Axl is a cell surface receptor tyrosine kinase, and activation of the Axl attenuates inflammation induced by various stimuli. Growth arrest-specific 6 (Gas6) has high affinity for Axl receptor. The ...role of Gas6/Axl signaling in ischemia-reperfusion-induced acute lung injury (IR-ALI) has not been explored previously. We hypothesized that Gas6/Axl signaling regulates IR-induced alveolar inflammation via a pathway mediated by suppressor of cytokine signaling 3 (SOCS3).
IR-ALI was induced by producing 30 min of ischemia followed by 90 min of reperfusion in situ in an isolated and perfused rat lung model. The rats were randomly allotted to a control group and IR groups, which were treated with three different doses of Gas6. Mouse alveolar epithelium MLE-12 cells were cultured in control and hypoxia-reoxygenation (HR) conditions with or without Gas6 and Axl inhibitor R428 pretreatment.
We found that Gas6 attenuated IR-induced lung edema, the production of proinflammatory cytokines in perfusates, and the severity of ALI ex vivo. IR down-regulated SOCS3 expression and up-regulated NF-κB, and Gas6 restored this process. In the model of MLE-12 cells with HR, Gas6 suppressed the activation of TRAF6 and NF-κB by up-regulating SOCS3. Axl expression of alveolar epithelium was suppressed in IR-ALI but Gas6 restored phosphorylation of Axl. The anti-inflammatory effect of Gas6 was antagonized by R428, which highlighted that phosphorylation of Axl mediated the protective role of Gas6 in IR-ALI.
Gas6 up-regulates phosphorylation of Axl on alveolar epithelium in IR-ALI. The Gas6/Axl signaling activates the SOCS3-mediated pathway and attenuates IR-related inflammation and injury.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
MicroRNAs (miRNAs) have a major impact on regulatory networks in human carcinogenesis. In this study, we sought to investigate the prognostic significance of miRNAs in patients with oral cavity ...squamous cell carcinoma (OSCC). In a discovery phase, RNA was extracted from 58 OSCC tumor samples and paired normal tissues. MiRNAs expression was evaluated with TaqMan Array Card and TaqMan MicroRNA assays. The prognostic significance of the miRNA signature identified in the discovery phase was validated by qRT-PCR in a replication set consisting of 141 formalin-fixed, paraffin-embedded (FFPE) samples. We identified a miRNA regulatory network centered on the three hub genes (SP1, MYC, and TP53) that predicted distinct clinical endpoints. Three miRNAs (miR-218, miR-125b, and let-7g) and their downstream response genes had a concordant prognostic significance on disease-free survival and disease-specific survival rates. In addition, patients with a reduced expression of miR-218, miR-125b, and let-7g have a higher risk of poor outcomes in presence of specific risk factors (p-stage III-IV, pT3-4, or pN+). Our findings indicate that specific miRNAs have prognostic significance in OSCC patients and may improve prognostic stratification over traditional risk factors.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Multistage tumorigenesis is a dynamic process characterized by the accumulation of mutations. Thus, a tumor mass is composed of genetically divergent cell subclones. With the advancement of ...next-generation sequencing (NGS), mathematical models have been recently developed to decompose tumor subclonal architecture from a collective genome sequencing data. Most of the methods focused on single-nucleotide variants (SNVs). However, somatic copy number aberrations (CNAs) also play critical roles in carcinogenesis. Therefore, further modeling subclonal CNAs composition would hold the promise to improve the analysis of tumor heterogeneity and cancer evolution. To address this issue, we developed a two-way mixture Poisson model, named CloneDeMix for the deconvolution of read-depth information. It can infer the subclonal copy number, mutational cellular prevalence (MCP), subclone composition, and the order in which mutations occurred in the evolutionary hierarchy. The performance of CloneDeMix was systematically assessed in simulations. As a result, the accuracy of CNA inference was nearly 93% and the MCP was also accurately restored. Furthermore, we also demonstrated its applicability using head and neck cancer samples from TCGA. Our results inform about the extent of subclonal CNA diversity, and a group of candidate genes that probably initiate lymph node metastasis during tumor evolution was also discovered. Most importantly, these driver genes are located at 11q13.3 which is highly susceptible to copy number change in head and neck cancer genomes. This study successfully estimates subclonal CNAs and exhibit the evolutionary relationships of mutation events. By doing so, we can track tumor heterogeneity and identify crucial mutations during evolution process. Hence, it facilitates not only understanding the cancer development but finding potential therapeutic targets. Briefly, this framework has implications for improved modeling of tumor evolution and the importance of inclusion of subclonal CNAs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The preservation of indoor environmental quality (IEQ) is key to the well-being and productivity of office occupants. In Taiwan, the green building certification system established IEQ criteria to ...evaluate the performance of buildings in acoustics, lighting, ventilation and decoration but not the performance in delivering thermal comfort. This study investigated and compared the green and conventional office buildings in middle Taiwan on various aspects of IEQ during a period of active air-conditioning use. Among the monitored environmental variables, the levels of noise, illumination, and carbon dioxide in both types of buildings were in compliance with international or Taiwan's regulatory standards, but not that of volatile organic compounds. The degrees of overall IEQ satisfaction as well as the proportion of occupants voting for satisfaction in the green buildings were both greater than their counterparts in the conventional buildings. Of the specific areas of IEQ evaluated, including the acoustics, lighting, perception of thermal comfort of the occupants toward the thermal environment, and indoor air quality, a statistically significant difference was found between the mean score of satisfaction in the green buildings and that in the conventional buildings. The occupants sharing a concern on energy conservation were more amenable to slightly deficient IEQ. The system of green building certification in Taiwan was able to facilitate proper IEQ performance of the buildings, although a re-visit of the current criteria to incorporate thermal comfort-related criteria may be adequate.
•We evaluated indoor environmental quality in relation to green buildings in Taiwan.•Green buildings provided better quality in temp, illumination, CO2/VOC concentration.•Occupants in green buildings were more satisfied with overall environmental quality.•Thermal comfort evaluation in Taiwan's green building certification may be needed.
Molecular methods for predicting prognosis in patients with oral cavity squamous cell carcinoma (OSCC) are urgently needed, considering its high recurrence rate and tendency for metastasis. The ...present study investigated the genetic basis of variations in gene expression associated with poor prognosis in OSCC using Affymetrix SNP 6.0 and Affymetrix GeneChip Human Gene 1.0 ST arrays. We identified recurrent DNA amplifications scattered from 8q22.2 to 8q24.3 in 112 OSCC specimens. These amplicons demonstrated significant associations with increased incidence of extracapsular spread, development of second primary malignancies, and poor survival. Fluorescence in situ hybridization, in a validation panel consisting of 295 cases, confirmed these associations. Assessment of the effects of copy number variations (CNVs) on genome-wide variations in gene expression identified a total of 85 CNV-associated transcripts enriched in the MYC-centered regulatory network. Twenty-four transcripts associated with increased risk of second primary malignancies, tumor relapse, and poor survival. Besides MYC itself, a novel dysregulated MYC module plays a key role in OSCC carcinogenesis. This study identified a candidate molecular signature associated with poor prognosis in OSCC patients, which may ultimately facilitate patient-tailored selection of therapeutic strategies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In the context of behavior recognition, the emerging bed-exit monitoring system demands a rapid deployment in the ward to support mobility and personalization. Mobility means the system can be ...installed and removed as required without construction; personalization indicates human body tracking is limited to the bed region so that only the target is monitored. To satisfy the above-mentioned requirements, the behavior recognition system aims to: (1) operate in a small-size device, typically an embedded system; (2) process a series of images with narrow fields of view (NFV) to detect bed-related behaviors. In general, wide-range images are preferred to obtain a good recognition performance for diverse behaviors, while NFV images are used with abrupt activities and therefore fit single-purpose applications. This paper develops an NFV-based behavior recognition system with low complexity to realize a bed-exit monitoring application on embedded systems. To achieve effectiveness and low complexity, a queueing-based behavior classification is proposed to keep memories of object tracking information and a specific behavior can be identified from continuous object movement. The experimental results show that the developed system can recognize three bed behaviors, namely off bed, on bed and return, for NFV images with accuracy rates of 95~100%.
Abstract
Dysbiosis of oral microbiome may dictate the progression of oral squamous cell carcinoma (OSCC). Yet, the composition of oral microbiome fluctuates by saliva and distinct sites of oral ...cavity and is affected by risky behaviors (smoking, drinking and betel quid chewing) and individuals’ oral health condition. To characterize the disturbances in the oral microbial population mainly due to oral tumorigenicity, we profiled the bacteria within the surface of OSCC lesion and its contralateral normal tissue from discovery (n = 74) and validation (n = 42) cohorts of male patients with cancers of the buccal mucosa. Significant alterations in the bacterial diversity and relative abundance of specific oral microbiota (most profoundly, an enrichment for genus Fusobacterium and the loss of genus Streptococcus in the tumor sites) were identified. Functional prediction of oral microbiome shown that microbial genes related to the metabolism of terpenoids and polyketides were differentially enriched between the control and tumor groups, indicating a functional role of oral microbiome in formulating a tumor microenvironment via attenuated biosynthesis of secondary metabolites with anti-cancer effects. Furthermore, the vast majority of microbial signatures detected in the discovery cohort was generalized well to the independent validation cohort, and the clinical validity of these OSCC-associated microbes was observed and successfully replicated. Overall, our analyses reveal signatures (a profusion of Fusobacterium nucleatum CTI-2 and a decrease in Streptococcus pneumoniae) and functions (decreased production of tumor-suppressive metabolites) of oral microbiota related to oral cancer.
We demonstrated that oral microbiota is compositionally and functionally associated with the development of oral cancer. Our study implicates specific oral microbes as a potential biomarker for early diagnosis and prognosis monitoring of this deadly malignancy.
The bulk matrix domain of the Martian breccia NWA 7034 was examined petrographically and isotopically to better understand the provenance and age of the source material that make up the breccia. Both ...147Sm‐143Nd and 146Sm‐142Nd age results for mineral separates from the bulk matrix portion of breccia NWA 7034 suggest that various lithological components in the breccia probably formed contemporaneously ~4.44 Ga ago. This old age is in excellent agreement with the upper intersection ages (4.35–4.45 Ga) for U‐Pb discordia and also concordia defined by zircon and baddeleyite grains in matrix and igneous‐textured clasts. Consequently, we confirm an ancient age for the igneous components that make up the NWA 7034 breccia. Substantial disturbance in the Rb‐Sr system was detected, and no age significance could be gleaned from our Rb‐Sr data. The disturbance to the Rb‐Sr system may be due to a thermal event recorded by bulk‐rock K‐Ar ages of 1.56 Ga and U‐Pb ages of phosphates at about 1.35–1.5 Ga, which suggest partial resetting from an unknown thermal event(s), possibly accompanying breccia formation. The NWA 7034 bulk rock is LREE enriched and similar to KREEP‐rich lunar rocks, which indicates that the earliest Martian crust was geochemically enriched. This enrichment supports the idea that the crust is one of the enriched geochemical reservoirs on Mars that have been detected in studies of other Martian meteorites.
Formal volunteering holds great importance for the recipients of volunteer services, individuals who volunteer, and the wider society. However, how much recent birth cohorts volunteer in middle and ...late adulthood compared with earlier birth cohorts is not well understood. Even less well-known are the age and cohort trends in informal helping provided to friends and neighbors in later adulthood. Using longitudinal data from the Health and Retirement Study, we estimated age and cohort trends in formal volunteering and informal helping from 1998 to 2018 for a wide range of birth cohorts born between 1909 and 1958. We used multivariate, multilevel models based on Bayesian generalized modeling methods to estimate the probabilities of volunteering and informal helping simultaneously in a single model. Despite having advantages in human and health capital, recent birth cohorts showed volunteering levels in late adulthood that are similar to those of their predecessors. Moreover, more recent birth cohorts were consistently less engaged in informal helping than earlier birth cohorts throughout the observation period. More research is needed to illuminate the sociocultural drivers of changes in helping behaviors and overall prosocial and civic engagement.
With the increasing use of targeted anticancer drugs and immunotherapies, there have been a substantial number of reports concerning life-threatening severe cutaneous adverse reactions (SCARs), ...including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms, drug-induced hypersensitivity syndrome, and acute generalized exanthematous pustulosis. Although the potential risks and characteristics for targeted anticancer agent- and immunotherapy-induced SCAR were not well understood, these serious adverse reactions usually result in morbidity and sequela. As a treatment guideline for this devastating condition is still unavailable, prompt withdrawal of causative drugs is believed to be a priority of patient management. In this review, we outline distinct types of SCARs caused by targeted anticancer therapies and immunotherapies. Also, we discuss the clinical course, latency, concomitant medication, tolerability of rechallenge or alternatives, tumor response, and mortality associated with these devastating conditions. Imatinib, vemurafenib, and rituximab were the top three offending medications that most commonly caused SJS/TEN, while EGFR inhibitors were the group of drugs that most frequently induced SJS/TEN. For drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome and acute generalized exanthematous pustulosis, imatinib was also the most common offending drug. Additionally, we delineated 10 SCAR cases related to innovative immunotherapies, including PD1 and CTLA4 inhibitors. There was a wide range of latency periods: 5.5-91 days (median). Only eight of 16 reported patients with SCAR showed clinical responses. Targeted anticancer drugs and immunotherapies can lead to lethal SCAR (14 deceased patients were identified as suffering from SJS/TEN). The mortality rate of TEN was high: up to 52.4%. The information compiled herein will serve as a solid foundation to formulate ideas for early recognition of SCAR and to discontinue offending drugs for better management.
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