Single-cell analysis of the cellular landscape of vulvar melanoma provides new insight for immunotherapy administration.

BACKGROUND: Vulvar and vaginal melanoma (VuM & VaM) is a rare gynecologic malignancy with high mortality but low effectiveness to checkpoint immunotherapy compared to cutaneous melanoma. This article aims to elucidate the role of the disordered immune microenvironment in cancer progression in VuM. METHODS: At first, this article applied single-cell RNA sequencing (scRNA-seq) to the VuM obtained from a 68-year-old female patient, and constructed a single-cell atlas of VuM consist of 12,243 single cells. Then this article explores the genomic complexity and core signal channel in VuM microenvironment. RESULTS: This article provides new insights about the pathogenesis of VuM based on single-cell resolution data. It was found that the activation of CD8+ T cell contributed to induce tumor angiogenesis and immune escape, and the activation of the antigen-presenting molecular function participated in melanoma metastasis. CONCLUSION: This article provided new insights into underlining VuM molecular regulation and potential signaling involved in immunotherapy, which would benefit the clinical practice and administration.

Correlation between pulmonary embolism and blood cell count changes.

Pulmonary embolism is one of the acute diseases of the respiratory system. This study investigates changes in red blood cell counts in pulmonary embolisms confirmed by scintigraphy. Counting red blood cells is essential in diseases, especially pulmonary embolism, because of the vital role of these cells.  In this study, 25 patients with pulmonary embolism were selected. A group of 25 healthy volunteers was also considered as a control. At zero, 30, 60 minutes, 24, 48, and 72 hours, blood samples were taken from both control and patient groups, and red blood cells were counted according to the standard method. After extracting technetium-99m from the molybdenum generator, this substance was added to the MAA drug kit under particular conditions. After preparation, radiopharmaceutical 99mTC-MAA with 1.5 millicuries was injected intravenously into both groups. In this study, a significant increase in the red blood cell count of the patient group was observed on the first and second days of the disease. On the third day, this count returned to normal. These changes indicate the functioning of the body's defense system and a response to reduce the complications caused by pulmonary embolism. Therefore, paying more attention to counting red blood cells in pulmonary embolism, along with other care, is recommended due to their particular function.

Multi-pathway on peroxymonosulfate activation by single cobalt atoms incorporated on CuO with enriched oxygen vacancies for high-efficient oxidation of tetracycline.

The development of single atom catalysts (SACs) with superior catalytic performance is a long-term goal for peroxymonosulfate (PMS) activation in advanced oxidation processes (AOPs). A novel SACs that single Co atoms anchored on CuO with enriched oxygen vacancies (Ov) is synthesized successfully by choosing a metal oxide as the carrier creatively. 100% of tetracycline (TC) can be removed by Co-CuO (Ov)/PMS system within 3 min. The corresponding reaction rate constant is 3.1068 min-1, which is much higher than that of CuO (Ov), ZIF-CoN4-C, Co-CuO (without Ov) and CoNP-CuO (Ov), respectively. Co(II) is the primary source of radical pathway (·OH and SO4·-), and its regeneration is promoted by Cu(Ⅰ). The enriched Ov is the major contribution to the nonradical pathway, which promotes the singlet oxygen (1O2) generation together with accelerates the electron transfer from TC to catalyst-PMS*. Besides, the Co-CuO (Ov) exhibits an excellent stability and anti-interference capability. This study highlights a novel strategy to promote PMS activation by incorporating the single metal atoms on a metal oxide carrier with defects to accelerate the redox of dominate metal and stabilize the metal atoms simultaneously, which may inform the design for the next generation of SACs in AOPs.

Single cell RNA-seq resolution revealed CCR1+/SELL+/XAF+ CD14 monocytes mediated vascular endothelial cell injuries in Kawasaki disease and COVID-19.

INTRODUCTION: The COVID-19 pandemic provide the opportunities to explore the numerous similarities in clinical symptoms with Kawasaki disease (KD), including severe vasculitis. Despite this, the underlying mechanisms of vascular injury in both KD and COVID-19 remain elusive. To identify these mechanisms, this study employs single-cell RNA sequencing to explore the molecular mechanisms of immune responses in vasculitis, and validate the results through in vitro experiments. METHOD: The single-cell RNA sequencing (scRNA-seq) analysis of peripheral blood mononuclear cells (PBMCs) was carried out to investigate the molecular mechanisms of immune responses in vasculitis in KD and COVID-19. The analysis was performed on PBMCs from six children diagnosed with complete KD, three age-matched KD healthy controls (KHC), six COVID-19 patients (COV), three influenza patients (FLU), and four healthy controls (CHC). The results from the scRNA-seq analysis were validated through flow cytometry and immunofluorescence experiments on additional human samples. Subsequently, monocyte adhesion assays, immunofluorescence, and quantitative polymerase chain reaction (qPCR) were used to analyze the damages to endothelial cells post-interaction with monocytes in HUVEC and THP1 cultures. RESULTS: The scRNA-seq analysis revealed the potential cellular types involved and the alterations in genetic transcriptions in the inflammatory responses. The findings indicated that while the immune cell compositions had been altered in KD and COV patients, and the ratio of CD14+ monocytes were both elevated in KD and COV. While the CD14+ monocytes share a large scale of same differentiated expressed geens between KD and COV. The differential activation of CD14 and CD16 monocytes was found to respond to both endothelial and epithelial dysfunctions. Furthermore, SELL+/CCR1+/XAF1+ CD14 monocytes were seen to enhance the adhesion and damage to endothelial cells. The results also showed that different types of B cells were involved in both KD and COV, while only the activation of T cells was recorded in KD. CONCLUSION: In conclusion, our study demonstrated the role of the innate immune response in the regulation of endothelial dysfunction in both KD and COVID-19. Additionally, our findings indicate that the adaptive immunity activation differs between KD and COVID-19. Our results demonstrate that monocytes in COVID-19 exhibit adhesion to both endothelial cells and alveolar epithelial cells, thus providing insight into the mechanisms and shared phenotypes between KD and COVID-19.

Effect of thymoquinone on sepsis-induced cardiac damage via anti-inflammatory and anti-apoptotic mechanisms.

OBJECTIVE: Sepsis is a systemic and deleterious host reaction to severe infection. Cardiac dysfunction is an established serious outcome of multiorgan failure associated with this condition. Therefore, it is important to develop drugs targeting sepsis-induced cardiac damage and inflammation. Thymoquinone (TQ) has anti-inflammatory, anti-oxidant, anti-fibrotic, anti-tumor, and anti-apoptotic effects. This study examined the effects of thymoquinone on sepsis-induced cardiac damage. METHODS: Male BALB/c mice were randomly segregated into four groups: control, TQ, cecal ligation and puncture (CLP), and CLP + TQ groups. CLP was performed after gavaging the mice with TQ for 2 weeks. After 48 hours, we estimated the histopathological changes in the cardiac tissue and the serum levels of cardiac troponin-T. We evaluated the expression of factors associated with inflammation, apoptosis, oxidative stress, and the PI3K/AKT pathway. RESULTS: TQ significantly reduced intestinal histological alterations and inhibited the upregulation of interleukin-6, tumor necrosis factor-α, Bax, NOX4, p-PI3K, and p-AKT. TQ also increased Bcl-2, HO-1, and NRF2 expression. CONCLUSION: These results suggest that TQ effectively modulates pro-inflammatory, apoptotic, oxidative stress, and PI3K/AKT pathways, making it indispensable in the treatment of sepsis-induced cardiac damage.

The effect of fenofibrate, a peroxisome proliferator-activated receptor α agonist, on cardiac damage from sepsis in BALB/c mice.

Cardiac dysfunction can be a fatal consequence of sepsis and lead to increased inflammatory responses or reduced fatty acid oxidation and final ATP depletion. Fenofibrate, which is an agonist of peroxisome proliferator-activated receptor α, has been used primarily in hypercholesterolemia and mixed dyslipidemia. Recent studies found that fenofibrate could alleviate energy metabolism and inflammation caused by cardiac damage during sepsis, and thus it had been paid great attention. This study was to investigate the possible protective roles of fenofibrate against cardiac damage in septic BALB/c mice. Methods: Forty male BALB/c mice aged 8 weeks old were divided randomly into four groups: control group; fenofibrate group; cecal ligation and puncture (CLP) group; and fenofibrate + CLP group. After administering fenofibrate or saline for 2 weeks, CLP was performed. Cardiac tissue and plasma were obtained 48 hours later. Plasma Troponin-T (Tnt), ATP, ADP and reactive oxygen species (ROS) levels were determined. PPARα and 53 protein levels were detected using western blotting. IL-6 and tumor necrosis factor-α (TNFα) were also assayed. We found that fenofibrate decreased plasma cTnT, ROS and increased the ratio of ATP/ADP. The elevations of IL-6, TNFα and P53 induced by sepsis were significantly suppressed by fenofibrate. Our results suggest that fenofibrate can regulate energy metabolism efficiently, which makes it a possible agent for treating sepsis-induced cardiac damage.

Transcriptomic landscape of persistent diarrhoea in rhesus macaques and comparison with humans and mouse models with inflammatory bowel disease.

Diarrhoea is a widespread disease in captive rhesus macaques (Macaca mulatta) and a small proportion of individuals may experience persistent diarrhoea. Persistent diarrhoea can lead to a compromised immune system, intestinal inflammation and malnutrition. We analyzed the blood transcriptomes of 10 persistent diarrhoeal and 12 healthy rhesus macaques to investigate the gene expression differences between the two groups. We identified 330 DEGs between persistent diarrhoeal and healthy rhesus macaques. The 211 up-regulated DEGs in the diarrhoeal group were mainly enriched in immune-related and interleukin-related categories. Among them, three interleukin (IL) 18 related DEGs (IL18, IL18R1, and IL18BP) played important roles in actively regulating pro-inflammatory responses. Interestingly, the up- and down-regulated DEGs were both enriched in the same immune-related categories. Thus, we applied a new method to examine the distribution of DEGs in all child categories. We found that interleukin and T cell related categories were mainly occupied by up-regulated DEGs, while immunoglobulin production and B cell related categories were enriched by down-regulated DEGs. We also compared rhesus macaque DEGs with the DEGs of inflammatory bowel disease (IBD) humans and IBD mouse models and found that 30-40% of macaque DEGs were shared with IBD humans and mouse models. In conclusion, our results showed that there were significant immune differences between persistent diarrhoeal rhesus macaques and healthy macaques, which was similar to the expression differences in IBD patients and mouse models.

Protective role of fenofibrate in sepsis-induced acute kidney injury in BALB/c mice.

Acute kidney injury (AKI) is a severe complication of sepsis, which largely contributes to the associated high mortality rate. Fenofibrate, a peroxisome proliferator activated receptor α (PPARα) agonist, has received considerable attention because of its effects related to renal damage-related energy metabolism and inflammation. The present study investigated the effects of fenofibrate on sepsis-associated AKI in BALB/c mice subjected to caecal ligation and puncture (CLP). Eight-week-old male BALB/c mice were divided into four groups: control group, fenofibrate group, caecal ligation and puncture (CLP) group, and fenofibrate + CLP group. CLP was performed after mice were gavaged with fenofibrate for 2 weeks. After 48 hours, we measured the histopathological alterations of the kidney tissue and plasma levels of serum creatinine (CRE), neutrophil gelatinase-associated lipocalin (NGAL), reactive oxygen species (ROS), ATP, and ADP. We evaluated PPARα and P53 protein levels as well as interleukin (IL)-1ß, IL-6, and tumour necrosis factor-α mRNA levels. Our results showed that administering fenofibrate significantly reduced kidney histological alterations caused by CLP. Fenofibrate inhibited the plasma levels of ROS, CRE, NGAL, and increased the ATP/ADP ratio. Fenofibrate significantly inhibited elevations in P53, IL-1ß, IL-6, and tumour necrosis factor-α expression. The results suggest that fenofibrate administration effectively modulates energy metabolism and may be a novel approach to treat sepsis-induced renal damage.

Long-term outcome of microvascular decompression for hemifacial spasm.

AIM: To investigate the long term outcomes of microvascular decompression (MVD) for hemifacial spasm (HFS) and to identify any prognostic factors. METHODS: A retrospective analysis of 189 consecutive patients with typical HFS who underwent MVD. Multiple logistic regression analysis of variables at various time points including at least immediate time point and one at no less than six years was performed. RESULTS: Short-term follow-up showed a cure rate of 91%, including 51 cases of delayed resolution (27%). At two years or more information was available in 148 (out of 189) cases of patients. 101 cases (68% - of 148 cases) had complete recovery, 28 cases (19%) achieved a partial though worthwhile recovery, so that the effective rate of symptoms relief at six years was 87%. Complications were found (66/189, 34.92%) and cured within the follow-up period (cure rate of 100%). In both the univariate and multivariate analyses, the postoperative findings of clinical outcomes showed that preoperative illness duration, compressive pattern, the intraoperative indentation of the root exit zone (REZ) of the facial nerve and intraoperative AMR disappearance were negative predictors and age considered to be positive, which significantly predicted the clinical outcome of patients following MVD. CONCLUSIONS: MVD may be a safe and effective strategy for HFS patients in view of relatively higher cure rates and lower complication risks within follow-up. Besides, patients' age, duration of disease, intraoperative indentation of the REZ of the facial nerve, and disappearance of AMR were the major influential variables may be useful for the prediction of prognosis in the patients underwent MVD.

Retraction. rhBNP therapy can improve clinical outcomes and reduce in-hospital mortality compared with dobutamine in heart failure patients: a meta-analysis.

AIMS: A meta-analysis was performed to compare the therapeutic outcomes in patients treated for heart failure (HF) with recombinant human brain natriuretic peptide (rhBNP) and dobutamine. METHODS: PubMed, Embase and the Chinese Biomedical Database were exhaustively searched to identify studies relevant to this meta-analysis. Eight cohort studies were found suitable for inclusion. Data regarding trial validity, methodological processes and clinical outcomes were extracted. RESULTS: Patients treated with rhBNP showed statistically significant reduction of in-hospital mortality and re-admission rates compared with the dobutamine treated patient group (both P < 0.05). Further, the rhBNP treated patient group showed higher survival outcomes, compared with dobutamine treated patients, when the post-treatment follow-up period was longer than 6 months (P < 0.05). Stratified analysis based on ethnicity showed a dramatic decrease of in-hospital mortality among mixed race HF patients receiving rhBNP treatment (P < 0.05), but such decreases were not statistically significant in Asian and Caucasian populations (both P > 0.05). On the other hand, re-admission rates were significantly lower in rhBNP treated Caucasian and mixed race populations (both P < 0.05). Notably, in rhBNP treated group, dose levels of 0.015 and 0.03 incrementally lowered the re-admission rates, displaying dose effect, and the re-admission rates at both rhBNP doses were significantly lower than the dobutamine treated group (both P < 0.05). CONCLUSIONS: Our meta-analysis results suggested that rhBNP therapy is associated with lower in-hospital mortality and re-admission rates in HF patients compared to the dobutamine regimen. Nevertheless, large scale prospective, randomized trials are necessary to confirm these findings.