Proper chromatin function and maintenance of genomic stability depends on spatiotemporal coordination between the transcription and replication machinery. Loss of this coordination can lead to DNA ...damage from increased transcription-replication collision events. We report that deregulated transcription following BRD4 loss in cancer cells leads to the accumulation of RNA:DNA hybrids (R-loops) and collisions with the replication machinery causing replication stress and DNA damage. Whole genome BRD4 and γH2AX ChIP-Seq with R-loop IP qPCR reveals that BRD4 inhibition leads to accumulation of R-loops and DNA damage at a subset of known BDR4, JMJD6, and CHD4 co-regulated genes. Interference with BRD4 function causes transcriptional downregulation of the DNA damage response protein TopBP1, resulting in failure to activate the ATR-Chk1 pathway despite increased replication stress, leading to apoptotic cell death in S-phase and mitotic catastrophe. These findings demonstrate that inhibition of BRD4 induces transcription-replication conflicts, DNA damage, and cell death in oncogenic cells.
Lung cancer remains a major health problem despite the considerable research into prevention and treatment methods. Through a deeper understanding of tumors, patient‐specific ex vivo spheroid models ...with high specificity can be used to accurately investigate the cause, metastasis, and treatment strategies for lung cancer. Biofabricate lung tumors are presented, consisting of patient‐derived tumor spheroids, endothelial cells, and lung decellularized extracellular matrix, which maintain a radial oxygen gradient, as well as biophysicochemical behaviors of the native tumors for precision medicine. It is also demonstrated that the developed lung‐cancer spheroid model reproduces patient responses to chemotherapeutics and targeted therapy in a co‐clinical trial, with 85% accuracy, 86.7% sensitivity, and 80% specificity. RNA sequencing analysis validates that the gene expression in the spheroids replicates that in the patient's primary tumor. This model can be used as an ex vivo predictive model for personalized cancer therapy and to improve the quality of clinical care.
A facile route to construct a highly accurate sophisticated ex vivo lung tumor spheroid model for considering patient‐specific therapies. The LdECM provides native‐tissue‐mimetic physicochemical cues that support the organization of spheroids with a hypoxic signature. The developed patient‐derived tumor spheroid model for the prediction of the optimal chemotherapy or target therapy drug for the patient.
There are some limitations of standard chemotherapy for acute leukemia. Vincristine and doxorubicin are commonly used for acute leukemia, but they may induce serious side effects such as ...cardiomyopathy and neurotoxicity. Furthermore, chemotherapy resistance occurs more and more frequently. Therefore, effective treatment strategies are needed. Histone deacetylase 6 inhibition is considered as a potential therapeutic strategy for acute leukemia, since it is observed that HDAC6 is overexpressed in acute leukemia and regulates tumor survival. Combination therapy for cancer is used to minimize adverse drug effects, reduce drug dosage, enhance efficacy, and prevent drug resistance. In order to improve efficacy of chemotherapy agents of acute leukemia, this study will investigate the effects of combination MPT0G211, a novel histone deacetylase 6 inhibitor, with doxorubicin or vincristine on human acute leukemia cells.
MPT0G211 combined with doxorubicin induces DNA damage response on human acute myeloid leukemia cells. MPT0G211 can additionally increase Ku70 acetylation and release BAX to mitochondria. Ectopic expression of HDAC6 successively reversed the apoptosis triggered by the combined treatment. Moreover, co-treatment of MPT0G211 and vincristine may alter microtubule dynamics, triggering acute lymphoblastic leukemia cells arrest in mitotic phase followed by induction of the apoptotic pathway. Finally, MPT0G211 plus doxorubicin or vincristine can significantly improve the tumor growth delay in a tumor xenograft model.
Collectively, our data highlighted that MPT0G211 in combination with chemotherapy drugs has significant anticancer activity, suggesting a novel strategy for the treatment of acute leukemia.
Background： Atopic dermatitis （AD） is an inflammatory skin disease characterized by chronic recurrent dermatitis with profound itching. Most patients have personal and/or family history of atopic ...diseases. Several criteria have been proposed for the diagnosis of AD. Although the clinical features of childhood AD have been widely studied, there has been less large-scale study on adult/adolescent AD. The aim of this study was to investigate the clinical features of adult/adolescent patients with chronic symmetrical eczemaJAD and to propose Chinese diagnostic criteria for adult/adolescent AD. Methods： A hospital-based study was performed. Forty-two dermatological centers participated in this study. Adult and adolescent patients （12 years and over） with chronic symmetrical eczema or AD were included in this study. Questionnaires were completed by both patients and-investigators. The valid questionnaires were analyzed using EpiData 3.1 and SPSS 17.0 software. Results： A total of 2662 valid questionnaires were collected （1369 male and 1293 female）. Of all 2662 patients, 2062 （77.5%） patients had the disease after 12 years old, while only 600 （22.5%） patients had the disease before 12 years old, suggesting late-onset eczema/AD is common. Two thousand one hundred and thirty-nine （80.4%） patients had the disease for more than 6 months. One thousand one hundred and forty-four （43.0%） patients had a personal and/or family history of atopic diseases. One thousand five hundred and forty-eight （58.2%） patients had an elevated total serum IgE and/or eosinophilia and/or positive allergen-specific IgE. Based on these clinical and laboratory features, we proposed Chinese criteria for adult/adolescent AD. Of all 2662 patients, 60.3% were satisfied with our criteria, while only 48.2% satisfied with Hanifin Rajka criteria and 32.7% satisfied with Williams criteria, suggesting a good sensitivity of our criteria in adult/adolescent AD patients. Conclusion： Late-onset of eczema or AD is common. The clinical manifestations of AD are heterogeneous. We have proposed Chinese diagnostic criteria for adolescent and adult AD, which are simple and sensitive for diagnosis of adult/adolescent AD.
The microbial profiles of peri-implantitis and periodontitis (PT) are inconclusive. The controversies mainly arise from the differences in sampling sites, targeted gene fragment, and microbiome ...analysis techniques. The objective of this study was to explore the microbiomes of peri-implantitis (PI), control implants (CI), PT and control teeth (CT), and the microbial change of PI after nonsurgical treatment (PIAT).
Twenty-two patients diagnosed with both PT and peri-implantitis were recruited. Clinical periodontal parameters and radiographic bone levels were recorded. In each patient, the subgingival and submucosal plaque samples were collected from sites with PI, CI, PT, CT, and PIAT. Microbiome diversity was analyzed by high-throughput amplicon sequencing using full-length of 16S rRNA gene by next generation sequencing.
The 16S rRNA gene sequencing analysis revealed 512 OTUs in oral microbiome and 377 OTUs reached strain levels. The PI and PT groups possessed their own unique core microbiome. Treponema denticola was predominant in PI with probing depth of 8-10 mm. Interestingly, Thermovirga lienii DSM 17291 and Dialister invisus DSM 15470 were found to associate with PI. Nonsurgical treatment for peri-implantitis did not significantly alter the microbiome, except Rothia aeria.
Our study suggests Treponemas species may play a pivotal role in peri-implantitis. Nonsurgical treatment did not exert a major influence on the peri-implantitis microbiome in short-term follow-up. PT and peri-implantitis possess the unique microbiome profiles, and different therapeutic strategies may be suggested in the future.
•We show microRNA-210 promotes in vivo regeneration of adult mice sciatic nerve and in vitro axon regrowth from dissociated dorsal root ganglion (DRG) cultures.•We reveal a new in vivo ...electroporation approach to transfect siRNAs to DRG neurons.•We provide the first evidence miR-210-EFNA3 as a new signaling pathway can regulate sensory axon regeneration.
Axon regeneration as a critical step in nerve repairing and remodeling after peripheral nerve injury relies on regulation of gene expression. MicroRNAs are emerging to be important epigenetic regulators of gene expression to control axon regeneration. Here we used a novel in vivo electroporation approach to transfect microRNA-210 (miR-210) or siRNAs to adult mice dorsal root ganglion (DRG) neurons, measured the axon length 3days after sciatic nerve crush or dissociated DRG cultures in vitro to detect the effect of miR-210 in sensory axon regeneration. Importantly, we found that miR-210 overexpression could promote sensory axon regeneration and inhibit apoptsosis by ephrin-A3 (EFNA3). In addition, inhibition of endogenous miR-210 in DRG neurons impaired axon regeneration in vitro and in vivo, the regulatory effect of miR-210 was mediated by increased expression of EFNA3 because downregulation of EFNA3 fully rescued axon regeneration. We thus demonstrate that miR-210 is a new physiological regulator of sensory axon regeneration, and EFNA3 may be the functional target of miR-210. We conclude that miR-210 may play an important role in sensory axon regeneration.
Both psoriasis and periodontal diseases are characterized by an exaggerated immune response to the microbiota residing on epithelial surfaces. This study aimed to explore the associations between the ...severity of psoriasis and periodontal destruction in patients with psoriasis.
Thirty-three patients diagnosed with psoriasis were referred from the dermatology clinic of National Taiwan University Hospital. Full-mouth periodontal examination was performed and saliva was collected after patients signed informed consent forms. The Psoriasis Area Severity Index (PASI) as well as clinical periodontal parameters including probing depth (PD), plaque index (PI), gingival index (GI), and clinical attachment level (CAL) were evaluated. Salivary cytokines including interleukin (IL)-1β, IL-12, IL-17, interferon-γ, and tumor necrosis factor (TNF)-α were tested with the Luminex Bio-Plex system. Anti-inflammatory medication, tobacco use, and underlying comorbidities were included in the analysis.
Baseline PASI was significantly associated with PI. PASI at follow-up was positively correlated with CAL ≥ 4 mm (%) and saliva IL-1β levels. Psoriasis patients who used non-steroidal anti-inflammatory drugs or topical steroids had significantly lower GI, PD ≥ 4 mm (%), and saliva IL-1β and TNF-α levels. Moreover, a history of tobacco use was associated with higher PD ≥ 4 mm (%).
PI, CAL, and salivary IL-1β were associated with PASI. Periodontal severity was associated with psoriasis involvement. Periodontal inflammation in psoriasis may be modified by anti-inflammatory medication and tobacco use. Additional large-scale longitudinal and mechanistic studies are needed.
The acquisition of fine motor skills is considered to be a crucial developmental milestone throughout early childhood. This study aimed to investigate the fine motor performance of young children ...with different disability diagnoses.
We enrolled a sample of 1,897 young children under the age of 6 years who were at risk of developmental delays and were identified by a transdisciplinary team. A series of standardized developmental assessments included the Bayley Scales of Infant Development-Third Edition, Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition, Peabody Developmental Motor Scale-Second Edition, and Movement Assessment Battery for Children-Second Edition were used. Retrospective chart reviews were conducted on all children to identify specific developmental disorders. The number of autism spectrum disorder (ASD), intellectual disability (ID), attention-deficit/hyperactivity disorder (ADHD), comorbidity, motor dysfunction, and unspecified developmental delays (DD) were 363 (19.1%), 223 (11.8%), 234 (12.3%), 285 (15.0%), 128 (6.7%), and 590 (31.1%), respectively.
Young children with ID, comorbidity, and motor dysfunction demonstrated significant difficulty in performing manual dexterity and visual motor integration tasks and scored significantly lower in these areas than children with ASD, ADHD, and unspecified DD. In addition, fine motor performance was associated with cognitive ability in children with different disability diagnoses, indicating that young children showed better fine motor performance when they demonstrated better cognitive ability.
Our findings support that differences in fine motor performance differ by disability type. Close links between fine motor performance and cognitive ability in children under the age of 6 years were seen in all disability types.
Objective
Epidemiological studies suggested that individuals suffering from periodontitis present with greater prevalence of metabolic syndrome (MetS) and diabetes. We used a large health check‐up ...data set in Taiwan to investigate this association.
Design and methods
Data from 33,740 individuals, who undertook comprehensive health check‐up at a university hospital in Taipei, Taiwan, were analysed. The dental examinations were undertaken by experienced dentists, and the diagnosis of MetS was made according to the criteria defined by the Third Adult Treatment Panel of the National Cholesterol Education Program.
Results
After adjusting for potential confounders, females and males in the periodontitis group had higher levels of blood pressure, blood glucose, triglyceride and body mass index, but lower high‐density lipoprotein compared to controls. Females in the gingivitis and periodontitis group showed greater odds ratios 1.42 (95% CI: 1.30–1.56) and 1.52 (1.41–1.63) respectively of being diagnosed with MetS, whereas males in the gingivitis and periodontitis group presented with odds ratios of being diagnosed with MetS of 1.06 (0.94–1.18) and 1.04 (0.96–1.12) respectively.
Conclusions
A small but statistically significant association between MetS and the diagnosis of periodontal diseases was found in Taiwanese women and a weaker association in Taiwanese men.
•A method is proposed for extracting all drought events from long time series and constructing the 3D drought structure.•The 3D threshold isosurfaces are plotted to display the spatio-temporal ...distribution pattern of drought events.•The method can accurately identify mild drought events that are easily overlooked in the 3D clustering algorithm proposed previously.•The spatio-temporal evolution characteristics of meteorological drought in the Huai River basin for the period 1961–2015 are quantified.
Drought events often exhibit distinct spatio-temporal heterogeneity and coupling properties at different spatio-temporal scales. In previous studies, the spatial and temporal evolution of drought events were considered in a separate manner, and some mild drought events were likely to be missed in the identification process. This paper proposed a new drought structure extraction method for extracting all drought events from long time series data and constructing the 3D drought structure, and analyzed their spatio-temporal distribution patterns and characteristics under the interweaving of spatial and temporal dimensions. The 3D threshold isosurface was plotted to cluster temporally and spatially interconnected grid points, so that a 3D drought structure was formed to represent a drought event and describe the spatio-temporal distribution pattern in long time series and the spatial–temporal variability in the development process. On this basis, the geometric and physical characteristics inside and outside the drought structure were analyzed using seven characteristic indicators, such as drought duration, drought area, drought mass, drought volume, drought density, drought aggregation index, and longitude and latitude coordinates of drought centroid. The meteorological drought events in the Huai River basin for the period 1961–2015 were identified and their spatio-temporal distribution pattern and variation were characterized. Finally, Pearson correlation analysis, M−K trend analysis and wavelet analysis were performed to quantify the evolution of drought events. The results show that (1) the drought structure extraction method can reflect the spatio-temporal evolution characteristics and the development trend of multiple drought events according to the outer contour, the internal color and the migration of the location of the drought structure; (2) the drought area in the Huai River basin shows a decreasing trend, but the severity shows an increasing trend due to the increase in drought duration and intensity, and thus the shape of the drought structure is slender and the spatial distribution of drought events becomes more discrete; and (3) there is a good agreement in the identification between the 3D clustering method and the drought structure extraction method. However, the drought structure extraction method can accurately identify mild drought events that are easily overlooked in the 3D clustering method. The proposed drought structure extraction method has the potential to review the development and evolution trend of drought events and thus it is of practical significance for drought mitigation.
PDF
