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Abstract Background Protein phosphatase 2A (PP2A) is one of the major protein phosphatases in eukaryotic cells and is essential for cellular homeostasis. PP2A is a heterotrimer comprising the dimeric AC core enzyme and a highly variable regulatory B subunit. Distinct B subunits help the core enzyme gain full activity toward specific substrates and contribute to diverse cellular roles of PP2A. PP2A has been thought to play a tumor suppressor and the B56γ3 regulatory subunit was shown to play a key tumor suppressor regulatory subunit of PP2A. Nevertheless, we uncovered a molecular mechanism of how B56γ3 may act as an oncogene in colorectal cancer (CRC). Methods Polyclonal pools of CRC cells with stable B56γ3 overexpression or knockdown were generated by retroviral or lentiviral infection and subsequent drug selection. Co-immunoprecipitation(co-IP) and in vitro pull-down analysis were applied to analyze the protein–protein interaction. Transwell migration and invasion assays were applied to investigate the role of B56γ3 in affecting motility and invasive capability of CRC cells. The sensitivity of CRC cells to 5-fluorouracil (5-FU) was analyzed using the PrestoBlue reagent assay for cell viability. Immunohistochemistry (IHC) was applied to investigate the expression levels of phospho-AKT and B56γ3 in paired tumor and normal tissue specimens of CRC. DataSets of TCGA and GEO were analyzed to investigate the correlation of B56γ3 expression with overall survival rates of CRC patients. Results We showed that B56γ3 promoted epithelial-mesenchymal transition (EMT) and reduced the sensitivity of CRC cells to 5-FU through upregulating AKT activity. Mechanistically, B56γ3 upregulates AKT activity by targeting PP2A to attenuate the p70S6K-mediated negative feedback loop regulation on PI3K/AKT activation. B56γ3 was highly expressed and positively correlated with the level of phospho-AKT in tumor tissues of CRC. Moreover, high B56γ3 expression is associated with poor prognosis of a subset of patients with CRC. Conclusions Our finding reveals that the B56γ3 regulatory subunit-containing PP2A plays an oncogenic role in CRC cells by sustaining AKT activation through suppressing p70S6K activity and suggests that the interaction between B56γ3 and p70S6K may serve as a therapeutic target for CRC. Video Abstract

Background: Renal cell carcinoma with rhabdoid features (RCC-RF) is an aggressive histologic variant in the adults and is usually unresponsive to standard chemotherapy. Methods: Expression of SMARCB1/INI1 was examined in primary RCC-RF (n = 5). Stable INI1 with/without prostaglandin E2 receptor 1 (EP1) knockdown cell lines were created in the ACHN and 786-O RCC cell lines and measured for epidermal growth factor receptor (EGFR)-related signaling pathways. Chemosensitivity to targeted drugs in vitro was tested after knocking down of INI1 in both cell lines. The outcome of co-targeting of INI1 and EP1 in RCC was examined using a tumorigenicity assay. Results: Expression of INI1 was markedly reduced at both transcriptional and translational levels in primary RCC-RF. Immunohistochemical expression of INI1 protein was lost in the nuclei of rhabdoid cells compared with conventional RCC (n = 8). Using two cell lines with different genetic background, we showed that knocking down of INI1 activates the EGFR signaling with up-regulated AKT and ERK pathways and sensitizes cancer cells to Erlotinib treatment in vitro. However, cell-line dependent effects were also demonstrated with reference to impact of INI1 or EP1 on cell growth, migration and response to Gefitinib or Everolimus treatment in vitro. Conclusion: Inactivation of INI1 may play a role in the pathogenesis of RCC-RF. Erlotinib is recommended in the management of patients with INI1-related RCC.

Background: In our preliminary screening, expression of miR-338-5p was found to be higher in primary colorectal cancer (CRC) with metastasis. The autophagy related gene- phosphatidylinositol 3-kinase, catalytic subunit type 3 (PIK3C3) appeared to be targeted by miR-338-5p. Here, we provide solid evidence in support of PIK3C3 involved in miR-338-5p related metastasis of CRC in vitro and in vivo. Methods: The potential clinical relevance of miR-338-5p and its target gene was analysed on benign colorectal polyps and primary CRCs by QPCR. Mouse spleen xenograft experiment was performed to examine the importance of miR-338-5p for metastasis. Findings: PIK3C3 was one of target genes of miR-338-5p. In primary CRCs, expression of miR-338-5p is positively related to tumour staging, distant metastasis and poor patient survival. Patients with higher ratios of miR-338-5p/PIK3C3 also had significantly poor overall survival, supporting their significance in the progression of CRC. Over-expression of miR-338-5p promotes CRC metastasis to the liver and lung in vivo, in which PIK3C3 was down-regulated in the metastatic tumours. In contrast, overexpression of PIK3C3 in miR-338-5p stable cells inhibited the growth of metastatic tumours. Both migration and invasion of CRC in vitro induced by miR-338-5p are mediated by suppression of PIK3C3. Using forward and reverse approaches, autophagy was proved to involve in CRC migration and invasion induced by miR-338-5p. Interpretation: MiR-338-5p induces migration, invasion and metastasis of CRC in part through PIK3C3-related autophagy pathway. The miR-338-5p/PIK3C3 ratio may become a prognostic biomarker for CRC patients. Fund: NCKU Hospital, Taiwan, Ministry of Science and Technology, Taiwan. Keywords: miR-338-5p, PIK3C3, Autophagy and colorectal cancer

Fiber-wireless and fiber-invisible laser light communication (IVLLC) convergences that adopt the Mach-Zehnder modulator-optoelectronic oscillator (MZM-OEO)-based broadband light source for microwave (MW)/millimeter-wave (MMW)/baseband (BB) signal transmission are proposed and demonstrated. For downlink transmission, light is optically promoted from 15- and 25-GHz radio-frequency (RF) signals to 10-Gb/s/30-GHz MW, 15-Gb/s/50-GHz MMW, 20-Gb/s/60-GHz MMW, and 25-Gb/s/100-GHz MMW data signals based on fiber-wireless and fiber-IVLLC integrations. Bit error rate (BER) performs efficiently in the 40-km single-mode fiber (SMF) and the 10-m RF/25-m optical wireless transport scenarios. For uplink transmission, downstream light is successfully intensity-modulated with a 25-Gb/s BB data stream based on fiber-IVLLC integration. BER performs efficiently in the 40-km SMF and the 100-m optical wireless transport scenario. Such a hybrid MW/MMW/BB lightwave transmission system is an attractive alternative. It is shown to be a prominent one to present advancements in integrating fiber backbone and radio-frequency (RF)/optical wireless feeder networks.

A 50-m/40-Gb/s 680-nm vertical-cavity surface-emitting laser (VCSEL)-based free-space optical (FSO) communication employing three-stage injection-locked technique and the afocal scheme is proposed and experimentally demonstrated. The three-stage injection-locked technique, which can significantly increase the resonant frequency of the VCSEL, is expected to provide higher transmission rate in FSO communication. The afocal scheme, which can reduce the beam size of laser beam, is expected to provide longer free-space link in FSO communication. As far as we know, it is the first time that a three-stage injection-locked 680-nm VCSEL transmitter and afocal scheme that will successfully build up a 50-m/40-Gb/s FSO communication has been employed. Such a 50-m/40-Gb/s FSO communication provides the advantages of optical wireless links for longer transmission distance and higher transmission rate, which is thoroughly useful for high-speed light-based WiFi (LiFi) applications.

An 8 m/9.6 Gbps underwater wireless optical communication (UWOC) system based on a two-stage injection-locked 405 nm blue light laser diode (LD) transmitter with a 16-quadrature amplitude modulation (QAM)-orthogonal frequency-division multiplexing (OFDM) modulating signal is proposed and experimentally demonstrated. To the best of our knowledge, it is the first one that employs a two-stage injection-locked technique to improve the transmission performance of UWOC systems. With the assistance of an equalizer at the receiver site, acceptable bit error rate (BER) performance and a constellation map are obtained over an 8-m underwater link. Such a two-stage injection-locked 405 nm blue light LD transmitter-based UWOC system is shown to be a promising alternative, presenting its feasibility for long-range and high-speed underwater links.

An innovative free-space optical (FSO) link using laser light propagation to achieve transmission rate of 40 Gb/s at a wavelength of 1550 nm is proposed and experimentally demonstrated. Over a 20-m free-space link, brilliant bit-error-rate performance and clear eye diagram are obtained in the proposed 1550-nm distributed feedback (DFB) laser diode (LD)-based FSO links. As far as we know, it is the first time that a 1550-nm externally modulated laser transmitter cascaded with an erbium-doped fiber amplifier and a pair of fiber collimators to successfully set up a 20-m/40-Gb/s FSO link has been employed. Compared with the 680-nm vertical-cavity surface-emitting laser-based FSO link, this proposed 1550-nm DFB LD-based FSO link is attractive not only because it has longer free-space transmission distance but because it supplies higher bandwidth operation as well. Such a 1550-nm DFB LD-based FSO link provides the benefits of optical wireless communications for longer transmission distance and higher transmission rate, which is thoroughly helpful for optical wireless network applications.

This paper proposes and validates a bidirectional hybrid lightwave transport system based on fiber-invisible laser light communication (IVLLC) and fiber-visible laser light communication (VLLC) convergences with light injection and optoelectronic feedback techniques. This paper is also the first to employ light injection and optoelectronic feedback techniques in a bidirectional lightwave transport system based on fiber-IVLLC and fiber-VLLC integration. Light is successfully modulated directly with cable television (CATV), 16-quadrature amplitude modulation (QAM), and 16-QAM-orthogonal frequency-division multiplexing (OFDM) signals. Good carrier-to-noise ratio, composite second order, composite triple beat, and bit error rate (BER) are obtained for CATV, 16-QAM, and 16-QAM-OFDM signal transmissions over a combined 40-km single-mode fiber, a 1.43-km photonic crystal fiber, and 6-m free-space transmission. The proposed bidirectional hybrid lightwave transport system exhibits significant potential in providing broadband integrated services, such as CATV, Internet, and telecommunication, via optical fiber and free-space indoor networks.

This study proposes and demonstrates a bidirectional wireless-over-fiber (WoF) transport system based on an optical interleaver, a phase modulator, and an optical bandpass filter (OBPF)-based phase-modulation-to-intensity-modulation converter that can deliver intensity-modulated 60 GHz millimeter-wave (MMW), 30 GHz microwave (MW), and phase-remodulated 15 GHz MW data signals. A broadband light source, comprising an optoelectronic oscillator scheme and an optical signal-to-noise ratio (OSNR) enhancement scheme, is deployed in these bidirectional 60 GHz/30 GHz/15 GHz WoF transport systems. For downlink transmission, light is promoted optically from a 5 Gbps/ 15 GHz MW data signal to 5 Gbps/60 GHz MMW and 5 Gbps/30 GHz MW data signals in fiber-wireless convergence. The downstream light is phase remodulated successfully using a 5 Gbps/15 GHz MW data signal for uplink transmission. Through a thorough examination of such bidirectional 60 GHz/30 GHz/15 GHz WoF transport systems, the bit error rate (BER) is observed to perform well over a 40 km single-mode fiber and a 4 m RF wireless transmission. This bidirectional 60 GHz/30 GHz/15 GHz WoF transport system is a prominent alternative not only because of its advancement in integrating optical fiber and RF wireless networks but because of the benefits of communication links for broader bandwidth and higher transmission rate as well.

Backgroud: This prospective randomized trial evaluated the clinical efficacy of inhaled colistin administered through two distinct nebulizer types, a vibrating mesh nebulizer (VMN) and a jet nebulizer (JN), in the treatment of ventilator-associated pneumonia caused by multidrug-resistant bacteria. In addition, an in vitro model was used to determine the optimal delivery of colistin. Method: Thirty-two patients prescribed intravenous (IV) colistin inhalation were randomized to receive either a VMN (n = 17) or a JN (n = 15), then compared to the control group (IV alone) over a 7-to 10-day period. The primary endpoint was the clinical pulmonary infection score (CPIS), and the secondary endpoints were the Sequential Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation (APACE) score, and duration of ventilator use. Results: Results from in vitro testing demonstrated that VMN delivered a significantly higher colistin dose than JN (35.68 ± 3.55% vs. 23.56 ± 3.31%; p < 0.001) when positioned at the humidifier inlet. Compared to the IV alone group, the IV with inhalation group yielded significant improvements in CPIS, SOFA score, and APACHE score on day 7; nevertheless, clinical outcomes between the two nebulizers were statistically indistinguishable. Conclusions: In conclusion, although VMN delivers a higher dose in vitro, both nebulizers yielded comparable clinical outcomes. This study was registered at US Clinical Trial Registration (NCT04633317).

As the proportion of the population comprising the elderly cohort increases, so too does the demand for medical care for long-term conditions among this demographic. The advent of information technology and artificial intelligence has prompted a crucial examination of the potential of smart medical technology and equipment to enhance the quality of long-term care and the operational efficiency of long-term care facilities. The introduction of smart healthcare into long-term care is influenced by a few factors, and expert opinions often exhibit ambiguity and subjectivity in the evaluation process. As Z-numbers are capable of adequately expressing the ambiguity of expert assessments and the degree of certainty associated with them, they are employed in this study to convey the opinions of the experts. Furthermore, the Decision-Making Trial and Evaluation Laboratory (DEMATEL) method is an effective approach to analyzing the relationships between factors. Consequently, this study integrates the Z-numbers and DEMATEL methods for empirical analysis. The present study focuses on two long-term care institutions with different natures as empirical subjects. The findings of the study indicate that Institution A identifies the “Internet of Things” as the most pivotal key factor, whereas Institution B deems “Smart clinics and urgent care centers” to be the most crucial key factor. The analysis demonstrates that three factors—global positioning systems, telemedicine, and electronic medical records—are all regarded as significant influencing factors for different long-term care institutions. Consequently, the analytical model of this study is not only theoretically sound but also effective in identifying the key factors and importance of introducing smart healthcare into long-term care institutions.

Hair cortisol concentration (HCC) is a valuable biomarker for evaluating chronic stress in preschoolers. However, few studies have explored early life HCC and its associated factors. This prospective cohort study analysed the HCC in children aged 6–48 months and its associations with parental HCC as well as positive and negative parental mental health outcomes. We used data from the ongoing Longitudinal Examination Across Prenatal and Postpartum Health in Taiwan (LEAPP‐HIT) project, conducted in Taipei between 2020 and 2024. Hair samples were collected from both parents and children in 177 families (91 samples obtained during pregnancy and 86 during the postpartum period). The parents also completed self‐reported questionnaires. Multiple linear regression was conducted to analyse the data. We observed a significant positive correlation between parents' and preschoolers' HCC. Furthermore, maternal depression (adjusted beta coefficient [aβ] = 0.09, 95% confidence interval [CI] = 0.02, 0.16) and perceived stress (aβ = 0.15, 95% CI = 0.02, 0.26) were positively associated with preschoolers' HCC. By contrast, higher maternal eudaimonia was associated with lower HCC in preschoolers (aβ = −0.11, 95% CI = −0.20, −0.01). For parents, maternal depression, anxiety, and perceived stress were independently associated with an increased HCC during the postnatal period, whereas maternal eudaimonia was negatively associated with HCC. Our results indicate that both mothers and fathers affect children's responses to stress. Assessment of cortisol stress hormone concentrations through hair samples can be a key means of detecting preschoolers' stress levels and enabling early intervention. [ABSTRACT FROM AUTHOR]

Elevated levels of Epstein-Barr virus (EBV) gp350 and gH/gL antibodies have been associated with a lower risk of developing nasopharyngeal carcinoma (NPC), although the evidence remains inconclusive and unexplained. We conducted a longitudinal study within a high-risk Taiwanese cohort, analyzing total immunoglobulin against EBV-gp350 and -gH/gL in blood and EBV DNA shedding in saliva. Contrary to our hypothesis—that elevated levels of antibodies previously shown to be associated with a lower NPC risk should result in a decrease in EBV shedding in saliva—higher anti-gp350 antibodies at baseline were significantly associated with detectable EBV DNA in saliva at follow-up (odds ratio [OR], 1.99 [95% confidence interval {CI}, 1.03–3.97]; P =.04). Higher anti-EBV-gH/gL antibodies at baseline were not significantly associated with risk of detectable EBV DNA at follow-up (OR, 0.69 [95% CI,.35–1.32]; P =.26). These findings underscore the complexity of virus–host interactions and emphasize the need for further investigations into their role in EBV-associated diseases. [ABSTRACT FROM AUTHOR]

Dengue virus (DENV) which infects about 390 million people per year in tropical and subtropical areas manifests various disease symptoms, ranging from fever to life-threatening hemorrhage and even shock. To date, there is still no effective treatment for DENV disease, but only supportive care. DENV nonstructural protein 1 (NS1) has been shown to play a key role in disease pathogenesis. Recent studies have shown that anti-DENV NS1 antibody can provide disease protection by blocking the DENV-induced disruption of endothelial integrity. We previously demonstrated that anti-NS1 monoclonal antibody (mAb) protected mice from all four serotypes of DENV challenge. Here, we generated humanized anti-NS1 mAbs and transferred them to mice after DENV infection. The results showed that DENV-induced prolonged bleeding time and skin hemorrhage were reduced, even several days after DENV challenge. Mechanistic studies showed the ability of humanized anti-NS1 mAbs to inhibit NS1-induced vascular hyperpermeability and to elicit Fcγ-dependent complement-mediated cytolysis as well as antibody-dependent cellular cytotoxicity of cells infected with four serotypes of DENV. These results highlight humanized anti-NS1 mAb as a potential therapeutic agent in DENV infection.

Affected by the fluctuation of the market and economic environment during the epidemic period, the capital pressure of companies has increased sharply, which increases the possibility of risk transmission in the same industry and poses new challenges to the operation and financing of companies. From the perspective of preventive motivation of corporate cash holding, we creatively use the industry working capital shortfall as the explanatory variable to construct an Extended Cash Holding Model and a Cash Holding Value Regression Model. Taking the panel data of A-share listed companies in Shanghai and Shenzhen as samples, this paper uses the Classical Linear Regression Model and Fixed Effects Regression Model to study the relationship between industry working capital shortfall and cash holdings in the same industry, as well as the relationship between industry working capital shortfall and cash holding value. The empirical results show that industry working capital shortfall has an important impact on the cash holding level within the same industry, and the cash holding level is significantly and positively correlated with industry working capital shortfall. Moreover, this study also reveals that the industry working capital shortfall has a dual impact on cash holdings. Specifically, the higher the risk of industry working capital shortfall, the lower the value of company cash holdings. The conclusions of this paper not only extend the research on cash holding but also provide support and reference for companies to optimize the cash holding value.