Targeting tumor suppressor p53 for organ fibrosis therapy.

Fibrosis is a reparative and progressive process characterized by abnormal extracellular matrix deposition, contributing to organ dysfunction in chronic diseases. The tumor suppressor p53 (p53), known for its regulatory roles in cell proliferation, apoptosis, aging, and metabolism across diverse tissues, appears to play a pivotal role in aggravating biological processes such as epithelial-mesenchymal transition (EMT), cell apoptosis, and cell senescence. These processes are closely intertwined with the pathogenesis of fibrotic disease. In this review, we briefly introduce the background and specific mechanism of p53, investigate the pathogenesis of fibrosis, and further discuss p53's relationship and role in fibrosis affecting the kidney, liver, lung, and heart. In summary, targeting p53 represents a promising and innovative therapeutic approach for the prevention and treatment of organ fibrosis.

[Effect of Polyethylene Microplastics on the Microbial Community of Saline Soils].

Mulching to conserve moisture has become an important agronomic practice in saline soil cultivation, and the effects of the dual stress of salinity and microplastics on soil microbes are receiving increasing attention. In order to investigate the effect of polyethylene microplastics on the microbial community of salinized soils, this study investigated the effects of different types (chloride and sulphate) and concentrations (weak, medium, and strong) of polyethylene (PE) microplastics (1% and 4% of the dry weight mass of the soil sample) on the soil microbial community by simulating microplastic contamination in salinized soil environments indoors. The results showed that:PE microplastics reduced the diversity and abundance of microbial communities in salinized soils and were more strongly affected by sulphate saline soil treatments. The relative abundance of each group of bacteria was more strongly changed in the sulphate saline soil treatment than in the chloride saline soil treatment. At the phylum level, the relative abundance of Proteobacteria was positively correlated with the abundance of fugitive PE microplastics, whereas the relative abundances of Bacteroidota, Actinobacteriota, and Acidobacteria were negatively correlated with the abundance of fugitive PE microplastics. At the family level, the relative abundances of Flavobacteriaceae, Alcanivoracaceae, Halomonadaceae, and Sphingomonasceae increased with increasing abundance of PE microplastics. The KEGG metabolic pathway prediction showed that the relative abundance of microbial metabolism and genetic information functions were reduced by the presence of PE microplastics, and the inhibition of metabolic functions was stronger in sulphate saline soils than in chloride saline soils, whereas the inhibition of genetic information functions was weaker than that in chloride saline soils. The secondary metabolic pathways of amino acid metabolism, carbohydrate metabolism, and energy metabolism were inhibited. It was hypothesized that the reduction in metabolic functions may have been caused by the reduced relative abundance of the above-mentioned secondary metabolic pathways. This study may provide a theoretical basis for the study of the effects of microplastics and salinization on the soil environment under the dual pollution conditions.

Immune signatures predict response to house dust mite subcutaneous immunotherapy in patients with allergic rhinitis.

BACKGROUND: Identifying predictive biomarkers for allergen immunotherapy response is crucial for enhancing clinical efficacy. This study aims to identify such biomarkers in patients with allergic rhinitis (AR) undergoing subcutaneous immunotherapy (SCIT) for house dust mite allergy. METHODS: The Tongji (discovery) cohort comprised 72 AR patients who completed 1-year SCIT follow-up. Circulating T and B cell subsets were characterized using multiplexed flow cytometry before SCIT. Serum immunoglobulin levels and combined symptom and medication score (CSMS) were assessed before and after 12-month SCIT. Responders, exhibiting ≥30% CSMS improvement, were identified. The random forest algorithm and logistic regression analysis were used to select biomarkers and establish predictive models for SCIT efficacy in the Tongji cohort, which was validated in another Wisco cohort with 43 AR patients. RESULTS: Positive SCIT response correlated with higher baseline CSMS, allergen-specific IgE (sIgE)/total IgE (tIgE) ratio, and frequencies of Type 2 helper T cells, Type 2 follicular helper T (TFH2) cells, and CD23+ nonswitched memory B (BNSM) and switched memory B (BSM) cells, as well as lower follicular regulatory T (TFR) cell frequency and TFR/TFH2 cell ratio. The random forest algorithm identified sIgE/tIgE ratio, TFR/TFH2 cell ratio, and BNSM frequency as the key biomarkers discriminating responders from nonresponders in the Tongji cohort. Logistic regression analysis confirmed the predictive value of a combination model, including sIgE/tIgE ratio, TFR/TFH2 cell ratio, and CD23+ BSM frequency (AUC = 0.899 in Tongji; validated AUC = 0.893 in Wisco). CONCLUSIONS: A T- and B-cell signature combination efficiently identified SCIT responders before treatment, enabling personalized approaches for AR patients.

Aberrant follicular regulatory T cells associate with immunoglobulin hyperproduction in nasal polyps with ectopic lymphoid tissues.

BACKGROUND: Ectopic lymphoid tissues (eLTs) and associated follicular helper T (TFH) cells contribute to local immunoglobulin hyperproduction in nasal polyps (NPs). Follicular regulatory T (TFR) cells in secondary lymphoid organs counteract TFH cells and suppress immunoglobulin production; however, the presence and function of TFR cells in eLTs in peripheral diseased tissues remain poorly understood. OBJECTIVE: We sought to investigate the presence, phenotype, and function of TFR cells in NPs. METHODS: The presence, abundance, and phenotype of TFR cells in NPs were examined using single-cell RNA sequencing, immunofluorescence staining, and flow cytometry. Sorted polyp and circulating T-cell subsets were cocultured with autologous circulating naïve B cells, and cytokine and immunoglobulin production were measured by ELISA. RESULTS: TFR cells were primarily localized within eLTs in NPs. TFR cell frequency and TFR cell/TFH cell ratio were decreased in NPs with eLTs compared with NPs without eLTs and control inferior turbinate tissues. TFR cells displayed an overlapping phenotype with TFH cells and FOXP3+ regulatory T cells in NPs. Polyp TFR cells had reduced CTLA-4 expression and decreased capacity to inhibit TFH cell-induced immunoglobulin production compared with their counterpart in blood and tonsils. Blocking CTLA-4 abolished the suppressive effect of TFR cells. Lower vitamin D receptor expression was observed on polyp TFR cells compared with TFR cells in blood and tonsils. Vitamin D treatment upregulated CTLA-4 expression on polyp TFR cells and restored their suppressive function in vitro. CONCLUSIONS: Polyp TFR cells in eLTs have decreased CLTA-4 and vitamin D receptor expression and impaired capacity to suppress TFH cell-induced immunoglobulin production, which can be reversed by vitamin D treatment in vitro.

Unraveling intratumoral complexity in metastatic dermatofibrosarcoma protuberans through single-cell RNA sequencing analysis.

Dermatofibrosarcoma protuberans (DFSP) stands as a rare and locally aggressive soft tissue tumor, characterized by intricated molecular alterations. The imperative to unravel the complexities of intratumor heterogeneity underscores effective clinical management. Herein, we harnessed single-cell RNA sequencing (scRNA-seq) to conduct a comprehensive analysis encompassing samples from primary sites, satellite foci, and lymph node metastases. Rigorous preprocessing of raw scRNA-seq data ensued, and employing t-distributed stochastic neighbor embedding (tSNE) analysis, we unveiled seven major cell populations and fifteen distinct subpopulations. Malignant cell subpopulations were delineated using infercnv for copy number variation calculations. Functional and metabolic variations of diverse malignant cell populations across samples were deciphered utilizing GSVA and the scMetabolism R packages. Additionally, the exploration of differentiation trajectories within diverse fibroblast subpopulations was orchestrated through pseudotime trajectory analyses employing CytoTRACE and Monocle2, and further bolstered by GO analyses to elucidate the functional disparities across distinct differentiation states. In parallel, we segmented the cellular components of the immune microenvironment and verified the presence of SPP1+ macrophage, which constituted the major constituent in lymph node metastases. Remarkably, the CellChat facilitated a comprehensive intercellular communication analysis. This study culminates in an all-encompassing single-cell transcriptome atlas, propounding novel insights into the multifaceted nature of intratumor heterogeneity and fundamental molecular mechanisms propelling metastatic DFSP.

Can the establishment of an innovative city improve the level of technological entrepreneurship?

Based on the data of 278 prefecture-level city panels in China from 2008 to 2020, this paper presents the policy of innovative pilot city as a quasi-natural experiment. It is found that (1) the implementation of innovative urban policy can significantly improve the level of science and technology entrepreneurship, but the pilot policy has a time lag effect and has a continuous promoting effect since the third year. (2) For large cities, areas with high levels of economic development, central and eastern regions and cities with high new infrastructure, innovative cities can improve the level of technological entrepreneurship; (3) Innovative cities improve the level of technological entrepreneurship by improving the incubator of technological enterprises and strengthening the flow of human capital; (4) The effect of the establishment of innovative cities on the level of technological entrepreneurship mainly shows that the siphon effect does not show radiation effect, and this siphon effect mainly improves the level of technological entrepreneurship by increasing the number of incubators of technological enterprises.

Laser treatment for Cafe-au-lait Macules: a systematic review and meta-analysis.

Nowadays, laser is the mainstay treatment for cafe-au-lait macules (CALMs), but no systematic review has been published to demonstrate the overall efficacy and it's still controversial which type of laser is optimal. Thus, we conduct the meta-analysis to evaluate the effectiveness and side effects of various types of lasers in treating CALMs. Original articles reporting the efficacy and side effects for CALMs in laser treatment were identified in PubMed, EMBASE, and Web of Science from 1983 to April 11, 2023. Using R software and the 'meta' package, meta-analysis was conducted for clearance and recurrence for evaluation of efficacy. And the occurrence of hypopigmentation and hyperpigmentation rate was pooled for safety evaluation. We used RoB2 and ROBINS-I tools to assess the risks of bias in RCT studies and non-RCT studies, respectively. The Grading of Recommendations, Assessment, Development and Evaluation system was used to assess the quality of the evidence. Nineteen studies involving 991 patients were included, which had a very low to moderate quality of evidence. The pooled 75% clearance rate was 43.3% (95% CI 31.8-54.7%, I2 = 96%), 50% clearance rate was 75% (95% CI 62.2-85.9%, I2 = 89%) and the recurrence rate was 13% (95% CI 3.2-26.5%, I2 = 88%). The pooled hypopigmentation and hyperpigmentation rates were 1.2% (95% CI 0.3-2.1%, I2 = 0%) and 1.2% (95% CI 0.3-2%, I2 = 0%), respectively. Subgroup analysis revealed that QS-1064-nm Nd:YAG laser treatment not only achieved more than 75% clearance rate in 50.9% of patients (95% CI 26.9-74.4%, I2 = 90%) but also resulted in the lowest hypopigmentation and hyperpigmentation rate of 0.5% (95% CI 0.0-2.5%, I2 = 26%) and 0.4% (95% CI 0.0-2.5%, I2 = 0%). To draw a conclusion, the laser treatment could reach an overall clearance rate of 50% for 75% of the patients with CALMs, for 43.3% of the patients, the clearance rate could reach 75%. When looking at different wavelength subgroups, QS-1064-nm Nd:YAG laser exhibited the best treatment capability. Laser of all the wavelength subgroups presented acceptable safety regarding of the low occurrence of side effects, namely, hypopigmentation and hyperpigmentation.

Long History of Multiple Painless Scalp Nodules in a Middle-aged Woman.

A woman in her late 40s presented with a 40-year history of hard nodules on the scalp, feet, trunk, and lower extremities. What is your diagnosis?

Tropomyosin receptor kinase B (TrkB) signalling: targeted therapy in neurogenic tumours.

Tropomyosin receptor kinase B (TrkB), a transmembrane receptor protein, has been found to play a pivotal role in neural development. This protein is encoded by the neurotrophic receptor tyrosine kinase 2 (NTRK2) gene, and its abnormal activation caused by NTRK2 overexpression or fusion can contribute to tumour initiation, progression, and resistance to therapeutics in multiple types of neurogenic tumours. Targeted therapies for this mechanism have been designed and developed in preclinical and clinical studies, including selective TrkB inhibitors and pan-TRK inhibitors. This review describes the gene structure, biological function, abnormal TrkB activation mechanism, and current-related targeted therapies in neurogenic tumours.

Transdural circumferential decompression for thoracic spinal stenosis caused by beak-type ossification of the posterior longitudinal ligament: a technical note.

PURPOSE: Thoracic myelopathy caused by ossification of the posterior longitudinal ligament (OPLL) in the thoracic spine is usually progressive and responds poorly to conservative therapy, making surgery the only effective treatment option. A variety of surgical procedures have been developed to treat thoracic OPLL. However, the optimal surgical approach for removal of thoracic OPLL remains unclear. In the present study, we described a newly modified posterior approach for the removal of OPLL: circular decompression via dural approach, and complete removal of OPLL can be achieved under direct vision and without neurological deficit. MATERIALS AND METHODS: Three patients with beak-type thoracic OPLL presented with progressive thoracic myelopathy and leg weakness. Magnetic resonance imaging showed the spinal cord severely compressed. The surgical management of the three patients involved the 'cave-in' circular decompression and transdural resection of OPLL. RESULTS: Transdural circumferential decompression was successfully performed in all three patients. Clinical outcome measures, including pre- and postoperative radiographic parameters, were assessed. All of the patients were followed up for an average of 12 months (ranging from 10 to 15 months), and no surgery-related complications occurred. Weakness relief and neural function recovery were satisfactorily achieved in all patients by the final follow-up. CONCLUSIONS: Transdural circumferential decompression was an effective method for thoracic spinal stenosis caused by concurrent beak-type OPLL, by which OPLL could be safely removed. It is especially useful when there is a severe adhesion between the dura OPLL.

Case Report: Differential diagnosis for tuberous sclerosis and neurofibromatosis type 1 diagnostic pitfall of aggressively enlarged right upper limb.

Tuberous sclerosis complex (TSC) is an inherited disorder that typically presents with seizures, developmental delay, cutaneous lesions, and facial angiomas. Clinical diagnosis of TSC based on symptoms is sometimes challenging due to its clinical similarities with neurofibromatosis type 1 (NF1), another type of neurogenetic tumor syndrome. Differential diagnosis should be carefully performed on the basis of clinical presentations, imaging, laboratory, and genetic testing. Here, we presented a case of a patient with an aggressively enlarged right upper limb in the NF1 clinic, who was initially suspected of a giant plexiform neurofibroma. However, differential diagnosis revealed TSC as the final diagnosis. The treatments for NF1 and TSC vary significantly, and misdiagnoses can lead to serious threat to the patients' health. We also systematically reviewed all previous cases regarding differential diagnoses between NF1 and TSC. This case report can help clinicians make more accurate diagnoses and benefit the potential patient community.

Role of nerves in neurofibromatosis type 1-related nervous system tumors.

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that affects nearly 1 in 3000 infants. Neurofibromin inactivation and NF1 gene mutations are involved in various aspects of neuronal function regulation, including neuronal development induction, electrophysiological activity elevation, growth factor expression, and neurotransmitter release. NF1 patients often exhibit a predisposition to tumor development, especially in the nervous system, resulting in the frequent occurrence of peripheral nerve sheath tumors and gliomas. Recent evidence suggests that nerves play a role in the development of multiple tumor types, prompting researchers to investigate the nerve as a vital component in and regulator of the initiation and progression of NF1-related nervous system tumors. CONCLUSION: In this review, we summarize existing evidence about the specific effects of NF1 mutation on neurons and emerging research on the role of nerves in neurological tumor development, promising a new set of selective and targeted therapies for NF1-related tumors.

Primary squamous cell carcinoma with sarcomatoid differentiation of the kidney associated with ureteral stone obstruction: A case report.

BACKGROUND: Primary squamous cell carcinoma (SCC) with sarcomatoid differentiation of the kidney was rarely reported. This disease is usually related to renal stones, and due to a lack of symptoms and radiological features, patients usually attend the hospital with late stage disease. CASE SUMMARY: A 54-years-old female presented with left flank pain and an abdominal mass for 6 mo. Imaging studies revealed that the left kidney was enlarged and massive hydronephrosis was present. A stone was seen in the ureteropelvic junction. The patient subsequently underwent left radical nephrectomy, and histopathological examination of the mass revealed a poorly differentiated renal SCC with sarcomatoid differentiation. After primary surgery, the patient received four cycles of tirelizumab. Four months later, the patient developed adrenal, lymph, and uterine appendage metastases. CONCLUSION: SCC of the kidney has a poor prognosis, and should be considered in patients with a renal mass, long-standing urinary calculi and massive hydronephrosis.

The aldolase inhibitor aldometanib mimics glucose starvation to activate lysosomal AMPK.

The activity of 5'-adenosine monophosphate-activated protein kinase (AMPK) is inversely correlated with the cellular availability of glucose. When glucose levels are low, the glycolytic enzyme aldolase is not bound to fructose-1,6-bisphosphate (FBP) and, instead, signals to activate lysosomal AMPK. Here, we show that blocking FBP binding to aldolase with the small molecule aldometanib selectively activates the lysosomal pool of AMPK and has beneficial metabolic effects in rodents. We identify aldometanib in a screen for aldolase inhibitors and show that it prevents FBP from binding to v-ATPase-associated aldolase and activates lysosomal AMPK, thereby mimicking a cellular state of glucose starvation. In male mice, aldometanib elicits an insulin-independent glucose-lowering effect, without causing hypoglycaemia. Aldometanib also alleviates fatty liver and nonalcoholic steatohepatitis in obese male rodents. Moreover, aldometanib extends lifespan and healthspan in both Caenorhabditis elegans and mice. Taken together, aldometanib mimics and adopts the lysosomal AMPK activation pathway associated with glucose starvation to exert physiological roles, and might have potential as a therapeutic for metabolic disorders in humans.

Neurofibroma Development in Neurofibromatosis Type 1: Insights from Cellular Origin and Schwann Cell Lineage Development.

BACKGROUND: Neurofibromatosis type 1 (NF1), a genetic tumor predisposition syndrome that affects about 1 in 3000 newborns, is caused by mutations in the NF1 gene and subsequent inactivation of its encoded neurofibromin. Neurofibromin is a tumor suppressor protein involved in the downregulation of Ras signaling. Despite a diverse clinical spectrum, one of several hallmarks of NF1 is a peripheral nerve sheath tumor (PNST), which comprises mixed nervous and fibrous components. The distinct spatiotemporal characteristics of plexiform and cutaneous neurofibromas have prompted hypotheses about the origin and developmental features of these tumors, involving various cellular transition processes. METHODS: We retrieved published literature from PubMed, EMBASE, and Web of Science up to 21 June 2022 and searched references cited in the selected studies to identify other relevant papers. Original articles reporting the pathogenesis of PNSTs during development were included in this review. We highlighted the Schwann cell (SC) lineage shift to better present the evolution of its corresponding cellular origin hypothesis and its important effects on the progression and malignant transformation of neurofibromas. CONCLUSIONS: In this review, we summarized the vast array of evidence obtained on the full range of neurofibroma development based on cellular and molecular pathogenesis. By integrating findings relating to tumor formation, growth, and malignancy, we hope to reveal the role of SC lineage shift as well as the combined impact of additional determinants in the natural history of PNSTs.

[Effect of Microplastics on Soil Water Infiltration and Evaporation].

In order to explore the influences of microplastics with different abundances (0.5%, 1%, and 2% of the dry weight of the soil) and different types (PP, PVC, and PE) on the moisture infiltration and evaporation of the soil, we adopted the method of indoor soil column simulation to elaborate the influences of the microplastics with different abundances and different types on the moisture accumulated infiltration time, moisture containing rate, wetting front, and evaporation characteristics, among which the A1, A2, and A3; Q1, Q2, and Q3; and Z1, Z2, and Z3 respectively represented the experimental number of PE, PVC, and PP under the abundances of 0.5%, 1%, and 2%. The influences of the microplastics with different types and different abundances on the moisture infiltration and evaporation of the soil showed obvious differentiation. Under the same types of conditions, when the abundances of the microplastics increased, the accumulated infiltration time also increased significantly. However, under the occurrence condition of the microplastics of different types but the same abundances, the accumulated infiltration time of the PP experiment group>that of the PVC experiment group>that of the PE experiment group>that of the blank experiment group. Under the occurrence condition of microplastics, the maximum moisture rate of the soil basically appeared at the depth from 10 to 25 cm, and the CK of the blank group appeared at the depth from 20-25 cm. Within the same infiltration time, when the abundances of the microplastics increased, the moving distance and the moving rate of wetting front of the soil decreased accordingly. When the infiltration time was 60 minutes, the wetting moving distances of A1, A2, and A3; Q1, Q2, and Q3; and Z1, Z2, and Z3, respectively, decreased 4.38%, 8.76%, and 10.58%; 7.30%, 10.22%, and 14.60%; and 10.95%, 13.14%, and 15.33% compared to those of the CK groups, among which the influence of PP microplastics was the most significant. The occurrence of the microplastics had a prohibition function to the moisture evaporation of the soil; when the microplastics had the same types, the accumulated amount of the soil decreased with the increase in abundance. When evaporating for 27 hours, the accumulated evaporation amount of the experiment soil column of PP, PVC, and PE microplastics with the added abundances of 2% respectively decreased 22.9%, 19.4%, and 13.3% compared to that in the CK. The Rose evaporation model relatively truly reflected the changing situation of the soil accumulated evaporation amount with time under the occurrence situation of the microplastics. This research can provide a theoretical basis for the changing study of the soil moisture movement under the occurrence condition of microplastics.

Study on the Polycrystalline Mechanism of Polycrystalline Diamond Synthesized from Graphite by Direct Detonation Method.

In this paper, a polycrystalline diamond was synthesized by the direct detonation method using graphite as the carbon source. By comparing the numbers of the obtained diamond particles and the original graphite particles, it was found that when the graphite phase transformed into the polycrystalline diamond during the detonation process, a single graphite particle would form multiple diamond nuclei, and the nuclei would grow simultaneously to form polycrystals. Accordingly, a validation experiment was designed, which added different ratios of inert additives while keeping the ratio of graphite to hexogen (RDX) unchanged. It was found that increasing the ratio of inert additives within a certain range could increase the grain size of a polycrystalline diamond, which is consistent with the obtained polycrystalline mechanism.