Effect of menopausal hormonal therapy on cardiovascular risks in Korean postmenopausal women: A nationwide cohort study.

OBJECTIVE: To evaluate the association between menopausal hormonal therapy (MHT) and the risk of cardiovascular disease (CVD), according to various regimens, dosages, routes of administration and starting ages of MHT. DESIGN: A population-based cohort study using the Korean National Health Insurance Services database. SETTING: Nationwide health insurance database. POPULATION: Women who reported entering menopause at an age of ≥40 years with no history of CVD in the national health examination. METHODS: The study population comprised 1 120 705 subjects enrolled between 2002 and 2019, categorised according to MHT status (MHT group, n = 319 007; non-MHT group, n = 801 698). MAIN OUTCOME MEASURES: Incidence of CVD (a composite of myocardial infarction and stroke). RESULTS: The incidence of CVD was 59 266 (7.4%) in the non-MHT group and 17 674 (5.5%) in the MHT group. After adjusting for confounding factors, an increased risk of CVD was observed with the administration of tibolone (hazard ratio, HR 1.143, 95% CI 1.117-1.170), oral estrogen (HR 1.246, 95% CI 1.198-1.295) or transdermal estrogen (HR 1.289, 95% CI 1.066-1.558), compared with the non-MHT group; the risk was based on an increased risk of stroke. The risk trends were consistent regardless of the age of starting MHT or the physicians' specialty. Among tibolone users, a longer period from entering menopause to taking tibolone and the use of any dosage (1.25 or 2.5 mg) were linked with a higher risk of CVD, compared with non-MHT users. CONCLUSIONS: This nationwide cohort study demonstrated an increased risk of CVD, driven mainly by an increased risk of stroke, among tibolone and oral or transdermal estrogen users, compared with that of non-MHT users.

Nested Biofabrication: Matryoshka-Inspired Intra-Embedded Bioprinting.

Engineering functional tissues and organs remains a fundamental pursuit in bio-fabrication. However, the accurate constitution of complex shapes and internal anatomical features of specific organs, including their intricate blood vessels and nerves, remains a significant challenge. Inspired by the Matryoshka doll, here a new method called "Intra-Embedded Bioprinting (IEB)" is introduced building upon existing embedded bioprinting methods. a xanthan gum-based material is used which served a dual role as both a bioprintable ink and a support bath, due to its unique shear-thinning and self-healing properties. IEB's capabilities in organ modeling, creating a miniaturized replica of a pancreas using a photocrosslinkable silicone composite is demonstrated. Further, a head phantom and a Matryoshka doll are 3D printed, exemplifying IEB's capability to manufacture intricate, nested structures. Toward the use case of IEB and employing an innovative coupling strategy between extrusion-based and aspiration-assisted bioprinting, a breast tumor model that included a central channel mimicking a blood vessel, with tumor spheroids bioprinted in proximity is developed. Validation using a clinically-available chemotherapeutic drug illustrated its efficacy in reducing the tumor volume via perfusion over time. This method opens a new way of bioprinting enabling the creation of complex-shaped organs with internal anatomical features.

Nested biofabrication: Matryoshka-inspired Intra-embedded Bioprinting.

Engineering functional tissues and organs remains a fundamental pursuit in biofabrication. However, the accurate constitution of complex shapes and internal anatomical features of specific organs, including their intricate blood vessels and nerves, remains a significant challenge. Inspired by the Matryoshka doll, we here introduce a new method called 'Intra-Embedded Bioprinting (IEB),' building upon existing embedded bioprinting methods. We used a xanthan gum-based material, which served a dual role as both a bioprintable ink and a support bath, due to its unique shear-thinning and self-healing properties. We demonstrated IEB's capabilities in organ modelling, creating a miniaturized replica of a pancreas using a photocrosslinkable silicone composite. Further, a head phantom and a Matryoshka doll were 3D printed, exemplifying IEB's capability to manufacture intricate, nested structures. Towards the use case of IEB and employing innovative coupling strategy between extrusion-based and aspiration-assisted bioprinting, we developed a breast tumor model that included a central channel mimicking a blood vessel, with tumor spheroids bioprinted in proximity. Validation using a clinically-available chemotherapeutic drug illustrated its efficacy in reducing the tumor volume via perfusion over time. This method opens a new way of bioprinting enabling the creation of complex-shaped organs with internal anatomical features.

Association between breast diseases and symptomatic uterine fibroids by using South Korean National Health Insurance database.

Both the uterus and breasts have sex hormone dependence, yet there are few studies on the association between breast disease and uterine fibroids (UFs). The purpose of this study was to investigate the incidence of benign breast disease (BBD), carcinoma in situ (CIS), and breast cancer (BC) in women treated for UFs compared to women who were not treated for UFs. This retrospective cohort study used national health insurance data from January 1st, 2011, to December 31st, 2020. We selected women between 20 and 50 years old who (1) were treated for UFs (UF group) or (2) visited medical institutions for personal health screening tests without UFs (control group). We analyzed independent variables such as age, socioeconomic status (SES), region, Charlson comorbidity index (CCI), delivery status, menopausal status, menopausal hormone therapy (MHT), endometriosis, hypertension (HTN), diabetes mellitus (DM), and dyslipidemia based on the first date of uterine myomectomy in the UF group and the first visiting date for health screening in the non-UF group. There were 190,583 and 439,940 participants in the UF and control groups, respectively. Compared with those of the control group, the RRs of BBD, CIS, and BC were increased in the UF group. The hazard ratios (HRs) of BBD, CIS, and BC in the UF group were 1.335 (95% confidence interval (CI) 1.299-1.372), 1.796 (95% CI 1.542-2.092), and 1.3 (95% CI 1.198-1.41), respectively. When we analyzed the risk of BC according to age at inclusion, UFs group had the increased risk of BCs in all age groups in comparison with control group. Women with low SES (HR 0.514, 95% CI 0.36-0.734) and living in rural areas (HR 0.889, 95% CI 0.822-0.962) had a lower risk of BC. Our study showed that women with UFs had a higher risk of BBD, CIS, and BC than those without UFs. This result suggests that women with UFs should be more conscious of BC than those without UFs. Therefore, doctors should consider recommending regular breast self-exams, mammography, or ultrasound for the early detection of BC in women with UFs.

The increased risk of colorectal cancer in the women who underwent hysterectomy from the South Korean National Health Insurance Database.

BACKGROUND: Several population-based studies and observational studies have shown that oophorectomy is associated with an increased risk of colorectal cancer (CRC), and hormone replacement therapy has been associated with a reduction in the risk of colorectal cancer. This study was carried out to investigate whether hysterectomy, which may affect the levels of female hormones, is associated with a risk of cancer of the specific gastrointestinal tract. METHODS: This population-based retrospective cohort study was conducted using insurance data provided by the Health Insurance Review and Assessment Service (HIRA) from January 1, 2007, to December 31, 2020. The hysterectomy group included 40- to 59-year-old women who underwent hysterectomy with uterine leiomyoma or uterine endometriosis from January 1, 2011, to December 31, 2014. The control group included women aged 40 to 59 years who visited medical institutions for medical examination from January 1, 2011 to December 31, 2014. RESULTS: The hysterectomy and non-hysterectomhy groups comprised 66,204 and 89,768 subjects, respectively. The median ages in the non-hysterectomy group and hysterectomy group were 48 (range: 43-53) and 46 (range: 44-49) years, respectively. In the unadjusted results of the analysis, all colorectal cancer (CRC) increased in the hysterectomy alone group (HR 1.222, 95% confidence interval (CI) 1.016-1.47, p = 0.033), sigmoid colon cancer increased in the hysterectomy alone group (HR 1.71, 95% CI 1.073-2.724, p = 0.024), and rectal cancer increased in the hysterectomy with adnexal surgery group (HR 1.924, 95% CI 1.073-2.724, p = 0.002). The adjusted results showed that all CRC increased in the hysterectomy alone group (HR 1.406, 95% CI 1.057-1.871, p = 0.019), colon cancer increased in the hysterectomy alone group (HR 1.523, 95% CI 1.068-2.17, p = 0.02), and rectal cancer increased in the hysterectomy with adnexal surgery group (HR 1.933, 95% CI 1.131-3.302, p = 0.016). The all-cause mortality of GI cancer increased in the hysterectomy alone group (HR 3.495, 95% CI 1.347-9.07, p = 0.001). CONCLUSIONS: This study showed that the risk of all CRC increased in women who underwent hysterectomy compared with women who did not. In particular, the risk of rectal cancer was significantly higher in the women who underwent hysterectomy with adnexal surgery than in the controls. There was no association between hysterectomy and other GI cancers.

Biofabrication of anin-vitrobone model for Gaucher disease.

Gaucher disease (GD), the most prevalent lysosomal disorder, is caused byGBA1gene mutations, leading to deficiency of glucocerebrosidase, and accumulation of glycosphingolipids in cells of the mononuclear phagocyte system. While skeletal diseases are the leading cause of morbidity and reduced quality of life in GD, the pathophysiology of bone involvement is not yet fully understood, partly due to lack of relevant human model systems. In this work, we present the first 3D human model of GD using aspiration-assisted freeform bioprinting, which enables a platform tool with a potential for decoding the cellular basis of the developmental bone abnormalities in GD. In this regard, human bone marrow-derived mesenchymal stem cells (obtained commercially) and peripheral blood mononuclear cells derived from a cohort of GD patients, at different severities, were co-cultured to form spheroids and differentiated into osteoblast and osteoclast lineages, respectively. Co-differentiated spheroids were then 3D bioprinted into rectangular tissue patches as a bone tissue model for GD. The results revealed positive alkaline phosphatase (ALP) and tartrate-resistant ALP activities, with multi-nucleated cells demonstrating the efficacy of the model, corroborating with gene expression studies. There were no significant changes in differentiation to osteogenic cells but pronounced morphological deformities in spheroid formation, more evident in the 'severe' cohort, were observed. Overall, the presented GD model has the potential to be adapted to personalized medicine not only for understanding the GD pathophysiology but also for personalized drug screening and development.

Association of Early Hysterectomy With Risk of Cardiovascular Disease in Korean Women.

Importance: Women who undergo surgical hysterectomy before natural menopause may have an earlier increase in hematocrit and storage iron levels than those who continue menstruation, thereby increasing the risk of cardiovascular disease (CVD) at ages younger than usually seen. Examining this issue may provide important implications for women's cardiovascular health to both physicians and patients. Objective: To evaluate the association of hysterectomy with the risk of incident CVD among women before age 50 years. Design, Setting, and Participants: In this Korean population-based cohort study, 135 575 women aged 40 to 49 years were evaluated from January 1, 2011, to December 31, 2014. After propensity score matching in covariates including age, socioeconomic status, region, Charlson Comorbidity Index, hypertension, diabetes, dyslipidemia, menopause, menopausal hormone therapy, and adnexal surgery before inclusion, 55 539 pairs were included in the hysterectomy and nonhysterectomy groups. Participants were followed up until December 31, 2020. Data analysis was conducted from December 20, 2021, to February 17, 2022. Main Outcomes and Measures: The primary outcome was an incidental CVD, a composite of myocardial infarction, coronary artery revascularization, and stroke. The individual components of the primary outcome were also evaluated. Results: A total of 55 539 pairs were included; median age in the combined groups was 45 (IQR, 42-47) years. During median follow-up periods in the hysterectomy group of 7.9 (IQR, 6.8-8.9) years and nonhysterectomy group of 7.9 (IQR, 6.8-8.8) years, the incidence of CVD was 115 per 100 000 person-years for the hysterectomy group and 96 per 100 000 person-years for the nonhysterectomy group. After adjusting for confounding factors, the hysterectomy group had an increased risk of CVD compared with the nonhysterectomy group (hazard ratio [HR], 1.25; 95% CI, 1.09-1.44). The incidences of myocardial infarction and coronary artery revascularization were comparable between the groups, whereas the risk of stroke was significantly higher in the hysterectomy group (HR, 1.31; 95% CI, 1.12-1.53). Even after excluding women who underwent oophorectomy, the hysterectomy group had higher risks of CVD (HR, 1.24; 95% CI, 1.06-1.44). Conclusions and Relevance: The findings of this cohort study suggest early menopause owing to hysterectomy was associated with increased risks for a composite of CVD, particularly stroke.

High-throughput microgel biofabrication via air-assisted co-axial jetting for cell encapsulation, 3D bioprinting, and scaffolding applications.

Microgels have recently received widespread attention for their applications in a wide array of domains such as tissue engineering, regenerative medicine, and cell and tissue transplantation because of their properties like injectability, modularity, porosity, and the ability to be customized in terms of size, form, and mechanical properties. However, it is still challenging to mass (high-throughput) produce microgels with diverse sizes and tunable properties. Herein, we utilized an air-assisted co-axial device (ACAD) for continuous production of microgels in a high-throughput manner. To test its robustness, microgels of multiple hydrogels and their combination, including alginate (Alg), gelatin methacrylate (GelMA) and Alg-GelMA, were formed at a maximum production rate of ∼65 000 microgels s-1while retaining circularity and a size range of 50-500µm based on varying air pressure levels. The ACAD platform allowed single and multiple cell encapsulation with 74 ± 6% efficiency. These microgels illustrated appealing rheological properties such as yield stress, viscosity, and shear modulus for bioprinting applications. Specifically, Alg microgels have the potential to be used as a sacrificial support bath while GelMA microgels have potential for direct extrusion both on their own or when loaded in a bulk GelMA hydrogel. Generated microgels showed high cell viability (>90%) and proliferation of MDA-MB-231 and human dermal fibroblasts over seven days in both encapsulation and scaffolding applications, particularly for GelMA microgels. The developed strategy provides a facile and rapid approach without any complex or expensive consumables and accessories for scalable high-throughput microgel production for cell therapy, tissue regeneration and 3D bioprinting applications.

Tet Enzyme-Mediated Response in Environmental Stress and Stress-Related Psychiatric Diseases.

Mental disorders caused by stress have become a worldwide public health problem. These mental disorders are often the results of a combination of genes and environment, in which epigenetic modifications play a crucial role. At present, the genetic and epigenetic mechanisms of mental disorders such as posttraumatic stress disorder or depression caused by environmental stress are not entirely clear. Although many epigenetic modifications affect gene regulation, the most well-known modification in eukaryotic cells is the DNA methylation of CpG islands. Stress causes changes in DNA methylation in the brain to participate in the neuronal function or mood-modulating behaviors, and these epigenetic modifications can be passed on to offspring. Ten-eleven translocation (Tet) enzymes are the 5-methylcytosine (5mC) hydroxylases of DNA, which recognize 5mC on the DNA sequence and oxidize it to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Tet regulates gene expression at the transcriptional level through the demethylation of DNA. This review will elaborate on the molecular mechanism and the functions of Tet enzymes in environmental stress-related disorders and discuss future research directions.

Cognitive and behavioral effects of the anti-epileptic drug cenobamate (YKP3089) and underlying synaptic and cellular mechanisms.

Antiseizure medication is the mainstay of treatment for seizures, and adjunctive therapy is widely used to achieve adequate seizure control in patients with epilepsy who fail to respond to the first monotherapy. The newly developed antiepileptic drug cenobamate (YKP3089) as an adjunctive therapy improved seizure control in patients with uncontrolled focal seizures. Cenobamate is thought to reduce neuronal excitability through action on multiple targets, including GABA A receptors (GABAARs) and voltage-gated sodium channels. However, its effects on brain function and synaptic plasticity are unclear. Here, we explored the behavioral, synaptic, and cellular actions of cenobamate. Cenobamate influenced novel object recognition, object location memory, and Morris water maze performance in mice. Cenobamate enhanced inhibitory postsynaptic potentials by prolonging inhibitory postsynaptic current (IPSC) decay without affecting presynaptic GABA release or the peak amplitude of IPSCs. In addition, cenobamate suppressed hippocampal excitatory synaptic transmission by reducing the excitability of Schaffer collaterals and interfered with the induction of long-term potentiation. A reduction in neuronal excitability induced by cenobamate was associated with an elevation of action potential (AP) threshold, and which progressively increased in later APs during repetitive firing, indicating the activity-dependent modulation of neuronal sodium currents. Cenobamate suppressed neuronal excitability under the condition that GABAergic neurotransmission is excitatory, and administration of cenobamate rapidly enhanced the phosphorylation of eukaryotic elongation factor 2 in the hippocampus of adult and neonatal mice. Collectively, these results suggest that the combined action of cenobamate on sodium currents and GABAAR-mediated synapse responses results in reduced excitability in neurons.

Suppression of exaggerated NMDAR activity by memantine treatment ameliorates neurological and behavioral deficits in aminopeptidase P1-deficient mice.

Inborn errors of metabolism (IEMs) are common causes of neurodevelopmental disorders, including microcephaly, hyperactivity, and intellectual disability. However, the synaptic mechanisms of and pharmacological interventions for the neurological complications of most IEMs are unclear. Here, we report that metabolic dysfunction perturbs neuronal NMDA receptor (NMDAR) homeostasis and that the restoration of NMDAR signaling ameliorates neurodevelopmental and cognitive deficits in IEM model mice that lack aminopeptidase P1. Aminopeptidase P1-deficient (Xpnpep1-/-) mice, with a disruption of the proline-specific metalloprotease gene Xpnpep1, exhibit hippocampal neurodegeneration, behavioral hyperactivity, and impaired hippocampus-dependent learning. In this study, we found that GluN1 and GluN2A expression, NMDAR activity, and the NMDAR-dependent long-term potentiation (LTP) of excitatory synaptic transmission were markedly enhanced in the hippocampi of Xpnpep1-/- mice. The exaggerated NMDAR activity and NMDAR-dependent LTP were reversed by the NMDAR antagonist memantine. A single administration of memantine reversed hyperactivity in adult Xpnpep1-/- mice without improving learning and memory. Furthermore, chronic administration of memantine ameliorated hippocampal neurodegeneration, hyperactivity, and impaired learning and memory in Xpnpep1-/- mice. In addition, abnormally enhanced NMDAR-dependent LTP and NMDAR downstream signaling in the hippocampi of Xpnpep1-/- mice were reversed by chronic memantine treatment. These results suggest that the metabolic dysfunction caused by aminopeptidase P1 deficiency leads to synaptic dysfunction with excessive NMDAR activity, and the restoration of synaptic function may be a potential therapeutic strategy for the treatment of neurological complications related to IEMs.

Bioanalytical methods for the detection of duloxetine and thioctic acid in plasma using ultra performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS).

Duloxetine and thioctic acid (TA) are standard drugs for treating diabetic neuropathy, a primary complication associated with diabetes. In this study, ultra performance liquid chromatography coupled with tandem mass spectrometry methods was successfully developed and validated for quantifying duloxetine and TA in biological samples. The protein precipitation method was used to extract duloxetine, TA and their internal standards from beagle dog plasma. A Hypersil Gold C18 column (150 × 2.1 mm, 1.9 µm) was used for the experiment. Isocratic elution with 0.1% formic acid in acetonitrile (A) and 0.1% formic acid (B) was used for duloxetine, whereas a gradient elution with 0.03% acetic acid (A) and acetonitrile (B) was used for TA. The validated parameters included linearity, sensitivity, accuracy, precision, selectivity, matrix effect, stability, and recovery under different conditions. The linear ranges of the calibration curves for duloxetine and TA were 5-800 ng/mL and 5-1,000 ng/mL, respectively. An intra- and inter-run precision of ± 15% can be observed in all quality control samples. These methods were successfully used for pharmacokinetics (PKs) studies in beagle dogs to compare PK differences in a fixed-dose combination including duloxetine and TA and co-administration of the 2 drugs.

miRNA induced 3D bioprinted-heterotypic osteochondral interface.

The engineering of osteochondral interfaces remains a challenge. MicroRNAs (miRs) have emerged as significant tools to regulate the differentiation and proliferation of osteogenic and chondrogenic formation in the human musculoskeletal system. Here, we describe a novel approach to osteochondral reconstruction based on the three-dimensional (3D) bioprinting of miR-transfected adipose-derived stem cell (ADSC) spheroids to produce a heterotypic interface that addresses the intrinsic limitations of the traditional approach to inducing zonal differentiation via the use of diffusible cytokines. We evaluated the delivery of miR-148b for osteogenic differentiation and the codelivery of miR-140 and miR-21 for the chondrogenic differentiation of ADSC spheroids. Our results demonstrated that miR-transfected ADSC spheroids exhibited upregulated expression of osteogenic and chondrogenic differentiation related gene and protein markers, and enhanced mineralization and cell proliferation compared to spheroids differentiated using a commercially-available differentiation medium. Upon confirmation of the osteogenic and chondrogenic potential of miR-transfected ADSC spheroids, using aspiration-assisted bioprinting, these spheroids were 3D bioprinted into a dual-layer heterotypic osteochondral interface with a stratified arrangement of distinct osteogenic and chondrogenic zones. The proposed approach holds great promise for the biofabrication of stratified tissues, not only for the osteochondral interfaces presented in this work, but also for other composite tissues and tissue interfaces, such as, but not limited to, the bone-tendon-muscle interface and craniofacial tissues.

Tunable near-infrared Gires-Tournois resonators based on vanadium dioxide on gold film.

Vanadium dioxide (VO2) has been proposed as a phase-change material in tunable photonic and optoelectronic devices. In such devices, a thin layer of VO2 is typically deposited on metallic or insulating surfaces. In this Letter, we report the reflectance spectra of a subwavelength structure consisting of a thin layer of VO2 deposited on a gold film in the near-infrared spectral range, particularly near the wavelength of 1550 nm, which is significant for telecommunication applications. Our results indicate that in the insulating phase of VO2, the air/VO2/Au structure can be considered as a Gires-Tournois resonant cavity whose maximum absorption wavelength can be tuned by adjusting the thickness of the VO2 layer. In contrast, in the metallic phase of VO2, the reflectance of the structure increases by an amount of the order of a few tens of units. The proposed structure can prospectively lead to new design concepts in tunable photonic and optoelectronic devices.

Aspiration-assisted freeform bioprinting of mesenchymal stem cell spheroids within alginate microgels.

Aspiration-assisted freeform bioprinting (AAfB) has emerged as a promising technique for precise placement of tissue spheroids in three-dimensional (3D) space enabling tissue fabrication. To achieve success in embedded bioprinting using AAfB, an ideal support bath should possess shear-thinning behavior and yield-stress to facilitate tight fusion and assembly of bioprinted spheroids forming tissues. Several studies have demonstrated support baths for embedded bioprinting in the past few years, yet a majority of these materials poses challenges due to their low biocompatibility, opaqueness, complex and prolonged preparation procedures, and limited spheroid fusion efficacy. In this study, to circumvent the aforementioned limitations, we present the feasibility of AAfB of human mesenchymal stem cell (hMSC) spheroids in alginate microgels as a support bath. Alginate microgels were first prepared with different particle sizes modulated by blending time and concentration, followed by determination of the optimal bioprinting conditions by the assessment of rheological properties, bioprintability, and spheroid fusion efficiency. The bioprinted and consequently self-assembled tissue structures made of hMSC spheroids were osteogenically induced for bone tissue formation. Alongside, we investigated the effects of peripheral blood monocyte-derived osteoclast incorporation into the hMSC spheroids in heterotypic bone tissue formation. We demonstrated that alginate microgels enabled unprecedented positional accuracy (∼5%), transparency for visualization, and improved fusion efficiency (∼97%) of bioprinted hMSC spheroids for bone fabrication. This study demonstrates the potential of using alginate microgels as a support bath for many different applications including but not limited to freeform bioprinting of spheroids, cell-laden hydrogels, and fugitive inks to form viable tissue constructs.

Incidence and risk of venous thromboembolism according to primary treatment type in women with endometrial cancer: a population-based study.

BACKGROUND: Current prophylaxes and treatments for venous thromboembolism (VTE) in women with gynecologic cancer are mainly guided by studies on solid cancers because studies in gynecologic cancer did not provide sufficient data. Large-scale studies evaluating the incidence and risk of VTE according to therapeutic modality may guide prophylaxis and treatment of VTE in gynecologic cancer. This study was performed to determine the incidence and risk of VTE according to primary treatment type in Korean women with endometrial cancer. METHODS: We selected 26,256 women newly diagnosed with endometrial cancer between 2009 and 2018 from the Korean Health Insurance Review and Assessment Service database. During the total follow-up period and first six months after primary treatments initiation, the incidence and risk of VTE were evaluated according to primary treatment type, that is, no treatment, surgery, radiotherapy, chemotherapy, or hormone therapy. RESULTS: VTE occurred in 136 per 10,000 women during the total follow-up period and in 54 per 10,000 women during the first six months with the highest frequency in women that underwent chemotherapy. During the first year, the monthly incidence of VTE decreased with time among women that underwent no treatment, surgery, or hormone therapy and remained unchanged in those that received radiotherapy or chemotherapy. Compared with women that received no treatment, VTE risk, especially of PE significantly increased in women that underwent chemotherapy (VTE: hazard ratio (HR), 2.334; 95% CI, 1.38-3.949; P = 0.002) (PE: HR, 2.742; 95% CI, 1.424-5.278; P = 0.003) or hormone therapy (VTE: HR, 2.073; 95% CI, 1.356-3.17; P = 0.001) (PE: HR, 2.086; 95% CI, 1.19-3.657; P = 0.01) during the total follow-up period and women that underwent only chemotherapy during the first six months (VTE: HR, 2.532; 95% CI, 1.291-4.966; P = 0.007) (PE: HR, 3.366; 95% CI, 1.496-7.576; P = 0.003). CONCLUSIONS: In this cohort study, the incidence and risk of VTE were highest in women with endometrial cancer that underwent chemotherapy as a primary treatment. Notably, the incidence of VTE decreased over time in women that received no treatment, surgery, or hormone therapy. This study can help guide therapies for prophylaxis and treatment of VTE in women with endometrial cancer.

The phosphorylation status of eukaryotic elongation factor-2 indicates neural activity in the brain.

Assessment of neural activity in the specific brain area is critical for understanding the circuit mechanisms underlying altered brain function and behaviors. A number of immediate early genes (IEGs) that are rapidly transcribed in neuronal cells in response to synaptic activity have been used as markers for neuronal activity. However, protein detection of IEGs requires translation, and the amount of newly synthesized gene product is usually insufficient to detect using western blotting, limiting their utility in western blot analysis of brain tissues for comparison of basal activity between control and genetically modified animals. Here, we show that the phosphorylation status of eukaryotic elongation factor-2 (eEF2) rapidly changes in response to synaptic and neural activities. Intraperitoneal injections of the GABA A receptor (GABAAR) antagonist picrotoxin and the glycine receptor antagonist brucine rapidly dephosphorylated eEF2. Conversely, potentiation of GABAARs or inhibition of AMPA receptors (AMPARs) induced rapid phosphorylation of eEF2 in both the hippocampus and forebrain of mice. Chemogenetic suppression of hippocampal principal neuron activity promoted eEF2 phosphorylation. Novel context exploration and acute restraint stress rapidly modified the phosphorylation status of hippocampal eEF2. Furthermore, the hippocampal eEF2 phosphorylation levels under basal conditions were reduced in mice exhibiting epilepsy and abnormally enhanced excitability in CA3 pyramidal neurons. Collectively, the results indicated that eEF2 phosphorylation status is sensitive to neural activity and the ratio of phosphorylated eEF2 to total eEF2 could be a molecular signature for estimating neural activity in a specific brain area.

Does the Summer Season Affect the Amniotic Fluid Volume during Pregnancy?

Amniotic fluid is crucial for the well-being of the fetus. Recent studies suggest that dehydration in a pregnant woman leads to oligohydramnios. We assessed the variation in the amniotic fluid index (AFI) during the summer and non-summer seasons and evaluated neonatal outcomes. We retrospectively reviewed electrical medical records of pregnant women who visited the Konkuk University Medical Center for antenatal care, between July 2005 and July 2019. A total of 19,724 cases from 6438 singleton pregnant women were included after excluding unsuitable cases. All AFI values were classified as 2nd and 3rd trimester values. Additionally, borderline oligohydramnios (AFI, 5-8) and normal AFI (AFI, 8-24) were assessed according to the seasons. The average AFI between the summer and non-summer season was statistically different only in the 3rd trimester; but the results were not clinically significant. In the 3rd trimester, the summer season influenced the increased incidence of borderline oligohydramnios. The borderline oligohydramnios group showed an increased small-for-gestational-age (SGA) rate and NICU admission rate. In the summer season, the incidence of borderline oligohydramnios was seen to increase. This result would be significant for both physicians and pregnant women.

miRNA induced co-differentiation and cross-talk of adipose tissue-derived progenitor cells for 3D heterotypic pre-vascularized bone formation.

Engineered bone grafts require a vascular network to supply cells with oxygen, nutrients and remove waste. Using heterotypic mature cells to create these graftsin vivohas resulted in limited cell density, ectopic tissue formation and disorganized tissue. Despite evidence that progenitor cell aggregates, such as progenitor spheroids, are a potential candidate for fabrication of native-like pre-vascularized bone tissue, the factors dictating progenitor co-differentiation to create heterotypic pre-vascularized bone tissue remains poorly understood. In this study, we examined a three-dimensional heterotypic pre-vascularized bone tissue model, using osteogenic and endotheliogenic progenitor spheroids induced by miR-148b and miR-210 mimic transfection, respectively. Spheroids made of transfected cells were assembled into heterotypic structures to determine the impact on co-differentiation as a function of micro-RNA (miRNA) mimic treatment group and induction time. Our results demonstrated that miRNAs supported the differentiation in heterotypic structures, and that developing heterotypic structures is determined in part by progenitor maturity, as confirmed by gene and protein markers of osteogenic and endotheliogenic differentiation and the mineralization assay. As a proof of concept, miRNA-transfected spheroids were also bioprinted using aspiration-assisted bioprinting and organized into hollow structures to mimic the Haversian canal. Overall, the presented approach could be useful in fabrication of vascularized bone tissue using spheroids as building blocks.

Incidence and risk of venous thromboembolism according to primary treatment in women with ovarian cancer: A retrospective cohort study.

OBJECTIVE: This study aimed to investigate incidence and risk for venous thromboembolism (VTE) according to primary treatment in women with ovarian cancer. METHODS: We selected 26,863 women newly diagnosed with ovarian cancer between 2009 and 2018 from the Korean Health Insurance Review and Assessment Service databases. During the total follow-up period and the first six months after initiation of primary treatments, incidence and risk of VTE were evaluated according to primary treatment as no treatment, surgery, radiotherapy, or chemotherapy. RESULTS: The mean follow-up period was 1285.5±6 days. The VTE incidence was highest in women who underwent chemotherapy (306 per 10,000 women). Among women who underwent surgery, VTE was highest in surgery with neoadjuvant chemotherapy (536 per 10,000 women), followed by surgery with adjuvant chemotherapy (360 per 10,000 women) and surgery alone (132 per 10,000 women). During the first 12 months, monthly incidence of VTE decreased. Compared with women with no treatment, risk of VTE significantly increased in women undergoing chemotherapy (HR 1.297; 95% CI, 1.08-1.557; P = 0.005) during the total follow-up period and decreased in women undergoing surgery (HR 0.557; 95% CI, 0.401-0.775; P<0.001) and radiotherapy (HR 0.289; 95% CI, 0.119-0.701; P = 0.006) during the first six months. Among women who underwent surgery, VTE risk significantly increased in surgery with neoadjuvant chemotherapy (HR 4.848; 95% CI, 1.86-12.632; P = 0.001) followed by surgery with adjuvant chemotherapy (HR 2.807; 95% CI, 1.757-4.485; P<0.001) compared with surgery alone during the total follow-up period and in surgery with neoadjuvant chemotherapy (HR 4.223; 95% CI, 1.37-13.022; P = 0.012) during the first six months. CONCLUSIONS: In this large Korean cohort study, incidence and risk of VTE were highest in women with ovarian cancer who underwent chemotherapy and surgery with neoadjuvant chemotherapy as a primary cancer treatment. Incidence of VTE decreased over time.