Efficacy, tolerability, and bone density outcomes of elagolix with add-back therapy for endometriosis-associated pain: 12 months of an ongoing randomized phase 3 trial.

BACKGROUND: Elagolix, an approved oral treatment for endometriosis-associated pain, has been associated with hypoestrogenic effects when used as monotherapy. Hormonal add-back therapy has the potential to mitigate these effects. OBJECTIVE: To evaluate efficacy, tolerability, and bone density outcomes of elagolix 200 mg twice daily with 1 mg estradiol /0.5 mg norethindrone acetate (add-back) therapy once daily compared with placebo in premenopausal women with moderate-to-severe endometriosis-associated pain. STUDY DESIGN: This ongoing, 48-month, phase 3 study consists of a 12-month, double-blind period, with randomization 4:1:2 to elagolix 200 mg twice daily with add-back therapy, elagolix 200 mg twice daily monotherapy for 6 months followed by elagolix with add-back therapy, or placebo. The co-primary endpoints were proportion of patients with clinical improvement (termed "responders") in dysmenorrhea and nonmenstrual pelvic pain at month 6. We report 12-month results on efficacy of elagolix with add-back therapy versus placebo in reducing dysmenorrhea, nonmenstrual pelvic pain, dyspareunia, and fatigue. Tolerability assessments include adverse events and change from baseline in bone mineral density. RESULTS: A total of 679 patients were randomized to elagolix with add-back therapy (n=389), elagolix monotherapy (n=97), or placebo (n=193). Compared with patients randomized to placebo, a significantly greater proportion of patients randomized to elagolix with add-back therapy responded with clinical improvement in dysmenorrhea (62.8% versus 23.7%; P≤.001) and nonmenstrual pelvic pain (51.3% versus 36.8%; P≤.001) at 6 months. Compared with placebo, elagolix with add-back therapy produced significantly greater improvement from baseline in 7 hierarchically ranked secondary endpoints including dysmenorrhea (months 12, 6, 3), nonmenstrual pelvic pain (months 12, 6, 3), and fatigue (months 6) (all P<.01). Overall, the incidence of adverse events was 73.8% with elagolix plus add-back therapy and 66.8% with placebo. The rate of severe and serious adverse events did not meaningfully differ between treatment groups. Study drug discontinuations associated with adverse events were low in patients receiving elagolix with add-back therapy (12.6%) and those receiving placebo (9.8%). Patients randomized to elagolix monotherapy exhibited decreases from baseline in bone mineral density of -2.43% (lumbar spine), -1.54% (total hip), and -1.78% (femoral neck) at month 6. When add-back therapy was added to elagolix at month 6, the change from baseline in bone mineral density remained in a similar range of -1.58% to -1.83% at month 12. However, patients who received elagolix plus add-back therapy from baseline exhibited little change from baseline in bone mineral density (<1% change) at months 6 and 12. CONCLUSION: Compared with placebo, elagolix with add-back therapy resulted in significant, clinically meaningful improvement in dysmenorrhea, nonmenstrual pelvic pain, and fatigue at 6 months that continued until month 12 for both dysmenorrhea and nonmenstrual pelvic pain. Elagolix with add-back therapy was generally well tolerated. Loss of bone mineral density at 12 months was greater in patients who received elagolix with add-back therapy than those who received placebo. However, the change in bone mineral density with elagolix plus add-back therapy was < 1% and was attenuated compared with bone loss observed with elagolix monotherapy.

[Correlation between intestinal toxicity and composition changes of toxic parts from Euphorbia ebracteolata before and after Terminalia chebula soup processing].

This study aims to explore the correlation between intestinal toxicity and composition changes of Euphorbia ebracteolata before and after Terminalia chebula soup(TCS) processing. Intragastric administration was performed on the whole animal model. By using fecal water content, inflammatory causes, and pathological damage of different parts of the intestinal tract of mice as indexes, the differences in intestinal toxicity of dichloromethane extraction of raw E. ebracteolata(REDE), dichloromethane extraction of TCS, and dichloromethane extraction of E. ebracteolata after simulated TCS processing(STREDE) were compared, so as to investigate the effect of TCS processing on the intestinal toxicity of E. ebracteolata. At the same time, the component databases of E. ebracteolata and T. chebula were constructed, and the composition changes of diterpenoids, tannins, and phenolic acids in the three extracted parts were analyzed by HPLC-TOF-MS. HPLC was used to compare the content of four diterpenoids including ent-11α-hydroxyabicta-8(14), 13(15)-dien-16, 12-olide(HAO), jolkinolide B(JNB), fischeria A(FA), and jolkinolide E(JNE) in the E. ebracteolata before and after processing and the residue of container wall after processing, so as to investigate the effect of TCS processing on the content and structure of the diterpenoids. The results showed that the REDE group could significantly increase the fecal water content and the release levels of TNF-α and IL-1ß from each intestinal segment, and intestinal tissue damage was accompanied by significant infiltration of inflammatory cells. However, compared with the REDE group, the intestinal tissue damage in the STREDE group was alleviated, and the infiltration of inflammatory cells decreased. The intestinal toxicity significantly decreased. Mass spectrometry analysis showed that there was no significant difference in the content of diterpenoids of REDE before and after simulated TCS processing, but a large number of tannins and phenolic acids were added. The results of HPLC showed that the content of four diterpenoids of E. ebracteo-lata decreased to varying degrees after TCS processing, ranging from-0.35% to-19.74%, and the decreased part mainly remained in the container wall, indicating that the structure of toxic diterpenoids of E. ebracteolata was not changed after TCS processing. The antagonistic effect of tannic and phenolic acids in the TCS may be the main reason for the reduced intestinal toxicity of E. ebracteolata after TCS processing. The TCS processing for E. ebracteolata is scientific.

Radon and lung cancer: Current status and future prospects.

Beyond tobacco smoking, radon takes its place as the second most significant contributor to lung cancer, excluding hereditary and other biologically related factors. Radon and its byproducts play a pivotal role in exposing humans to elevated levels of natural radiation. Approximately 10-20 % of lung cancer cases worldwide can be attributed to radon exposure, leading to between 3 % and 20 % of all lung cancer-related deaths. Nevertheless, a knowledge gap persists regarding the association between radon and lung cancer, impeding radon risk reduction initiatives globally. This review presents a comprehensive overview of the current state of research in epidemiology, cell biology, dosimetry, and risk modeling concerning radon exposure and its relevance to lung cancer. It also delves into methods for measuring radon concentrations, monitoring radon risk zones, and identifying priorities for future research.

Effects of beef fat enriched with trans vaccenic acid and cis9, trans11-CLA on glucose homoeostasis and hepatic lipid accumulation in high-fat diet-induced obese mice.

Trans vaccenic acid (TVA, trans11-18 : 1) and cis9, trans11-CLA (also known as rumenic acid; RA) have received widespread attention as potentially beneficial trans-FA due to their putative health benefits, including anti-diabetic properties. The objective of this study was to determine the effects of beef fat naturally enriched with TVA and RA on parameters related to glucose homoeostasis and associated metabolic markers in diet-induced obese (DIO) mice. Thirty-six male C57BL/6J mice (8 weeks old) were fed for 19 weeks with either a control low-fat diet (CLF), a control high-fat diet (CHF), or a TVA+RA-enriched high-fat diet (EHF). Compared with CLF, feeding either CHF or EHF resulted in adverse metabolic outcomes associated with high-fat diets, including adiposity, impaired glucose control and hepatic steatosis. However, the EHF diet induced a significantly higher liver weight TAG content and elevated plasma alanine transaminase levels compared with the CHF diet. Collectively, the findings from this study suggest that EHF does not improve glucose tolerance and worsens liver steatosis in DIO mice. However, the adverse effects of EHF on the liver could be in part related to the presence of other trans-FA in the enriched beef fat.

Ion Resource Recovery via Electrodialysis Fabricated with Poly(Arylene Ether Sulfone)-Based Anion Exchange Membrane in Organic Solvent System.

Ion resource recovery from organic wastewater is beneficial for achieving emission peaks and carbon neutrality targets. Advanced organic solvent-resistant anion exchange membranes (AEMs) for treating organic wastewater via electrodialysis (ED) are of significant interest. Herein, a kind of 3D network AEM based on poly(arylene ether sulfone) cross-linked with a flexible cross-linker (DBH) for ion resource recovery via ED in organic solvent system is reported. Investigations demonstrate that the as-prepared AEMs show excellent dimensional stability in 60% DMSO (aq.), 60% ethanol (aq.), and 60% acetone (aq.), respectively. For example, the optimized AEM shows very low swelling ratios of 1.04-1.10% in the organic solvents. ED desalination ratio can reach 99.1% after exposure of the AEM to organic solvents for 30 days, and remain > 99% in a mixture solution containing organic solvents and 0.5 m NaCl. Additionally, at a current density of 2.5 mA cm-2, the optimized AEM soaked in organic solvents for 30 days shows a high perm-selectivity (Cl-/SO4 2-) of 133.09 (vs 13.11, Neosepta ACS). The superior ED performance is attributed to the stable continuous sub-nanochannels within AEM confirmed by SAXS, rotational energy barriers, etc. This work shows the potential application of cross-linked AEMs for resource recovery in organic wastewater.

Water-soluble organic macrocycles based on dye chromophores and their applications.

Traditional water-soluble organic macrocyclic receptors generally lack photofunctionality, thus monitoring the drug delivery and the phototheranostic applications of these host-guest macrocyclic systems has been greatly restricted. To address this issue, incorporating π-conjugated dye chromophores as building blocks into macrocyclic molecules is a straightforward and promising strategy. This approach not only imparts intrinsic optical features to the macrocycles themselves but also enhances the host-guest binding ability due to the large planar structures of the dyes. In this feature article, we focus on recent advances in water-soluble macrocyclic compounds based on organic dye chromophores, such as naphthalimide (NDI), perylene diimides (PDI), azobenzene (azo), tetraphenylethylene (TPE) and anthracene, and provide an overview of their various applications including molecular recognition, drug release, biological imaging, photothermal therapy, etc. We hope that this article could be helpful and instructive for the design of water-soluble dye-based macrocycles and the further development of their biomedical applications, particularly in combination with drug therapy and phototheranostics.

Identifying the Environmental Determinants of Lung Cancer: A Case Study of Henan, China.

Lung cancer has become one of the most prevalent cancers in the last several decades. Studies have documented that most cases of lung cancer are caused by inhaling environmental carcinogens while how external environmental factors lead to individual lung cancer is still an open issue as the pathogenesis may come from the combined action of multiple environmental factors, and such pathogenic mechanism may vary from region to region. Based on the data of lung cancer cases from hospitals at the county level in Henan from 2016 to 2020, we analyzed the response relationship between lung cancer incidence and physical ambient factors (air quality, meteorological conditions, soil vegetation) and socioeconomic factors (occupational environment, medical level, heating mode, smoking behavior). We used a Bayesian spatio-temporal interaction model to evaluate the relative risk of disease in different regions. The results showed that smoking was still the primary determinant of lung cancer, but the influence of air quality was increasing year by year, with meteorological conditions and occupational environment playing a synergistic role in this process. The high-risk areas were concentrated in the plains of East and Central Henan and the basin of South Henan, while the low-risk areas were concentrated in the hilly areas of North and West Henan, which were related to the topography of Henan. Our study provides a better understanding of the environmental determinants of lung cancer which will help refine existing prevention strategies and recognize the areas where actions are required to prevent environment and occupation related lung cancer.

Semirigid Highly Conjugated Zirconium-Organic Framework for the Capture of Micropollutants and Solar-Light Photodegradation.

Micro-organic pollutants, particularly organic dyes and personal care products (PPCPs), are widely present in wastewater, and thus pose a serious risk to human health. The capture and solar-light photodegradation of micro-organic pollutants are highly challenging tasks, which require the design and synthesis of microporous materials with specific structures. As we know, organic dyes and PPCPs can be absorbed via π-π* stacking. In this paper, an iron-based metal-organic framework (Fe-UiO-68-terNap) containing semirigid conjugated aromatic ligands is prepared for the capture and solar-light photodegradation of multiple water contaminants. UiO-68-terNap was synthesized based on ternaphthalene with π-π* stacking, which would increase the adsorption capacities of organic micropollutants in wastewater. Additionally, the formation of Fe-O-Zr enhances the charge-separation ability resulting in the successful degradation of micropollutants in 240 min. The novel material has been elucidated by single-crystal X-ray diffraction and Fe K-edge XANES, which provide key insights at a molecular level for the design of novel materials for the capture and photodegradation of organic micropollutants.

Nuclear complement C3b promotes paclitaxel resistance by assembling the SIN3A/HDAC1/2 complex in non-small cell lung cancer.

In addition to the classical role as a serum effector system of innate immunity, accumulating evidence suggests that intracellular complement components have indispensable functions in immune defense, T cell homeostasis, and tumor cell proliferation and metastasis. Here, we revealed that complement component 3 (C3) is remarkably upregulated in paclitaxel (PTX)-resistant non-small cell lung cancer (NSCLC) cells and that knockdown of C3 promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy. Ectopic C3 decreased PTX-induced apoptosis and induced resistance to PTX treatment in original NSCLC cells. Interestingly, C3b, the activated fragment of C3, was found to translocate into the nucleus and physically associate with the HDAC1/2-containing SIN3A complex to repress the expression of GADD45A, which plays an important role in cell growth inhibition and apoptosis induction. Importantly, C3 downregulated GADD45A by enhancing the binding of the SIN3A complex with the promoter of GADD45A, thus decreasing the H3Ac level to compress chromatin around the GADD45A locus. Subsequently, ectopic GADD45A promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy, and insufficiency of GADD45A in original cancer cells induced resistance to PTX treatment. These findings identify a previously unknown nucleus location and oncogenic property for C3 in chemotherapy and provide a potential therapeutic opportunity to overcome PTX resistance.

Correction: Deep Shotgun metagenomic and 16S rRNA analysis revealed the microbial diversity of lactic acid bacteria in traditional fermented foods of eastern Hainan, China.

Correction for 'Deep Shotgun metagenomic and 16S rRNA analysis revealed the microbial diversity of lactic acid bacteria in traditional fermented foods of eastern Hainan, China' by Yuqing Wu et al., Food Funct., 2022, 13, 12938-12952, https://doi.org/10.1039/D2FO02501A.

Manipulating Host-Guest Charge Transfer of a Water-Soluble Double-Cavity Cyclophane for NIR-II Photothermal Therapy.

Water-soluble small organic photothermal agents (PTAs) over NIR-II biowindow (1000-1350 nm) are highly desirable, but the rarity greatly limits their applications. Based on a water-soluble double-cavity cyclophane GBox-44+ , we report a class of host-guest charge transfer (CT) complexes as structurally uniform PTAs for NIR-II photothermal therapy. As a result of its high electron-deficiency, GBox-44+ can bind different electron-rich planar guests with a 1 : 2 host/guest stoichiometry to readily tune the CT absorption band that extends to the NIR-II region. When using a diaminofluorene guest substituted with an oligoethylene glycol chain, the host-guest system realized both good biocompatibility and enhanced photothermal conversion at 1064 nm, and was then exploited as a high-efficiency NIR-II PTA for cancer cell and bacterial ablation. This work broadens the potential applications of host-guest cyclophane systems and provides a new access to bio-friendly NIR-II photoabsorbers with well-defined structures.

A discrete-choice experiment study of physicians' prioritization of attributes of medical treatments for endometriosis-associated pain.

BACKGROUND: Physicians' preferences for attributes of medical treatments for endometriosis-associated pain have not previously been quantified. METHODS: US obstetrician-gynecologists completed an online discrete-choice experiment survey. In a series of questions, physicians chose a medical treatment for a hypothetical patient with endometriosis experiencing severe, persistent dysmenorrhea, nonmenstrual pelvic pain, and/or dyspareunia. Each question presented two hypothetical medical treatments for endometriosis-associated pain, defined by seven attributes with varying levels. Preferences weights and conditional relative importance (CRI) were calculated using a random-parameters logit model. RESULTS: Respondents (N = 250) had an average age of 53 years; 36% were female. The most important attribute, conditional on the attributes and levels evaluated, was risk of moderate-to-severe hot flashes (CRI, 3.34). In descending order of importance, the CRIs of the other attributes were 2.13 for improvement in nonmenstrual pelvic pain, 2.04 for improvement in dyspareunia, 1.88 for improvement in dysmenorrhea, 1.16 for risk of pregnancy-related complications if pregnancy occurs during treatment, 0.62 for increased risk of bone fracture later in life, and 0.48 for mode of administration. CONCLUSIONS: In addition to valuing pain reduction, respondents prioritized avoiding moderate-to-severe hot flashes, followed by less common and less immediate risks of pregnancy-related complications and bone fracture.

RASSF1A inhibits epithelial-mesenchymal transition of gastric cancer cells by downregulating P-JNK.

Gastric cancer (GC) is one of the most common gastrointestinal tumors. In this study, we assessed the biological role of Ras association domain family 1 isoform A (RASSF1A) in GC cells. Expressions of RASSF1A and the relationship of RASSF1A with epithelial-mesenchymal transformation (EMT)-related proteins were assessed in five cell lines using Western blot. GC cells with RASSF1A overexpression were used to study sensitivity to cisplatin, migration, invasion, and the expression of EMT-associated biomarkers. GC cells showed profound downregulation of RASSF1A expression compared with normal human gastric mucosal cells. High RASSF1A expression was associated with increased overall survival. Overexpression of RASSF1A regulates GC cells activity and the expression of EMT-associated biomarkers. RASSF1A regulates E-cadherin and Vimentin through P-JNK pathway. Our results revealed that RASSF1A can inhibit the proliferation, migration, and invasion of GC cells via E-cadherin. Our study provides insights for further research on GC.

The Utility and Impact of the Painful Periods Screening Tool (PPST) to Improve Healthcare Delivery for People with Symptoms of Pelvic Pain.

The objective of this study was to evaluate the utility and impact of the Painful Periods Screening Tool (PPST) to improve healthcare delivery for people with symptoms of pelvic pain. The design of this study was a survey study. After IRB approval, patients aged 18-55 years with self-reported pelvic, abdominal, or lower back pain before, during, or after menstrual periods were invited to participate in the study from September 2020 to June 2021. Participants filled out the PPST questionnaire on the day of their Johns Hopkins clinic visit and the follow-up questionnaire 1-14 days after the clinic visit. Demographics and duration of pain were assessed, and participants who completed the PPST questionnaire were sent a follow-up questionnaire to assess utility and impact of PPST. Of the 1352 patients who met study eligibility, 1000 participants responded to both questionnaires. Most subjects (82.9%; 95% CI: 80.4-85.2%) reported having severe pelvic/abdominal or lower back pain during menses. Nine hundred fifteen participants (91.5%; 95% CI: 89.6-93.2%) reported that if given regularly, the PPST would help women discuss their pain symptoms with their healthcare provider. Six hundred seventy-eight participants (67.8%; 95% CI: 64.8-70.7%) reported that the PPST helped them initiate a conversation about their symptoms. Seven hundred seven participants (70.7%; 95% CI: 67.8-73.5%) were more comfortable discussing symptoms of pelvic pain with their provider after filling out the PPST. These findings support the utility of PPST as an endometriosis screening tool and suggest that this tool facilitated communication between patients and providers about pain symptoms.

Two sides of the same coin: Meta-analysis uncovered the potential benefits and risks of traditional fermented foods at a large geographical scale.

Traditional fermented foods, which are well-known microbial resources, are also bright national cultural inheritances. Recently, traditional fermented foods have received great attention due to their potential probiotic properties. Based on shotgun metagenomic sequencing data, we analyzed the microbial diversity, taxonomic composition, metabolic pathways, and the potential benefits and risks of fermented foods through a meta-analysis including 179 selected samples, as well as our own sequencing data collected from Hainan Province, China. As expected, raw materials, regions (differentiated by climatic zones), and substrates were the main driving forces for the microbial diversity and taxonomic composition of traditional fermented foods. Interestingly, a higher content of beneficial bacteria but a low biomass of opportunistic pathogens and antibiotic resistance genes were observed in the fermented dairy products, indicating that fermented dairy products are the most beneficial and reliable fermented foods. In contrast, despite the high microbial diversity found in the fermented soy products, their consumption risk was still high due to the enrichment of opportunistic pathogens and transferable antibiotic resistance genes. Overall, we provided the most comprehensive assessment of the microbiome of fermented food to date and generated a new view of its potential benefits and risks related to human health.

Deep Shotgun metagenomic and 16S rRNA analysis revealed the microbial diversity of lactic acid bacteria in traditional fermented foods of eastern Hainan, China.

The eastern part of Hainan, China, has a flat terrain and a suitable climate with abundant sunshine and rain. This unique environment makes the tropical microbial resources of natural fermented food unique and rich. Therefore, we combined Shotgun metagenomic sequencing, 16S rRNA sequencing and pure culture technology to analyze the microbial diversity, microbiota composition, species differences and correlation of 30 traditional fermented food samples collected from Wenchang, Qionghai, Wanning and Lingshui in the eastern part of Hainan province, and isolated, identified and preserved the microorganisms in them. The results showed that the microbial community structure differs significantly between samples from different regions and between different substrates. The alpha diversity of microorganisms in traditional fermented foods in the Wanning area was higher than those of the other three areas. The beta diversity indicated that the microbiota structural difference between Wanning and Qionghai was smaller. This is consistent with the fact that the precipitation in the Wanning area is the highest and similar to that of Qionghai. The alpha diversity of microorganisms was the highest in fermented vegetables, followed by fermented grains, and the lowest in fermented seafood. Beta diversity showed that the microbiota composition of fermented grains and fermented vegetables is very similar, but that of fermented seafood is significantly different. The results of microbiota structural analysis showed that firmicutes and proteobacteria are the dominant bacterial phyla, and Lactobacillus plantarum and Lactobacillus fermentum are the dominant species in traditional fermented foods in eastern Hainan. Lactic acid bacteria are the dominant species in traditional fermented foods from the eastern Hainan region of China, regardless of the substrate used in fermentation. According to the microbial functional characteristics, the microbial metabolism and biosynthesis pathways in traditional fermented foods in Hainan tend to be active. In addition, combined with pure culture technology, we isolated, identified and preserved 342 lactic acid bacteria strains from traditional fermented food in eastern Hainan province. This study helped us understand the different characteristics of microbial communities in tropical southern China and supplement the Lactobacillus species resource pool in tropical southern China. Moreover, it provided new insights and directions for the development and utilization of fermented foods.

Population flow based spatial-temporal eigenvector filtering modeling for exploring effects of health risk factors on COVID-19.

The COVID-19 pandemic has had great impact on human health and social economy. Several studies examined spatial and temporal patterns of health risk factors associated with COVID-19, but population flow spillover effect has not been sufficiently considered. In this paper, a population flow-based spatial-temporal eigenvector filtering model (FLOW-ESTF) was developed to consider spatial-temporal patterns and population flow connectivity simultaneously. The proposed FLOW-ESTF method efficiently improved model prediction accuracy, which could help the government aware of the infection risk level and to make suitable control policies. The selected population flow spatial-temporal eigenvector contributed most to modeling and the visualization of corresponding eigenvector set helped to explore the underlying spatial-temporal patterns and pandemic transmission nodes. The model coefficients could reflect how health risk factors contribute the modeling of state-level COVID-19 weekly increased cases and how their influence changed through time, which could help people and government to better aware the potential health risks and to adjust control measures at different stage. The extracted population flow spatial-temporal eigenvector not only represents influence of population flow and its spillover effects but also represents some possible omitted health risk factors. This could provide an efficient path to solve the problem of spatial and temporal autocorrelation in COVID-19 modeling and an intuitive way to discover underlying spatial patterns, which will partially compensate for the problems of insufficient consideration of potential risk variables and missing data.

CD59-Regulated Ras Compartmentalization Orchestrates Antitumor T-cell Immunity.

T cell-mediated immunotherapy represents a promising strategy for cancer treatment; however, it has achieved satisfactory clinical responses in only a limited population. Thus, a broader view of the T-cell immune response is required. The Ras/MAPK pathway operates in many important signaling cascades and regulates multiple cellular activities, including T-cell development, proliferation, and function. Herein, we found that the typical membrane-bound complement regulatory protein CD59 is located intracellularly in T cells and that the intracellular form is increased in the T cells of patients with cancer. When intracellular CD59 is abundant, it facilitates Ras transport to the inner plasma membrane via direct interaction; in contrast, when CD59 is insufficient or deficient, Ras is arrested in the Golgi, thus enhancing Ras/MAPK signaling and T-cell activation, proliferation, and function. mCd59ab deficiency almost completely abolished tumor growth and metastasis in tumor-bearing mice, in which CD4+ and CD8+ T cells were significantly increased compared with their proportions in wild-type littermates, and their proportions were inversely correlated with tumor growth. Using bone marrow transplantation and CD4+ and CD8+ T-cell depletion assays, we further demonstrated the critical roles of these cells in the potent antitumor activity induced by mCd59ab deficiency. Reducing CD59 expression also enhanced MAPK signaling and T-cell activation in human T cells. Therefore, the subcellular compartmentalization of Ras regulated by intracellular CD59 provides spatial selectivity for T-cell activation and a potential T cell-mediated immunotherapeutic strategy.

How to Make Primary Healthcare More Popular: Evidence from the Middle-Aged and Elderly in China.

Since 2001, China has been an aging society; it is expected to become superaged by 2033. This rapid aging trend poses a challenge to the elderly regarding their pension services and healthcare. Primary healthcare has great potential for serving older adults in the community, yet it is not popular. This study used 1977 samples from the 2018 China Health and Retirement Longitudinal Study database to explore the use of outpatient services in primary care institutions among the middle-aged and elderly. Using a structural equations model, we constructed a framework to explore pathways leading to primary outpatient use. We discovered that the supply of primary health services had a significant direct and mediating effect on the utilization of primary outpatient services, and that community pension services may indirectly discourage it. In addition, the supply of primary health services has a suppressor effect between medical insurance and primary outpatient utilization. Health insurance directly promotes primary outpatient utilization, while the supply of primary care institutions suppresses the positive influence of medical insurance on the utilization of primary outpatient services. Therefore, community pension services should pay attention to differentiated services. Moreover, adjusting the coordinated development of medical insurance and the supply of primary healthcare could enhance the positive effects of medical insurance for outpatients.

Spatial and sentiment analysis of public opinion toward COVID-19 pandemic using twitter data: At the early stage of vaccination.

During the crisis of Coronavirus pandemic, social media, like Twitter, have been the platforms on which people have been able to share their opinions and obtain information. The present study provides a detailed spatial-temporal analysis of the Twitter online discourse (approximately 280 thousand tweets) in Ohio and Michigan at the early stage of vaccination rollout (January 2021, till March 2021). This work aims to explore how people were feeling about the pandemic, the most frequent topics people were talking about, and how the topics spatially were distributed. Moreover, state government responses and important news were gathered to analyze their impacts on public opinion based on the temporal analysis of the tweets. In this project, Natural Language Processing using the LDA method was employed to identify 11 topics and 8 sub-topics in the Twitter data. The temporal analysis of topics shows the sensitivity of the online discourse to the significant state news and the local government's reactions to the pandemic. Moreover, the spatial distribution of Coronavirus-related tweets and sentiments demonstrates concentrations in the more populated urban areas with a high rate of COVID-19 cases in Ohio and Michigan. The government's economic and financial policies taken during this time, the vaccination timeline phases specified by each state, and the pandemic-related information can contribute to public opinion and sentiment trends. The findings of this study can help explore public demands, and reactions, follow the impacts of the local authorities' policies at the county level and manage their future responses to such a pandemic.