Use of statins and risks of ovarian, uterine, and cervical diseases: a cohort study in the UK Biobank.

PURPOSE: To examine the associations between use of statins and risks of various ovarian, uterine, and cervical diseases, including ovarian cancer, endometrial cancer, cervical cancer, ovarian cyst, polycystic ovarian syndrome, endometriosis, endometrial hyperplasia, endometrial polyp, and cervical polyp. METHODS: We conducted a cohort study among female participants in the UK Biobank. Information on the use of statins was collected through verbal interview. Outcome information was obtained by linking to national cancer registry data and hospital inpatient data. We used Cox proportional hazards regression to examine the associations. RESULTS: A total of 180,855 female participants (18,403 statin users and 162,452 non-users) were included. Use of statins was significantly associated with increased risks of cervical cancer (adjusted hazard ratio (HR), 1.55; 95% confidence interval (95% CI), 1.05-2.30) and polycystic ovarian syndrome (adjusted HR, 4.39; 95% CI, 1.68-11.49). However, we observed no significant association between use of statins and risk of ovarian cancer, endometrial cancer, ovarian cyst, endometriosis, endometrial hyperplasia, endometrial polyp, or cervical polyp. CONCLUSION: Our findings suggest that use of statins is associated with increased risks of cervical cancer and polycystic ovarian syndrome, but is not associated with increased or decreased risk of ovarian cancer, endometrial cancer, ovarian cyst, endometriosis, endometrial polyp, or cervical polyp.

[Effect of Short-Term Exposure to Air Pollutants on Hospital Admissions for End-Stage Renal Disease Patients Undergoing Hemodialysis]. / çŸ­æœŸç©ºæ°”æ±¡æŸ“ç‰©æš´éœ²å¯¹ç»ˆæœ«æœŸè‚¾è„ç— è¡€æ¶²é€æžæ‚£è€ å ¥é™¢æ¬¡æ•°çš„å½±å“.

Objective: To evaluate the association between short-term exposure to air pollutants of end-stage renal disease (ESRD) patients on maintenance hemodialysis and the number of daily hospital admissions. Methods: The data on hospitalizations were obtained from the database of the municipal Urban Employees' Basic Medical Insurance and Urban Residents' Basic Medical Insurance of a city in Southwest China. Single and multiple pollutant generalized additive models were utilized to estimate the effect of air pollutants (CO, NO2, O3, PM10, PM2.5, and SO2) on patient admissions after the lag time of different numbers of days. In addition, subgroup analyses stratified by sex, age, PM2.5 and PM10 concentration thresholds, seasonality, and comorbidity status for cardiovascular diseases and hypertension were conducted. Results: In the single pollutant models, the pollutants significantly associated with patient admissions and the corresponding lag time of the strongest association were as follows, every time CO increased by 0.1 mg/m3, there was a 2.39% increase (95% confidence interval [CI]: 0.96%-3.83%) in patient admissions after 7 days of lag time; every time NO2, O3, PM2.5, PM10, and SO2 increased by 10 µg/m3, patient admissions increased by 4.02% (95% CI: 1.21%-6.91%) after 7 days of lag time, 3.57% (95% CI: 0.78%-6.44%) after 0-4 days of lag time, 2.00% (95% CI: 1.07%-2.93%) after 6 days of lag time, 1.19% (95% CI: 0.51%-1.88%) after 7 days of lag time, and 8.37% (95% CI: 3.08%-13.93%) after 7 days of lag time, respectively. In the multiple pollutant model, every time O3 and PM2.5 increased by 10 µg/m3, there was an increase of 3.18% (95% CI: 0.34%-6.09%) in daily patient admissions after 0-4 days of lag time and an increase of 1.85% (95% CI: 0.44%-3.28%) after 7 days of lag time. Furthermore, subgroup analyses showed that seasonality, the severity of air pollution, and patients' comorbidities might be the effect modifiers for the association between ambient air pollution and hospital admissions in ESRD patients receiving maintenance hemodialysis. Conclusion: Air pollution is closely associated with hospital admissions in ESRD patients undergoing maintenance hemodialysis and the strength of this association varies according to seasonality, the severity of air pollution, and patients' status of comorbidities.

The role of genetic predisposition in cardiovascular risk after cancer diagnosis: a matched cohort study of the UK Biobank.

BACKGROUND: Evidence is scarce regarding the potential modifying role of disease susceptibility on the association between a prior cancer diagnosis and cardiovascular disease (CVD). METHODS: We conducted a matched cohort study of UK Biobank including 78,860 individuals with a cancer diagnosis between January 1997 and January 2020, and 394,300 birth year and sex individually matched unexposed individuals. We used Cox model to assess the subsequent relative risk of CVD, which was further stratified by individual genetic predisposition. RESULTS: During nearly 23 years of follow-up, an elevated risk of CVD was constantly observed among cancer patients, compared to their matched unexposed individuals. Such excess risk was most pronounced (hazard ratio [HR] = 5.28, 95% confidence interval [CI] 4.90-5.69) within 3 months after a cancer diagnosis, which then decreased rapidly and stabilised for >6 months (HR = 1.22, 95% CI 1.19-1.24). For all the studied time periods, stratification analyses by both levels of polygenic risk score for CVD and by family history of CVD revealed higher estimates among individuals with lower genetic risk predisposition. CONCLUSIONS: Our findings suggest that patients with a recent cancer diagnosis were at an increased risk of multiple types of CVD and the excess CVD risk was higher among individuals with lower genetic susceptibility to CVD, highlighting a general need for enhanced psychological assistance and clinical surveillance of CVD among newly diagnosed cancer patients.

The influence of childhood asthma on adult height: evidence from the UK Biobank.

BACKGROUND: To elucidate the influence of childhood asthma on adult height after consideration of genetic heterogeneity in height. METHODS: Based on the UK Biobank, we conducted a matched cohort study, including 13,602 European individuals with asthma diagnosed before 18 years old and 136,008 matched unexposed individuals without such an experience. Ascertainment of asthma was based on self-reported data (97.6%) or clinical diagnosis in healthcare registers (2.4%). We studied three height outcomes, including (1) the attained adult height (in centimeters), (2) the height deviation measured as the difference between a person's rank of genetically determined height (based on generated polygenetic risk score) and their rank of attained adult height in the study population (deviation in % of height order after standardization), and (3) the presence of height deficit comparing genetically determined and attained height (yes or no). We applied linear mixed-effect models to assess the associations of asthma diagnosed at different ages with attained adult height and height deviation, and conditional logistic regression models to estimate the associations of asthma with the risk of height deficit. RESULTS: 40.07% (59,944/149,610) of the study participants were born before 1950, and most of them were men (57.65%). After controlling for multiple covariates, childhood asthma was associated with shorter attained adult height, irrespective of age at asthma diagnosis. However, in the analysis of height deviation (deviation in %), we observed the greatest height deviation among individuals with asthma diagnosed before 4 years of age (- 2.57 [95% CI - 4.14 to - 1.00] and - 2.80 [95% CI - 4.06 to - 1.54] for the age of ≤ 2 and 3-4 years, respectively). The magnitude of height deviation in relation to asthma declined thereafter and became null after age 6. Similarly, there was a statistically significant height deficit in relation to an asthma diagnosis at ages ≤ 2 and 3-4 (odds ratios = 1.21, 95% CI 1.04 to 1.40, and 1.15, 95% CI 1.02 to 1.29) but not thereafter. The result pattern was similar when separately analyzing asthma with or without inhaled glucocorticoid (ICS) use, despite that the estimates were consistently stronger among asthma individuals who used ICS. CONCLUSIONS: Our results suggest a notable association of childhood asthma, primarily asthma diagnosed at an early age, with adult height, after consideration of genetic heterogeneity in height and use of ICS. This finding highlights the need for surveillance on the growth problems among children with asthma.

Genetic predispositions to psychiatric disorders and the risk of COVID-19.

BACKGROUND: Whether a genetic predisposition to psychiatric disorders is associated with coronavirus disease 2019 (COVID-19) is unknown. METHODS: Our analytic sample consisted of 287,123 white British participants in UK Biobank who were alive on 31 January 2020. We performed a genome-wide association study (GWAS) analysis for each psychiatric disorder (substance misuse, depression, anxiety, psychotic disorder, and stress-related disorders) in a randomly selected half of the study population ("base dataset"). For the other half ("target dataset"), the polygenic risk score (PRS) was calculated as a proxy of individuals' genetic predisposition to a given psychiatric phenotype using discovered genetic variants from the base dataset. Ascertainment of COVID-19 was based on the Public Health England dataset, inpatient hospital data, or death registers in UK Biobank. COVID-19 cases from hospitalization records or death records were considered "severe cases." The association between the PRS for psychiatric disorders and COVID-19 risk was examined using logistic regression. We also repeated PRS analyses based on publicly available GWAS summary statistics. RESULTS: A total of 143,562 participants (including 10,868 COVID-19 cases) were used for PRS analyses. A higher genetic predisposition to psychiatric disorders was associated with an increased risk of any COVID-19 and severe COVID-19. The adjusted odds ratio (OR) for any COVID-19 was 1.07 (95% confidence interval [CI] 1.02-1.13) and 1.06 (95% CI 1.01-1.11) among individuals with a high genetic risk (above the upper tertile of the PRS) for substance misuse and depression, respectively, compared with individuals with a low genetic risk (below the lower tertile). Slightly higher ORs were noted for severe COVID-19, and similar result patterns were obtained in analyses based on publicly available GWAS summary statistics. CONCLUSIONS: Our findings suggest a potential role of genetic factors in the observed phenotypic association between psychiatric disorders and COVID-19. Our data underscore the need for increased medical surveillance for this vulnerable population during the COVID-19 pandemic.

Disease trajectories and mortality among individuals diagnosed with depression: a community-based cohort study in UK Biobank.

Patients with depression are at increased risk for a range of comorbid diseases, with, however, unclear explanations. In this large community-based cohort study of the UK Biobank, 24,130 patients diagnosed with depression were compared to 120,366 matched individuals without such a diagnosis. Follow-up was conducted from 6 months after the index date until death or the end of 2019, for the occurrence of 470 medical conditions and 16 specific causes of death. The median age at the time of the depression diagnosis was 62.0 years, and most of the patients were female (63.63%). During a median follow-up of 4.94 years, 129 medical conditions were found to be significantly associated with a prior diagnosis of depression, based on adjusted Cox regression models. Using disease trajectory network analysis to visualize the magnitude of disease-disease associations and the temporal order of the associated medical conditions, we identified three main affected disease clusters after depression (i.e., cardiometabolic diseases, chronic inflammatory diseases, and diseases related to tobacco abuse), which were further linked to a wider range of other conditions. In addition, we also identified three depression-mortality trajectories leading to death due to cardiovascular disease, respiratory system disease and malignant neoplasm. In conclusion, an inpatient diagnosis of depression in later life is associated with three distinct network-based clusters of medical conditions, indicating alterations in the cardiometabolic system, chronic status of inflammation, and tobacco abuse as key pathways to a wide range of other conditions downstream. If replicated, these pathways may constitute promising targets for the health promotion among depression patients.

COVID-19 related outcomes among individuals with neurodegenerative diseases: a cohort analysis in the UK biobank.

BACKGROUND: An increased susceptibility to COVID-19 has been suggested for individuals with neurodegenerative diseases, but data are scarce from longitudinal studies. METHODS: In this community-based cohort study, we included 96,275 participants of the UK Biobank who had available SARS-CoV-2 test results in Public Health England. Of these, 2617 had a clinical diagnosis of neurodegenerative diseases in the UK Biobank inpatient hospital data before the outbreak of COVID-19 (defined as January 31st, 2020), while the remaining participants constituted the reference group. We then followed both groups from January 31st, 2020 to June 14th, 2021 for ascertainment of COVID-19 outcomes, including any COVID-19, inpatient care for COVID-19, and COVID-19 related death. Logistic regression was applied to estimate the association between neurogenerative disease and risks of COVID-19 outcomes, adjusted for multiple confounders and somatic comorbidities. RESULTS: We observed an elevated risk of COVID-19 outcomes among individuals with a neurodegenerative disease compared with the reference group, corresponding to a fully adjusted odds ratio of 2.47 (95%CI 2.25-2.71) for any COVID-19, 2.18 (95%CI 1.94-2.45) for inpatient COVID-19, and 3.67 (95%CI 3.11-4.34) for COVID-19 related death. Among individuals with a positive test result for SARS-CoV-2, individuals with neurodegenerative diseases had also a higher risk of COVID-19 related death than others (fully adjusted odds ratio 2.08; 95%CI 1.71-2.53). CONCLUSION: Among UK Biobank participants who received at least one test for SARS-CoV-2, a pre-existing diagnosis of neurodegenerative disease was associated with a subsequently increased risk of COVID-19, especially COVID-19 related death.

The validity and reliability of the PHQ-9 on screening of depression in neurology: a cross sectional study.

BACKGROUND: This study aimed to explore the validity and reliability of the Patient Health Questionnaire-9 (PHQ-9) on screening of depression among patients with neurological disorders, and to explore factors influencing such patients. METHODS: In this study, 277 subjects who were admitted to the department of neurology of our hospital due to different neurological disorders completed the PHQ-9 questionnaire. The Mini-International Neuropsychiatric Interview (MINI) and Hamilton Rating Scale for Depression (HAMD) were employed to evaluate the depressive symptoms of patients who completed the PHQ-9 questionnaire. The internal consistency, criterion validity, structural validity, and optimal cut-off values of PHQ-9 were evaluated, and the consistency assessment was conducted between the depression severity as assessed by PHQ-9, HAMD and MINI. Logistic regression analysis was used to calculate the risk factors of depression. RESULTS: The Cronbach's α coefficient of the PHQ-9 was 0.839. The Pearson's correlation coefficient among the 9 items of the PHQ-9 scale was 0.160 ~ 0.578 (P < 0.01), and the Pearson's correlation coefficient between each item and the total score was at the range of 0.608 ~ 0.773. Taking the results of MINI as the gold standard, the area under the receiver operating characteristic (ROC) curve of the PHQ-9 results for all the subjects (n = 277) was 0.898 (95% confidence interval (CI): 0.859 ~ 0.937, P < 0.01). When the cut-off score was equal to 5, the values of sensitivity, specificity, and the Youden's index were 91.2, 76.6%, and 0.678, respectively. Multivariate logistic regression analysis showed that the influence of unemployment on the occurrence of depression was statistically significant (P = 0.027, OR = 3.080, 95%CI: 1.133 ~ 8.374). CONCLUSIONS: The application of PHQ-9 for screening of depression among Chinese patients with neurological disorders showed a good reliability and validity.

Regulating Crystal Packing by Terminal tert-Butylation for Enhanced Solid-State Emission and Efficacious Charge Transport in an Anthracene-Based Molecular Crystal.

Organic semiconductors with combinative high carrier mobility and efficient solid-state emission are full of challenges but urgently pursued for developing new emerging optoelectronics. Herein, by delicately regulating the crystal packing of an anthracene-based molecular crystal via terminal tert-butylation, we developed a superior high mobility emissive molecule, 2,6-di(6-tert-butylnaphthyl)anthracene (TBU-DNA). The unique "slipped herringbone" packing motif of TBU-DNA enables its appropriate exciton-exciton coupling and electron-phonon coupling, thus resulting in remarkably high solid-state emission (photoluminescence quantum yield, ΦF ≈74.9 %) and efficacious charge transport (carrier mobility, µ=5.0 cm2 V-1 s-1 ). Furthermore, OLETs based on TBU-DNA show an external quantum efficiency (EQE) of 1.8 %, which is among the highest EQE values for single component OLETs reported till now. This work presents a crystal engineering strategy via exquisite molecular design to realize high mobility emissive organic semiconductors.

COVID-19 and risk of subsequent life-threatening secondary infections: a matched cohort study in UK Biobank.

BACKGROUND: With the increasing number of people infected with and recovered from coronavirus disease 2019 (COVID-19), the extent of major health consequences of COVID-19 is unclear, including risks of severe secondary infections. METHODS: Based on 445,845 UK Biobank participants registered in England, we conducted a matched cohort study where 5151 individuals with a positive test result or hospitalized with a diagnosis of COVID-19 were included in the exposed group. We then randomly selected up to 10 matched individuals without COVID-19 diagnosis for each exposed individual (n = 51,402). The life-threatening secondary infections were defined as diagnoses of severe secondary infections with high mortality rates (i.e., sepsis, endocarditis, and central nervous system infections) from the UK Biobank inpatient hospital data, or deaths from these infections from mortality data. The follow-up period was limited to 3 months after the initial COVID-19 diagnosis. Using a similar study design, we additionally constructed a matched cohort where exposed individuals were diagnosed with seasonal influenza from either inpatient hospital or primary care data between 2010 and 2019 (6169 exposed and 61,555 unexposed individuals). After controlling for multiple confounders, Cox models were used to estimate hazard ratios (HRs) of life-threatening secondary infections after COVID-19 or seasonal influenza. RESULTS: In the matched cohort for COVID-19, 50.22% of participants were male, and the median age at the index date was 66 years. During a median follow-up of 12.71 weeks, the incidence rate of life-threatening secondary infections was 2.23 (123/55.15) and 0.25 (151/600.55) per 1000 person-weeks for all patients with COVID-19 and their matched individuals, respectively, which corresponded to a fully adjusted HR of 8.19 (95% confidence interval [CI] 6.33-10.59). The corresponding HR of life-threatening secondary infections among all patients with seasonal influenza diagnosis was 4.50, 95% CI 3.34-6.08 (p for difference < 0.01). Also, elevated HRs were observed among hospitalized individuals for life-threatening secondary infections following hospital discharge, both in the COVID-19 (HR = 6.28 [95% CI 4.05-9.75]) and seasonal influenza (6.01 [95% CI 3.53-10.26], p for difference = 0.902) cohorts. CONCLUSION: COVID-19 patients have increased subsequent risks of life-threatening secondary infections, to an equal extent or beyond risk elevations observed for patients with seasonal influenza.

Exciton Transport in Molecular Semiconductor Crystals for Spin-Optoelectronics Paradigm.

Organic semiconductors with long-range exciton diffusion length are highly desirable for optoelectronics but currently remain rare. Here, the estimated diffusion length of singlet excitons (LD ) in 2,6-diphenyl anthracene (DPA) crystals grown by solvent evaporation was shown to be up to approximately 124 nm. These crystals showed a previously unseen parallelogram morphology with layer-by-layer edge-on molecular stacking, isotropic optical waveguiding, radiation rate and non-radiation rate constants of 0.15 and 0.26 ns-1 respectively, as well as good field-effect transistor hole mobility and theoretically computed strong electronic couplings as high as 109 meV. Photoresponse experiments revealed that the photoconductivity of DPA crystals is surprisingly not related to the radiative pathway but associated with rapid exciton diffusion to the crystal surface for charge separation and carrier bimolecular recombination. Taken together, DPA was shown to be a promising semiconducting material for a new organic optoelectronics paradigm.

Synthesis of nature product kinsenoside analogues with anti-inflammatory activity.

Kinsenoside is the major bioactive component from herbal medicine with a broad range of pharmacological functions. Goodyeroside A, an epimer of kinsenoside, remains less explored. In this report we chemically synthesized kinsenoside, goodyeroside A and their analogues with glycan variation, chirality inversion at chiral center(s), and bioisosteric replacement of lactone with lactam. Among these compounds, goodyeroside A and its mannosyl counterpart demonstrated superior anti-inflammatory efficacy. Furthermore, goodyeroside A was found to suppresses inflammatory through inhibiting NF-κB signal pathway, effectively. Structure-activity relationship is also explored for further development of more promising kinsenoside analogues as drug candidates.

Computational Study on the Charge Transport and Optical Spectra of Anthracene Derivatives in Aggregates.

A recent experiment [Angew. Chem. Int. Ed. 2017, 56, 722-727] found that a (1 : 9) blend film of two anthracene derivatives, 2-fluorenyl-2-anthracene (FlAnt) and 2-anthryl-2-anthracence (2 A), exhibit both efficient white light emission and high hole mobility, thus promising for organic light-emitting transistors (OLETs). Employing quantum chemistry at the polarizable continuum model (PCM) and the quantum mechanics/molecular mechanics (QM/MM) levels, we investigated the excited-state structures, optical spectra, band structure and the carrier mobility for FlAnt and 2 A from solution to aggregate phases. We suggest using the ratio of intermolecular excitonic coupling J and intramolecular excited state relaxation energy E to judge the bathochromic shift in optical emission in aggregates. For FlAnt, ρ=J/E is calculated to be less than 0.17, a critical value we identified earlier, and the spectra in solution and aggregate phases present quite similar features (blue emission). However, ρ is ∼0.5 for 2 A systems, and the calculated emission in the aggregate phase exhibits a remarkable bathochromic shift. In addition, the 0-0 emission is strongly suppressed in the herringbone stacking. These observations justify the experimental findings that (i) 2 A is blue emissive in solution but yellow-green in the aggregate phase, whereas FlAnt is always blue, and (ii) the blend of them show white emission. By using the "quantum nuclear tunneling" model we proposed earlier, we found the hole mobility for FlAnt and 2 A are 0.5 and 4.2 cm2 V-1 s-1 , respectively, indicating both are good hole transport materials.

Dihydroartemisinin Prevents Distant Metastasis of Laryngeal Carcinoma by Inactivating STAT3 in Cancer Stem Cells.

BACKGROUND Accumulating evidence indicates that cancer stem cells (CSCs) are a minor subpopulation of cancer cells that may be the primary source of cancer invasion, migration, and widespread metastasis. MATERIAL AND METHODS We investigated the effects of dihydroartemisinin (DHA) on distant metastasis of laryngeal carcinoma and the relevant mechanism. In vitro, we used the Hep-2 human laryngeal squamous carcinoma cell line (Hep-2 cells) to assemble CSCs, using CD133 as the cell surface marker. Our data demonstrate that the CD133⁺ subpopulation of Hep-2 cells has greater invasion and migration capabilities than CD133⁻ cells. We also evaluated the effects of DHA, a newly defined STAT3 inhibitor, on the invasion and migration of CD133⁺ Hep-2 cells under hypoxia and IL-6 stimulation, both of which can activate STAT3 phosphorylation. RESULTS CSCs exhibited a significant decrease in the ability of migration and invasion upon the application of DHA, along with simultaneous alterations in related proteins, both in cultured cells and in xenograft tumors. The associated signaling proteins included phosphorylated STAT3 (p-STAT3), matrix metalloproteinase-9 (MMP-9), and E-cadherin, which are closely involved in cancer invasion and metastasis. In vivo, we found that DHA can reduce lung metastasis formation caused by CSCs and prolong survival in mice, and can inhibit STAT3 activation, downregulate MMP-9, and upregulate E-cadherin in lung metastatic tumors. CONCLUSIONS Taken together, our findings indicate that CSCs possess stronger invasive and metastatic capabilities than non-CSCs, and DHA inhibits invasion and prevents metastasis induced by CSCs by inhibiting STAT3 activation.

Bronchiolar adenoma with diffuse pulmonary nodules: a extremely rare case report and review of literature.

BACKGROUND: Bronchiolar adenoma(BA) is a recently recognized, rare tumor of the bronchioles. It can be divided into proximal and distal types according to the proportion of mucinous and ciliated cells on the luminal surface. BA is often misdiagnosed because it has similar ultrasonographic, gross and histological presentations as other diseases. Here, we report a rare case of BA characterized by many fused nodules. CASE PRESENTATION: A 68-year-old woman attended the Tianjin Taida Hospital surgical Clinic mainly because of "intermittent cough for >1 month". Chest computed tomography (CT) showed multiple solid nodules in the upper and lower left lung. The nodules had irregular outlines, with a maximum diameter of 65 mm. A double needle lung biopsy specimen was removed guided by ultrasound under local anesthesia. Histologically, the biopsy specimen was finally diagnosed as the distal type of BA. CONCLUSION: BA with diffuse pulmonary nodules is rare. Diagnosis of BA needs comprehensive analysis of imaging, gross specimen analysis, histopathology, and immunohistochemical staining to make a correct diagnosis and avoid misdiagnosis. There are few studies on prognosis, which needs close follow-up and more data accumulation.

Lattice thermal conductivity of monolayer AsP from first-principles molecular dynamics.

Few-layered arsenic-phosphorus alloys, AsxP(1-x), with a puckered structure have been recently synthesized and demonstrated with fully tunable band gaps and optical properties. It is predicted that the carrier mobility of monolayer AsP compounds is even higher than that of black phosphorene (b-P). The anisotropic and orthogonal electrical and thermal transport properties of the puckered group VA elements make them intriguing materials for thermoelectric applications. Herein, we investigated the thermal transport properties of AsP based on first-principles molecular dynamics and the Boltzmann transport equation. We reveal that monolayer AsP with three different chemical structures possesses thermal conductivities lower than b-P, but with increased anisotropy. Further, these structures behave profoundly different on heat conduction. This can be attributed to the distinct low-frequency optical modes associated with their bonding nature. Our results highlight the impact of atomic arrangement on the thermal conductivity of AsP, and the structure-property relationship established may guide the fabrication of thermoelectric materials via the engineered alloying method.

Electrical stimulation characteristics of denervated orbicularis oculi muscle.

This research is to study the electrical stimulation characteristics of orbicularis oculi muscle and the characteristics of the mechanical contraction. We observed the stimulus current diffusion regularity and its relationship with mechanical contraction in the orbicularis oculi muscle using an electrode gathering line. Under different stimulus intensities of 2 or 4 mA, the closer the recording electrodes were to the stimulating electrode, the larger was the amplitude. When the recording electrode and stimulating electrode distance increased, the amplitude declined linearly with decreasing function. In addition, current conduction across the muscle fiber was studied. Under different stimulus intensities of 2 or 4 mA, it was found that the closer the recording electrodes were to the stimulating electrode, the larger was the amplitude. When the recording electrode and stimulating electrode distance increased, the amplitude declined linearly with decreasing function. The transverse current reached a maximum 4 mA range, and increasing the current intensity did not increase the propagation range. Under different stimulation intensities, the larger the stimulus intensity, the greater is the potential change and the faster is the attenuation. Longitudinal current, even in the range of 6 mm, can still record electrical activity. While a transverse current diffuser has a maximum range of 4 mm, increasing the current intensity does not increase the propagation range.

Quantitative image analysis of intracellular protein translocation in 3-dimensional tissues for pharmacodynamic studies of immunogenic cell death.

A recent development in cancer chemotherapy is to use cytotoxics to induce tumor-specific immune response through immunogenic cell death (ICD). In ICD, calreticulin is translocated from endoplasmic reticulum to cell membrane (ecto-CRT) which serves as the 'eat-me-signal' to antigen-presenting cells. Ecto-CRT measurements, e.g., by ecto-CRT immunostaining plus flow cytometry, can be used to study the pharmacodynamics of ICD in single cells, whereas ICD studies in intact 3-dimensional tissues such as human tumors require different approaches. The present study described a method that used (a) immunostaining with fluorescent antibodies followed by confocal microscopy to obtain the spatial locations of two molecules-of-interest (CRT and a marker protein WGA), and (b) machine-learning (trainable WEKA segmentation) and additional image processing tools to locate the target molecules, remove the interfering signals in the nucleus, cytosol and extracellular space, enable the distinction of the inner and outer edges of the cell membrane and thereby identify the cells with ecto-CRT. This method, when applied to 3-dimensional human bladder cancer cell spheroids, yielded drug-induced ecto-CRT measurements that were qualitatively comparable to the flow cytometry results obtained with single cells disaggregated from spheroids. This new method was applied to study drug-induced ICD in short-term cultures of surgical specimens of human patient bladder tumors.

Pharmacokinetics of Fipaxalparant, a Small-Molecule Selective Negative Allosteric Modulator of Lysophosphatidic Acid Receptor 1, and the Effect of Food in Healthy Volunteers.

Dysregulated lysophosphatidic acid receptor 1 (LPAR1) signaling is implicated in fibrotic diseases, including systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF). Fipaxalparant (HZN-825) is a small molecule acting as a negative allosteric modulator of LPAR1 and is in phase 2 clinical evaluations for treating diffuse cutaneous SSc and IPF. This open-label, phase 1 study examined the pharmacokinetics (PKs), food effect, and safety of fipaxalparant in healthy volunteers. Dose proportionality was evaluated for fipaxalparant single doses of 150, 300, and 450 mg under fasted conditions. Food effect was tested with a 450-mg single dose under fasted conditions or with a high-fat meal. Multiple-dose PKs for twice-daily dosing of either 300 or 450 mg with low- or high-fat meals was also assessed. Fipaxalparant was safe and well tolerated in healthy volunteers (n = 36) under all conditions. Fipaxalparant exposure increased in a less than dose-proportional manner from 150 to 450 mg. At 450 mg, a high-fat meal increased the maximum observed concentration and area under the curve by approximately 1.9- and 2.1-fold, respectively. These results, combined with prior preclinical and phase 2a data, informed dose selection of fipaxalparant 300 mg once and twice daily with a meal for phase 2b studies.

Effective glioblastoma immune sonodynamic treatment mediated by macrophage cell membrane cloaked biomimetic nanomedicines.

Glioblastoma (GBM) as one of the most lethal brain tumours, remains poor therapeutic index due to its typical characters including heterogeneous, severe immune suppression as well as the existence of blood brain barrier (BBB). Immune sonodynamic (ISD) therapy combines noninvasive sonodynamic therapy with immunotherapy, which has great prospects for the combinational treatment of GBM. Herein, we develop macrophage cell membrane cloaked reactive oxygen species (ROS) responsive biomimetic nanoparticles, co-delivering of sonosensitizer Ce6 and JQ1 (a bromo-domain protein 4 (BRD4) inhibitor which can down-regulate PD-L1) and realizing potent GBM ISD therapy. The ApoE peptide decorated macrophage membrane coating endows these biomimetic nanoparticles with low immunogenicity, efficient BBB permeability, prolonged blood circulation half-live and good biocompatibility. The ROS responsive polymeric inner core could be readily degraded as triggered by excessive ROS under the ultrasound once they accumulated in tumour cells, fast release encapsulated drugs. The generation of ROS not only killed tumour cells via sonodynamic therapy, but also induced immunogenic cell death (ICD) and further activated the anti-tumour immune response. The released JQ1 inhibited tumour cell proliferation and augmented the immune activities by inhibiting the PD-L1 expression on the surface of tumour cells. The cascade sonodynamic and immune therapy resulted in significantly improved median survival time in both orthotopic GL261 and PTEN deficient immunosuppressive CT2A GBM mice models. Therefore, our developed biomimetic nanoparticle platform provides a promising combinational therapy strategy to treat immune suppressive GBM.