A new gold(I) phosphine complex induces apoptosis in prostate cancer cells by increasing reactive oxygen species.

Thioredoxin reductase (TrxR) is a pivotal regulator of redox homeostasis. It is frequently overexpressed in various cancer cells, including prostate cancer, making it a promising target for the development of anti-cancer drugs. In this study, we screened a series of newly designed complexes of gold(I) phosphine. Specifically, Compound 5 exhibited the highest cytotoxicity against prostate cancer cells and demonstrated stronger antitumor effects than commonly used drugs, such as cisplatin and auranofin. Importantly, our mechanistic study revealed that Compound 5 effectively inhibits the TrxR system in vitro. Additionally, Compound 5 promoted intracellular accumulation of reactive oxygen species (ROS), leading to mitochondrial dysfunction and irreversible apoptosis in prostate cancer cells. Our in vivo xenograft study further demonstrated that Compound 5 has excellent antitumor activity against prostate cancer cells, but does not cause severe side effects. These findings provide a promising lead Compound for the development of novel antitumor agents targeting prostate cancer and offer a valuable tool for investigating biological pathways involving TrxR and ROS modulation.

Cancer incidence trends in New York State and associations with common population-level exposures 2010-2018: an ecological study.

The impact of common environmental exposures in combinations with socioeconomic and lifestyle factors on cancer development, particularly for young adults, remains understudied. Here, we leveraged environmental and cancer incidence data collected in New York State at the county level to examine the association between 31 exposures and 10 common cancers (i.e., lung and bronchus, thyroid, colorectal, kidney and renal pelvis, melanoma, non-Hodgkin lymphoma, and leukemia for both sexes; corpus uteri and female breast cancer; prostate cancer), for three age groups (25-49, 50-69, and 70-84 year-olds). For each cancer, we stratified by age group and sex, and applied regression models to examine the associations with multiple exposures simultaneously. The models included 642,013 incident cancer cases during 2010-2018 and found risk factors consistent with previous reports (e.g., smoking and physical inactivity). Models also found positive associations between ambient air pollutants (ozone and PM2.5) and prostate cancer, female breast cancer, and melanoma of the skin across multiple population strata. Additionally, the models were able to better explain the variation in cancer incidence data among 25-49 year-olds than the two older age groups. These findings support the impact of common environmental exposures on cancer development, particularly for younger age groups.

ATIP/ATIP1 regulates prostate cancer metastasis through mitochondrial dynamic-dependent signaling.

Mitochondria play a fundamental role in cell survival and motility. Abnormalities in mitochondria are associated with carcinogenesis, especially with tumor metastasis. In this study, we explore the biological function of ATIP1, which is a mitochondrial-located isoform of angiotensin II AT2 receptor interacting proteins (ATIPs) in prostate cancer cells. The results showed that ATIP is downregulated in prostate cancer tissues and is negatively correlated with the disease-free survival rate of prostate cancer patients. Silencing of ATIP promotes mitochondrial fission and enhances tumor cell migration and invasion. Reconstitution of ATIP1 in ATIP-deficient cells significantly attenuates mitochondrial trafficking and tumor cell movement. Therefore, ATIP1 is a negative regulator of mitochondrial dynamics and tumor cell motility and is also a potential biomarker for predicting prostate cancer malignancy.

Proton-transfer salts of diphenylphosphinic acid with substituted 2-aminopyridine: crystal structure, spectroscopic and DFT studies.

Three proton-transfer salts of diphenylphosphinic acid (DPPA) with 2-amino-5-(X)-pyridine (AMPY, X = Cl, CN or CH3), namely, 2-amino-5-chloropyridinium diphenylphosphinate, C5H6ClN2+·C12H10O2P- (1, X = Cl), 2-amino-5-cyanopyridinium diphenylphosphinate, C6H6N3+·C12H10O2P- (2, X = CN), and 2-amino-5-methylpyridinium diphenylphosphinate, C6H9N2+·C12H10O2P- (3, X = CH3), have been synthesized and characterized by FT-IR and 1H NMR spectroscopy, and X-ray crystallography. The crystal structures of compounds 1-3 were determined in the space group P-1 for 1 and 2, and C2/c for 3. All three compounds contain N-H...O hydrogen-bonding interactions due to proton transfer from the O=P-OH group of DPPA as donor to the pyridine N atom of AMPY as acceptor. The proton transfer of compounds 1-3 was also verified by 1H NMR and FT-IR spectroscopy. The stoichiometry of all three proton-transfer salts was determined to be 1:1 and the Benesi-Hildebrand equation was applied to determine the formation constant (KCT) and the molar extinction coefficient (ϵCT) in each case. Theoretical density functional theory (DFT) calculations were performed to investigate the optimized geometries, the molecular electrostatic potentials (MEP) and the highest occupied molecular orbitals (HOMO) and lowest unoccupied molecular orbitals (LUMO) of all three proton-transfer salts. The results showed good agreement between the experimental data and the DFT computational analysis.

Lentiviral Gene Therapy of Chronic Granulomatous Disease: Functional Assessment of Universal and Tissue-Specific Promoters.

Chronic granulomatous disease (CGD) is a rare congenital immunodeficiency characterized by a defect in nicotinamide adenine dinucleotide phosphate oxidase required for phagocytosis. Hematopoietic stem cell (HSC) transplantation is currently the only curative treatment, but it is ladened with morbidities and mortality. Gene therapy is a promising treatment for CGD. However, if not properly designed, the gene therapy approach may not be successful. We engineered lentiviral vectors (LVs) carrying a universal promoter (EF1a) and two myeloid-specific promoters (miR223 and CD68) to drive the expression of green fluorescence protein (GFP) or CYBB, one of the key defective genes causing CGD. Tissue-specific LV expression was investigated in vitro and in a CGD mouse model. We compared GFP expression in both myeloid differentiated and undifferentiated HSCs. The CGD mice were transplanted with LV-modified mouse HSCs to investigate expression of CYBB and restoration of reactive oxygen species. The LV promoters were further compared under low and high-transgenic conditions to assess safety and therapeutic efficacy. A pneumonia disease model based on pathogenic Staphylococcus aureus challenge was established to assess the survival rate and body weight change. All three promoters demonstrated ectopic CYBB expression in vitro and in vivo. The EF1a promoter showed the highest expression of GFP or CYBB in transduced cells, including HSCs without cytotoxicity, whereas the LV-miR223 showed the highest transgene delivery efficiency with high myeloid specificity. Importantly, under low-transgenic condition, only the LV-EF1a-CYBB showed high antibacterial activity in vivo.

Bean Dreg-Hydrocalumite Composite as a Highly Efficient Thermal Stabilizer for Poly(vinyl chloride).

Bean dreg (BD)-hydrocalumite composites were prepared by a hydrothermal method with BD, Ca(OH)2, Al(OH)3, and Na2CO3 as raw materials. The samples were characterized by powder X-ray diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, and N2 physical adsorption-desorption. Their properties as a thermal stabilizer for poly(vinyl chloride) were tested using a torque rheometer and static thermal aging method. Compared with traditional hydrocalumite, the crystal size of the BD-hydrocalumite composite was relatively small, which made it exhibit good dispersion and better thermal stability for poly(vinyl chloride). In addition, the effects of preparation conditions on the properties of BD-hydrocalumite as a heat stabilizer were also investigated. Under the conditions of n[Ca(OH)2/Al(OH)3/Na2CO3] = 4.4:2:1, a BD dosage of 5%, a crystallization temperature of 90 °C, and 19 h, the prepared BD-hydrocalumite showed the best performance, and the dynamic thermal stability time of poly(vinyl chloride) reached 2149 s.

Interactions among common non-SARS-CoV-2 respiratory viruses and influence of the COVID-19 pandemic on their circulation in New York City.

BACKGROUND: Non-pharmaceutical interventions (NPIs) and voluntary behavioral changes during the COVID-19 pandemic have influenced the circulation of non-SARS-CoV-2 respiratory infections. We aimed to examine interactions among common non-SARS-CoV-2 respiratory virus and further estimate the impact of the COVID-19 pandemic on these viruses. METHODS: We analyzed incidence data for seven groups of respiratory viruses in New York City (NYC) during October 2015 to May 2021 (i.e., before and during the COVID-19 pandemic). We first used elastic net regression to identify potential virus interactions and further examined the robustness of the found interactions by comparing the performance of Seasonal Auto Regressive Integrated Moving Average (SARIMA) models with and without the interactions. We then used the models to compute counterfactual estimates of cumulative incidence and estimate the reduction during the COVID-19 pandemic period from March 2020 to May 2021, for each virus. RESULTS: We identified potential interactions for three endemic human coronaviruses (CoV-NL63, CoV-HKU, and CoV-OC43), parainfluenza (PIV)-1, rhinovirus, and respiratory syncytial virus (RSV). We found significant reductions (by ~70-90%) in cumulative incidence of CoV-OC43, CoV-229E, human metapneumovirus, PIV-2, PIV-4, RSV, and influenza virus during the COVID-19 pandemic. In contrast, the circulation of adenovirus and rhinovirus was less affected. CONCLUSIONS: Circulation of several respiratory viruses has been low during the COVID-19 pandemic, which may lead to increased population susceptibility. It is thus important to enhance monitoring of these viruses and promptly enact measures to mitigate their health impacts (e.g., influenza vaccination campaign and hospital infection prevention) as societies resume normal activities.

Factors affecting the transmission of SARS-CoV-2 in school settings.

BACKGROUND: Several studies have reported SARS-CoV-2 outbreaks in schools, with a wide range of secondary attack rate (SAR; range: 0-100%). We aimed to examine key risk factors to better understand SARS-CoV-2 transmission in schools. METHODS: We collected records of 35 SARS-CoV-2 school outbreaks globally published from January 2020 to July 2021 and compiled information on hypothesized risk factors. We utilized the directed acyclic graph (DAG) to conceptualize risk mechanisms, used logistic regression to examine each risk-factor group, and further built multirisk models. RESULTS: The best-fit model showed that the intensity of community transmission (adjusted odds ratio [aOR]: 1.11, 95% CI: 1.06-1.16, for each increase of 1 case per 10 000 persons per week) and individualism (aOR: 2.72, 95% CI: 1.50-4.95, above vs. below the mean) was associated higher risk, whereas preventive measures (aOR: 0.25, 95% CI: 0.19-0.32, distancing and masking vs. none) and higher population immunity (aOR: 0.57, 95% CI: 0.46-0.71) were associated with lower risk of SARS-CoV-2 transmission in schools. Compared with students in high schools, the aOR was 0.47 (95% CI: 0.23-0.95) for students in preschools and 0.90 (95% CI: 0.76-1.08) for students in primary schools. CONCLUSIONS: Preventive measures in schools (e.g., social distancing and mask wearing) and communal efforts to lower transmission and increase vaccination uptake (i.e., vaccine-induced population immunity) in the community should be taken to collectively reduce transmission and protect children in schools.

Factors affecting the transmission of SARS-CoV-2 in school settings.

BACKGROUND: Several studies have reported SARS-CoV-2 outbreaks in schools, with a wide range of secondary attack rate (SAR; range: 0-100%). We aimed to examine key risk factors to better understand SARS-CoV-2 transmission in schools. METHODS: We collected records of 39 SARS-CoV-2 school outbreaks globally published through July 2021 and compiled information on hypothesized risk factors. We utilized the directed acyclic graph (DAG) to conceptualize risk mechanisms, used logistic regression to examine each risk-factor group, and further built multi-risk models. RESULTS: The best-fit model showed that the intensity of concurrent community transmission (adjusted odds ratio [aOR]: 1.2, 95% CI: 1.17 - 1.24, for each increase of 1 case per 10,000 persons per week), individualism (aOR: 1.72, 95% CI: 1.19 - 2.5, above vs. below the median) were associated higher risk, whereas preventive measures (aOR: 0.22, 95% CI: 0.17 - 0.29, distancing and masking vs. none) and higher population immunity (aOR: 0.28, 95% CI: 0.22 - 0.35) were associated with lower risk of SARS-CoV-2 transmission in schools. Compared to students in pre-schools, the aOR was 0.35 (95% CI: 0.23 - 0.54) for students in primary schools and 1.3 (95% CI: 0.9 - 1.88) for students in high schools. CONCLUSIONS: Preventive measures in schools (e.g. social distancing and mask-wearing) and communal efforts to lower transmission and increase vaccination uptake (i.e. vaccine-induced population immunity) in the community should be taken to collectively reduce transmission and protect children in schools. Flexible reopening policies may be considered for different levels of schools given their risk differences.

Modeling influenza seasonality in the tropics and subtropics.

Climate drivers such as humidity and temperature may play a key role in influenza seasonal transmission dynamics. Such a relationship has been well defined for temperate regions. However, to date no models capable of capturing the diverse seasonal pattern in tropical and subtropical climates exist. In addition, multiple influenza viruses could cocirculate and shape epidemic dynamics. Here we construct seven mechanistic epidemic models to test the effect of two major climate drivers (humidity and temperature) and multi-strain co-circulation on influenza transmission in Hong Kong, an influenza epidemic center located in the subtropics. Based on model fit to long-term influenza surveillance data from 1998 to 2018, we found that a simple model incorporating the effect of both humidity and temperature best recreated the influenza epidemic patterns observed in Hong Kong. The model quantifies a bimodal effect of absolute humidity on influenza transmission where both low and very high humidity levels facilitate transmission quadratically; the model also quantifies the monotonic but nonlinear relationship with temperature. In addition, model results suggest that, at the population level, a shorter immunity period can approximate the co-circulation of influenza virus (sub)types. The basic reproductive number R0 estimated by the best-fit model is also consistent with laboratory influenza survival and transmission studies under various combinations of humidity and temperature levels. Overall, our study has developed a simple mechanistic model capable of quantifying the impact of climate drivers on influenza transmission in (sub)tropical regions. This model can be applied to improve influenza forecasting in the (sub)tropics in the future.