Therapy-induced senescent tumor cell-derived extracellular vesicles promote colorectal cancer progression through SERPINE1-mediated NF-κB p65 nuclear translocation.

BACKGROUND: Cellular senescence frequently occurs during anti-cancer treatment, and persistent senescent tumor cells (STCs) unfavorably promote tumor progression through paracrine secretion of the senescence-associated secretory phenotype (SASP). Extracellular vesicles (EVs) have recently emerged as a novel component of the SASP and primarily mediate the tumor-promoting effect of the SASP. Of note, the potential effect of EVs released from STCs on tumor progression remains largely unknown. METHODS: We collected tumor tissues from two cohorts of colorectal cancer (CRC) patients to examine the expression of p16, p21, and SERPINE1 before and after anti-cancer treatment. Cohort 1 included 22 patients with locally advanced rectal cancer (LARC) who received neoadjuvant therapy before surgical resection. Cohort 2 included 30 patients with metastatic CRC (mCRC) who received first-line irinotecan-contained treatment. CCK-8, transwell, wound-healing assay, and tumor xenograft experiments were carried out to determine the impacts of EVs released from STCs on CRC progression in vitro and in vivo. Quantitative proteomic analysis was applied to identify protein cargo inside EVs secreted from STCs. Immunoprecipitation and mass spectrometer identification were utilized to explore the binding partners of SERPINE1. The interaction of SERPINE1 with p65 was verified by co-immunoprecipitation, and their co-localization was confirmed by immunofluorescence. RESULTS: Chemotherapeutic agents and irradiation could potently induce senescence in CRC cells in vitro and in human CRC tissues. The more significant elevation of p16 and p21 expression in patients after anti-cancer treatment displayed shorter disease-free survival (DFS) for LARC or progression-free survival (PFS) for mCRC. We observed that compared to non-STCs, STCs released an increased number of EVs enriched in SERPINE1, which further promoted the progression of recipient cancer cells. Targeting SERPINE1 with a specific inhibitor, tiplaxtinin, markedly attenuated the tumor-promoting effect of STCs-derived EVs. Additionally, the patients with greater increment of SERPINE1 expression after anti-cancer treatment had shorter DFS for LARC or PFS for mCRC. Mechanistically, SERPINE1 bound to p65, promoting its nuclear translocation and subsequently activating the NF-κB signaling pathway. CONCLUSIONS: We provide the in vivo evidence of the clinical prognostic implications of therapy-induced senescence. Our results revealed that STCs were responsible for CRC progression by producing large amounts of EVs enriched in SERPINE1. These findings further confirm the crucial role of therapy-induced senescence in tumor progression and offer a potential therapeutic strategy for CRC treatment.

Varied immune responses of HBV-specific B cells in patients undergoing pegylated interferon-alpha treatment for chronic hepatitis B.

BACKGROUND & AIMS: The changes of HBV-specific B-cells in chronic hepatitis B (CHB) patients underwent pegylated interferon-alfa (PEG-IFNα) treatment and achieved functional cure remain unclear. We aimed to evaluate the alterations in HBV-specific B-cells during treatment and therefore explored the mechanism of functional recovery of HBsAg-specific B-cells. METHODS: We included 39 nucleos(t)ide analogues-treated CHB patients who received sequential combination therapy with PEG-IFNα and 8 treatment-naive CHB patients. HBV-specific B-cells were characterized ex vivo using fluorescent labeled HBsAg and HBcAg. The frequency, phenotype, and subsets of HBV-specific B-cells and follicular helper T cells (Tfh-cells) were detected using flow cytometry. The functionality of HBV-specific B-cells was quantified through ELISpot assays. RESULTS: During treatment, the fraction of activated memory B-cells (MBCs) among HBsAg-specific B-cells and the expression of IgG, CXCR3, and CD38 increased. Antibody-secretion capacity of HBsAg-specific B-cell was restored after treatment only in patients with a functional cure and it showed a positive correlation with serum hepatitis B surface antibody levels. The phenotype and function of HBsAg-specific B-cells differed between patients with and without functional cure. Patients with functional cure exhibited IgG+ classical MBCs and plasmablasts in HBsAg-specific B-cells. HBcAg-specific B-cells displayed both attenuated antibody secretion with reduced IgG expression and an IgM+ atypical type of MBCs after treatment, irrespective of with and without functional cure. The number of CD40L+ Tfh-cells increased after PEG-IFNα treatment and positively correlated with HBsAg-specific B-cell activation. CONCLUSIONS: After PEG-IFNα treatment, HBsAg- and HBcAg-specific B-cells exhibit various changes in antibody secretion. Their functional differences are reflected in the alterations in phenotypes and subtypes. The presence of CD40L+ Tfh-cells is associated with the active recovery of HBsAg-specific B-cells. IMPACT AND IMPLICATIONS: HBV-related complications and hepatocellular carcinoma remain the leading causes of mortality from chronic liver disease worldwide, and a cure is rarely achieved with antiviral therapies. Elucidating the immunological mechanisms underlying the functional cure of CHB patients offers a promising therapeutic strategy for viral clearance, such as therapeutic vaccine. We analyzed the alterations in HBV-specific B-cells in patients treated with PEG-IFNα and identified novel pathways for immunotherapeutic boosting of B cell immunity.

An investigation into the present status and influencing factors of nurse retention in grade-a tertiary general hospitals in Shanxi Province within the framework of the magnet hospital concept.

BACKGROUND: The attrition of nursing staff significantly contributes to the shortage of healthcare professionals. This study entailed an examination of the propensity of nurses to sustain employment within Grade-A tertiary general hospitals and the various influencing factors. METHODS: A total of 2,457 nurses from three grade-A tertiary general hospitals were surveyed. The survey instruments included a general information questionnaire, a scale measuring their willingness to continue working, and a Chinese version of the Magnet Hospital Factor scale. RESULTS: The scores of the willingness to continue working scale and the Magnet Hospital Factor scale were 21.53 ± 4.52 and 145.46 ± 25.82, respectively. There were statistically significant differences in the scores of willingness of nurses to continue working across various factors, including the department, age, marital status, family location, length of service as nurses, professional title, position, and employment type, upon comparison (P < 0.001). The correlation analysis showed that there was a positive correlation between the willingness of nurses to continue working and the magnet hospital factors, with a correlation coefficient of 0.523 (P < 0.01). Regression analysis showed that department, length of service as nurses, professional title, position, average monthly income, number of night shifts, medical care relationship, educational support, and nursing manager support among the magnet hospital factors were important predictors of willingness to continue working (P < 0.001). CONCLUSION: The willingness of nurses to continue working in grade-A tertiary general hospitals in Shanxi Province was determined to be at an upper-middle level. The magnet status of grade-A tertiary general hospitals needs to be improved, and there are many factors that influenced willingness of nurses to continue working. To cultivate a more favorable environment and bolster nurse recruitment and retention, all healthcare institutions should strive to establish a magnet nursing environment, thereby fostering the robust development of the nursing team.

Linewidth Measurement of a Narrow-Linewidth Laser: Principles, Methods, and Systems.

Narrow-linewidth lasers mainly depend on the development of advanced laser linewidth measurement methods for related technological progress as key devices in satellite laser communications, precision measurements, ultra-high-speed optical communications, and other fields. This manuscript provides a theoretical analysis of linewidth characterization methods based on the beat frequency power spectrum and laser phase noise calculations, and elaborates on existing research of measurement technologies. In addition, to address the technical challenges of complex measurement systems that commonly rely on long optical fibers and significant phase noise jitter in the existing research, a short-delay self-heterodyne method based on coherent envelope spectrum demodulation was discussed in depth to reduce the phase jitter caused by 1/f noise. We assessed the performance parameters and testing conditions of different lasers, as well as the corresponding linewidth characterization methods, and analyzed the measurement accuracy and error sources of various methods.

Positive effects of brisk walking and Tai Chi on cognitive function in older adults: An fNIRS study.

Exercise has shown to have beneficial effects on cognition in older adults. The purpose of this study was to investigate the cortical hemodynamic responses during the word-color Stroop test (WCST) prior and after acute walking and Tai Chi exercise by functional near-infrared spectroscopy (fNIRS). Twenty participants (9 males, mean age 62.8 ± 5.2), first underwent a baseline WCST test, after which they took three WCST tests in a randomized order, (a) after sitting rest (control), (b) after 6 minutes performing Tai Chi Quan, and (c) after a bout of 6 minutes brisk walking. During these four WCST tests cortical hemodynamic changes in the prefrontal area were monitored with fNIRS. Both brisk walking and Tai Chi enhanced hemodynamic activity during the Stroop incongruent tasks, leading to improved cognitive performance (quicker reaction time). Brisk walking induced a greater hemodynamic activity in the right dorsolateral prefrontal cortex (DLPFC) and ventrolateral prefrontal cortex (VLPFC) area, whereas Tai Chi induced a greater bilateral hemodynamic activity in the DLPFC and VLPFC areas. The present study provided empirical evidence of enhanced hemodynamic response in task- specific regions of the brain that can be achieved by a mere six minutes of brisk walking or Tai Chi in older adults.

ScrollTimes: Tracing the Provenance of Paintings as a Window Into History.

The study of cultural artifact provenance, tracing ownership and preservation, holds significant importance in archaeology and art history. Modern technology has advanced this field, yet challenges persist, including recognizing evidence from diverse sources, integrating sociocultural context, and enhancing interactive automation for comprehensive provenance analysis. In collaboration with art historians, we examined the handscroll, a traditional Chinese painting form that provides a rich source of historical data and a unique opportunity to explore history through cultural artifacts. We present a three-tiered methodology encompassing artifact, contextual, and provenance levels, designed to create a "Biography" for handscroll. Our approach incorporates the application of image processing techniques and language models to extract, validate, and augment elements within handscroll using various cultural heritage databases. To facilitate efficient analysis of non-contiguous extracted elements, we have developed a distinctive layout. Additionally, we introduce ScrollTimes, a visual analysis system tailored to support the three-tiered analysis of handscroll, allowing art historians to interactively create biographies tailored to their interests. Validated through case studies and expert interviews, our approach offers a window into history, fostering a holistic understanding of handscroll provenance and historical significance.