Cancer SLC6A6-mediated taurine uptake transactivates immune checkpoint genes and induces exhaustion in CD8+ T cells.

Taurine is used to bolster immunity, but its effects on antitumor immunity are unclear. Here, we report that cancer-related taurine consumption causes T cell exhaustion and tumor progression. The taurine transporter SLC6A6 is correlated with aggressiveness and poor outcomes in multiple cancers. SLC6A6-mediated taurine uptake promotes the malignant behaviors of tumor cells but also increases the survival and effector function of CD8+ T cells. Tumor cells outcompete CD8+ T cells for taurine by overexpressing SLC6A6, which induces T cell death and malfunction, thereby fueling tumor progression. Mechanistically, taurine deficiency in CD8+ T cells increases ER stress, promoting ATF4 transcription in a PERK-JAK1-STAT3 signaling-dependent manner. Increased ATF4 transactivates multiple immune checkpoint genes and induces T cell exhaustion. In gastric cancer, we identify a chemotherapy-induced SP1-SLC6A6 regulatory axis. Our findings suggest that tumoral-SLC6A6-mediated taurine deficiency promotes immune evasion and that taurine supplementation reinvigorates exhausted CD8+ T cells and increases the efficacy of cancer therapies.

Optimal folic acid dosage in lowering homocysteine: Precision Folic Acid Trial to lower homocysteine (PFAT-Hcy).

BACKGROUND: While folic acid (FA) is widely used to treat elevated total homocysteine (tHcy), promoting vascular health by reducing vascular oxidative stress and modulating endothelial nitric oxide synthase, the optimal daily dose and individual variation by MTHFR C677T genotypes have not been well studied. Therefore, this study aimed to explore the efficacy of eight different FA dosages on tHcy lowering in the overall sample and by MTHFR C677T genotypes. METHODS: This multicentered, randomized, double-blind, controlled clinical trial included 2697 eligible hypertensive adults with elevated tHcy (≥ 10 mmol/L) and without history of stroke and cardiovascular disease. Participants were randomized into eight dose groups of FA combined with 10 mg enalapril maleate, taken daily for 8 weeks of treatment. RESULTS: The intent to treat analysis included 2163 participants. In the overall sample, increasing FA dosage led to steady tHcy reduction within the FA dosing range of 0-1.2 mg. However, a plateau in tHcy lowering was observed in FA dose range of 1.2-1.6 mg, indicating a ceiling effect. In contrast, FA doses were positively and linearly associated with serum folate levels without signs of plateau. Among MTHFR genotype subgroups, participants with the TT genotype showed greater efficacy of FA in tHcy lowering. CONCLUSIONS: This randomized trial lent further support to the efficacy of FA in lowering tHcy; more importantly, it provided critically needed evidence to inform optimal FA dosage. We found that the efficacy of FA in lowering tHcy reaches a plateau if the daily dosage exceeds 1.2 mg, and only has a small gain by increasing the dosage from 0.8 to 1.2 mg. GOV IDENTIFIER: NCT03472508 (Registration Date: March 21, 2018).

Renin imprinted Poly(methyldopa) for biomarker detection and disease therapy.

Conventional molecularly imprinted polymers (MIPs) perform their functions principally depended on their three dimensional (3D) imprinted cavities (recognition sites) of templates. Here, retaining the function of recognition sites resulted from the imprinting of template molecules, the role of functional monomers is explored and expanded. Briefly, a class of dual-functional renin imprinted poly(methyldopa) (RMIP) is prepared, consisting of a drug-type function monomer (methyldopa, clinical high blood pressure drug) and a corresponding disease biomarker (renin, biomarker for high blood pressure disease). To boost target-to-receptor binding ratio and sensitivity, the microstructure of recognition sites is beforehand calculated and designed by Density Functional Theory calculations, and the whole interfacial structure, property and thickness of RMIP film is regulated by adjusting the polymerization techniques. The dual-functional applications of RMIP for biomarker detection and disease therapy in vivo is explored. Such RMIP-based biosensors achieves highly sensitive biomarker detection, where the LODs reaches down to 1.31 × 10-6 and 1.26 × 10-6 ng mL-1 for electrochemical and chemical polymers, respectively, and the application for disease therapy in vivo has been verified where displays the obviously decreased blood pressure values of mice. No acute and long-term toxicity is found from the pathological slices, declaring the promising clinical application potential of such engineered RMIP nanostructure.

N6-methyladenosine reader hnRNPA2B1 recognizes and stabilizes NEAT1 to confer chemoresistance in gastric cancer.

BACKGROUND: Chemoresistance is a major cause of treatment failure in gastric cancer (GC). Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is an N6-methyladenosine (m6A)-binding protein involved in a variety of cancers. However, whether m6A modification and hnRNPA2B1 play a role in GC chemoresistance is largely unknown. In this study, we aimed to investigate the role of hnRNPA2B1 and the downstream mechanism in GC chemoresistance. METHODS: The expression of hnRNPA2B1 among public datasets were analyzed and validated by quantitative PCR (qPCR), Western blotting, immunofluorescence, and immunohistochemical staining. The biological functions of hnRNPA2B1 in GC chemoresistance were investigated both in vitro and in vivo. RNA sequencing, methylated RNA immunoprecipitation, RNA immunoprecipitation, and RNA stability assay were performed to assess the association between hnRNPA2B1 and the binding RNA. The role of hnRNPA2B1 in maintenance of GC stemness was evaluated by bioinformatic analysis, qPCR, Western blotting, immunofluorescence, and sphere formation assays. The expression patterns of hnRNPA2B1 and downstream regulators in GC specimens from patients who received adjuvant chemotherapy were analyzed by RNAscope and multiplex immunohistochemistry. RESULTS: Elevated expression of hnRNPA2B1 was found in GC cells and tissues, especially in multidrug-resistant (MDR) GC cell lines. The expression of hnRNPA2B1 was associated with poor outcomes of GC patients, especially in those who received 5-fluorouracil treatment. Silencing hnRNPA2B1 effectively sensitized GC cells to chemotherapy by inhibiting cell proliferation and inducing apoptosis both in vitro and in vivo. Mechanically, hnRNPA2B1 interacted with and stabilized long noncoding RNA NEAT1 in an m6A-dependent manner. Furthermore, hnRNPA2B1 and NEAT1 worked together to enhance the stemness properties of GC cells via Wnt/ß-catenin signaling pathway. In clinical specimens from GC patients subjected to chemotherapy, the expression levels of hnRNPA2B1, NEAT1, CD133, and CD44 were markedly elevated in non-responders compared with responders. CONCLUSION: Our findings indicated that hnRNPA2B1 interacts with and stabilizes lncRNA NEAT1, which contribute to the maintenance of stemness property via Wnt/ß-catenin pathway and exacerbate chemoresistance in GC.

Associations of total homocysteine and kidney function with all-cause and cause-specific mortality in hypertensive patients: a mediation and joint analysis.

Plasma total homocysteine (tHcy) and kidney function are both associated with mortality risk, but the degree to which kidney function modifies the impact of tHcy on mortality remains unknown. This prospective cohort study included a total of 14,225 hypertensive adults. Cox proportional hazard regression was used to analyze the separate and combined association of tHcy and estimated glomerular filtration rate (eGFR) with all-cause and cause-specific mortality. Mediation analysis was conducted to explore the mediating effect of eGFR. During a median follow-up of 4.0 years, 805 deaths were identified, including 397 deaths from cardiovascular disease (CVD). There were significant, positive relationships of tHcy with all-cause mortality (per 5 µmol/L; HR: 1.09; 95% CI: 1.07, 1.11), CVD mortality (HR: 1.11; 95% CI: 1.08, 1.13), and non-CVD mortality (HR: 1.07; 95% CI: 1.04, 1.10). The proportions of eGFR mediating these relationships were 39.1%, 35.7%, and 49.7%, respectively. There were additive interactions between tHcy and eGFR. Compared with those with low tHcy (<15 µmol/L) and high eGFR (≥90 mL·min-1·1.73 m-2), participants with high tHcy (≥20 µmol/L) and low eGFR (<60 mL·min-1·1.73 m-2) had the highest risk of all-cause mortality (HR: 4.89; 95% CI: 3.81, 6.28), CVD mortality (HR: 5.80; 95% CI: 4.01, 8.40), and non-CVD mortality (HR: 4.25; 95% CI: 3.02, 5.97). In conclusion, among Chinese hypertensive adults, high tHcy and impaired kidney function were independently and jointly associated with higher risks of all-cause and cause-specific mortality. Importantly, kidney function explained most (nearly 40%) of the increased risk of mortality conferred by high tHcy.

Mitochondria-targeted photodynamic therapy triggers GSDME-mediated pyroptosis and sensitizes anti-PD-1 therapy in colorectal cancer.

BACKGROUND: The effectiveness of immune checkpoint inhibitors in colorectal cancer (CRC) is limited due to the low tumor neoantigen load and low immune infiltration in most microsatellite-stable (MSS) tumors. This study aimed to develop a mitochondria-targeted photodynamic therapy (PDT) approach to provoke host antitumor immunity of MSS-CRC and elucidate the underlying molecular mechanisms. METHODS: The role and mechanism of mitochondria-targeted PDT in inhibiting CRC progression and inducing pyroptosis were evaluated both in vitro and in vivo. The immune effects of PDT sensitization on PD-1 blockade were also assessed in CT26 and 4T1 tumor-bearing mouse models. RESULTS: Here, we report that PDT using IR700DX-6T, a photosensitizer targeting the mitochondrial translocation protein, may trigger an antitumor immune response initiated by pyroptosis in CRC. Mechanistically, IR700DX-6T-PDT produced reactive oxygen species on light irradiation and promoted downstream p38 phosphorylation and active caspase3 (CASP3)-mediated cleavage of gasdermin E (GSDME), subsequently inducing pyroptosis. Furthermore, IR700DX-6T-PDT enhanced the sensitivity of MSS-CRC cells to PD-1 blockade. Decitabine, a demethylation drug used to treat hematologic neoplasms, disrupted the abnormal methylation pattern of GSDME in tumor cells, enhanced the efficacy of IR700DX-6T-PDT, and elicited a potent antitumor immune response in combination with PD-1 blockade and IR700DX-6T-PDT. CONCLUSION: Our work provides clear a understanding of immunogenic cell death triggered by mitochondria-targeted PDT, offering a new approach for enhancing the efficacy of PD-1 blockade in CRC.

Fibroblasts in immune-mediated inflammatory diseases: The soil of inflammation.

As one of the most abundant stromal cells, fibroblasts are primarily responsible for the production and remodeling of the extracellular matrix. Traditionally, fibroblasts have been viewed as quiescent cells. However, recent advances in multi-omics technologies have demonstrated that fibroblasts exhibit remarkable functional diversity at the single-cell level. Additionally, fibroblasts are heterogeneous in their origins, tissue locations, and transitions with stromal cells. The dynamic nature of fibroblasts is further underscored by the fact that disease stages can impact their heterogeneity and behavior, particularly in immune-mediated inflammatory diseases such as psoriasis, inflammatory bowel diseases, and rheumatoid arthritis, etc. Fibroblasts can actively contribute to the disease initiation, progression, and relapse by responding to local microenvironmental signals, secreting downstream inflammatory factors, and interacting with immune cells during the pathological process. Here we focus on the development, plasticity, and heterogeneity of fibroblasts in inflammation, emphasizing the need for a developmental and dynamic perspective on fibroblasts.

ROS-Activated TRPM2 Channel: Calcium Homeostasis in Cardiovascular/renal System and Speculation in Cardiorenal Syndrome.

The transient receptor potential melastatin 2 (TRPM2) channel is a nonselective calcium channel that is sensitive to oxidative stress (OS), and is widely expressed in multiple organs, such as the heart, kidney, and brain, which is inextricably related to calcium dyshomeostasis and downstream pathological events. Due to the increasing global burden of kidney or cardiovascular diseases (CVDs), safe and efficient drugs specific to novel targets are imperatively needed. Notably, investigation of the possibility to regard the TRPM2 channel as a new therapeutic target in ROS-related CVDs or renal diseases is urgently required because the roles of the TRPM2 channel in heart or kidney diseases have not received enough attention and thus have not been fully elaborated. Therefore, we aimed to review the involvement of the TRPM2 channel in cardiovascular disorders related to kidney or typical renal diseases and attempted to speculate about TRPM2-mediated mechanisms of cardiorenal syndrome (CRS) to provide representative perspectives for future research about novel and effective therapeutic strategies.

FPR1 contributes to epidermal barrier dysfunction-induced skin inflammation through NLRC4-dependent keratinocyte activation.

BACKGROUND: Skin barrier dysfunction may both initiate and aggravate skin inflammation. However, the mechanisms involved have remained largely unknown. OBJECTIVE: We sought to determine how skin barrier dysfunction enhances skin inflammation and the molecular mechanisms. METHODS: Skin barrier defect mice were established by tape stripping or topical use of acetone on wild type mice, or filaggrin (FLG) deficiency. RNA-sequencing was employed to dissect the differentially expressed genes in skin barrier defect mice. Primary human keratinocytes were transfected with formylpeptide receptor 1 (FPR1) or PERK small interfering RNA (siRNA) to examine the effects of these gene targets. The expressions of inflammasome NLRC4, epidermal barrier genes, and inflammatory mediators were evaluated. RESULTS: Mechanical (tape stripping), chemical (acetone), or genetic (filaggrin deficiency) barrier disruption in mice amplified the expression of pro-inflammatory genes, with transcriptomic profiling revealing overexpression of formylpeptide receptor (Fpr1) in the epidermis. Treatment with the FPR1 agonist fMLP in keratinocytes up-regulated the expression of the NLRC4 inflammasome and increased IL-1ß secretion through modulation of endoplasmic reticulum stress via the PERK-eIF2α-CHOP pathway. The activation of FPR1-NLRC4 axis was also observed in skin specimens from old healthy individuals with skin barrier defect or elderly mice. Conversely, topical administration with an FPR1 antagonist, or Nlrc4 silencing, led to the normalization of barrier dysfunction and alleviation of inflammatory skin responses in vivo. CONCLUSION: In summary, our findings show that the FPR1-NLRC4 inflammasome axis is activated upon skin barrier disruption and may explain exaggerated inflammatory responses that are seen in disease states characterized by epidermal dysfunction. Pharmacological inhibition of FPR1 or NLRC4 represents a potential therapeutic target.

Measurement of carbon effect in land consolidation projects and evaluation of low-carbon promotion paths: a case study of Wudi County, Shandong Province, China.

Against the backdrop of China's "double carbon" objective, the exploration of low-carbon land consolidation has become a prominent area of focus for enhancing the development of ecological civilization. In this study, three typical projects at different time points (2016, 2019, and 2022) in Wudi County were selected to measure the carbon effect of land consolidation from four perspectives: artificial and industrial materials, mechanical shift consumption, land use structure, and farmland ecosystem. Based on the calculation of carbon effect of land consolidation by using carbon emission coefficient method, the changes of land use structure and carbon storage of farmland ecosystem before and after land consolidation were corrected by using GIS tools and net ecosystem productivity (NEP) model based on remote sensing technology, and the carbon emission intensity of each land consolidation project was finally obtained. The study summarized the influencing factors of carbon emissions through the above analysis and uses the fuzzy interpretation structure (FISM) model to provide the hierarchy of influencing factors of carbon emissions, thus proposing a low-carbon promotion path for land consolidation. The findings of this study can serve as a useful reference for low-carbon land consolidation efforts. The results showed that (1) the first, second, and third projects emitted 6140.06 t, 1243.78 t, and 17,604.62 t of carbon, respectively. Among them, the largest contributors to these emissions were labor and industrial materials, followed by mechanical shift; land use structure and farmland ecosystem were the main sources of carbon sinks and have a positive impact on the carbon cycle. (2) The carbon emission intensity of project one, project two, and project three after standardization is 0.26, 0.49, and 0.25, respectively, which are all at a high level. (3) According to the FISM model categorized 15 low-carbon upgrading paths, it was recommended that the government take a leading role in Wudi County by developing a scientific and rational construction plan. Additionally, efforts were made to actively protect farmland and forest land from destruction, reduce energy and material consumption, increase carbon storage in the farmland ecosystem, and promote low carbonization of land consolidation to the fullest extent possible.

Transcriptome profiling and ceRNA network of small extracellular vesicles from resting and degranulated mast cells.

Aim: This study aimed to investigate the transcriptomic characteristics and interactions between competitive endogenous RNAs (ceRNAs) within small extracellular vesicles (sEVs) derived from mast cells (MCs). Methods: Transcriptome sequencing analyzed lncRNA, circRNA and mRNA expression in resting and degranulated MC-derived sEVs. Constructed ceRNA regulatory network through correlation analysis and target gene prediction. Results: Differentially expressed 1673 mRNAs, 173 lncRNAs and 531 circRNAs were observed between resting and degranulated MCs-derived sEVs. Enrichment analysis revealed involvement of neurodegeneration, infection and tumor pathways. CeRNA networks included interactions between lncRNA-miRNA, circRNA-miRNA and miRNA-mRNA, targeting genes in the hippo and wnt signaling pathways linked to tumor immune regulation. Conclusion: This study provides valuable insights into MC-sEV molecular mechanisms, offering significant data resources for further investigations.

Mast cells (MCs) are important for various health conditions, including allergies, infections, tumors and brain disorders. MCs release tiny structures called small extracellular vesicles (sEVs) that carry different molecules, such as genetic material, to communicate with other cells in the body's immune system. However, we still do not know much about how these sEVs work. In this study, we examined the sEVs from MCs and found specific genetic molecules that change when MCs become activated. We discovered that these molecules are involved in important processes related to diseases like neurodegeneration and infection. We also identified networks of molecules that interact with each other, influencing immune regulation of tumor. By studying this, we gain new knowledge about how MCs use sEVs to communicate with other cells in our body during immune responses.

Insights on therapeutic potential of clemastine in neurological disorders.

Clemastine, a Food and Drug Administration (FDA)-approved compound, is recognized as a first-generation, widely available antihistamine that reduces histamine-induced symptoms. Evidence has confirmed that clemastine can transport across the blood-brain barrier and act on specific neurons and neuroglia to exert its protective effect. In this review, we summarize the beneficial effects of clemastine in various central nervous system (CNS) disorders, including neurodegenerative disease, neurodevelopmental deficits, brain injury, and psychiatric disorders. Additionally, we highlight key cellular links between clemastine and different CNS cells, in particular in oligodendrocyte progenitor cells (OPCs), oligodendrocytes (OLs), microglia, and neurons.

The association between retina thinning and hippocampal atrophy in Alzheimer's disease and mild cognitive impairment: a meta-analysis and systematic review.

Introduction: The retina is the "window" of the central nervous system. Previous studies discovered that retinal thickness degenerates through the pathological process of the Alzheimer's disease (AD) continuum. Hippocampal atrophy is one of the typical clinical features and diagnostic criteria of AD. Former studies have described retinal thinning in normal aging subjects and AD patients, yet the association between retinal thickness and hippocampal atrophy in AD is unclear. The optical coherence tomography (OCT) technique has access the non-invasive to retinal images and magnetic resonance imaging can outline the volume of the hippocampus. Thus, we aim to quantify the correlation between these two parameters to identify whether the retina can be a new biomarker for early AD detection. Methods: We systematically searched the PubMed, Embase, and Web of Science databases from inception to May 2023 for studies investigating the correlation between retinal thickness and hippocampal volume. The Newcastle-Ottawa Quality Assessment Scale (NOS) was used to assess the study quality. Pooled correlation coefficient r values were combined after Fisher's Z transformation. Moderator effects were detected through subgroup analysis and the meta-regression method. Results: Of the 1,596 citations initially identified, we excluded 1,062 studies after screening the titles and abstract (animal models, n = 99; irrelevant literature, n = 963). Twelve studies met the inclusion criteria, among which three studies were excluded due to unextractable data. Nine studies were eligible for this meta-analysis. A positive moderate correlation between the retinal thickness was discovered in all participants of with AD, mild cognitive impairment (MCI), and normal controls (NC) (r = 0.3469, 95% CI: 0.2490-0.4377, I2 = 5.0%), which was significantly higher than that of the AD group (r = 0.1209, 95% CI:0.0905-0.1510, I2 = 0.0%) (p < 0.05). Among different layers, the peripapillary retinal nerve fiber layer (pRNFL) indicated a moderate positive correlation with hippocampal volume (r = 0.1209, 95% CI:0.0905-0.1510, I2 = 0.0%). The retinal pigmented epithelium (RPE) was also positively correlated [r = 0.1421, 95% CI:(-0.0447-0.3192), I2 = 84.1%]. The retinal layers and participants were the main overall heterogeneity sources. Correlation in the bilateral hemisphere did not show a significant difference. Conclusion: The correlation between RNFL thickness and hippocampal volume is more predominant in both NC and AD groups than other layers. Whole retinal thickness is positively correlated to hippocampal volume not only in AD continuum, especially in MCI, but also in NC. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, CRD42022328088.

TECO: A Unified Feature Map Compression Framework Based on Transform and Entropy.

The massive memory accesses of feature maps (FMs) in deep neural network (DNN) processors lead to huge power consumption, which becomes a major energy bottleneck of DNN accelerators. In this article, we propose a unified framework named Transform and Entropy-based COmpression (TECO) scheme to efficiently compress FMs with various attributes in DNN inference. We explore, for the first time, the intrinsic unimodal distribution characteristic that widely exists in the frequency domain of various FMs. In addition, a well-optimized hardware-friendly coding scheme is designed, which fully utilizes this remarkable data distribution characteristic to encode and compress the frequency spectrum of different FMs. Furthermore, the information entropy theory is leveraged to develop a novel loss function for improving the compression ratio and to make a fast comparison among different compressors. Extensive experiments are performed on multiple tasks and demonstrate that the proposed TECO achieves compression ratios of 2.31 × in ResNet-50 on image classification, 3.47 × in UNet on dark image enhancement, and 3.18 × in Yolo-v4 on object detection while keeping the accuracy of these models. Compared with the upper limit of the compression ratio for original FMs, the proposed framework achieves the compression ratio improvement of 21%, 157%, and 152% on the above models.

High-performance and compact integrated photonic dichroic filters and triplexer realized by an efficient inverse design.

Integrated optical filters are key components in various photonic integrated circuits for applications of communication, spectroscopy, etc. The dichroic filters can be flexibly cascaded to construct filters with various channel numbers and bandwidths. Therefore, the development of high-performance and compact dichroic filters is crucial. In this work, we develop the dichroic filters with 1.49/1.55-µm channels by an inverse design. Benefiting from a search-space-dimension control strategy and advanced optimization algorithm, our efficient design method results in two high-performance dichroic filters without and with subwavelength gratings (SWGs). The comparison suggests that SWGs in filters can be useful for loss reduction and footprint compression by dispersion engineering. The developed dichroic filter with SWGs exhibits measured bandwidths of 26/29 nm, excess losses of < 0.5 dB, and crosstalks of <-10 dB with a compact footprint of 2.5 × 22.0 µm2. It has advantages in performance or compactness compared to the previously reported counterparts. A triplexer with a footprint of 10.5 × 117 µm2 is developed based on the dichroic filters, also showing decent overall performance and compactness.

Cross-disease characterization of fibroblast heterogeneities and their pathogenic roles in skin inflammation.

Fibroblasts are critical pro-inflammatory regulators in chronic inflammatory and fibrotic skin diseases. However, fibroblast heterogeneity and the absence of a unified cross-disease taxonomy have hindered our understanding of the shared/distinct pathways in non-communicable skin inflammation. By integrating 10× single-cell data from 75 skin samples, we constructed a single-cell atlas across inflammatory and fibrotic skin diseases and identified 9 distinct subsets of skin fibroblasts. We found a shared subset of CCL19+ fibroblasts across these diseases, potentially attracting and educating immune cells. Moreover, COL6A5+ fibroblasts were a distinct subset implicated in the initiation and relapse of psoriasis, which tended to differentiate into CXCL1+ fibroblasts, inducing neutrophil chemotaxis and infiltration; while CXCL1+ fibroblasts exhibited a more heterogeneous response to certain inflammatory conditions. Differentiation trajectory and regulatory factors of these fibroblast subsets were also revealed. Therefore, our study presents a comprehensive atlas of skin fibroblasts and highlights pathogenic fibroblast subsets in skin disorders.

Simultaneous thulium laser resection of the prostate and transperineal prostate biopsy in clinically diagnosed metastatic prostate cancer with bladder outlet obstruction.

Metastatic prostate cancer (mPCa) patients complicated with bladder outlet obstruction (BOO) are often referred to a urologist. Androgen deprivation therapy (ADT) combined with indwelling catheter usually be the initial management. To retrospectively analysis the safety and efficacy of simultaneous thulium laser resection of the prostate (TmLRP) and transperineal prostate biopsy in metastatic prostate cancer with bladder outlet obstruction. From January 2016 to December 2021, 67 clinically diagnosed mPCa with BOO patients were included in this study. All patients were preoperatively assessed with international prostate symptom score (IPSS), QoL, serum prostate-specific antigen (PSA), prostate volume evaluation by transrectal ultrasound, postvoid residual urine volume (PVR), and maximum flow rate (Qmax). Preoperative and perioperative parameters at 1-, 3-, and 6-month follow-up were also evaluated. All complications were recorded. Simultaneous TmLRP and transperineal prostate biopsy had obvious advantages for clinically diagnosed mPCa patients with BOO, including short overall operation time (52 ± 23.3 min), little hemoglobin decrease (0.6 ± 0.7 g/l), and short hospital stay (average 3.8 days). In addition, simultaneous TmLRP and transperineal prostate biopsy also brought them significant improvement on IPSS, QoL score, Qmax, and PVR volume (P < 0.001) at 1-, 3-, and 6-month follow-up after operation compared to preoperative parameters. Complications were in a low incidence. Simultaneous TmLRP and transperineal prostate biopsy is a bloodless operation with immediate effect and little perioperative complication. Importantly, it is a promising technology in the diagnosis and treatment of clinically diagnosed mPCa patients with BOO.

Rapamycin and Low-dose IL-2 Mediate an Immunosuppressive Microenvironment to Inhibit Benign Prostatic Hyperplasia.

Benign prostatic hyperplasia (BPH) is a condition that becomes more common with age and manifests itself primarily as the expansion of the prostate and surrounding tissues. However, to date, the etiology of BPH remains unclear. In this respect, we performed single-cell RNA sequencing of prostate transition zone tissues from elderly individuals with different prostate volumes to reveal their distinct tissue microenvironment. Ultimately, we demonstrated that a reduced Treg/CD4+ T-cell ratio in the large-volume prostate and a relatively activated immune microenvironment were present, characterized partially by increased expression levels of granzymes, which may promote vascular growth and profibrotic processes and further exacerbate BPH progression. Consistently, we observed that the prostate gland of patients taking immunosuppressive drugs usually remained at a smaller volume. Furthermore, in mouse models, we confirmed that both suppression of the immune system with rapamycin and induction of Treg proliferation with low doses of IL-2 therapy indeed prevented the progression of BPH. Taken together, our findings suggest that an activated immune microenvironment is necessary for prostate volume growth and that Tregs can reverse this immune activation state, thereby inhibiting the progression of BPH.

Lipoxin A4 methyl ester attenuated ketamine-induced neurotoxicity in SH-SY5Y cells via regulating leptin pathway.

Ketamine, the widely used intravenous anesthetic, has been reported to cause neurotoxicity and disturbs normal neurogenesis. However, the efficacy of current treatment strategies targeting ketamine's neurotoxicity remains limited. Lipoxin A4 methyl ester (LXA4 ME) is relatively stable lipoxin analog, which serves an important role in protecting against early brain injury. The purpose of this study was to investigate the protective effect of LXA4 ME on ketamine-caused cytotoxicity in SH-SY5Y cells, as well as the underlying mechanisms. Cell viability, apoptosis and endoplasmic reticulum stress (ER stress) were detected by adopting experimental techniques including CCK-8 assay, flow cytometry, western blotting and transmission electron microscope. Furthermore, examining the expression of leptin and its receptor (LepRb), we also measured the levels of activation of the leptin signaling pathway. Our results showed that LXA4 ME intervention promoted the cell viability, inhibited cell apoptosis, and reduced the expression of ER stress related protein and morphological changes induced by ketamine. In addition, inhibition of leptin signaling pathway caused by ketamine could be reversed by LXA4 ME. However, as the specific inhibitor of leptin pathway, leptin antagonist triple mutant human recombinant (leptin tA) attenuated the cytoprotective effect of LXA4 ME against ketamine-induced neurotoxicity. In conclusion, our findings demonstrated LXA4 ME could exert a neuroprotective effect on ketamine-induced neuronal injury via activation of the leptin signaling pathway.