CALB2 drives pancreatic cancer metastasis through inflammatory reprogramming of the tumor microenvironment.

BACKGROUND: Early dissemination to distant organs accounts for the dismal prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). Chronic, dysregulated, persistent and unresolved inflammation provides a preferred tumor microenvironment (TME) for tumorigenesis, development, and metastasis. A better understanding of the key regulators that maintain inflammatory TME and the development of predictive biomarkers to identify patients who are most likely to benefit from specific inflammatory-targeted therapies is crucial for advancing personalized cancer treatment. METHODS: This study identified cell-specific expression of CALB2 in human PDAC through single-cell RNA sequencing analysis and assessed its clinicopathological correlations in tissue microarray using multi-color immunofluorescence. Co-culture systems containing cancer-associated fibroblasts (CAFs) and patient-derived organoids (PDOs) in vitro and in vivo were employed to elucidate the effects of CALB2-activated CAFs on PDAC malignancy. Furthermore, CUT&RUN assays, luciferase reporter assays, RNA sequencing, and gain- or loss-of-function assays were used to unravel the molecular mechanisms of CALB2-mediated inflammatory reprogramming and metastasis. Additionally, immunocompetent KPC organoid allograft models were constructed to evaluate CALB2-induced immunosuppression and PDAC metastasis, as well as the efficacy of inflammation-targeted therapy. RESULTS: CALB2 was highly expressed both in CAFs and cancer cells and correlated with an unfavorable prognosis and immunosuppressive TME in PDAC patients. CALB2 collaborated with hypoxia to activate an inflammatory fibroblast phenotype, which promoted PDAC cell migration and PDO growth in vitro and in vivo. In turn, CALB2-activated CAFs upregulated CALB2 expression in cancer cells through IL6-STAT3 signaling-mediated direct transcription. In cancer cells, CALB2 further activated Ca2+-CXCL14 inflammatory axis to facilitate PDAC metastatic outgrowth and immunosuppression. Genetic or pharmaceutical inhibition of CXCL14 significantly suppressed CALB2-mediated metastatic colonization of PDAC cells in vivo and extended mouse survival. CONCLUSIONS: These findings identify CALB2 as a key regulator of inflammatory reprogramming to promote PDAC metastatic progression. Combination therapy with αCXCL14 monoclonal antibody and gemcitabine emerges as a promising strategy to suppress distant metastasis and improve survival outcomes in PDAC with CALB2 overexpression.

Single-cell RNA-seq reveals heterogeneity in metastatic renal cell carcinoma and effect of anti-angiogenesis therapy in the pancreas metastatic lesion.

Metastatic clear cell renal cell carcinoma has heterogenous tumor microenvironment (TME). Among the metastatic lesions, pancreas metastasis is rare and controversy in treatment approaches. Here, extensive primary and metastatic lesion samples were included by single-cell RNA-seq to decipher the distinct metastasis TME. The hypoxic and inflammatory TME of pancreas metastasis was decoded in this study, and the activation of PAX8-myc signaling, and metabolic reprogramming were observed. The active components including endothelial cells, fibroblasts and T cells were profiled. Meanwhile, we also evaluated the effect of anti-angiogenesis treatment in the pancreas metastasis patient. The potential mechanisms of pancreatic tropism, instability of genome, and the response of immunotherapy were also discussed in this work. Taken together, our findings suggest a clue to the heterogeneity in metastasis TME and provide evidence for the treatment of pancreas metastasis in renal cell carcinoma patients.

Washout CYFRA 21-1: A tool to improve diagnostic accuracy of fine needle aspiration in the diagnosis of metastatic lymph nodes in papillary thyroid cancer.

Thyroid carcinoma has an increasing incidence of endocrine system cancers. Fine needle aspiration cytology (FNAC) and thyroglobulin (Tg) are the primary diagnostic modalities employed for assessing metastatic lymph nodes (LNs) in thyroid cancer. Due to the limited accuracy, rare patients benefited from these procedures. In this research, we aimed to discover a dependable biomarker that could increase the accuracy of FNAC's ability to diagnose metastatic LNs among patients suffering from papillary thyroid cancer (PTC). From March 2021 to July 2023, 99 LNs from PTC patients who had thyroid ultrasonography suspicions of metastases were examined. All patients underwent FNAC, washout Tg and CYFRA 21-1 measurements. Surgical histology and a subsequent FNAC were utilized to validate the outcomes of LNs. In our study, the optimal cut-off value for CYFRA 21-1 washout fluid was 1.145 ng/mL, with a specificity of 94.00 % (slightly lower than Tg and FNAC at 98 %). However, CYFRA 21-1 demonstrated significantly higher diagnostic sensitivity (85.71 %) and accuracy (86.41 %) compared to Tg (71.43 %, 81.55 %) and FNAC (69.39 %, 80.58 %). Furthermore, FNAC plus washout CYFRA 21-1 performed better in diagnosing the metastatic LNs in PTC than FNAC plus Tg, which may indicate a novel solution for metastatic LNs diagnosis in PTC.

Neuroprotective effect of green tea extract (-)-epigallocatechin-3-gallate in a preformed fibril-induced mouse model of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra (SN). The main bioactive component of green tea polyphenols (-)-epigallocatechin-3-gallate (EGCG) exerts protective effects against diseases such as neurodegenerative diseases and cancer. Therefore, this study investigated the effect of EGCG on the amelioration of neural damage in a chronic PD mouse model induced by α-synuclein preformed fibrils (α-syn-PFFs). A total of 20 C57BL/6J female mice were randomly divided into 3 groups: control group (saline, n = 6), model group (PFFs, n = 7), and prevention group (EGCG+PFFs, n = 7). A chronic PD mouse model was obtained by the administration of α-syn-PFFs by stereotaxic localization in the striatum. Behavioral tests were performed to evaluate PD-related anxiety-like behavior and motor impairments in the long-term PD progression. Tyrosine hydroxylase (TH) immuno-positive neurons and Ser129-phosphorylated α-syn (p-α-syn) were identified by immunohistochemistry. Pro-inflammatory and anti-inflammatory cytokines were measured by real-time quantitative PCR. EGCG pretreatment reduced anxiety-like behavior and motor impairments as revealed by the long-term behavioral test (2 weeks, 1 month, 3 months, and 6 months) on PD mice. EGCG also ameliorated PFF-induced degeneration of TH immuno-positive neurons and accumulation of p-α-syn in the SN and striatum at 6 months. Additionally, EGCG reduced the expression of pro-inflammatory cytokines while promoting the release of anti-inflammatory cytokines. EGCG exerts a neuroprotective effect on long-term progression of the PD model.

Epidemiology of pancreatic cancer: New version, new vision.

Pancreatic cancer (PC) is a devastating malignancy with an extremely high mortality rate and poses significant challenges to healthcare systems worldwide. The prevalence of PC risk factors spiked over the years, leading to a global increase in PC incidence rates. The contribution of different risk factors, however, varied from region to region due to genetic predisposition, environmental, social, and political factors underlying disease prevalence in addition to public health strategies. This comprehensive review aims to provide a thorough analysis of the epidemiology of PC, discussing its incidence, risk factors, screening strategies and socioeconomic burden. We compiled a wide range of seminal studies as well as epidemiological investigations to serve this review as a comprehensive guide for researchers, healthcare professionals, and policymakers keen for a more profound understanding of PC epidemiology. This review highlights the essentiality of persistent research efforts, interdisciplinary collaboration, and public health initiatives to address the expanding burden of this malignancy.

Hyaluronic acid methacrylate/laponite hydrogel loaded with BMP4 and maintaining its bioactivity for scar-free wound healing.

Scar-free wound healing is a challenging process due to the excessive deposition of extracellular matrix and collagen. To overcome this issue, hydrogels with superior biochemical and mechanical properties have been used in combination with medicinal compounds as wound dressings. In this study, a novel composite hydrogel consisting of double-crosslinked photocurable hyaluronic acid methacrylate (HAMA) and Laponite (Lap) loaded with bioactive bone morphogenetic protein 4 (BMP4) was developed and thoroughly characterized for its properties such as degradation, morphology, porosity, compression, skin adhesion and load release. The effect of the HAMA/Lap/BMP4 hydrogel was evaluated through both in vitro and in vivo experiments. In the in vivo rabbit ear-scar model, the HAMA/Lap/BMP4 hydrogel dressing was found to reduce scar-related expressions of α-SAM and decrease the ratio of collagen Ι/III in wounded tissue. Additionally, histopathological examination indicated that the HAMA/Lap/BMP4 hydrogel-treated groups exhibited enhanced wound repair and increased levels of collagen maintenance compared to other standard groups, ultimately leading to scarless wound healing. Therefore, this sustained-release photocurable HAMA/Lap/BMP4 hydrogel offers a therapeutic approach for scar-free wound healing.

Effects of sources of social support and resilience on the mental health of different age groups during the COVID-19 pandemic.

BACKGROUND: A pandemic is a very stressful event, especially for highly vulnerable people (e.g., older adults). The purpose of the current study was to investigate the main and interactive relationships of social support and resilience on individual mental health during the COVID-19 pandemic across three age groups: emerging adults, adults, and older adults. METHODS: A survey was conducted with 23,192 participants aged 18-85. Respondents completed a questionnaire, including items on the COVID-19-related support they perceived from different sources, the abbreviated version of the Connor-Davidson Resilience Scale, and the Mental Health Inventory. RESULTS: Latent profile analysis identified five profiles of social support, and the patterns of potential profiles were similar in all groups. However, category distribution in the five profiles was significantly different among the age groups. Furthermore, analysis using the BCH command showed significant differences in mental health among these profiles. Lastly, interactive analyses indicated resilience had a positive relationship with mental health, and social support served as a buffer against the negative impact of low resilience on mental health. CONCLUSIONS: This study provides quantitative evidence for socioemotional selectivity theory (SST) and enables several practical implications for helping different age groups protecting mental health during pandemic.

Sr-HA scaffolds fabricated by SPS technology promote the repair of segmental bone defects.

BACKGROUND: Ideal bone defect repair scaffolds should be biodegradable, biocompatible, bioactive, porous, and provide adequate mechanical support. However, it is challenging to fabricate such an ideal bone repair scaffold. Previously, we showed that 5 wt.% strontium-doped hydroxyapatite (Sr-HA) scaffolds prepared by spark plasma sintering (SPS) technology exhibited good biocompatibility. Moreover, unlike pure hydroxyapatite (HA) scaffolds, HA scaffolds containing strontium (Sr) exhibited superior bioactivity, higher proliferation rate of BMSCs and MG-63 osteoblast cells, as well as enhanced BMSCs differentiation. METHODS: In this study, we prepared pure HA scaffolds and 5 wt.% strontium containing Sr-HA scaffolds by SPS technology without adhesive, ammonium bicarbonate as pore former. Subsequently, scanning electron microscope (SEM) and X-Ray diffraction (XRD) were used to characterize the properties of Sr-HA and HA scaffolds. The ability of the scaffolds to repair bone defects was evaluated using a critical-sized rabbit tibia-bone defect rabbit model. Thirty 3-month-old New Zealand white rabbits were randomly divided into three groups (blank control group, Sr-HA scaffolds implanted group and HA scaffolds implanted group) with 10 rabbits in each group. These rabbits are sacrificed after 8 weeks and 16 weeks of surgery, and the repair effects of each scaffold were evaluated with X-ray, micro-CT, and HE staining. The three-point bending test was employed to assess the mechanical property of repaired bones. RESULTS: XRD pattern indicated that Sr-HA and HA scaffolds possess a similar crystal structure after sintering, and that incorporation of strontium did not form impure phase. SEM showed that the porosity of Sr-HA and HA scaffolds was about 40 %. Universal Testing Machine tests showed that Sr-HA scaffolds had better compressive strength than HA scaffolds. Bone defect was obvious, and the fibrous tissue was formed in the bone defects of rabbits in the blank control group after 8 weeks of surgery. Sr-HA and HA scaffolds enhanced osteointegration of the host bone, and extensive woven bone was formed on the surface of the Sr-HA scaffolds. After 16 weeks, the bone strump became blunt and a small amount of callus was formed in the blank control group. Comparatively, the scaffolds were substantially degraded in the Sr-HA scaffolds implanted group while scaffolds shadows still were observed in the HA implanted group. Bone remodeling and cavity recanalization were completely developed in the Sr-HA scaffolds group. The compressive strength of repaired bone in the Sr-HA scaffolds implantation group was higher than that of HA scaffolds implantation group after 8 weeks and 16 weeks of surgery. CONCLUSIONS: Our results show that the Sr-HA composite scaffolds can effectively repair bone defects and have good biodegradable properties.

Three-Wave Longitudinal Survey on the Relationship between Neuroticism and Depressive Symptoms of First-Year College Students: Addictive Use of Social Media as a Moderated Mediator.

First-year college students' adaptation problems and related mental health have attracted researchers' attention. The current research focuses on the depressive symptoms of first-year college students and aims to explore the relationship between the neuroticism trait and depressive symptoms, the mediating effect of addictive use of social media, and the moderating effect of psychological resilience. Three-wave longitudinal data from 1128 first-year students at a university in Fujian Province, China, were collected within three months of their enrollment. PROCESS macro for SPSS with bootstrapping was used to test the model. Results showed that the prevalence of moderate to severe severity of depressive symptoms in first-year students was 10.28% (T1) and 11.17% (T3). Addictive use of social media (T2) plays a moderated mediator role in the relationship between neuroticism (T1) and depressive symptoms (T3) of first-year students. Specifically, a low neuroticism individual does not necessarily have a less addictive use of social media. Psychological resilience (T1) moderated the above mediation. Implications for research and practice are discussed.

On the inclusion of the diagonal Born-Oppenheimer correction in surface hopping methods.

The diagonal Born-Oppenheimer correction (DBOC) stems from the diagonal second derivative coupling term in the adiabatic representation, and it can have an arbitrary large magnitude when a gap between neighbouring Born-Oppenheimer (BO) potential energy surfaces (PESs) is closing. Nevertheless, DBOC is typically neglected in mixed quantum-classical methods of simulating nonadiabaticdynamics (e.g., fewest-switch surface hopping (FSSH) method). A straightforward addition of DBOC to BO PESs in the FSSH method, FSSH+D, has been shown to lead to numerically much inferior results for models containing conical intersections. More sophisticated variation of the DBOC inclusion, phase-space surface-hopping (PSSH) was more successful than FSSH+D but on model problems without conical intersections. This work comprehensively assesses the role of DBOC in nonadiabaticdynamics of two electronic state problems and the performance of FSSH, FSSH+D, and PSSH methods in variety of one- and two-dimensional models. Our results show that the inclusion of DBOC can enhance the accuracy of surface hopping simulations when two conditions are simultaneously satisfied: (1) nuclei have kinetic energy lower than DBOC and (2) PESs are not strongly nonadiabatically coupled. The inclusion of DBOC is detrimental in situations where its energy scale becomes very high or even diverges, because in these regions PESs are also very strongly coupled. In this case, the true quantum formalism heavily relies on an interplay between diagonal and off-diagonal nonadiabatic couplings while surface hopping approaches treat diagonal terms as PESs and off-diagonal ones stochastically.