Differential diagnosis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma by ultrasonography combined with multiphase enhanced computed tomography.

Purpose: Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are primary liver cancers with different therapeutic methods and prognoses. This study aims to investigate the ultrasonography and enhanced computed tomography (CT) features of these cancers and improve the early diagnosis rate. Methods: We retrospectively analyzed the clinical and imaging data of 319 patients diagnosed with HCC and 124 patients diagnosed with ICC, confirmed by pathology. Results: A total of 443 patients were eligible in this study. From the perspective of clinical data, between HCC and ICC patients existed significant differences in age, gender, hepatic background, serum tumor markers of AFP and CA19.9, chronic hepatitis B/C and lymph node infiltration (p<0.05), but not in tumor size, microvascular invasion, serum tumor markers of CEA and CA125 (P>0.05). With respect to ultrasonography features, HCC patients had a higher proportion than ICC patients in splenomegaly (p=0.001), while ICC patients had a higher proportion than HCC patients in absence/not rich vascularity and intrahepatic bile duct dilatation (p<0.05). With respect to CT features, HCC patients were significantly different from ICC patients in the three-phase enhanced CT value mean, enhanced intensity and homogeneity of nodules (P<0.05). A multivariate logistic regression analysis was performed to further clarify the correlation of these indices. However, only age≤60 years (OR=1.861, P=0.045), male (OR=3.850, P<0.001), AFP>7ng/ml (OR=0.119, P<0.001), lymph node infiltration (OR=5.968, P<0.001), intrahepatic bile duct dilatation (OR=2.414, P=0.04), splenomegaly (OR=0.081, P<0.001), rim APHE (OR=3.109, P=0.002), and iso- or hyper enhancement (OR=0.188, P<0.001) were independent risk factors. Conclusions: While there are overlapping ultrasonography and CT features between HCC and ICC, the integration of tumor markers and specific imaging characteristics can be beneficial in distinguishing between the two.

The first diagnosis of Severe Fever with Thrombocytopenia Syndrome caused by tick-borne Severe Fever with Thrombocytopenia Syndrome virus in Chongqing, China: A case report and literature review.

BACKGROUND: Severe Fever with Thrombocytopenia Syndrome (SFTS) is a tick-borne disease caused by the SFTS virus (SFTSV) which has the potential to become a pandemic and is currently a major public health concern. CASE PRESENTATION: We present the case of a 74-year-old female from an urban area of Chongqing, with leukocytopenia, thrombocytopenia, organ function, inflammatory, blood coagulation, and immune abnormalities. SFTSV infection was confirmed through molecular detection and metagenomic next-generation sequencing (mNGS) analysis, indicating a diagnosis of SFTS due to the patient's history of tick bites. The patient received symptomatic and supportive therapy, including antibiotics, antiviral treatment, and antifungal therapy, and finally discharged from the hospital on day 18. CONCLUSIONS: This study highlights the need for increased awareness, early diagnosis, and prompt treatment for tick-borne SFTS. It also provides a comprehensive understanding of the disease's characteristics, pathogenesis, detection methods, and available treatments.

Nomogram to predict recurrence risk factors in patients with non-valvular paroxysmal atrial fibrillation after catheter radiofrequency ablation.

BACKGROUND: Radiofrequency catheter ablation (RFCA) is an effective method for controlling the heart rate of paroxysmal atrial fibrillation (PAF). However, recurrence is trouble under the RFCA. To gain a deeper understanding of the risk factors for recurrence in patients, we created a nomogram model to provide clinicians with treatment recommendations. METHODS: A total of two hundred thirty-three patients with PAF treated with RFCA at Guizhou Medical University Hospital between January 2021 and December 2022 were consecutively included in this study, and after 1 year of follow-up coverage, 166 patients met the nadir inclusion criteria. Patients with AF were divided into an AF recurrence group and a non-recurrence group. The nomogram was constructed using univariate and multivariate logistic regression analyses. By calculating the area under the curve, we analyzed the predictive ability of the risk scores (AUC). In addition, the performance of the nomogram in terms of calibration, discrimination, and clinical utility was evaluated. RESULTS: At the 12-month follow-up, 48 patients (28.92%) experienced a recurrence of AF after RFCA, while 118 patients (71.08%) maintained a sinus rhythm. In addition to age, sex, and TRV, LAD, and TTPG were independent predictors of recurrence of RFCA. The c-index of the nomogram predicted AF recurrence with an accuracy of .723, showing good decision curves and a calibrated nomogram, as determined by internal validation using a bootstrap sample size of 1000. CONCLUSION: We created a nomogram based on multifactorial logistic regression analysis to estimate the probability of recurrence in patients with atrial fibrillation 1 year after catheter ablation. This plot can be utilized by clinicians to predict the likelihood of recurrence.

Lipoamide Attenuates Hypertensive Myocardial Hypertrophy Through PI3K/Akt-Mediated Nrf2 Signaling Pathway.

The process of myocardial hypertrophy in hypertension can lead to excessive activation of oxidative stress. Lipoamide (ALM) has significant antioxidant and anti-inflammatory effects. This study aimed to investigate the effects of ALM on hypertension-induced cardiac hypertrophy, as well as explore its underlying mechanisms. We evaluated the effects of ALM on spontaneously hypertensive rats and rat cardiomyocytes treated with Ang II. We found that ALM was not effective in lowering blood pressure in SHR, but it attenuated hypertension-mediated cardiac fibrosis, oxidative stress, inflammation, and hypertrophy in rats. After that, in cultured H9C2 cells stimulated with Ang II, ALM increased the expression of antioxidant proteins that were decreased in the Ang II group. ALM also alleviated cell hypertrophy and the accumulation of ROS, while LY294002 partially abrogated these effects. Collectively, these results demonstrate that ALM could alleviate oxidative stress in cardiac hypertrophy, potentially through the activation of the PI3K/Akt-mediated Nrf2 signaling pathway.

Pretargeted radiotherapy and synergistic treatment of metastatic, castration-resistant prostate cancer using cross-linked, PSMA-targeted lipoic acid nanoparticles.

Metastatic castration-resistant prostate cancer (CRPC) is a currently incurable disease associated with high mortality. Novel therapeutic approaches for CRPC are urgently needed to improve prognosis. In this study, we developed cross-linked, PSMA-targeted lipoic acid nanoparticles (cPLANPs), which can interact with transmembrane glycoprotein to accumulate inside prostate cancer cells, where they upregulate caspase-3, downregulate anti-apoptotic B-cell lymphoma-2 (BCL-2), and thereby induce apoptosis. The trans-cyclooctene (TCO) decoration on cPLANPs acts as a bioorthogonal handle allowing pretargeted single-photon emission computed tomography and radiotherapy, which revealed significantly enhanced tumor accumulation and minimal off-target toxicity in our experiments. The developed strategy showed a strong synergistic anti-cancer effect in vivo, with a tumor inhibition rate of up to 95.6% after 14 days of treatment. Our results suggest the potential of combining bioorthogonal pretargeted radiotherapy with suitable PSMA-targeted nanoparticles for the treatment of metastatic CRPC.

Differential miRNA Profiling Reveals miR-4433a-5p as a Key Regulator of Chronic Obstructive Pulmonary Disease Progression via PIK3R2- mediated Phenotypic Modulation.

OBJECTIVE: In this study, a high-throughput sequencing technology was used to screen the differentially expressed miRNA in the patients with "fast" and "slow" progression of chronic obstructive pulmonary disease (COPD). Moreover, the possible mechanism affecting the progression of COPD was preliminarily analyzed based on the target genes of candidate miRNAs. METHODS: The "fast" progressive COPD group included 6 cases, "slow" and Normal progressive COPD groups included 5 cases each, and COPD group included 3 cases. The peripheral blood samples were taken from the participants, followed by total RNA extraction and high throughput miRNA sequencing. The differentially expressed miRNAs among the progressive COPD groups were identified using bioinformatics analysis. Then, the candidate miRNAs were externally verified. In addition, the target gene of this miRNA was identified, and its effects on cell activity, cell cycle, apoptosis, and other biological phenotypes of COPD were analyzed. RESULTS: Compared to the Normal group, a total of 35, 16, and 7 differentially expressed miRNAs were identified in the "fast" progressive COPD, "slow" progressive COPD group, and COPD group, respectively. The results were further confirmed using dual-luciferase reporter assay and transfection tests with phosphoinositide- 3-kinase, regulatory subunit 2 (PIK3R2) as a target gene of miR-4433a-5p; the result showed a negative regulatory correlation between the miRNA and its target gene. The phenotype detection showed that the activation of the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) signaling pathway might participate in the progression of COPD by promoting the proliferation of inflammatory A549 cells and inhibiting cellular apoptosis. CONCLUSIONS: MiR-4433a-5p can be used as a marker and potential therapeutic target for the progression of COPD. As a target gene of miR-4433a-5p, PIK3R2 can affect the progression of COPD by regulating phenotypes, such as cellular proliferation and apoptosis.

A gene signature of cancer-associated fibroblasts predicts prognosis and treatment response in bladder cancer.

OBJECTIVE: Due to the pivotal role cancer-associated fibroblasts (CAFs) play in tumor progression, our study aimed to develop a signature of CAFs-related gene (CRG) to predict the survival outcomes and treatment response of bladder cancer (BLCA). METHODS: The transcriptome data and relevant clinical information about BLCA were collected from publicly available databases, including The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Weighted gene co-expression network analysis was utilized to uncover CAFs-associated hub genes, and subsequently, a risk model for survival prognosis was constructed using LASSO-Cox regression. The immune microenvironment, immune infiltration, immunotherapy response, and drug sensitivity were explored using ESTIMATE, CIBERSORT, TIDE, and oncoPredict algorithms. To verify the expression of the CRGs, additional analyses were performed using online databases (HPA, CCLE, TIMER, cBioPortal, and TISCH). RESULTS: Our study developed a CRG signature and constructed a prognostic model. Significant differences in overall survival were observed between the two risk stratifications. The risk score increased with the infiltration of CAFs and tumor staging progression, while closely correlating with immune checkpoint expression and infiltration of CD8 T cells, follicular helper T cells, regulatory T cells, activated dendritic cells, M0 macrophages, M2 macrophages, and resting mast cells. Furthermore, a higher proportion of patients in the low-risk stratification exhibited responsiveness to immunotherapy, and significant variances in sensitivity to multiple chemotherapy medications were observed between the two risk stratifications. CONCLUSION: The construction of the risk model based on the CRG signature offers new avenues for the prognosis evaluation and development of personalized treatment strategies for BLCA.

Multifunctional photothermally responsive hydrogel as an effective whole-process management platform to accelerate chronic diabetic wound healing.

The management of chronic diabetic wounds is a complex issue that requires wound repair, regulation of inflammatory levels, and intervention to prevent bacterial infection. To address this issue, we developed a multifunctional photothermally responsive hydrogel (PAG-CuS) as an effective platform for managing the entire wound-healing process, including promoting wound healing, providing anti-inflammatory therapy, and performing photothermal sterilization. Constructed through copolymerization of acrylic acid (AA), methacrylic anhydride-modified gelatin (GelMA), and lipoic acid sodium (LAS) coated copper sulfide nanoparticles (CuS@LAS), PAG-CuS possessed a porous three-dimensional structure that promoted cell adhesion and had a substantial water-holding capacity. Additionally, the internal CuS@LAS not only conferred photothermal antibacterial properties to the hydrogel but also served as physical cross-linking agents, thus enhancing its mechanical strength. Under the NIR-induced photothermal effect, the porous hydrogel liberates CuS@LAS, and later CuS@LAS expels LAS via micelle deassembly to eliminate intracellular ROS. This results in the down-regulation of MMP-9 expression, promoting ECM production and facilitating wound healing. Meanwhile, the release of Cu2+ from PAG-CuS could enhance CD31 expression in endothelial cells, promoting microvessel formation, which is crucial for wound healing. In the diabetic wound model of GK rats, the PAG-CuS hydrogel reduced ROS levels, increased microvessel count, improved epithelialization, and enhanced wound healing. Therefore, this versatile photothermal hydrogel has the potential to be applied in sterilization, scavenging free radicals, and promoting angiogenesis, making it an effective and comprehensive solution to manage the challenges of diabetic wounds. STATEMENT OF SIGNIFICANCE: Assessment of functional recovery and timely adjustment of treatment strategy is critical in the management of chronic diabetic wounds. In this work, we prepared PAG-CuS composite hydrogels by integrating in situ reduction, chemical crosslinking, and nanoenhancement techniques. The near-infrared light-induced photothermal effect of PAG-CuS gel rapidly kills bacteria at the lesion site, and the generated heat simultaneously promotes the multilevel release of LAS from the gel, which could regulate the levels of ROS and MMP-9 to promote extracellular matrix formation. In addition, the Cu2+ released from the gel can promote the formation of blood vessels to improve blood oxygenation. Therefore, this project proposes a synergistic solution to realize the whole process of management to accelerate chronic diabetic wound healing.

BST-1 aggravates aldosterone-induced cardiac hypertrophy via the Ca2+ /CaN/NFATc3 pathway.

BST-1 (bone marrow stromal cell antigen-1) is thought to be a key molecule involved in regulating the functional activity of cells in various tissues and organs. BST-1 can catalyze the hydrolysis of nicotinamide adenine dinucleotide (NAD+) to produce cyclic ADP ribose (cADPR), which activates the activity of intracellular Ca2+ signaling. Currently, the role of BST-1 regulation of Ca2+ signaling pathway in pathological myocardial hypertrophy is unclear. We found elevated expression of BST-1 in cardiac hypertrophy tissues of spontaneously hypertensive rats in our vivo study, subsequently; the mechanism of BST-1 action on myocardial hypertrophy was explored in vitro experiment. We used aldosterone (ALD) to induce H9C2 cellular hypertrophy. cADPR levels and intracellular Ca2+ concentrations declined and calcium-regulated neurophosphatase (CaN) activity and protein expression were decreased after BST-1 knockdown. And then activated T-cell nuclear factor (NFATc3) entry nucleus was inhibited. All of the above resulted in that H9C2 cells size was reduced by rhodamine-phalloidin staining. Thus, BST-1 may exacerbate cardiac hypertrophy by activating the Ca2+/CaN/NFATc3 pathway.

Knockdown of KAT5/KIF11 induces autophagy and promotes apoptosis in anaplastic thyroid cancer cells.

K (lysine) acetyltransferase (KAT) 5, which is a member of the KAT family of enzymes, has been found to act as a regulatory factor in various types of cancer. However, the role of KAT5 in anaplastic thyroid carcinoma (ATC) and its underlying mechanism is still elusive. The expression levels of KAT5 and kinesin family member 11 (KIF11) in ATC cells were assessed utilizing reverse transcription-quantitative PCR and western blot analyses. The cell proliferative ability was assessed via Cell Counting Kit-8 assay and using 5-ethynyl-2'-deoxyuridine staining. Flow cytometry and western blot analyses were applied for the assessment of cell apoptosis. Cell autophagy was investigated by employing western blot analysis and immunofluorescence staining. In addition, the enrichment of histone H3 lysine 27 acetylation (H3K27ac) and RNA polymerase II (RNA pol II) was analyzed by chromatin immunoprecipitation assay. It was shown that KAT5 expression was markedly increased in ATC cells. KAT5 depletion suppressed the cell proliferative capability but promoted the induction of apoptosis and autophagy. In addition, the autophagy inhibitor 3-methyladenine reversed the effects of KAT5 deficiency on the proliferative and apoptotic activities of 8505C cells. With regard to the mechanism, it was found that KAT5 inhibited the expression of KIF11 by repressing the enrichment of H3K27ac and RNA pol II. Upregulation of KIF11 expression reversed the effects of KAT5 silencing on the proliferative activity, apoptosis and autophagy of 8505C cells. In conclusion, the results indicated that KAT5 induced autophagy and promoted apoptosis of ATC cells by targeting KIF11, which may provide a promising target for the treatment of ATC.

eIF2α incites photoreceptor cell and retina damage by all-trans-retinal.

Dry age-related macular degeneration (AMD) and recessive Stargardt's disease (STGD1) lead to irreversible blindness in humans. The accumulation of all-trans-retinal (atRAL) induced by chaos in visual cycle is closely associated with retinal atrophy in dry AMD and STGD1 but its critical downstream signaling molecules remain ambiguous. Here, we reported that activation of eukaryotic translation initiation factor 2α (eIF2α) by atRAL promoted retinal degeneration and photoreceptor loss through activating c-Jun N-terminal kinase (JNK) signaling-dependent apoptosis and gasdermin E (GSDME)-mediated pyroptosis. We determined that eIF2α activation by atRAL in photoreceptor cells resulted from endoplasmic reticulum homeostasis disruption caused at least in part by reactive oxygen species production, and it activated JNK signaling independent of and dependent on activating transcription factor 4 and the activating transcription factor 4/transcription factor C/EBP homologous protein (CHOP) axis. CHOP overexpression induced apoptosis of atRAL-loaded photoreceptor cells through activating JNK signaling rather than inhibiting the expression of antiapoptotic gene Bcl2. JNK activation by eIF2α facilitated photoreceptor cell apoptosis caused by atRAL via caspase-3 activation and DNA damage. Additionally, we demonstrated that eIF2α was activated in neural retina of light-exposed Abca4-/-Rdh8-/- mice, a model that shows severe defects in atRAL clearance and displays primary features of human dry AMD and STGD1. Of note, inhibition of eIF2α activation by salubrinal effectively ameliorated retinal degeneration and photoreceptor apoptosis in Abca4-/-Rdh8-/- mice upon light exposure. The results of this study suggest that eIF2α is an important target to develop drug therapies for the treatment of dry AMD and STGD1.

Effect of nitric oxide synthase gene polymorphism on inflammatory response in patients with chronic obstructive pulmonary disease.

This study aimed to investigate the association between nitric oxide synthase gene polymorphisms and the inflammatory responses in patients with 'fast-' and 'slow-' developing chronic obstructive pulmonary disease (COPD). In the main process, 190 patients with slow-developing COPD, 94 patients with fast-developing COPD and 105 healthy volunteers were selected for inclusion. Endothelial nitric oxide synthase (eNOS) was detected using western-blot eNOS sites, and inducible nitric oxide synthase (iNOS) was detected through SNPshot. T helper 17 cells (Th17) and regulator T (Treg) cells were detected via flow cytometry, and interferon-gamma, tumour necrosis factor-alpha, interleukin (IL)-17, IL-10, IL-6, IL-4 and IL-2 were detected using a cytometric bead array. The final results and conclusions drawn from the tests suggest that Th17/Treg-mediated immune inflammation plays an important role in the pathogenesis of COPD, but whether it affects the development of COPD needs further investigation. Overall, COPD patients with a young age of onset, young age of smoking initiation and small body mass index, as well as COPD patients with CC at rs3729508 in the iNOS gene and non-GG at rs7830 in the eNOS gene, may be more likely to contract fast-developing COPD.

Copper-mediated chemodynamic therapy with ultra-low copper consumption by doping cupric ion on cross-linked (R)-(+)-lipoic acid nanoparticles.

Cu-mediated chemodynamic therapy (CDT) has attracted prominent attention owing to its advantages of pH independence and high efficiency comparing to Fe-mediated CDT, while the application of Cu-based CDT agents was impeded due to the high copper consumption caused by the metabolism loss of copper and the resultant potential toxicity. Herein, we developed a new copper-mediated CDT agent with extremely low Cu usage by anchoring copper on cross-linked lipoic acid nanoparticles (Cu@cLAs). After endocytosis into tumor cells, the Cu@cLAs were dissociated into LA and dihydrolipoic acid (DHLA) (reduced form of LA) and released Cu2+ and Cu+ (oxidized form of Cu2+), the two redox couples recycled each other in cells to achieve the efficient killing of cancer cells by delaying metabolic loss and increasing the ROS level of tumor cells. The self-recycling was confirmed in cells by the sustained high Cu/DHLA content and persistent ROS generation process. The antitumor study based on the MCF-7/R nude mice gave the Cu@cLAs a tumor inhibitory rate up to 77.9% at the copper of 0.05 mg kg-1, the first dosage reported so far lower than that of normal serum copper (0.83 ± 0.21 mg kg-1). This work provides not only a new promising clinical strategy for the copper excessive use in copper-mediated CDT, but also gives a clue for other metal mediated disease therapies with the high metal consumption.

Nanodrug constructed using dietary antioxidants for immunotherapy of metastatic tumors.

Immunogenic cell death (ICD) induced by reactive oxygen species (ROS) represents a particular form of tumor cell death for approaching the problem of low immunogenicity of tumors in immunotherapy, while the oxidative damage to normal cells of current ICD inducers hinders their clinical application. Herein, a new ICD inducer VC@cLAV constructed solely by dietary antioxidants, lipoic acid (LA) and vitamin C (VC), is developed, which could promote heavy intracellular ROS production in cancer cells for ICD induction while acting as an anti-oxidant in non-cancer cells for cytoprotection, and thus hold high biosafety. In vitro studies show that VC@cLAV induced a release of antigens and a maturation rate of DCs up to 56.5%, approaching the positive control (58.4%). In vivo combined with αPD-1, VC@cLAV showed excellent antitumor activity against both primary and distant metastatic tumors with an inhibition rate of 84.8% and 79.0% compared to 14.2% and 10.0% in the αPD-1 alone group. Notably, VC@cLAV established a long-term antitumor immune memory effect against tumor rechallenging. This study not only presents a new kind of ICD inducer but also provides an impetus for the development of dietary antioxidant-based cancer drugs.

Effect of palmitoylethanolamide on degeneration of a human-derived retinal pigment epithelial cell induced by all-trans retinal.

AIM: To study the effect of palmitoylethanolamide (PEA) on apoptosis of retinal pigment epithelial (RPE) cells induced by all-trans retinal (atRAL) and to explore the possible molecular mechanism. METHODS: CellTiter 96® Aqueous One Solution Cell Proliferation Assay (MTS) was used to detect the effect of PEA on human-derived retinal epithelial cells (ARPE-19) viability induced by atRAL. A Leica DMi8 inverted microscope was used to observe cell morphology. Reactive oxygen species (ROS) production was evaluated with 2',7'-dichlorodihydrof-luorescein diacetate (H2DCFDA) staining and fluorescence microscopy. Expression of c-Jun N-terminal kinase (JNK), phosphorylated JNK (p-JNK), c-Jun, phosphorylated c-Jun (p-c-Jun), Bak, cleaved caspase-3, C/EBP homologous protein (CHOP), and binding (Bip) protein levels were tested by Western blot. Abca4 -/- Rdh8 -/- mice, mouse models of atRAL clearance defects which displays some symbolic characteristics of dry age-related macular degeneration (AMD) and Stargardt disease (STGD1). In the animal models, PEA was injected intraperitoneally. The full-field electroretinogram was used to detect visual function under scotopic conditions traced from mice. Optical coherence tomography showed reconstitution or thickening of the retinal pigment epithelium layer. Effect of PEA on fundus injury induced by light in Abca4-/-Rdh8-/- mice was observed by fundus photography. RESULTS: PEA ameliorated ARPE-19 cells apoptosis and inhibited ROS (including mitochondrial ROS) production induced by atRAL. PEA improved the retinal functional, prohibited both RPE and photoreceptor from death, ameliorates light-induced fundus impairment in Abca4 -/- Rdh8 -/- mice. In vitro and in vivo, PEA inhibited JNK, p-JNK, c-Jun, p-c-Jun, Bak, cleaved caspase-3, CHOP, and Bip protein levels induced by all-trans retinal in ARPE-19 cells. CONCLUSION: PEA has effect on treating RPE cells apoptosis in retinopathy caused by atRAL accumulation. PEA is a potential treatment strategy for dry AMD and STGD1. The molecular mechanism is affecting the ROS-JNK-CHOP signaling pathway partly.

Aspirin-Loaded Cross-Linked Lipoic Acid Nanodrug Prevents Postoperative Tumor Recurrence by Residual Cancer Cell Killing and Inflammatory Microenvironment Improvement.

In addition to residual cancer cells, the surgery resection-induced hyperinflammatory microenvironment is a key factor that leads to postsurgical cancer recurrence. Herein, we developed a dual-functional nanodrug Asp@cLANVs for postsurgical recurrence inhibition by loading the classical anti-inflammatory drug aspirin (Asp) into cross-linked lipoic acid nanovesicles (cLANVs). The Asp@cLANVs can not only kill residual cancer cells at the doses comparable to common cytotoxic drugs by synergistic interaction between Asp and cLANVs, but also improve the postsurgical inflammatory microenvironment by their strongly synergistic anti-inflammation activity between Asp and cLANVs. Using mice bearing partially removed NCI-H460 tumors, we found that Asp@cLANVs gave a much lower recurrence rate (33.3%) compared with the first-line cytotoxic drug cisplatin (100%), and no mice died for at least 60 days after Asp@cLANV treatment while no mouse survived beyond day 43 in the cisplatin group. This dual-functional nanodrug constructs the first example that combines residual cancer cell killing and postoperative inflammation microenvironment improvement to suppress postsurgical cancer recurrence.

Primary Culture of Porcine Retinal Pigment Epithelial Cells.

The retinal pigment epithelium (RPE) is a monolayer of polarized pigmented epithelial cells, located between the choroid and neuroretina in the retina. Multiple functions, including phagocytosis, nutrient/metabolite transportation, vitamin A metabolism, etc., are conducted by the RPE on a daily basis. RPE cells are terminally differentiated epithelial cells with little or no regenerative capacity. Loss of RPE cells results in multiple eye diseases leading to visual impairment, such as age-related macular degeneration. Therefore, the establishment of an in vitro culture model of primary RPE cells, which more closely resembles the RPE in vivo than cell lines, is critical for the characteristic and mechanistic studies of RPE cells. Considering the fact that the source of human eyeballs is limited, we create a protocol to culture primary porcine RPE cells. By using this protocol, RPE cells can be easily dissociated from adult porcine eyeballs. Subsequently, these dissociated cells attach to culture dishes/inserts, proliferate to form a confluent monolayer, and quickly re-establish key features of epithelial tissue in vivo within 2 wks. By qRT-PCR, it is demonstrated that primary porcine RPE cells express multiple signature genes at comparable levels with native RPE tissue, while the expressions of most of these genes are lost/highly reduced in human RPE-like cells, ARPE-19. Moreover, the immunofluorescence staining shows the distribution of tight junction, tissue polarity, and cytoskeleton proteins, as well as the presence of RPE65, an isomerase critical for vitamin A metabolism, in cultured primary cells. Altogether, we have developed an easy-to-follow approach to culture primary porcine RPE cells with high purity and native RPE features, which could serve as a good model to understand RPE physiology, study cell toxicities, and facilitate drug screenings.

Dietary Antioxidant-Constructed Nanodrugs Can High-Efficiently Kill Cancer Cells while Protecting Noncancer Cells.

Despite great advances, the development of cancer drugs that can efficiently kill cancer cells while protecting noncancer cells has not been achieved. By using only dietary antioxidants vitamin C (VC) and (R)-(+)-lipoic acid (LA), we herein develop a nanodrug VC@cLAV featuring the above function. After entering cells, cLAV dissociates into LA and DHLA (dihydrolipoic acid, reduced form of LA) and releases VC and DHA (dehydroascorbate, oxidized form of VC). In cancer cells, the two redox pairs recycle each other and dramatically promote the intracellular reactive oxygen species production to kill cancer cells at low doses comparable to cytotoxic drugs. Oppositely in noncancer cells, the LA/DHLA and VC/DHA pairs exert anti-oxidant action to actively protect the organism by preventing the normal cells from oxidative stress and repairing cells suffering from oxidative stress. When compared with the first-line cytotoxic drug, VC@cLAV displayed superior therapeutic outcomes yet without side effects in diverse tumor models including patient-derived xenograft (PDX). This drug with efficient cancer cell killing and noncancer cell protection represents a new cancer therapy.

A mechanism for oxidative damage repair at gene regulatory elements.

Oxidative genome damage is an unavoidable consequence of cellular metabolism. It arises at gene regulatory elements by epigenetic demethylation during transcriptional activation1,2. Here we show that promoters are protected from oxidative damage via a process mediated by the nuclear mitotic apparatus protein NuMA (also known as NUMA1). NuMA exhibits genomic occupancy approximately 100 bp around transcription start sites. It binds the initiating form of RNA polymerase II, pause-release factors and single-strand break repair (SSBR) components such as TDP1. The binding is increased on chromatin following oxidative damage, and TDP1 enrichment at damaged chromatin is facilitated by NuMA. Depletion of NuMA increases oxidative damage at promoters. NuMA promotes transcription by limiting the polyADP-ribosylation of RNA polymerase II, increasing its availability and release from pausing at promoters. Metabolic labelling of nascent RNA identifies genes that depend on NuMA for transcription including immediate-early response genes. Complementation of NuMA-deficient cells with a mutant that mediates binding to SSBR, or a mitotic separation-of-function mutant, restores SSBR defects. These findings underscore the importance of oxidative DNA damage repair at gene regulatory elements and describe a process that fulfils this function.

Bacterial Colonization on Healthcare Workers' Mobile Phones and Hands in Municipal Hospitals of Chongqing, China: Cross-contamination and Associated Factors.

BACKGROUND: Mobile phones are widely used in clinical settings and could be colonized by potential pathogenic bacteria which may lead to hospital-acquired infections (HAIs) transmission. This study aimed to determine the prevalence of bacterial contamination of healthcare workers' (HCWs) mobile phones, identify bacterial isolates, and assess the factors associated with mobile phone contamination. METHODS: Self-administered questionnaire was used to collect the information on the demographic characteristics and the use of mobile phones. A total of 111 HCWs' hands and their mobile phones were swabbed, then bacterial culture, isolation, and identification were performed. Univariate and multivariable logistic regression were applied to identify factors associated with mobile phone bacterial contamination. RESULTS: Totally 106 (95.5%) of the 111 mobile phones investigated were contaminated with bacteria. Staphylococcus epidermidis (13/111), Acinetobacter baumannii (4/111) and Staphylococcus aureus (3/111) were the predominant bacterial isolates from HCWs' mobile phones. Univariate analyses showed that age, gender, profession and the frequency of mobile phone utilization were significantly associated with the number of bacterial colonization. Frequency of phone utilization (OR 8.366; 95% CI 1.496-46.797) was found to be the most significant factors associated with the qualified rate of mobile phones bacterial load. In addition, phone cover using was associated with the increased risk of mobile phone bacterial contamination. CONCLUSION: There was cross-contamination between hands and phones. It is necessary to develop guidelines for mobile phone cleaning. Special attention needs to be paid to the disinfection of mobile phone covers to reduce contamination and transmission of pathogens.