effects of miR-141 overexpression in ovarian cancer cells. In contrast, restoration of KLF12 in miR-141-expressing cells significantly attenuated anoikis resistance in ovarian cancer cells via interfering with Sp1-mediated survivin transcription, which inhibits the intrinsic apoptotic pathway and is crucial for ovarian cancer cell survival, anoikis resistance and peritoneal metastases. Immunohistochemical (IHC) and in situ hybridization (ISH) assays confirmed that miRNA-141 expression is inversely correlated with KLF12 expression and significantly associated with advanced ovarian cancers accompanied with distal metastases, underscoring the clinical relevance of our findings. CONCLUSIONS: Our data identify a novel signaling axis of miR-141/KLF12/Sp1/survivin in enhancing anoikis resistance and likely serves as a potential therapeutic target for metastatic ovarian cancer.

Differential expression of estrogen receptor subtypes and variants in ovarian cancer: effects on cell invasion, proliferation and prognosis.

BACKGROUND: Due to the presence of both classical estrogen receptor (ERα) and another ER subtype (ERß) in ovarian cancer, hormonal treatment is an attractive option. However, response to tamoxifen in ovarian cancer is modest. The presence of ERß variants further complicated the issue. We have recently shown that specifically targeting ER subtypes using selective ER modulators showed opposing functions of ER subtypes on cell growth. In the present study, the clinical significance of ERα and ERß variants (ß1, ß2 and ß5) and the functional effects of ERß2 and ERß5 in ovarian cancer was investigated. METHODS: ERα, ERß1, ERß2 and ERß5 expression were evaluated by immunohistochemistry in 106 ovarian cancer tissues. The association between ERs expression and clinicopathological parameters or prognosis was analyzed. Ectopic expression of ERß2 and ERß5 followed by functional assays were performed in ovarian cancer cell lines in order to detect their effects on cell invasion and proliferation. RESULTS: We found significantly higher nuclear (n)ERα and nERß5 and lower cytoplasmic (c)ERα expression in advanced cancers. Significantly lower ERß1 expression was also detected in high grade cancers. Significant loss of nERα and cERß2 expression were observed in clear cell histological subtypes. Higher nERß5 and lower cERß5 expression were associated with serous/clear cell subtypes, poor disease-free and overall survival. Positive cERα and higher cERß1 expression were significantly associated with better disease-free and overall survival. Furthermore, we found nERß5 as an independent prognostic factor for overall survival. Functionally, overexpression of ERß5 enhanced ovarian cancer cell migration, invasion and proliferation via FAK/c-Src activation whereas ERß2 induced cell migration and invasion. CONCLUSIONS: Since tamoxifen binds to both ERα and ERß1 which appear to bear opposing oncogenic roles, the histotypes-specific expression pattern of ERs indicates that personalized treatment for women based on ERs expression using selective estrogen receptor modulators may improve response rate. This study also suggests nERß5 as a potential prognostic marker and therapeutic target in ovarian cancer.