Comparison of efficacy and safety of conventional transarterial chemoembolization and drug-eluting bead transarterial chemoembolization in unresectable intrahepatic cholangiocarcinoma: A multicenter retrospective cohort study.

PURPOSE: The efficacy and safety of drug-eluting bead transarterial chemoembolization (DEB-TACE) and conventional TACE (c-TACE) in the treatment of patients with unresectable intrahepatic cholangiocarcinoma (ICC) remained controversial. Therefore, we aimed to compare the efficacy and safety between c-TACE and DEB-TACE among patients with ICC. METHOD: Between June 10, 2016 and November 19, 2022, consecutive patients with pathological diagnoses of ICC were divided into the DEB-TACE group and the c-TACE group based on the type of TACE treatment they received. The Kaplan-Meier method and log-rank test were used to compare overall survival (OS) between the two groups. Propensity score matching (PSM) was used to balance the characteristics between the c-TACE group and the DEB-TACE group. RESULTS: A total of 132 patients were included in this study, with 64 patients in the c-TACE group and 68 patients in the DEB-TACE group. The median OS for c-TACE and DEB-TACE was 5 and 12 months, respectively. The objective response rate (ORR) for c-TACE and DEB-TACE was 0 % and 66.2 %, respectively; the disease control rate (DCR) was 37.5 % and 91.2 %. There were no significant differences between c-TACE and DEB-TACE among adverse effects at 3 months after treatment (P > 0.05). The results remained consistent after PSM. The Cox regression demonstrated that the DEB-TACE was an independent protective factor for OS. CONCLUSIONS: Patients in the DEB-TACE group had longer OS and higher ORR and DCR than those in the c-TACE group, but no significant difference was observed between the two groups regarding adverse effects.

Systemic chemotherapy plus transarterial chemoembolization versus systemic chemotherapy alone for unresectable intrahepatic cholangiocarcinoma: a multicenter retrospective cohort study.

PURPOSE: Systemic chemotherapy (SYS) is the first-line treatment of unresectable intrahepatic cholangiocarcinoma (ICC). However, the survival benefit of SYS is still limited. This study compared the efficacy and safety of patients with unresectable ICC treated with transarterial chemoembolization (TACE) plus SYS to SYS alone. MATERIAL AND METHODS: The multicenter retrospective cohort study included patients aged ≥ 18 years old with pathologically diagnosed ICC. Patients with unmeasurable lesions, not receiving SYS treatment, Child-Pugh grade C, Eastern Cooperative Oncology Group performance status score of 3 or higher, prior liver resection, incomplete medical information, or discontinuation of the first SYS treatment were excluded. Data collection was mainly from the hospital system, and the survival outcome of patients was obtained through follow-up. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Propensity score matching at a 1:1 ratio using the nearest neighbor matching algorithm was performed to reduce selection bias between the TACE plus SYS and SYS alone groups. The Cox proportional hazards model was used to identify prognostic factors associated with OS and to estimate their hazard ratios. Modified Response Evaluation Criteria in Solid Tumors criteria were utilized to evaluate the response of tumors to therapy. RESULTS: Between June 2016 and February 2023, 118 unresectable ICC patients from three hospitals were included in this study. Of them, 37 were in the TACE plus SYS group and 81 were in the SYS alone group. The median OS in the combination group was 11.3 months, longer than the 6.4 months in the SYS alone group (P = 0.011). A greater objective response rate (ORR) and disease control rate (DCR) were observed in the combination group than in the SYS alone group (ORR, 48.65 vs. 6.17%, P < 0.001; DCR, 89.19 vs. 62.96%, P = 0.004). There were 16 patients in each group after matching, and the matched results remained consistent regarding OS and tumor response. Adverse events (AEs) were similar in the two groups after matching. CONCLUSION: Compared to SYS alone, the combination treatment of TACE plus SYS was more effective than SYS alone in improving OS, ORR, and DCR without any significant increase in AEs. TACE plus SYS may be a viable treatment option for patients with unresectable ICC.

Endogenous hsa-circ_0007113 binds hsa-miR-515-5p to regulate senescence in human embryonic lung fibroblasts.

BACKGROUND: Cellular senescence can lead to many diseases. However, the roles and regulation of circular RNAs (circRNAs) in senescence are poorly understood. OBJECTIVES: To investigate the altered expression pattern and mechanism of circRNA during cellular senescence and find potential targets to prevent senescence. MATERIAL AND METHODS: The Arraystar Human circRNA Array and bioinformatics were used to profile the differentially expressed circRNAs in human embryonic lung fibroblasts (IMR-90) between young cells and senescent cells and quantification in the clinical materials. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. The miRNA targets were predicted using TargetScan and miRanda. RESULTS: A total of 113 differentially expressed circRNAs were identified, including 109 upregulated and 4 downregulated circRNAs (fold change >2 and p-value <0.05). Real-time qualitative polymerase chain reaction (qPCR) showed that the expression levels of 4 circRNA were significantly increased in senescent cells, and that of hsa_circ_0007113 was significantly decreased, consistent with the microarray. siRNA against hsa_circ_0007113 increased p21 and p53 expression levels and ß-gal staining. The hsa_circ_0007113 has a binding site for miR-515-5p, which is involved in regulating the p53/p21 signaling pathway. The expression level of hsa_circ_0007113 was also decreased in aged people. CONCLUSIONS: The study showed an altered circRNA expression pattern in cellular senescence, which might play important roles in senescence-related physiological processes. These findings provide a new direction for studying the molecular mechanism underlying senescence and a new possibility for the treatment of senescence by modulating circRNAs.

MUE-CoT: multi-scale uncertainty entropy-aware co-training framework for left atrial segmentation.

Objective.Accurate left atrial segmentation is the basis of the recognition and clinical analysis of atrial fibrillation. Supervised learning has achieved some competitive segmentation results, but the high annotation cost often limits its performance. Semi-supervised learning is implemented from limited labeled data and a large amount of unlabeled data and shows good potential in solving practical medical problems.Approach. In this study, we proposed a collaborative training framework for multi-scale uncertain entropy perception (MUE-CoT) and achieved efficient left atrial segmentation from a small amount of labeled data. Based on the pyramid feature network, learning is implemented from unlabeled data by minimizing the pyramid prediction difference. In addition, novel loss constraints are proposed for co-training in the study. The diversity loss is defined as a soft constraint so as to accelerate the convergence and a novel multi-scale uncertainty entropy calculation method and a consistency regularization term are proposed to measure the consistency between prediction results. The quality of pseudo-labels cannot be guaranteed in the pre-training period, so a confidence-dependent empirical Gaussian function is proposed to weight the pseudo-supervised loss.Main results.The experimental results of a publicly available dataset and an in-house clinical dataset proved that our method outperformed existing semi-supervised methods. For the two datasets with a labeled ratio of 5%, the Dice similarity coefficient scores were 84.94% ± 4.31 and 81.24% ± 2.4, the HD95values were 4.63 mm ± 2.13 and 3.94 mm ± 2.72, and the Jaccard similarity coefficient scores were 74.00% ± 6.20 and 68.49% ± 3.39, respectively.Significance.The proposed model effectively addresses the challenges of limited data samples and high costs associated with manual annotation in the medical field, leading to enhanced segmentation accuracy.

The addition of nano zero-valent iron during compost maturation effectively removes intracellular and extracellular antibiotic resistance genes by reducing the abundance of potential host bacteria.

Applying compost to soil may lead to the spread of antibiotic resistance genes (ARGs) in the environment. Therefore, removing ARGs from compost is critical. In this study, for the first time, nano zero-valent iron (nZVI) was added to compost during the maturation stage to remove ARGs. After adding 1 g/kg of nZVI, the abundance of total intracellular and total extracellular ARGs was decreased by 97.62% and 99.60%, and that of total intracellular and total extracellular mobile genetic elements (MGEs) was decreased by 92.39% and 99.31%, respectively. A Mantel test and network analysis indicated that the reduction in potential host bacteria and intI1 after nZVI treatment promoted the removal of intracellular and extracellular ARGs. The addition of nZVI during composting reduced the horizontal transfer of ARGs and improve the total nitrogen and germination index of compost, allowing it to meet the requirements for organic fertilizers.

High expression level of homocitrulline is correlated with seborrheic keratosis and skin aging

Abstract Backgroud Homocitrulline (Hcit), is involved in the pathological processes of some diseases. However, the role and function of Hcit (CBL) in human skin remains largely obscure. Objective To investigate the correlation of the level of Hcit in seborrheic keratosis, skin aging, and its clinical significance. Methods Immunohistochemistry was used to analyze the level of Hcit in skin lesions of seborrheic keratosis (SK), unaffected skin (distant 0.5 centimeters from SK lesion), and normal skin of healthy subjects in the control group. ELISA test was used to detect the serum level of CBL in SK patients and healthy subjects of different ages. Results Hcit was mainly localized in the nucleus of epidermal cells. In healthy control skin, the expression of Hcit increased with age and showed a positive correlation with age (the correlation coefficient was 0.806, p = 0.0002). The expressional level of Hcit in SK lesions was higher than that in healthy control skin (Z = −3.703, p = 0.0002). The serum level of CBL in healthy subjects and in SK patients increased with age (the correlation coefficient were 0.5763, p = 0.0032; 0.682, p = 0.004. respectively). The serum level of CBL in SK patients was higher than that in healthy subjects (Z = −2.19, p = 0.030). Study limitations The small serum sample size in the study. Conclusion The high expressional level of Hcit is correlated with seborrheic keratosis and skin aging. HCit may be one of the potential biomarkers of skin aging.

Deficiency of angiopoietin-like 4 enhances CD8+ T cell bioactivity via metabolic reprogramming for impairing tumour progression.

Angiopoietin-like 4 (ANGPTL4) is a secreted metabolism-modulating glycoprotein involved in the progression of tumours, cardiovascular diseases, metabolic syndrome and infectious diseases. In this study, more CD8+ T cells were activated to be effector T cells in ANGPTL4-/- mice. Impaired growth of tumours implanted in 3LL, B16BL6 or MC38 cells and reduced metastasis by B16F10 cells were observed in ANGPTL4-/- mice. Bone marrow (BM) transplantation experiments displayed that deficiency of ANGPTL4 in either host or BM cells promoted CD8+ T cell activation. However, ANGPTL4 deficiency in CD8+ T cells themselves showed more efficient anti-tumour activities. Recombinant ANGPTL4 protein promoted tumour growth in vivo with the less CD8+ T cell infiltration and it directly downregulated CD8+ T cell activation ex vivo. Transcriptome sequencing and metabolism analysis identified that ANGPTL4-/- CD8+ T cells increased glycolysis and decreased oxidative phosphorylation, which was dependent on the PKCζ-LKB1-AMPK-mTOR signalling axis. Reverse correlation of elevated ANGPTL4 levels in sera and tumour tissues with activated CD8+ T cells in the peripheral blood was displayed in patients with colorectal cancer. These results demonstrated that ANGPTL4 decreased immune surveillance in tumour progression by playing an immune-modulatory role on CD8+ T cells via metabolic reprogramming. Efficient blockade of ANGPTL4 expression in tumour patients would generate an effective anti-tumour effect mediated by CD8+ T cells.

Organismal response to micro(nano)plastics at environmentally relevant concentrations: Toxicity and the underlying mechanisms.

The toxic effects of micro(nano)plastics are long-standing, flourishing and fadeless as a research topic because of its' underlying threats to the ecology and human health. Nevertheless, in most of the existing studies, some model organisms are exposed to micro(nano)plastics at a high concentration unlikely to occur in the real environment, and there is limited data available on the impact of micro(nano)plastics at environmentally relevant concentrations (ERC) on environmental organisms. To gain a better insight into micro(nano)plastic toxicity to the environmental organisms, here we integrate the related publications of micro(nano)plastic research at ERC in the past 10 years using a bibliometric analysis, and focus on the analysis of publication trends, research focuses, collaborations, and research status. In addition, we further analyze the 33 final filtered literature, and elucidate the organismal response to micro(nano)plastics at ERC from the perspective of in vivo toxic effects and mechanisms involved. This paper also puts forward some limitations of the current study and some suggestions for future research. Our study may be of great significance in further understanding the ecotoxicity of micro(nano)plastics.

High expression level of homocitrulline is correlated with seborrheic keratosis and skin aging.

BACKGROUD: Homocitrulline (Hcit), is involved in the pathological processes of some diseases. However, the role and function of Hcit (CBL) in human skin remains largely obscure. OBJECTIVE: To investigate the correlation of the level of Hcit in seborrheic keratosis, skin aging, and its clinical significance. METHODS: Immunohistochemistry was used to analyze the level of Hcit in skin lesions of seborrheic keratosis (SK), unaffected skin (distant 0.5 centimeters from SK lesion), and normal skin of healthy subjects in the control group. ELISA test was used to detect the serum level of CBL in SK patients and healthy subjects of different ages. RESULTS: Hcit was mainly localized in the nucleus of epidermal cells. In healthy control skin, the expression of Hcit increased with age and showed a positive correlation with age (the correlation coefficient was 0.806, p = 0.0002). The expressional level of Hcit in SK lesions was higher than that in healthy control skin (Z = -3.703, p = 0.0002). The serum level of CBL in healthy subjects and in SK patients increased with age (the correlation coefficient were 0.5763, p = 0.0032; 0.682, p = 0.004. respectively). The serum level of CBL in SK patients was higher than that in healthy subjects (Z = -2.19, p = 0.030). STUDY LIMITATIONS: The small serum sample size in the study. CONCLUSION: The high expressional level of Hcit is correlated with seborrheic keratosis and skin aging. HCit may be one of the potential biomarkers of skin aging.

Study on the correlation of high expression level of HuD with seborrheic keratosis and skin aging.

BACKGROUND: Currently, most studies of ELAV (Embryonic Lethal, Abnormal Vision, Drosophila)-like protein 4 (Hu antigen D, HuD) focus on nervous system-related diseases; the role of HuD in the occurrence of skin aging and seborrheic keratosis (SK) has not been reported. OBJECTIVE: To explore the role of HuD in the occurrence of SK and skin aging and its related clinical significance. METHODS: The expression levels of HuD in the skin and blood of healthy people at different ages, SK lesions, and perilesional skin of SK patients were detected by both immunohistochemistry and Western blotting. The mRNA expression levels of HuD in the skin and blood of healthy peoples at different ages were detected by quantitative real-time reverse transcription-polymerase chain reaction. The expression level of HuD was compared with the skin of healthy people, SK lesion, and perilesional skin of SK patients of the same age. RESULTS: The immunohistochemistry and Western blotting showed that the expression levels of HuD in SK lesions were higher than those in healthy skin and perilesional skin. The immunohistochemical staining intensity, protein and mRNA expression levels of HuD in the skin and blood of healthy people were correlated with age, which gradually increased with increasing age. CONCLUSION: HuD is highly expressed in SK lesion and aged skin, indicating that a higher HuD expression level is correlated with occurrence of SK and aging skin; however, its mechanism needs to be further studied.

Single-breath-hold T2WI MRI with artificial intelligence-assisted technique in liver imaging: As compared with conventional respiratory-triggered T2WI.

OBJECTIVE: To investigate the clinical feasibility of single-breath-hold T2-weighted (SBH-T2WI) liver MRI using Artificial Intelligence-assisted Compressed Sensing (ACS) technique in liver imaging as compared with conventional respiratory-triggered T2WI (RT-T2WI). METHODS: From January 2021 to October 2021, 81 patients suspected of liver lesions were enrolled in this prospective study. The liver MRI was performed, including both RT-T2WI and ACS SBH-T2WI. Two experienced radiologists reviewed all images of each studied sequence, and recorded the lesion location and the largest diameter of the lesions. The image quality was quantitatively and qualitatively analyzed regarding signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), contrast ratio (CR), motion artifact, lesion conspicuity, liver boundary sharpness, and overall image quality. The lesion detection and image quality were compared between two sequences using the Chi-square test or Wilcoxon signed-rank test. RESULTS: For lesion detection, 64 lesions were identified in 53 enrolled patients as the reference standard. The average size was 12.09 ± 7.4 mm for the benign lesions and 45.89 ± 22.01 mm for the malignant lesions. Of 64 liver lesions, ACS SBH-T2WI detected 60 lesions (93.8%), and RT-T2WI detected 58 lesions (90.6%). For image quality analysis, the motion artifact of ACS SBH-T2WI sequence was significantly reduced compared with the conventional RT-T2WI sequence (p < 0.05). The SNR, liver boundary sharpness, and overall image quality showed no statistical differences between the two sequences. While the CNR, CR, and lesion conspicuity of ACS SBH-T2WI were significantly better than RT-T2WI (all p < 0.05). CONCLUSIONS: The SBH-T2WI with ACS technique showed promising performance as it provided significantly better image quality and lesion detectability with a considerable decrease in scanning time as compared with the conventional RT-T2WI.

Toxicity assessments and transcriptional effects of monofunctionalized Pt(II) complex under dark and light irradiation condition in Caenorhabditis elegans.

In vivo toxicity of aromatic ring (BODIPY, 1,3,5,7,8-pentamethyl dipyrrin borondifluoride) attached monofunctional Pt(II) complexes mCBP {[cis-Pt(NH3)2Cl] 8-(para-pyridine-methylene),1,3,5,7-tetramethyl dipyrrin borondifluoride}+ Nitrate- and dCBP {[cis-Pt(NH3)2Cl]28-(1,3-pyrimidine-5-methylene),1,3,5,7-tetramethyl dipyrrin borondifluoride}2+ diNitrate2- were tested in Caenorhabditis elegans (C. elegans). dCBP showed promising reactive oxygen ROS (reactive oxygen species) generating capability. This complex resulted reduction of lifespan, body length and egg laying rate under dark and light irradiation in both N2 (wild-type, cisplatin resistant) and ok938 (asna-1, cisplatin sensitive) C. elegans. Expressional change of several key cancer related pathway (JNK (c-Jun N-terminal kinase) and Wnt/ß-catenin (Wingless/Integrated/ß-catenin)) related genes (for instance, jnk-1, wrm-1 and gst-4) were confirmed by RNA sequencing experiments. These transcriptional alternations could explain physiological parameters change in nematode and partially revealed how both Pt(II) based complexes influence cancer related pathways. Furthermore, these associated genes exhibited the function of apoptosis, reduced chemoresistance of cancer cells and most of those expressional changes were linked to extended survival of cancer patients.

Retinal Nerve Fiber Layer Thickness and Associations With Cognitive Impairment in Parkinson's Disease.

OBJECTIVE: This study intended to investigate whether retinal nerve fiber layer (RNFL) thickness could become a potential marker in patients with Parkinson's disease with cognitive impairment (PD-CI). METHODS: Fifty-seven PD patients and 45 age-matched healthy controls (HCs) were recruited in our cross-sectional study and completed optical coherence tomography (OCT) evaluations. PD with normal cognition (PD-NC) and cognitive impairment (PD-CI) patients were divided following the 2015 Movement Disorder Society criteria. RNFL thickness was quantified in subfields of the 3.0-mm circle surrounding the optic disk; while a battery of neuropsychiatric assessments was conducted to estimate the Parkinsonism severity. General linear models and one-way ANOVA were adopted to assess RNFL thickness between subgroups with different cognitive statuses; logistic regression analyses were applied to determine the relation between RNFL and PD-CI cases. RESULTS: Compared with HCs, more thinning of the RNFL was observed in the inferior and temporal sectors in PD patients, especially in the PD-CI group. Inferior RNFL thickness was reduced in PD-CI compared with PD-NC patients. Logistic regression analysis found that inferior RNFL thickness was independently associated with PD-CI cases (odds ratio = 0.923, p = 0.014). Receiver operating characteristic analysis showed that the RNFL-involved combined model provided a high accuracy in screening cognitive deficiency in PD cases (area under the curve = 0.85, p < 0.001). CONCLUSION: Reduced RNFL thickness especially in the inferior sector is independently associated with PD-CI patients. Our study present new perspectives into verifying possible indicators for neuropathological processes or disease severity in Parkinsonians with cognitive dysfunction.

Effect of gigantol on the proliferation of hepatocellular carcinoma cells tested by a network-based pharmacological approach and experiments.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common clinical malignant disease and the second leading cause of cancer-related death worldwide. Dendrobium is a commonly applied nourishing drug in traditional Chinese medicine. Gigantol is a phenolic compound extracted from Dendrobium. The compound has attracted attention for its anticancer effects. However, the mechanism of gigantol in HCC has not been extensively explored. METHODS: Potential targets of gigantol were predicted by SwissTargetPrediction. HCC-related genes were obtained from the GeneCards, Online Mendelian Inheritance in Man (OMIM), Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB), Therapeutic Target Database (TTD) and DrugBank databases. The "gigantol-target-disease" network was constructed using Cytoscape software. Protein interaction network analysis was performed using STRING software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were executed utilizing the R package to explore the possible regulatory mechanisms of gigantol in HCC. To authenticate the role of gigantol in HCC, Cell Counting Kit-8 (CCK-8) assay, 5-ethynyl-2'-deoxyuridine (EdU) assay, wound healing assay, Matrigel invasion assay and Western blot were performed. RESULTS: Three core genes were screened from 32 closely linked genes. Pathway analysis yielded many signaling pathways associated with cancer. The CCK-8 assay and EdU assay indicated that gigantol suppressed the growth of HCC cells. The wound healing assay and Matrigel invasion assay showed the inhibition of migration and metastasis of HCC cells by gigantol. We verified from molecular docking and protein level that gigantol can exert regulatory effects through three targets, ESR1, XIAP and HSP90AA1. Furthermore, Western blot results tentatively revealed that gigantol may inhibit HCC progression through the HSP90/Akt/CDK1 pathway. CONCLUSIONS: Our results confirms anti-HCC proliferation activity of gigantol through PI3K pathway described in existing literature by different experimental approaches. Furthermore, it has discovered other proteins regulated by the drug that was not previously reported in the literature.These findings provide potential molecular and cellular evidence that gigantol may be a promising antitumor agent.

Dl-3-n-Butylphthalide Rescues Dopaminergic Neurons in Parkinson's Disease Models by Inhibiting the NLRP3 Inflammasome and Ameliorating Mitochondrial Impairment.

Background: Neuroinflammation and mitochondrial impairment play important roles in the neuropathogenesis of Parkinson's disease (PD). The activation of NLRP3 inflammasome and the accumulation of α-synuclein (α-Syn) are strictly correlated to neuroinflammation. Therefore, the regulation of NLRP3 inflammasome activation and α-Syn aggregation might have therapeutic potential. It has been indicated that Dl-3-n-butylphthalide (NBP) produces neuroprotection against some neurological diseases such as ischemic stroke. We here intended to explore whether NBP suppressed NLRP3 inflammasome activation and reduced α-Syn aggregation, thus protecting dopaminergic neurons against neuroinflammation. Methods: In our study, we established a MPTP-induced mouse model and 6-OHDA-induced SH-SY5Y cell model to examine the neuroprotective actions of NBP. We then performed behavioral tests to examine motor dysfunction in MPTP-exposed mice after NBP treatment. Western blotting, immunofluorescence staining, flow cytometry and RT-qPCR were conducted to investigate the expression of NLRP3 inflammasomes, neuroinflammatory cytokines, PARP1, p-α-Syn, and markers of microgliosis and astrogliosis. Results: The results showed that NBP exerts a neuroprotective effect on experimental PD models. In vivo, NBP ameliorated behavioral impairments and reduced dopaminergic neuron loss in MPTP-induced mice. In vitro, treatment of SH-SY5Y cells with 6-OHDA (100uM,24 h) significantly decreased cell viability, increased intracellular ROS production, and induced apoptosis, while pretreatment with 5uM NBP could alleviated 6-OHDA-induced cytotoxicity, ROS production and cell apoptosis to some extent. Importantly, both in vivo and in vitro, NBP suppressed the activation of the NLRP3 inflammasome and the aggregation of α-Syn, thus inhibited neuroinflammation ameliorated mitochondrial impairments. Conclusions: In summary, NBP rescued dopaminergic neurons by reducing NLRP3 inflammasome activation and ameliorating mitochondrial impairments and increases in p-α-Syn levels. This current study may provide novel neuroprotective mechanisms of NBP as a potential therapeutic agent.

The Pathogenesis and Treatment of Cardiovascular Autonomic Dysfunction in Parkinson's Disease: What We Know and Where to Go.

Cardiovascular autonomic dysfunctions (CAD) are prevalent in Parkinson's disease (PD). It contributes to the development of cognitive dysfunction, falls and even mortality. Significant progress has been achieved in the last decade. However, the underlying mechanisms and effective treatments for CAD have not been established yet. This review aims to help clinicians to better understand the pathogenesis and therapeutic strategies. The literatures about CAD in patients with PD were reviewed. References for this review were identified by searches of PubMed between 1972 and March 2021, with the search term "cardiovascular autonomic dysfunctions, postural hypotension, orthostatic hypotension (OH), supine hypertension (SH), postprandial hypotension, and nondipping". The pathogenesis, including the neurogenic and non-neurogenic mechanisms, and the current pharmaceutical and non-pharmaceutical treatment for CAD, were analyzed. CAD mainly includes four aspects, which are OH, SH, postprandial hypotension and nondipping, among them, OH is the main component. Both non-neurogenic and neurogenic mechanisms are involved in CAD. Failure of the baroreflex circulate, which includes the lesions at the afferent, efferent or central components, is an important pathogenesis of CAD. Both non-pharmacological and pharmacological treatment alleviate CAD-related symptoms by acting on the baroreflex reflex circulate. However, pharmacological strategy has the limitation of failing to enhance baroreflex sensitivity and life quality. Novel OH treatment drugs, such as pyridostigmine and atomoxetine, can effectively improve OH-related symptoms via enhancing residual sympathetic tone, without adverse reactions of supine hypertension. Baroreflex impairment is a crucial pathological mechanism associated with CAD in PD. Currently, non-pharmacological strategy was the preferred option for its advantage of enhancing baroreflex sensitivity. Pharmacological treatment is a second-line option. Therefore, to find drugs that can enhance baroreflex sensitivity, especially via acting on its central components, is urgently needed in the scientific research and clinical practice.

BODIPY-Appended Pt(II) Complexes with High Toxicities and Anti-chemoresistance Performances in a Cisplatin Resistant In Vivo Model.

Two novel fluorophore (BODIPY)-bearing complexes, pyriplatin (mCBP) and pyrimidine-chelated cisplatin (dCBP), were synthesized and characterized. The additional BODIPY-pyridine/pyridimine motifs of the two Pt(II) complexes resulted in stronger interactions with DNA in comparison with those of cisplatin. mCBP and cisplatin caused relative decreases in life span and body length in a cisplatin resistant in vivo model, N2 (wild-type) Caenorhabditis elegans. In contrast, dCBP resulted in a dramatic reduction in the two physiological parameters in N2 C. elegans, indicating high toxicity and sensitivity. The resistance factors (RF) of cisplatin, mCBP, and dCBP were determined to be 2.46, 1.04, and 0.91, respectively. The increasing RF folds for mCBP and dCBP against cisplatin were 2.36 and 2.70, respectively. This suggested they were featured with improved anti-chemoresistance capabilities. It is noteworthy that dCBP showed lowest lethal concentration (LC50) values of 0.56 and 0.61 mM in cisplatin resistant and sensitive in vivo models, respectively. Upregulation of several evolutionary conservation genes that regulate cisplatin chemoresistance through cisplatin effluxing, the DNA damage response, the unfolded protein response, and detoxification (asna-1, parp-1, enpl-1, and skn-1) was observed upon exposure to cisplatin but not to mCBP and dCBP. This could explain the improved anti-chemoresistance performances of synthesized Pt(II) complexes.

Cancer-associated fibroblasts support bone tropic metastasis by acting as coordinators between the tumor microenvironment and bone matrix in breast cancer.

Bone is a common site of metastasis for various types of cancer cells, including breast cancer, and the consequent skeleton-related events observed in patients are severe and often fatal. Currently, it is widely accepted that cancer-associated fibroblasts (CAFs) confer a metastasis-promoting property to breast cancer cells. Furthermore, clinical observations suggest that CAFs mediate the bone tropism of metastatic breast cancer cells. Therefore, a deeper understanding of the mechanism by which CAFs are involved in the bone-tropic metastasis of breast cancer can facilitate the study of the novel and effective therapeutic drugs for the corresponding targets. In this review, we focused on the coordinator role of CAFs in remolding breast cancer cells and remodeling the bone marrow during metastasis. We discussed the potential roles of the CXCL12/CXCR4 axis, the CAFs-CSCs reinforcing loop, and exosomes in this malignant process. In summary, in agreement with Paget's theory, CAFs play a pivotal role in bone colonization by breast cancer cells by providing a "fertile soil" for the "selected seeds" by influencing tumor-intrinsic characteristics and microenvironment (ME).

Various Diseases and Clinical Heterogeneity Are Associated With "Hot Cross Bun".

Objective: To characterize the clinical phenotypes associated with the "hot cross bun" sign (HCBs) on MRI and identify correlations between neuroimaging and clinical characteristics. Methods: Firstly, we screened a cohort of patients with HCBs from our radiologic information system (RIS) in our center. Secondly, we systematically reviewed published cases on HCBs and classified all these cases according to their etiologies. Finally, we characterized all HCBs cases in detail and classified the disease spectra and their clinical heterogeneity. Results: Out of a total of 3,546 patients who were screened, we identified 40 patients with HCBs imaging sign in our cohort; systemic literature review identified 39 cases, which were associated with 14 diseases. In our cohort, inflammation [neuromyelitis optica spectrum disorders (NMOSD), multiple sclerosis (MS), and acute disseminated encephalomyelitis (ADEM)] and toxicants [toxic encephalopathy caused by phenytoin sodium (TEPS)] were some of the underlying etiologies. Published cases by systemic literature review were linked to metabolic abnormality, degeneration, neoplasm, infection, and stroke. We demonstrated that the clinical phenotype, neuroimaging characteristics, and HCBs response to therapy varied greatly depending on underlying etiologies. Conclusion: This is the first to report HCBs spectra in inflammatory and toxication diseases. Our study and systemic literature review demonstrated that the underpinning disease spectrum may be broader than previously recognized.