Prognostic significance of collagen signatures in pancreatic ductal adenocarcinoma obtained from second-harmonic generation imaging.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) ranks among the deadliest types of cancer, and it will be meaningful to search for new biomarkers with prognostic value to help clinicians tailor therapeutic strategies. METHODS: Here we tried to use an advanced optical imaging technique, multiphoton microscopy (MPM) combining second-harmonic generation (SHG) and two-photon excited fluorescence (TPEF) imaging, for the label-free detection of PDAC tissues from a cohort of 149 patients. An automated image processing method was used to extract collagen features from SHG images and the Kaplan-Meier survival analysis and Cox proportional hazards regression were used to assess the prognostic value of collagen signatures. RESULTS: SHG images clearly show the different characteristics of collagen fibers in tumor microenvironment. We gained eight collagen morphological features, and a Feature-score was derived for each patient by the combination of these features using ridge regression. Statistical analyses reveal that Feature-score is an independent factor, and can predict the overall survival of PDAC patients as well as provide well risk stratification. CONCLUSIONS: SHG imaging technique can potentially be a tool for the accurate diagnosis of PDAC, and this optical biomarker (Feature-score) may help clinicians make more approximate treatment decisions.

Fasting plasma glucose and fetal ultrasound predict the occurrence of neonatal macrosomia in gestational diabetes mellitus.

OBJECTIVE: The cause of fetal overgrowth during pregnancy is still unclear. This study aimed to analyze and predict the risk of macrosomia in pregnant women with gestational diabetes mellitus (GDM). METHODS: This study was a retrospective study collected from October 2020 to October 2021. A total of 6072 pregnant women with a routine 75-g oral glucose tolerance test (OGTT) during 24-28 gestational weeks were screened. Nearly equal numbers of pregnant women with gestational diabetes and with normal glucose tolerance (NGT) were included in the study. Multivariate logistic regression analysis and receiver operating characteristic (ROC) curve were performed to determine the index and inflection point for predicting macrosomia occurrence. RESULTS: The data of perinatal outcomes of 322 GDM and 353 NGT who had given birth to single live babies at term were analyzed. We found that significant cut-off values for the prediction of macrosomia are 5.13mmol/L in fasting plasma glucose (FPG), 12.25kg in gestational weight gain (GWG), 3,605g in ultrasound fetal weight gain (FWG) and 124mm in amniotic fluid index (AFI).The area under the ROC curve of this predictive model combined all variables reached 0.953 (95% CI: 0.914 ~ 0.993) with a sensitivity of 95.0% and a specificity of 85.4%. CONCLUSIONS: FPG is positively associated with newborn birth weight. An early intervention to prevent macrosomia may be possible by combining maternal GWG, FPG, FWG, and AFI in gestational diabetes.

The Pin1-CaMKII-AMPA Receptor Axis Regulates Epileptic Susceptibility.

Pin1 is a unique isomerase that regulates protein conformation and function after phosphorylation. Pin1 aberration contributes to some neurological diseases, notably Alzheimer's disease, but its role in epilepsy is not fully understood. We found that Pin1-deficient mice had significantly increased seizure susceptibility in multiple chemical inducing models and developed age-dependent spontaneous epilepsy. Electrophysiologically, Pin1 ablation enhanced excitatory synaptic transmission to prefrontal cortex (PFC) pyramidal neurons without affecting their intrinsic excitability. Biochemically, Pin1 ablation upregulated AMPA receptors and GluA1 phosphorylation by acting on phosphorylated CaMKII. Clinically, Pin1 was decreased significantly, whereas phosphorylated CaMKII and GluA1 were increased in the neocortex of patients with epilepsy. Moreover, Pin1 expression restoration in the PFC of Pin1-deficient mice using viral gene transfer significantly reduced phosphorylated CaMKII and GluA1 and effectively suppressed their seizure susceptibility. Thus, Pin1-CaMKII-AMPA receptors are a novel axis controlling epileptic susceptibility, highlighting attractive new therapeutic strategies.

Targeting PIN1 exerts potent antitumor activity in pancreatic ductal carcinoma via inhibiting tumor metastasis.

The human prolyl isomerase PIN1, best known for its association with carcinogenesis, has recently been indicated in the disease of pancreatic ductal adenocarcinoma (PDAC). However, the functions of PIN1 and the feasibility of targeting PIN1 in PDAC remain elusive. For this purpose, we examined the expression of PIN1 in cancer, related paracarcinoma and metastatic cancer tissues by immunohistochemistry and analyzed the associations with the pathogenesis of PDAC in 173 patients. The functional roles of PIN1 in PDAC were explored in vitro and in vivo using both genetic and chemical PIN1 inhibition. We showed that PIN1 was upregulated in pancreatic cancer and metastatic tissues. High PIN1 expression is significantly association with poor clinicopathological features and shorter overall survival and disease-free survival. Further stratified analysis showed that PIN1 phenotypes refined prognostication in PDAC. Inhibition of PIN1 expression with RNA interference or with all trans retinoic acid decreased not only the growth but also the migration and invasion of PDAC cells through regulating the key molecules of multiple cancer-driving pathways, simultaneously resulting in cell cycle arrest and mesenchymal-epithelial transition in vitro. Furthermore, genetic and chemical PIN1 ablation showed dramatic inhibition of the tumorigenesis and metastatic spread and then reduced the tumor burden in vivo. We provided further evidence for the use of PIN1 as a promising therapeutic target in PDAC. Genetic and chemical PIN1 ablation exerted potent antitumor effects through blocking multiple cancer-driving pathways in PDAC. More potent and specific PIN1 targeted inhibitors could be exploited to treat this aggressive cancer.

Diagnostic upgrade of atypical ductal hyperplasia of the breast based on evaluation of histopathological features and calcification on core needle biopsy.

AIMS: Atypical ductal hyperplasia (ADH) of breast is increasingly diagnosed in core needle biopsy (CNB). As higher-grade lesions were found in the excision in a substantial proportion of ADH on CNB, factors predicting risk of subsequent upgrade are clinically significant. This study aims to investigate relevant histopathological factors in CNB that could predict diagnostic upgrade at excision. METHODS AND RESULTS: One hundred and forty-three cases of CNB with paired subsequent excision were evaluated for multiple clinicopathological parameters related to CNB sampling, ADH morphology, calcification and other co-existing histological features, and which of these parameters were associated with diagnostic upgrade at subsequent excisions were determined. Forty-eight cases (34.3%) were upgraded to malignancy, including 15 invasive cancers and 33 ductal carcinomas in situ (DCIS). An increased tissue area occupied by ADH (P = 0.026), a higher number of ADH foci (P = 0.004), the presence of solid pattern (P = 0.037) and older age (P = 0.012) were positively associated with upgrade, while negative associations were found with the presence of micropapillary pattern (P = 0.025), co-existing columnar cell lesions (CCL) (P = 0.001) and the presence of calcifications (P = 0.009). Multivariate logistic regression analysis showed that the number of ADH foci (HR = 2.810, P = 0.013) was an independent positive predictor, while co-existing CCL (HR = 0.391, P = 0.013) was an independent negative predictor for upgrade. CONCLUSIONS: Patients with ADH in CNB showing the presence of co-existing CCL and a lower number of ADH foci have a lower risk of disease upgrade at excision, and are potential candidates for observation-only management.

Small lung lesions invisible under fluoroscopy are located accurately by three-dimensional localization technique on chest wall surface and performed bronchoscopy procedures to increase diagnostic yields.

BACKGROUND: Nowadays, small peripheral pulmonary lesions (PPLs) are frequently detected and the prognosis of lung cancer depends on the early diagnosis. Because of the high fee and requiring specialized training, many advanced techniques are not available in many developing countries and rural districts. METHODS: Three sets of opaque soft copper wires visible under the fluoroscopy (Flu) in the Flu-flexible bronchoscopy (FB) group (n = 24), which determined the three planes of the lesion, were respectively placed firmly on the surface of the chest wall with adhesive tape on the chest wall. The FB tip was advanced into the bronchus toward the crosspoint of the three perpendicular planes under Flu with careful rotation of a C-arm unit. Then the specimen were harvested focusing around the crosspoint for pathologic diagnosis. The rapid on-site evaluation (ROSE) procedure was also performed. The average Flu time during FB procedures were recorded and diagnostic accuracy rates in the Flu-FB group were compared with the other group guided by radial endobronchial ultrasound (R-EBUS) (n = 23). RESULTS: The location of the core point of the lesion, whether it was visible or not under the fluoroscopy could be recognized by three-dimensional localization technique. The accuracy rates of diagnostic yields were 62.5% in the Flu-FB group, and was similar as 65.2% in the R-EBUS group (P > 0.05). However, in the Flu-FB group, there was a decreasing tendency on accurate diagnosis rates of lower lobe (LL) lesions when comparing with non-LL lesions (3/8 = 37.5% vs 12/16 = 75%, P = 0.091) while in the R-EBUS group it was similar (9/12 = 75% vs 6/11 = 54.6%, P = 0.278). In the Flu-FB group, fluoroscopy time was negatively correlated with the lesion length (r = -0.613, P = 0.001), however, there was no significant difference between the lesions invisible or not (5.83 ± 1.45 min vs 7.67 ± 2.02 min, P = 0.116) under the fluoroscopy, as well as no significant difference among SPN, mGGO and GGO (6.12 ± 2.05 min, 7.25 ± 1.33 min and 7.80 ± 2.02 min, P > 0.05). CONCLUSIONS: Small PPL whether it is visible or not under fluoroscopy can be located accurately by our three-dimensional localization technique on chest wall surface and performed bronchoscopy procedures to increase diagnostic yields. It is more convenient, economical and reliable with the similar diagnostic yields than R-EBUS guided method. TRIAL REGISTRATION: Current Controlled Trials ChiCTR-DDD-16009715 . The date of registration: 3rd Nov, 2016. Retrospectively registered.

Bcl2 and Ki67 refine prognostication in luminal breast cancers.

Combined B-cell lymphoma 2 (Bcl2) and Ki67 expression for breast cancer prognostication has been proposed recently. However, the combinatorial relationship with patient outcome, clinico-pathologic features, and various biomarkers has not been fully explored. Bcl2 and Ki67 expression were examined in a large cohort of breast cancers. Differential Bcl2 and Ki67 combinatorial analysis, particularly in luminal cancers, were evaluated with respect to the clinico-pathologic features, biomarkers profile and outcome. Combined Bcl2/Ki67 phenotypes classified by Bcl2 and Ki67 cutoffs showed a better correlation with outcome. Multivariate analysis revealed this to be an independent prognostic factor in luminal cancers. Both Ki67 and Bcl2 contributed to the prognostic implications of different subgroups defined by Bcl2/Ki67 combination phenotypes with clinico-pathologic features and biomarkers profile. Ki67low/Bcl2high cases showed better DFS (HR = 2.17, P = 0.015) and OS (HR = 3.217, P = 0.015) compared to Ki67high/Bcl2low cases. Interestingly, Ki67low/Bcl2high cases also showed better outcome than other phenotypes in grade 2 cancers (log-rank = 4.844, P = 0.028) and TNM stage 2 cancers (log-rank = 8.161, P = 0.004). This classification by Bcl2/Ki67 combination phenotypes, together with PR expression, can also refine luminal A cancers prognostication. Not all PR low luminal A cases had poorer outcome compared to the PR high luminal A cases; poor prognosis was only limited to those with also low Bcl2 (log-rank = 23.568, P < 0.001 compared to PR high Bcl2 high cases). The combined Ki67/Bcl2 phenotyping was useful in luminal cancers prognostication. It also refined prognostication in intermediate groups (grade 2 and stage 2 cancers) of luminal cancers; and aided in further classification of luminal A cancers.

Enhancing Predictions of Drug Solubility through Multidimensional Structural Characterization Exploitation.

Solubility is not only a significant physical property of molecules but also a vital factor in smallmolecule drug development. Determining drug solubility demands stringent equipment, controlled environments, and substantial human and material resources. The accurate prediction of drug solubility using computational methods has long been a goal for researchers. In this study, we introduce MSCSol, a solubility prediction model that integrates multidimensional molecular structure information. We incorporate a graph neural network with geometric vector perceptrons (GVP-GNN) to encode 3D molecular structures, representing spatial arrangement and orientation of atoms, as well as atomic sequences and interactions. We also employ Selective Kernel Convolution combined with Global and Local attention mechanisms to capture molecular features context at different scales. Additionally, various descriptors are calculated to enrich the molecular representation. For the 2D and 3D structural data of molecules, we design different data augmentation strategies to enhance generalization ability and prevent the model from learning irrelevant information. Extensive experiments on benchmark and independent datasets demonstrate MSCSol's superior performance. Ablation studies further confirm the effectiveness of different modules. Interpretability analysis highlights the importance of various atomic groups and substructures for solubility and verifies that our model effectively captures functional molecular structures and higher-order knowledge. The source code and datasets are freely available at https://github.com/ZiyuFanCSU/MSCSol.

High-Throughput Screening of Surface Engineered Cyanine Nanodots for Active Transport of Therapeutic Antibodies into Solid Tumor.

The successful delivery of therapeutic biomacromolecules into solid tumor holds great challenge due to their high resistance to penetrate through the complex tumor microenvironments. Here, active-transporting nanoparticles are harnessed to efficiently deliver biomacromolecular drugs into solid tumors through cell transcytosis. A series of molecularly precise cyanine 5-cored polylysine G5 dendrimers (Cy5 nanodots) with different peripheral amino acids (G5-AA) is prepared. The capability of these positively charged nanodots to induce cell endocytosis, exocytosis, and transcytosis is evaluated via fluorescence-based high-throughput screen. The optimized nanodots (G5-R) are conjugated with αPD-L1 (a therapeutic monoclonal antibody binding to programmed-death ligand 1) (αPD-L1-G5-R) to demonstrate the nanoparticle-mediated tumor active transport. The αPD-L1-G5-R can greatly enhance the tumor-penetration capability through adsorption-mediated transcytosis (AMT). The effectiveness of αPD-L1-G5-R is tested in treating mice bearing partially resected CT26 tumors, mimicking the local immunotherapy of residual tumors post-surgery in clinic. The αPD-L1-G5-R embedded in fibrin gel can efficiently mediate tumor cell transcytosis, and deliver αPD-L1 throughout the tumor, thereby enhancing immune checkpoint blockade, reducing tumor recurrence, and significantly prolonging the survival time. The active-transporting nanodots are promising platforms for efficient tumor delivery of therapeutic biomacromolecules.

Gastric epithelial neoplasm of fundic-gland mucosa lineage: representative of the low atypia differentiated gastric tumor and Ki67 may help in their identification.

Background: Gastric epithelial neoplasm of the fundic-gland mucosa lineages (GEN-FGMLs) are rare forms of gastric tumors that encompass oxyntic gland adenoma (OGA), gastric adenocarcinoma of the fundic-gland type (GA-FG), and gastric adenocarcinoma of the fundic-gland mucosa type (GA-FGM). There is no consensus on the cause, classification, and clinicopathological features of GEN-FGMLs, and misdiagnosis is common because of similarities in symptoms. Methods: 37 cases diagnosed with GEN-FGMLs were included in this study. H&E-stained slides were reviewed and clinicopathological parameters were recorded. Immunohistochemical staining was conducted for MUC2, MUC5AC, MUC6, CD10, CD56, synaptophysin, chromograninA, p53, Ki67, pepsinogen-I, H+/K+-ATPase and Desmin. Results: The patients' ages ranged from 42 to 79 years, with a median age of 60. 17 were male and 20 were female. Morphologically, 19 OGAs, 16 GA-FGs, and two GA-FGMs were identified. Histopathological similarities exist between OGA, GA-FG, and GA-FGM. The tumors demonstrated well-formed glands, expanding with dense growth patterns comprising pale, blue-grey columnar cells with mild nuclear atypia. These cells resembled fundic gland cells. None of the OGA invaded the submucosal layer. The normal gastric pit epithelium covered the entire surface of the OGA and GA-FG, but the dysplasia pit epithelium covered the GA-FGM. Non-atrophic gastritis was observed in more than half of the background mucosa. All cases were diffusely positive for MUC6 and pepsinogen-I on immunohistochemistry. H+/K+-ATPase staining was negative or showed a scattered pattern in most cases. MUC5AC was expressed on the surface of GA-FGMs. p53 was focally expressed and the Ki67 index was low (1%-20%). Compared with OGA, GA-FG and GA-FGM were more prominent in the macroscopic view (p < 0.05) and had larger sizes (p < 0.0001). Additionally, GA-FG and GA-FGM exhibited higher Ki67 indices than OGA (p < 0.0001). Specimens with Ki-67 proliferation indices >2.5% and size >4.5 mm are more likely to be diagnosed with GA-FG and GA-FGM than OGA. Conclusion: GEN-FGMLs are group of well-differentiated gastric tumors with favourable biological behaviours, low cellular atypia, and low proliferation. Immunohistochemistry is critical for confirming diagnosis. Compared with OGA, GA-FG and GA-FGM have larger sizes and higher Ki67 proliferation indices, indicating that they play a critical role in the identification of GEN-FGML. Pathologists and endoscopists should be cautious to prevent misdiagnosis and overtreatment, especially in biopsy specimens.

Expression of histone methyltransferase WHSC1 in invasive breast cancer and its correlation with clinical and pathological data.

BACKGROUND: The WHSC1 protein facilitates specific dimethylation of histone H3 at the K36 position, enhancing gene transcription and expression. Studies have confirmed its high expression in diverse malignant tumors. We aimed to identify novel molecular markers to assess the biological behavior of breast cancer cells. METHODS: We conducted a comprehensive analysis of mRNA expression in breast cancer and adjacent tissues based on TCGA data. We enrolled 141 breast cancer patients treated at the First Affiliated Hospital of Fujian Medical University between 2012 and 2016. Patient clinical information and pathological specimens were obtained. We utilized tissue microarray (TMA) technology. We employed the chi-square test for between-group comparisons, with p < 0.05 indicating statistical significance. Furthermore, we analyzed the associations between WHSC1 expression and clinical or pathological data. RESULTS: WHSC1 mRNA expression was significantly higher in breast cancer tissues than in adjacent tissues (p < 0.001). Moreover, high WHSC1 protein expression in breast cancer was associated with several important clinical parameters, such as pathological type (p = 0.007), high Ki67 expression(Ki67＞20 %) (p < 0.001), lymph node metastasis (p < 0.001), T stage (p = 0.011), N stage (p < 0.001), postoperative pathological stage (p < 0.001), premenopausal status (p = 0.004), and positive HER2 status (p < 0.001). Multivariate regression analysis showed that high WHSC1 expression, elevated Ki67 levels, and positive HER2 status were independent risk factors for axillary lymph node metastasis in breast cancer patients. CONCLUSION: WHSC1 protein expression is upregulated in breast cancer patients and represents an independent risk factor influencing axillary lymph node metastasis, highlighting its potential significance as a strong candidate biomarker.

Identification of PPARG as key gene to link coronary atherosclerosis disease and rheumatoid arthritis via microarray data analysis.

BACKGROUND: Inflammation is the common pathogenesis of coronary atherosclerosis disease (CAD) and rheumatoid arthritis (RA). Although it is established that RA increases the risk of CAD, the underlining mechanism remained indefinite. This study seeks to explore the molecular mechanisms of RA linked CAD and identify potential target gene for early prediction of CAD in RA patients. MATERIALS AND METHODS: The study utilized five raw datasets: GSE55235, GSE55457, GSE12021 for RA patients, and GSE42148 and GSE20680 for CAD patients. Gene Set Enrichment Analysis (GSEA) was used to investigate common signaling pathways associated with RA and CAD. Then, weighted gene co-expression network analysis (WGCNA) was performed on RA and CAD training datasets to identify gene modules related to single-sample GSEA (ssGSEA) scores. Overlapping module genes and differentially expressed genes (DEGs) were considered as co-susceptible genes for both diseases. Three hub genes were screened using a protein-protein interaction (PPI) network analysis via Cytoscape plug-ins. The signaling pathways, immune infiltration, and transcription factors associated with these hub genes were analyzed to explore the underlying mechanism connecting both diseases. Immunohistochemistry and qRT-PCR were conducted to validate the expression of the key candidate gene, PPARG, in macrophages of synovial tissue and arterial walls from RA and CAD patients. RESULTS: The study found that Fc-gamma receptor-mediated endocytosis is a common signaling pathway for both RA and CAD. A total of 25 genes were screened by WGCNA and DEGs, which are involved in inflammation-related ligand-receptor interactions, cytoskeleton, and endocytosis signaling pathways. The principal component analysis(PCA) and support vector machine (SVM) and receiver-operator characteristic (ROC) analysis demonstrate that 25 DEGs can effectively distinguish RA and CAD groups from normal groups. Three hub genes TUBB2A, FKBP5, and PPARG were further identified by the Cytoscape software. Both FKBP5 and PPARG were downregulated in synovial tissue of RA and upregulated in the peripheral blood of CAD patients and differential mRNAexpreesion between normal and disease groups in both diseases were validated by qRT-PCR.Association of PPARG with monocyte was demonstrated across both training and validation datasets in CAD. PPARG expression is observed in control synovial epithelial cells and foamy macrophages of arterial walls, but was decreased in synovial epithelium of RA patients. Its expression in foamy macrophages of atherosclerotic vascular walls exhibits a positive correlation (r = 0.6276, p = 0.0002) with CD68. CONCLUSION: Our findings suggest that PPARG may serve as a potentially predictive marker for CAD in RA patients, which provides new insights into the molecular mechanism underling RA linked CAD.

Label-free assessment of pathological changes in pancreatic intraepithelial neoplasia by biomedical multiphoton microscopy.

Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion that has the potential to progress to invasive pancreatic cancer, and early and rapid detection may offer patients a chance for treatment before the development of invasive carcinoma. Therefore, the identification of PanIN holds significant clinical importance. In this study, we first used multiphoton microscopy (MPM) combining two-photon excitation fluorescence and second-harmonic generation imaging to label-free detect PanIN and attempted to differentiate between normal pancreatic ducts and different grades of PanIN. Then, we also developed an automatic image processing strategy to extract eight morphological features of collagen fibers from MPM images to quantify the changes in collagen fibers surrounding the ducts. Experimental results demonstrate that the combination of MPM and quantitative information can accurately identify normal pancreatic ducts and different grades of PanIN. This study may contribute to the rapid diagnosis of pancreatic diseases and may lay the foundation for further clinical application of MPM.

Targeting RCC1 to block the human soft-tissue sarcoma by disrupting nucleo-cytoplasmic trafficking of Skp2.

Soft-tissue sarcomas (STS) emerges as formidable challenges in clinics due to the complex genetic heterogeneity, high rates of local recurrence and metastasis. Exploring specific targets and biomarkers would benefit the prognosis and treatment of STS. Here, we identified RCC1, a guanine-nucleotide exchange factor for Ran, as an oncogene and a potential intervention target in STS. Bioinformatics analysis indicated that RCC1 is highly expressed and correlated with poor prognosis in STS. Functional studies showed that RCC1 knockdown significantly inhibited the cell cycle transition, proliferation and migration of STS cells in vitro, and the growth of STS xenografts in mice. Mechanistically, we identified Skp2 as a downstream target of RCC1 in STS. Loss of RCC1 substantially diminished Skp2 abundance by compromising its protein stability, resulting in the upregulation of p27Kip1 and G1/S transition arrest. Specifically, RCC1 might facilitate the nucleo-cytoplasmic trafficking of Skp2 via direct interaction. As a result, the cytoplasmic retention of Skp2 would further protect it from ubiquitination and degradation. Notably, recovery of Skp2 expression largely reversed the phenotypes induced by RCC1 knockdown in STS cells. Collectively, this study unveils a novel RCC1-Skp2-p27Kip1 axis in STS oncogenesis, which holds promise for improving prognosis and treatment of this formidable malignancy.

Elevated nutrients and surface chlorophyll-α associated with natural methane seeps in the Haima cold seep area of the Qiongdongnan Basin, northern South China Sea.

Cold seeps are a significant source of methane to the ocean. However, nutrients and Chl-α in the euphotic layer overlying cold seeps have been poorly studied. Variations in Chl-α, nutrients, environmental parameters, and CH4 concentrations in the Haima cold seeps were analyzed. Results show that the overlying water exhibits a typical low nutrient and low Chl-α marine environment. Phosphate and Chl-α were significantly elevated, and the average SCM in cold seeps was much higher than that in control stations. Spearman correlation analysis indicated Chl-α in cold seep was positively correlated with salinity and negatively with nutrient and CH4 concentrations. It implied that the CH4 concentrations may promote the increase of Chl-α, and may be linked to CH4 plumes, bringing cold, nutrient-rich waters to the thermocline. However, due to the CH4 plumes hardly to track, more sampling is needed to determine the effects on Chl-α and phytoplankton in the euphotic layer.

Impact of dust deposition on the growth of marine autotrophic and heterotrophic microorganisms: Evidence from the South China Sea.

Aeolian dust can provide nutrients for the ocean and affect the growth of phytoplankton. However, the impacts of dust deposition on autotrophic and heterotrophic microorganisms have rarely been studied. In this study, we conducted two microcosm experiments in the low-nutrient and low-chlorophyll environment of the South China Sea and found that dust did not stimulate the abundance of autotrophic and heterotrophic microorganisms. Our results show that dust contains most of the unreacted iron-bearing minerals, and thus provides limited bioavailable iron and nitrogen for bacterioplankton and phytoplankton growth. These results elucidate the overlooked impacts of the properties of the iron-bearing minerals in aeolian dust on microbial communities, which may play an important role in marine ecosystems and climate change.

Molecular evidence for the production of labile, sulfur-bearing dissolved organic matter in the seep sediments of the South China Sea.

Cold seeps with methane-rich fluids leaking out of the seafloor usually support massive biomass of chemosynthetic organisms and associated fauna. A substantial amount of methane is converted to dissolved inorganic carbon by microbial metabolism, and this process also releases dissolved organic matter (DOM) into pore water. Here, pore water samples from "Haima cold seeps" sediments and the non-seep reference sediments in the northern South China Sea were analyzed for optical properties and molecular compositions of pore water DOM. Our results showed that the relative abundance of protein-like DOM, H/Cwa and molecular lability boundary percentage (MLBL%) in the seep sediments were significantly higher than those in the reference sediments, indicating that more labile DOM related to unsaturated aliphatic compounds is produced in the seep sediments. Spearman's correlation of the fluoresce and molecular data suggested that the humic-like components (C1 and C2) mainly constituted the refractory compounds (CRAM, highly unsaturated and aromatics compounds). In contrast, the protein-like component (C3) had high H/C ratios featuring high degree of DOM lability. The amount of S-containing formulas (CHOS and CHONS) was greatly elevated in the seep sediments, likely caused by abiotic and biotic sulfurization of DOM in the sulfidic environment. Although the abiotic sulfurization was proposed to have a stabilizing effect on organic matter, our results implied that the biotic sulfurization in the cold seep sediments would increase DOM lability. Overall, the labile DOM accumulated in the seep sediments is closely linked to methane oxidation, which not only support heterotrophic communities and but also likely have an impact on carbon and sulfur cycling in the sediments and the ocean.

Morpholinyl silicon phthalocyanine nanoparticles with lysosome cell death and two-photon imaging functions for in vitro photodynamic therapy of cancer cells.

The lysosome is an important target for realizing antitumor therapy. Lysosomal cell death exerts significant therapeutic effects on apoptosis and drug-resistance. The development of lysosome-targeting nanoparticles to obtain efficient cancer treatment is challenging. In this article, nanoparticles composed of DSPE@M-SiPc and possessing bright two-photon fluorescence, lysosome targeting ability, and photodynamic therapy multifunctionalities are prepared by encapsulating morpholinyl-substituted silicon phthalocyanine (M-SiPc) with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(poly(ethylene glycol))-2000] (DSPE). Two photon fluorescence bioimaging showed that M-SiPc and DSPE@M-SiPc mainly locate in lysosomes after cellular internalization. Upon irradiation, DSPE@M-SiPc effectively generates reactive oxygen species and damages the function of lysosome, subsequently leading to lysosomal cell death. DSPE@M-SiPc is a promising photosensitizer for cancer treatment.

Chlorophenyl thiophene silicon phthalocyanine: Synthesis, two-photon bioimaging-guided lysosome target, and in vitro photodynamic efficacy.

The development of efficient photosensitizers with high singlet oxygen quantum yield, strong fluorescent emission, excellent photostability, and specific organelle targeting is in great demand for the enhancement of PDT treatment efficiency. This study designed and synthesized a new two-photon photosensitizer chlorophenyl thiophene axially substituted silicon (IV) phthalocyanine (CBT-SiPc). CBT-SiPc showed specific targeting of lysosomes in living cells and good biocompatibility. Furthermore, high 1O2 generation efficiency and high PDT efficiency in MCF-7 breast cancers under irradiation were also demonstrated. The novel CBT-SiPc showed great potential in the application of lysosome-targeted and two-photon bioimaging-guided photodynamic cancer therapy.

The tumor-stroma ratio and the immune microenvironment improve the prognostic prediction of pancreatic ductal adenocarcinoma.

Tumor-infiltrating immune cells and fibroblasts are significant components of the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC), and they participate in tumor progression as closely as tumor cells. However, the relationship between the features of the TME and patient outcomes and the interactions among TME components are still unclear. In this study, we evaluated the PDAC TME in terms of the quantity and location of cluster of differentiation (CD)4+ T cells, CD8+ T cells, macrophages, stromal maturity, and tumor-stroma ratio (TSR), as evaluated by immunohistochemical staining of serial whole-tissue sections from 116 patients with PDAC. The density of T cells and macrophages (mainly activated macrophages) was significantly higher at the invasive margins (IMs) than at the tumor center (TC). CD4+ T cells were significantly association with all the other tumor-associated immune cells (TAIs) including CD8, CD68 and CD206 positive cells. Tumors of the non-mature (intermediate and immature) stroma type harbored significantly more CD8+ T cells at the IMs and more CD68+ macrophages at the IMs and the TC. The density of CD4+, CD8+, and CD206+ cells at the TC; CD206+ cells at the IMs; and tumor-node-metastasis (TNM) staging were independent risk factors for patient outcomes, and the c-index of the risk nomogram for predicting the survival probability based on the TME features and TNM staging was 0.772 (95% confidence interval: 0.713-0.832). PDAC harbored a significantly immunosuppressive TME, of which the IMs were the hot zones for TAIs, while cells at the TC were more predictive of prognosis. Our results indicated that the model based on the features of the TME and TNM staging could predict patient outcomes.