Treatment of severe hidradenitis suppurativa with a combination of 5-aminolevulinic acid photodynamic therapy, surgery, and secukinumab.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by nodules, abscesses, fistulas, sinus tracts, and scars, typically in intertriginous areas (Sabat et al., 2022). Therapeutic options include medications, surgical interventions, and physiotherapy; however, clinical management is challenging. We report a case of HS that was refractory to multiple treatments and achieved complete remission with a combination therapy of surgery, 5-aminolevulinic acid photodynamic therapy (ALA-PDT), and secukinumab.

Identification of RAC1 in promoting brain metastasis of lung adenocarcinoma using single-cell transcriptome sequencing.

This study aims to give a new perspective to the biomarkers in the lung adenocarcinoma (LUAD) brain metastasis, pathways involved and potential therapeutics. We performed a comprehensive single-cell level transcriptomic analysis on one LUAD patient with circulating tumor cells (CTCs), primary tumor tissue and metastatic tumor tissue using scRNA-seq approach to identify metastasis related biomarkers. Further scRNA-seq were performed on 7 patients to validate the cancer metastatic hallmark. with single cells collected from either metastatic or primary LUAD tissues. Pathological and functional studies were also performed to evidence the critical role of RAC1 in the LUAD metastasis. Hallmark gene was verified based on immunohistochemistry staining, cytological experiment, survival information from The Cancer Genome Atlas (TCGA), and staining results from Human Protein Atlas (HPA) databases. PCA analysis revealed that CTCs were in the intermediate place between the metastatic group and primary group. In the unsupervised clustering analysis CTCs were closer to one of the metastatic tumor cells, implying heterogeneity of the metastatic tumor and origin of the CTCs were from metastatic site. Transitional phase related gene analysis identified RAC1 was enriched in metastatic tumor tissue (MTT) preferred gene set functioning as regulated cell death and apoptosis as well as promoted macromolecule organization. Compared with normal tissue, expression levels of RAC1 increased significantly in LUAD tissue based on HPA database. High expression of RAC1 predicts worse prognosis and higher-risk. EMT analysis identified the propensity of mesenchymal state in primary cells while epithelial signals were higher in the metastatic site. Functional clustering and pathway analyses suggested genes in RAC1 highly expressed cells played critical roles in adhesion, ECM and VEGF signaling pathways. Inhibition of RAC1 attenuates the proliferation, invasiveness and migration ability of lung cancer cells. Besides, through MRI T2WI results, we proved that RAC1 can promote brain metastasis in the RAC1-overexpressed H1975 cell burden nude mouse model. RAC1 and its mechanisms might promote drug design against LUAD brain metastasis.

Enterotype-Specific Effect of Human Gut Microbiota on the Fermentation of Marine Algae Oligosaccharides: A Preliminary Proof-of-Concept In Vitro Study.

The human gut microbiota plays a critical role in the metabolism of dietary carbohydrates. Previous studies have illustrated that marine algae oligosaccharides could be utilized and readily fermented by human gut microbiota. However, the human gut microbiota is classified into three different enterotypes, and how this may affect the fermentation processes of marine algae oligosaccharides has not been studied. Here, using in vitro fermentation and 16 S high-throughput sequencing techniques, we demonstrate that the human gut microbiota has an enterotype-specific effect on the fermentation outcomes of marine algae oligosaccharides. Notably, microbiota with a Bacteroides enterotype was more proficient at fermenting carrageenan oligosaccharides (KOS) as compared to that with a Prevotella enterotype and that with an Escherichia enterotype. Interestingly, the prebiotic effects of marine algae oligosaccharides were also found to be enterotype dependent. Altogether, our study demonstrates an enterotype-specific effect of human gut microbiota on the fermentation of marine algae oligosaccharides. However, due to the availability of the fecal samples, only one sample was used to represent each enterotype. Therefore, our research is a proof-of-concept study, and we anticipate that more detailed studies with larger sample sizes could be conducted to further explore the enterotype-specific prebiotic effects of marine oligosaccharides.

Calcitriol ameliorates renal injury with high-salt diet-induced hypertension by upregulating GLIS2 expression and AMPK/mTOR-regulated autophagy.

The goal of the present study was to investigate the protective effect of calcitriol on high-salt diet-induced hypertension. The hypertension rat model was established by a long-term high-salt diet (8% NaCl). Rats were treated with calcitriol, losartan, or their combination. Histological staining was used to confirm renal pathology. Global transcriptome analysis of renal tissues was performed, and the mechanism of the therapeutic effect of calcitriol was analysed by functional annotation and pathway analysis of the differentially expressed genes (DEGs) as well as by Western blotting analysis. The core genes for potential therapeutic regulation were identified through the coexpression gene network. For in vitro HK-2 cell experiments, small interfering RNA (siRNA) was used to knockdown key a transcription factor (TF) Glis2 to validate the therapeutic target of calcitriol. MAPK1 and CXCL12 expression was downregulated and the apoptosis pathway was significantly enriched by calcitriol treatment. The western blotting results showed that calcitriol treatment increased AMPK phosphorylation and decreased downstream mTOR phosphorylation, which was accompanied by a decrease in autophagy protein p62 expression and an increase in LC3-II/I expression. GLIS2 was identified as a specific therapeutic target for calcitriol. GLIS2 expression was upregulated by calcitriol and confirmed by HK-2 cells in vitro. Our omics data show that calcitriol can alleviate oxidative stress and fibrosis. Moreover, calcitriol can regulate the CXCL12/ERK1/2 cascade to inhibit the inflammatory response and renal cell apoptosis and induce renal autophagy through the AMPK/mTOR pathway. Our study partially elucidate the pathogenesis and treatment mechanism underlying hypertension, and provide new insights into the treatment of hypertension.

Traditional chinese medicine syndromes classification associates with tumor cell and microenvironment heterogeneity in colorectal cancer: a single cell RNA sequencing analysis.

BACKGROUND: Colorectal cancer (CRC) is one of the common gastrointestinal malignancies, tumor heterogeneity is the main cause of refractory CRC. Syndrome differentiation is the premise of individualized treatment of traditional Chinese medicine (TCM), but TCM syndrome lacks objective identification in CRC. This study is to investigate the correlation and significance of tumor heterogeneity and TCM syndromes classification in CRC. METHODS: In this study, we using scRNA-seq technology, investigate the significance of tumor heterogeneity in TCM syndromes classification on CRC. RESULTS: The results showed that 662 cells isolated from 11 primary CRC tumors are divided into 14 different cell clusters, and each cell subtype and its genes have different functions and signal transduction pathways, indicating significant heterogeneity. CRC tumor cell clusters have different proportions in Excess, Deficiency and Deficiency-Excess syndromes, and have their own characteristic genes, gene co-expression networks, gene functional interpretations as well as monocle functional evolution. Moreover, there were significant differences between the high expressions of MUC2, REG4, COL1A2, POSTN, SDPR, GPX1, ELF3, KRT8, KRT18, KRT19, FN1, SERPINE1, TCF4 and ZEB1 genes in Excess and Deficiency syndrome classification in CRC (P < 0.01). CONCLUSIONS: The Excess and Deficiency syndromes classification may be related to tumor heterogeneity and its microenvironment in CRC.

Loss of retinoic acid receptor-related receptor alpha (Rorα) promotes the progression of UV-induced cSCC.

Cutaneous squamous cell carcinoma (cSCC) is prevalent in the world, accounting for a huge part of non-melanoma skin cancer. Most cSCCs are associated with a distinct pre-cancerous lesion, the actinic keratosis (AK). However, the progression trajectory from normal skin to AK and cSCC has not been fully demonstrated yet. To identify genes involved in this progression trajectory and possible therapeutic targets for cSCC, here we constructed a UV-induced cSCC mouse model covering the progression from normal skin to AK to cSCC, which mimicked the solar UV radiation perfectly using the solar-like ratio of UVA and UVB, firstly. Then, transcriptome analysis and a series of bioinformatics analyses and cell experiments proved that Rorα is a key transcript factor during cSCC progression. Rorα could downregulate the expressions of S100a9 and Sprr2f in cSCC cells, which can inhibit the proliferation and migration in cSCC cells, but not the normal keratinocyte. Finally, further animal experiments confirmed the inhibitory effect of cSCC growth by Rorα in vivo. Our findings showed that Rorα would serve as a potential novel target for cSCC, which will facilitate the treatment of cSCC in the future.

The longitudinal change of circulating tumor cell during chemotherapy and its correlation with disease features, treatment response and survival profile of advanced gallbladder carcinoma.

The current study aimed to investigate the relation of circulating tumor cell (CTC) with clinicopathological features. In addition, its longitudinal change during chemotherapy and its correlation with prognosis in advanced gallbladder carcinoma (GBC) patients were explored. Totally 45 unresectable, locally advanced or metastatic GBC patients who underwent chemotherapy were enrolled in this prospective study. The CTC in 7.5 ml blood was detected at pre-treatment and 3 months post-treatment. CTC was almost detectable in all advanced GBC patients before treatment, whose count was positively correlated with metastatic disease (vs. local advanced disease) (P=0.002), number of organs with metastases (P=0.006), and CA199 level (P=0.002). After treatment, CTC count declined from 4.0 (range: 0.0-83.0) at pre-treatment to 2.0 (range: 0.0-36.0) at post-treatment (P=0.003). Interestingly, pre-treatment CTC count (P=0.270) was of no difference, while post-treatment CTC count was lower (P=0.038) in objective-response patients compared to that in non-objective-response patients; meanwhile, both pre-treatment CTC count (P=0.017) and post-treatment CTC count (P<0.001) were lower in disease-control patients compared with those in non-disease-control patients. Importantly, pre-treatment CTC count ≥2 (versus <2) was only correlated with worse progression-free survival (PFS) (P=0.014) but not overall survival (OS) (P=0.057); while pre-treatment CTC count ≥5 (versus <5), post-treatment CTC count ≥2 (versus <2), post-treatment CTC count ≥5 (versus <5), CTC count up (versus equal/down) were all correlated with poor PFS and OS (all P<0.050). In conclusion, higher CTC count during chemotherapy correlates with worse treatment response, PFS and OS in advanced GBC patients, which implies that CTC measurement may optimize the prognostication and individualized treatment in these patients.

Risk factors and socio-economic burden in pancreatic ductal adenocarcinoma operation: a machine learning based analysis.

BACKGROUND: Surgical resection is the major way to cure pancreatic ductal adenocarcinoma (PDAC). However, this operation is complex, and the peri-operative risk is high, making patients more likely to be admitted to the intensive care unit (ICU). Therefore, establishing a risk model that predicts admission to ICU is meaningful in preventing patients from post-operation deterioration and potentially reducing socio-economic burden. METHODS: We retrospectively collected 120 clinical features from 1242 PDAC patients, including demographic data, pre-operative and intra-operative blood tests, in-hospital duration, and ICU status. Machine learning pipelines, including Supporting Vector Machine (SVM), Logistic Regression, and Lasso Regression, were employed to choose an optimal model in predicting ICU admission. Ordinary least-squares regression (OLS) and Lasso Regression were adopted in the correlation analysis of post-operative bleeding, total in-hospital duration, and discharge costs. RESULTS: SVM model achieved higher performance than the other two models, resulted in an AU-ROC of 0.80. The features, such as age, duration of operation, monocyte count, and intra-operative partial arterial pressure of oxygen (PaO2), are risk factors in the ICU admission. The protective factors include RBC count, analgesic pump dexmedetomidine (DEX), and intra-operative maintenance of DEX. Basophil percentage, duration of the operation, and total infusion volume were risk variables for staying in ICU. The bilirubin, CA125, and pre-operative albumin were associated with the post-operative bleeding volume. The operation duration was the most important factor for discharge costs, while pre-lymphocyte percentage and the absolute count are responsible for less cost. CONCLUSIONS: We observed that several new indicators such as DEX, monocyte count, basophil percentage, and intra-operative PaO2 showed a good predictive effect on the possibility of admission to ICU and duration of stay in ICU. This work provided an essential reference for indication in advance to PDAC operation.

Changes in plasma bile acids are associated with gallbladder stones and polyps.

BACKGROUND: The development of gallbladder disease (GBD) is related to bile acid (BA) metabolism, and the rate of BA circulation increases the risk of biliary cancer. However, it is unclear whether patterns of circulating bile acids (BAs) change in patients with benign GBDs such as gallbladder stones and polyps. Herein, we compared and characterised plasma BA profiles in patients with cholecystolithiasis and non-neoplastic polyps with healthy controls, and explored relationships between plasma BA profiles, demographics, and laboratory test indices. METHODS: A total of 330 subjects (13 healthy controls, 292 cholecystolithiasis and 25 non-neoplastic polyps) were recruited and plasma BA profiles including 14 metabolites from patients with pathologically confirmed cholecystolithiasis and non-neoplastic polyps were compared with controls. BAs were quantitated by liquid chromatography and mass spectrometry, and statistical and regression analyses of demographics and laboratory test indices were performed. RESULTS: Females displayed a higher burden of GBD than males (63.36% cholecystolithiasis, 60% non-neoplastic polyps). Cholecystolithiasis and non-neoplastic polyps were associated with increased plasma total secondary BAs, while levels of primary BAs were lower than in healthy controls. Plasma ursodeoxycholic acid (UDCA), tauroursodeoxycholic acid (TUDCA), glycyurdeoxycholic acid (GUDCA), taurochenodeoxycholic acid (TCDCA) and glycochenodeoxycholic acid (GCDCA) were decreased significantly in GBDs, and ursodeoxycholic acid (UDCA) was negatively correlated with white blood cell count and neutrophil percentage. CONCLUSIONS: Secondary BA levels were higher in patients with cholecystolithiasis and non-neoplastic polyps. White blood cell count and percentage of neutrophil in peripheral blood were negatively correlated with UDCA, indicating an anti-inflammation effect of UDCA.

MicroRNA-128 is involved in dexamethasone-induced lipid accumulation via repressing SIRT1 expression in cultured pig preadipocytes.

In this study, pig preadipocytes were firstly treated with 10-6 M DEX for 48 h to explore the role of dexamethasone (DEX, a chemically synthesized long-acting glucocorticoid) on lipid accumulation. Then, miRNA scrambled control (miR-SC), miR-128 overexpression plasmid and miR-128 inhibitor were respectively transfected into pig preadipocytes at 24 h before DEX treatment for 48 h (miR-SC-DEX, miR-128-DEX and miR-128-inhibitor-DEX) to illustrate the regulatory role of miR-128 on DEX-induced lipid accumulation. Compared with control preadipocytes, 10-6 M Dex significantly increased triglyceride (TG) level, whereas the cell proliferation did not change. Moreover, 10-6 M Dex obviously decreased sirtuin 1 (SIRT1) and its related lipolysis genes adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL) mRNA expression and enzyme activity, while significantly increased expression of adipogenesis genes peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT/enhancer binding protein-α (C/EBP-α) and fatty acid synthase (FAS). In addition, 10-6 M DEX significantly upregulated miR-128 expression, which was confirmed to directly target SIRT1 by bioinformatics analysis and dual-luciferase reporter assay. Gain- and loss-of-function study also showed that when compared with miR-SC-DEX cells, miR-128-DEX cells showed significantly reduced SIRT1 expression and increased TG level, as well as elevated cellular levels of PPAR-γ, C/EBP-α and FAS and suppressed ATGL and HSL expression and enzyme activity. In contrast, miR-128-inhibitor-DEX cells precisely presented the opposite results. Collectively, these results indicate that miR-128 plays a role in the pathogenesis of glucocorticoid-related abnormal lipid accumulation via repressing SIRT1 expression, consequently, miR-128 inhibition may represent a novel potential therapeutic target in preventing DEX-induced abnormal lipid accumulation.