The Effect of Chemical Environment and Temperature on the Domain Structure of Free-Standing BaTiO3 via In Situ STEM.

Ferroelectrics, due to their polar nature and reversible switching, can be used to dynamically control surface chemistry for catalysis, chemical switching, and other applications such as water splitting. However, this is a complex phenomenon where ferroelectric domain orientation and switching are intimately linked to surface charges. In this work, the temperature-induced domain behavior of ferroelectric-ferroelastic domains in free-standing BaTiO3 films under different gas environments, including vacuum and oxygen-rich, is studied by in situ scanning transmission electron microscopy (STEM). An automated pathway to statistically disentangle and detect domain structure transformations using deep autoencoders, providing a pathway towards real-time analysis is also established. These results show a clear difference in the temperature at which phase transition occurs and the domain behavior between various environments, with a peculiar domain reconfiguration at low temperatures, from a-c to a-a at ≈60 °C. The vacuum environment exhibits a rich domain structure, while under the oxidizing environment, the domain structure is largely suppressed. The direct visualization provided by in situ gas and heating STEM allows to investigate the influence of external variables such as gas, pressure, and temperature, on oxide surfaces in a dynamic manner, providing invaluable insights into the intricate surface-screening mechanisms in ferroelectrics.

Ecological impacts of unsustainable sand mining: urgent lessons learned from a critically endangered freshwater cetacean.

Sand mining, which has tripled in the last two decades, is an emerging concern for global biodiversity. However, the paucity of sand mining data worldwide prevents understanding the extent of sand mining impacts and how it affects wildlife populations and ecosystems, which is critical for timely mitigation and conservation actions. Integrating remote sensing and field surveys over 14 years, we investigated mining impacts on the critically endangered Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis) in Dongting Lake, China. We found that sand mining presented a consistent, widespread disturbance in Dongting Lake. Porpoises strongly avoided mining sites, especially those of higher mining intensity. The extensive sand mining significantly contracted the porpoise's range and restricted their habitat use in the lake. Water traffic for sand transportation further blocked the species's river-lake movements, affecting the population connectivity. In addition, mining-induced loss of near-shore habitats, a critical foraging and nursery ground for the porpoise, occurred in nearly 70% of the water channels of our study region. Our findings provide the first empirical evidence of the impacts of unregulated sand extractions on species distribution. Our spatio-temporally explicit approach and findings support regulation and conservation, yielding broader implications for sustainable sand mining worldwide.

The sociodemographic characteristics and clinical features of the late-life depression patients: results from the Beijing Anding Hospital mental health big data platform.

BACKGROUND: The sociodemographic characteristics and clinical features of the Late-life depression (LLD) patients in psychiatric hospitals have not been thoroughly studied in China. This study aimed to explore the psychiatric outpatient attendance of LLD patients at a psychiatric hospital in China, with a subgroup analysis, such as with or without anxiety, gender differences. METHODS: This retrospective study examined outpatients with LLD from January 2013 to August 2019 using data in the Observational Medical Outcomes Partnership Common Data Model (OMOP-CDM) in Beijing Anding Hospital. Age, sex, number of visits, use of drugs and comorbid conditions were extracted from medical records. RESULTS: In a sample of 47,334 unipolar depression patients, 31,854 (67.30%) were women, and 15,480 (32.70%) were men. The main comorbidities of LDD are generalized anxiety disorder (GAD) (83.62%) and insomnia (74.52%).Among patients with unipolar depression, of which benzodiazepines accounted for the largest proportion (77.77%), Selective serotonin reuptake inhibitors (SSRIs) accounted for 59.00%, a noradrenergic and specific serotonergic antidepressant (NaSSAs) accounted for 36.20%. The average cost of each visit was approximately 646.27 yuan, and the cost of each visit was primarily attributed to Western medicine (22.97%) and Chinese herbal medicine (19.38%). For the cost of outpatient visits, depression comorbid anxiety group had a higher average cost than the non-anxiety group (p < 0.05). There are gender differences in outpatient costs, men spend more than women, for western medicine, men spend more than women, for Chinese herbal medicine, women spend more than men (all p < 0.05). The utilization rate of SSRIs and benzodiazepines in female patients is significantly higher than that in male patients (p < 0.05). CONCLUSION: LLD patients are more commonly women than men and more commonly used SSRIs and NaSSAs. Elderly patients with depression often have comorbid generalized anxiety. LLD patients spend most of their visits on medicines, and while the examination costs are lower.

Characteristics of PM2.5 emissions from six types of commercial cooking in Chinese cities and their health effects.

Commercial kitchens may pose significant health risks to workers because they generate large quantities of fine particulate matter (PM2.5). In our study, the concentrations and emission rates of PM2.5 in cooking environments were measured for six types of commercial kitchens that used electricity and natural gas (including traditional Chinese kitchens, western kitchens, teppanyaki kitchens, fried chicken kitchens, barbecue kitchens, and hotpot cooking area). Furthermore, a preliminary health risk assessment of the chefs was undertaken using the annual PM2.5 inhalation and PM2.5 deposition rates into the upper airways and tracheobronchial and alveolar regions of the human body. Results showed that cooking in the teppanyaki kitchen generated the highest amount of PM2.5, with a mean emission rate of 7.7 mg/min and a mean mass concentration of 850.4 ± 533.4 µg/m³ in the breathing zone. Therefore, teppanyaki kitchens pose highest PM2.5 exposure risks to chefs, with the highest rate of PM2.5 deposition in the upper airways (6.38 × 105 µg/year), followed by Chinese kitchens. The PM2.5 concentrations and emission rates of each kitchen varied greatly with the dishes cooked. The mean PM2.5 concentration was the highest during Chinese stir-frying, with the peak concentration reaching more than 20,000 µg/m3, followed by pan-frying, deep-frying, stewing, and boiling. A rise in PM2.5 concentration was also observed during the start of stir-frying and in the middle to late stages of pan-frying and grilling meat. The results obtained in our study may contribute in understanding the characteristics of PM2.5 emissions from various types of commercial kitchens and their health effects.

MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers.

Methylthioadenosine phosphorylase, an essential enzyme for the adenine salvage pathway, is often deficient (MTAPdef) in tumors with 9p21 loss and hypothetically renders tumors susceptible to synthetic lethality by antifolates targeting de novo purine synthesis. Here we report our single arm phase II trial (NCT02693717) that assesses pemetrexed in MTAPdef urothelial carcinoma (UC) with the primary endpoint of overall response rate (ORR). Three of 7 enrolled MTAPdef patients show response to pemetrexed (ORR 43%). Furthermore, a historic cohort shows 4 of 4 MTAPdef patients respond to pemetrexed as compared to 1 of 10 MTAP-proficient patients. In vitro and in vivo preclinical data using UC cell lines demonstrate increased sensitivity to pemetrexed by inducing DNA damage, and distorting nucleotide pools. In addition, MTAP-knockdown increases sensitivity to pemetrexed. Furthermore, in a lung adenocarcinoma retrospective cohort (N = 72) from the published BATTLE2 clinical trial (NCT01248247), MTAPdef associates with an improved response rate to pemetrexed. Our data demonstrate a synthetic lethal interaction between MTAPdef and de novo purine inhibition, which represents a promising therapeutic strategy for larger prospective trials.

Use of the 33-Item Hypomania Checklist (HCL-33) to Distinguish Bipolar Disorder From Major Depressive Disorder in Older Adults.

BACKGROUND: Bipolar disorder (BD) is often misdiagnosed as major depressive disorder (MDD) in older patients. This study examined the psychometric properties of the 33-item Hypomania Checklist (HCL-33) and its accuracy to differentiate BD from MDD among older adults. METHOD: A total of 215 depressed older patients were recruited; 107 were diagnosed with BD (71 with BD-type I and 36 with BD-type II) and 108 with MDD. Principal components analysis (PCA) was used to explore the factor structure of the HCL-33. Cronbach's alpha was calculated to test the internal consistency. Intra-class correlation coefficient (ICC) was used to measure test-retest reliability. The receiver operating characteristic (ROC) analysis was used to generate the optimal cut-off value to differentiate between BD and MDD. RESULTS: Two factors were identified in the PCA analysis accounting for 33.9% of the total variance. The Cronbach's alpha value for the HCL-33 was 0.912, with 0.922 for factor I and 0.664 for factor II. The test-retest reliability was excellent (ICC: 0.891). The optimal cut-off of the HCL-33 total score for discriminating between MDD and BD was 14, with a sensitivity of 88.8% and specificity of 82.4%. CONCLUSION: The HCL-33 had satisfactory reliability and validity and could be used to distinguish BD from MDD in older adults.

Comparing the Self- and External Assessment Versions of the HCL-33 as Screening Instruments for Bipolar Disorder in Older Depressed Patients.

Objectives: The misdiagnosis of bipolar disorder (BD) as major depressive disorder (MDD) is common in depressed older adults. The self-rated HCL-33 and its external assessment version (HCL-33-EA) have been developed to screen for hypomanic symptoms. This study compared the screening ability of these two instruments to discriminate BD from MDD. Methods: A total of 215 patients (107 with BD and 108 with MDD) and their carers were recruited. Patients and their carers completed the HCL-33 and HCL-33-EA, respectively. The consistency of the total score and the positive response to each item between the two scales was calculated with the intraclass correlation coefficient (ICC) and Cohen's kappa coefficient separately. Receiver operating characteristics (ROC) curves were drawn for both instruments. The optimal cut-off points were determined according to the maximum Youden's Index. The areas under the ROC curve (AUC) of the HCL-33 and HCL-33-EA were calculated separately and compared. The sensitivity and specificity at the optimal cut-off values were also calculated separately for the HCL-33 and HCL-33-EA. Results: The intraclass correlation coefficient (ICC) between the total scores of the HCL-33 and HCL-33-EA was 0.823 (95% CI = 0.774-0.862). The positive response rate on all items showed high agreement between the two instruments. ROC curve analysis demonstrated that the total scores of both HCL-33 and HCL-33-EA differentiated well between MDD and BD, while there was no significant difference in the AUCs between the two scales (Z = 0.422, P = 0.673). The optimal cutoff values for the HCL-33 and HCL-33-EA were 14 and 12, respectively. With the optimal cutoff value, the sensitivities of the HCL-33 and HCL-33-EA were 88.8% and 93.5%, and their specificities were 82.4% and 79.6%. Conclusion: Both the HCL-33 and HCL-33-EA had good screening ability for discriminating BD from MDD in depressed older adults.

A Phase l Study of a Tumor-targeted Systemic Nanodelivery System, SGT-94, in Genitourinary Cancers.

Gene therapy development has been limited by our inability to target multifocal cancer with systemic delivery. We developed a systemically administered, tumor-targeted liposomal nanodelivery complex (SGT-94) carrying a plasmid encoding RB94, a truncated form of the RB gene. In preclinical studies, RB94 showed marked cytotoxicity against tumor but not normal cells. SGT-94 was administered intravenously in a first-in-man study in metastatic genitourinary cancer. Minimal side effects were observed; dose-limiting toxicity (DLT) has not been reached in 11 evaluable patients. There was evidence of clinical activity at the 2.4 mg dose with one complete remission (CR) and one partial remission (PR). The patient in CR was retreated upon progression and had a second PR. Furthermore, there was tumor-specific targeting of the SGT-94 complex. One patient had wedge resections of two lung metastases which demonstrated RB94 expression at the DNA level by polymerase chain reaction (PCR) and at the protein level by Western blotting, with no RB94 present in normal contiguous lung. In conclusion, systemically delivered SGT-94 showed evidence of selective tumor targeting and was well tolerated with evidence of clinical activity. Additional studies are warranted to explore the activity of this drug as a single agent and in combination therapy.

Use of electroconvulsive therapy in older Chinese psychiatric patients.

OBJECTIVE: Little is known about the use of electroconvulsive therapy (ECT) in older Chinese psychiatric patients. This study examined the frequency of ECT and the demographic and clinical correlates in older psychiatric patients hospitalized in a large psychiatric institution in Beijing, China. METHODS: This was a retrospective chart review of 2339 inpatients aged 60 years and older treated over a period of 8 years (2007-2013) in a university-affiliated psychiatric institution in Beijing. Sociodemographic and clinical data were collected from the electronic chart management system for discharged patients. RESULTS: The rate of ECT use was 28.1% in the whole sample; 37.9% in those with bipolar disorders, 43.6% in major depression, 21.2% in schizophrenia, and 10.7% in other diagnoses. ECT ("ECT group") was associated with 60-65-year age group, high risk for suicide and low risk for falls at the time of admission, use of mood stabilizers and antidepressants, lack of health insurance, and having major medical conditions and diagnosis of major depression. The above significant correlates explained 24.9% of the variance of ECT use (p < 0.001). CONCLUSIONS: In a major psychiatric hospital in China, the use of ECT was common among older patients. ECT use in older patients treated in other clinical settings warrants further investigations.

Low molecular weight cyclin E is associated with p27-resistant, high-grade, high-stage and invasive bladder cancer.

Expression of low molecular weight (LMW) isoforms of cyclin E is a strong predictor of poor outcome in patients with breast cancer. The purpose of this study was to examine the expression of full-length and LMW cyclin E in bladder cancer cell lines and patient tumors. We used western blotting, immunoprecipitation and kinase assays to examine the expression and activity of key cell cycle-regulatory proteins in various human bladder cell lines, both tumorigenic and non-tumorigenic. We also analyzed cyclin E expression, kinase activity and immune complex binding partners in 43 tissue samples from grade 2 and 3 transitional cell carcinomas. Cyclin E was overexpressed and LMW isoforms were present only in bladder cancer cells. Overexpression of LMW isoforms of cyclin E and increased cyclin E kinase activity were both significantly associated with tumorigenicity of the bladder cell lines (p = 0.005 and 0.022, respectively). Binding of the cyclin-dependent kinase inhibitors p21 and p27 to LMW cyclin E did not inhibit the kinase activity of cyclin E and cyclin-dependent kinase 2 in primary tumor samples overexpressing LMW cyclin E. Full-length and LMW cyclin E were significantly overexpressed in grade 3 tumors compared with grade 2 tumors (p = 0.004). Finally, LMW cyclin E levels were significantly associated with a non-papillary growth pattern (p = 0.031) and invasiveness (p = 0.021) of the bladder tumors and poor overall survival (p = 0.06). These results suggest that LMW cyclin E can be used as a new prognostic marker for bladder cancer.

Tumor-targeting nanocomplex delivery of novel tumor suppressor RB94 chemosensitizes bladder carcinoma cells in vitro and in vivo.

PURPOSE: RB94, a truncated form of RB110, has enhanced tumor suppressor potency and activity against all tumor types tested to date including bladder carcinoma. However, efficient, systemic delivery of the gene encoding RB94 specifically to tumors, is an obstacle to clinical application as an anticancer therapeutic. We have developed a systemically given, nanosized liposome DNA delivery system that specifically targets primary and metastatic disease. The ability of RB94, delivered via this nanocomplex, to sensitize bladder carcinoma to chemotherapy in vitro and in vivo was assessed. EXPERIMENTAL DESIGN: The nanocomplex is an RB94 plasmid encapsulated by a cationic liposome, the surface of which is decorated with a tumor-targeting moiety, either transferrin (Tf/Lip/RB94) or an antitransferrin receptor single-chain antibody fragment (TfRScFv/Lip/RB94). The ability of the complex to sensitize human bladder carcinoma HTB-9 cells to chemotherapeutics was assessed in vitro by XTT assay. In vivo tumor specificity and efficacy were tested in mice carrying HTB-9 tumors by PCR and tumor growth inhibition, respectively. RESULTS: Transfection with Tf/Lip/RB94 significantly sensitized HTB-9 cells to chemotherapeutic agents in vitro. Tumor specificity of the complex was shown in an orthotopic bladder tumor model by immunohistochemistry and PCR. Moreover, in mice bearing subcutaneous HTB-9 tumors, the combination of systemically given Tf/Lip/RB94 or TfRScFv/Lip/RB94 plus gemcitabine resulted in significant (P<0.0005) tumor growth inhibition/regression and induction of apoptosis. CONCLUSIONS: Use of our tumor-targeting nanocomplex to specifically deliver the potent tumor suppressor RB94 efficiently to tumors has potential as a more effective treatment modality for genitourinary and other cancers.

Phosphorylation of Thr18 and Ser20 of p53 in Ad-p53-induced apoptosis.

The p53 protein plays a critical role in inducing cell cycle arrest or apoptosis. Because p53 is inactivated in human gliomas, restoring p53 function is a major focus of glioma therapy. The most clinically tested strategy for replacing p53 has been adenoviral-mediated p53 gene therapy (Ad-p53). In addition to their therapeutic implications, investigations into Ad-p53 provide model systems for understanding p53's ability to induce cell cycle arrest versus apoptosis, particularly because wild-type p53 cells are resistant to Ad-p53-induced apoptosis. Here we use Ad-p53 constructs to test the hypothesis that simultaneous phosphorylation of p53 at threonine 18 (Thr18) and serine 20 (Ser20) is causally associated with p53-mediated apoptosis. Studies using phosphorylation-specific antibodies demonstrated that p53-induced apoptosis correlates with phosphorylation of p53 at Thr18 and Ser20 but not with carboxy-terminal phosphorylation (Ser392). To prove a causal relationship between apoptosis and Thr18 and Ser20 phosphorylation of p53, the effects of an adenoviral p53 construct that was not phosphorylated (Ad-p53) was compared with a Thr18/Ser20 phosphomimetic construct (Ad-p53-18D20D) in wild-type p53 gliomas. Whereas treatment with Ad-p53 resulted only in cell cycle arrest, treatment with Ad-p53-18D20D induced dramatic apoptosis. Microarray and Western blot analyses showed that only Ad-p53-18D20D was capable of inducing expression of apoptosis-inducing proteins. Chromatin immunoprecipitation assays indicated that the protein product of Ad-p53-18D20D, but not Ad-p53, was capable of binding to apoptosis-related genes. We thus conclude that phosphorylation of Thr18 and Ser20 is sufficient for inducing p53-mediated apoptosis in glioma cells. These results have implications for p53 gene therapy and inform other strategies that aim to restore p53 function.

A phase I clinical trial of single-dose intrapleural IFN-beta gene transfer for malignant pleural mesothelioma and metastatic pleural effusions: high rate of antitumor immune responses.

PURPOSE: This phase 1 dose escalation study evaluated the safety and feasibility of single-dose intrapleural IFN-beta gene transfer using an adenoviral vector (Ad.IFN-beta) in patients with malignant pleural mesothelioma (MPM) and metastatic pleural effusions (MPE). EXPERIMENTAL DESIGN: Ad.IFN-beta was administered through an indwelling pleural catheter in doses ranging from 9 x 10(11) to 3 x 10(12) viral particles (vp) in two cohorts of patients with MPM (7 patients) and MPE (3 patients). Subjects were evaluated for (a) toxicity, (b) gene transfer, (c) humoral, cellular, and cytokine-mediated immune responses, and (d) tumor responses via 18-fluorodeoxyglucose-positron emission tomography scans and chest computed tomography scans. RESULTS: Intrapleural Ad.IFN-beta was generally well tolerated with transient lymphopenia as the most common side effect. The maximally tolerated dose achieved was 9 x 10(11) vp secondary to idiosyncratic dose-limiting toxicities (hypoxia and liver function abnormalities) in two patients treated at 3 x 10(12) vp. The presence of the vector did not elicit a marked cellular infiltrate in the pleural space. Intrapleural levels of cytokines were highly variable at baseline and after response to gene transfer. Gene transfer was documented in 7 of the 10 patients by demonstration of IFN-beta message or protein. Antitumor immune responses were elicited in 7 of the 10 patients and included the detection of cytotoxic T cells (1 patient), activation of circulating natural killer cells (2 patients), and humoral responses to known (Simian virus 40 large T antigen and mesothelin) and unknown tumor antigens (7 patients). Four of 10 patients showed meaningful clinical responses defined as disease stability and/or regression on 18-fluorodeoxyglucose-positron emission tomography and computed tomography scans at day 60 after vector infusion. CONCLUSIONS: Intrapleural instillation of Ad.IFN-beta is a potentially useful approach for the generation of antitumor immune responses in MPM and MPE patients and should be investigated further for overall clinical efficacy.

Intravesical Ad-IFNalpha causes marked regression of human bladder cancer growing orthotopically in nude mice and overcomes resistance to IFN-alpha protein.

We have produced prolonged, high local concentrations of interferon in vivo by intravesical instillation of adenoviruses encoding interferon-alpha (Ad-IFNalpha) together with the gene transfer-enhancing agent Syn3. We found sustained interferon protein levels for days, both in normal mouse urothelium and in human bladder cancer cells growing as superficial bladder tumors in nude mice using an orthotopic bladder model developed by us. Tumor burden in the bladder was determined utilizing cancer cells containing the green fluorescent protein. Marked tumor regression was observed following two 1-h exposures of Ad-IFNalpha/Syn3 and little or no cytotoxicity was detected in normal cells. Similar intravesical instillation of clinically relevant concentrations of IFN protein alone or Ad-IFNalpha without Syn3 was ineffective. Surprisingly, in vitro, Ad-IFNalpha also caused caspase-dependent death of bladder cancer cell lines that were resistant to high concentrations of IFN-alpha protein, including the cell line used in vivo. These findings demonstrate that Ad-IFNalpha can overcome resistance to IFN-alpha protein both in vitro and in vivo and support evaluation of intravesical Ad-IFNalpha/Syn3 for the treatment of superficial bladder cancer.

Adenoviral-mediated retinoblastoma 94 produces rapid telomere erosion, chromosomal crisis, and caspase-dependent apoptosis in bladder cancer and immortalized human urothelial cells but not in normal urothelial cells.

Retinoblastoma (RB)94, which lacks the NH(2)-terminal 112 amino acid residues of the full-length RB protein (RB110), is a more potent tumor and growth suppressor than RB110. In this study, Ad-RB94, but not Ad-RB110, produced marked growth inhibition, cytotoxicity, caspase-dependent apoptosis, and G(2)-M block in the human RB-negative, telomerase-positive bladder cancer cell line UM-UC14. This effect was completely inhibited by pretreatment with caspase inhibitors (P < 0.0001). Similar results were seen in RB-positive and other RB-negative bladder cancer cell lines. Ad-RB94 produced rapid telomere length shortening and loss of telomere signal, which was associated with polyploidy and chromosomal aberrations (P < 0.001). Ad-RB94, however, showed no cytotoxicity to telomerase-negative human normal urothelium cells but was highly cytotoxic to telomerase-positive human E6 and E7 immortalized urothelial cells (P < 0.0001). In addition, telomerase-negative cells, which maintain their telomere length through an alternative lengthening of telomeres DNA recombination pathway, showed no cytotoxicity to RB94. These results suggest that the induction of rapid telomere erosion and chromosomal crisis by RB94 in telomerase-positive cancer and in telomerase-expressing immortalized human cells is a major factor in its selective and potent tumor suppression and cytotoxic activity. The lack of cytotoxicity to normal cells should also provide a high therapeutic index when used in gene therapy protocols for the treatment of bladder and other cancers.

Syn3 provides high levels of intravesical adenoviral-mediated gene transfer for gene therapy of genetically altered urothelium and superficial bladder cancer.

Using our model to grow superficial human bladder cancer in the mouse bladder, we have found that the polyamide compound, Syn3, when injected intravesically for 1 hour at 1 mg/mL on two consecutive days, markedly increases rAd-beta-gal intravesical gene transfer and expression. This enhanced transgene expression was much greater than obtain by the use of 22% ethanol, which had previously been shown to increase intravesical adenoviral gene transfer, whereas little or no gene expression was seen with exposure to only rAd-beta-gal. beta-Galactosidase staining was seen in virtually every normal urothelial and superficial tumor cell present, including tumors that express little or no coxsackie-adenovirus receptors when Syn3 was present. High adenoviral-mediated gene transfer was also documented in the pig bladder using Syn3 in a similar protocol. Therefore, Syn3 may overcome the limitations of adequate intravesical adenoviral-mediated gene transfer and, when combined with an appropriate adenoviral-mediated gene, could offer an effective approach to the treatment of superficial bladder cancer and perhaps even genetically altered precursor lesions.