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.

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.

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?

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.

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.

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.

Image-Based Differentiation of Benign and Malignant Peripheral Nerve Sheath Tumors in Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a dominant hereditary disease characterized by the mutation of the NF1 gene, affecting 1/3000 individuals worldwide. Most NF1 patients are predisposed to benign peripheral nerve sheath tumors (PNSTs), including cutaneous neurofibromas (CNFs) and plexiform neurofibromas (PNFs). However, 5%-10% of PNFs will ultimately develop into malignant peripheral nerve sheath tumors (MPNSTs), which have a poor prognosis. Early and reliable differentiation of benign and malignant tumors in NF1 patients is of great necessity. Pathological evaluation is the "gold standard" for a definite diagnosis, but the invasive nature of the biopsy procedure restricts it from applying as a screening tool during the decades-long follow-up of these patients. Non-invasive image-based diagnostic methods such as CT and MRI are often considered essential screening tools for multiple types of tumors. For NF1 patients' lifelong regular follow-ups, these radiological methods are currently used for tumor evaluation. However, no consensus was established on screening the malignant transformation of benign PNSTs. Moreover, novel technologies like radiogenomics and PET-MRI have not been well evaluated and fully adopted for NF1 patients. This review summarizes current studies of different imaging methods for differentiating benign and malignant tumors in NF1. Meanwhile, we discussed the prospects of the usage of new tools such as radiogenomics and PET-MRI to distinguish MPNST from benign PNSTs more precisely. Summarizing these findings will help clarify the directions of future studies in this area and ultimately contribute to the radiology images-based clinical screening of MPNST in NF1 patients and finally improve the overall survival rates of these patients.

Low-dose metformin targets the lysosomal AMPK pathway through PEN2.

Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects1-4. For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a major role in its mechanism of action4,5; however, the direct molecular target of metformin remains unknown. Here we show that clinically relevant concentrations of metformin inhibit the lysosomal proton pump v-ATPase, which is a central node for AMPK activation following glucose starvation6. We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase7, as a binding partner of metformin with a dissociation constant at micromolar levels. Metformin-bound PEN2 forms a complex with ATP6AP1, a subunit of the v-ATPase8, which leads to the inhibition of v-ATPase and the activation of AMPK without effects on cellular AMP levels. Knockout of PEN2 or re-introduction of a PEN2 mutant that does not bind ATP6AP1 blunts AMPK activation. In vivo, liver-specific knockout of Pen2 abolishes metformin-mediated reduction of hepatic fat content, whereas intestine-specific knockout of Pen2 impairs its glucose-lowering effects. Furthermore, knockdown of pen-2 in Caenorhabditis elegans abrogates metformin-induced extension of lifespan. Together, these findings reveal that metformin binds PEN2 and initiates a signalling route that intersects, through ATP6AP1, the lysosomal glucose-sensing pathway for AMPK activation. This ensures that metformin exerts its therapeutic benefits in patients without substantial adverse effects.

Extrafollicular PD-1highCXCR5-CD4+ T cells participate in local immunoglobulin production in nasal polyps.

BACKGROUND: Local immunoglobulin hyperproduction is observed in nasal polyps (NPs) with and without ectopic lymphoid tissues (eLTs). OBJECTIVE: Our aim was to identify the T-cell subsets involved in local immunoglobulin production independent of eLTs in NPs. METHODS: The localization, abundance, and phenotype of CD4+ T-cell subsets were studied by immunofluorescence, flow cytometry, and single-cell RNA sequencing. Purified nasal T-cell subsets were cultured with autologous peripheral naive B cells to explore their function. Programmed death ligand 1 and programmed death ligand 2 expression in NPs was investigated by immunofluorescence staining and flow cytometry. RESULTS: Accumulation of PD-1highCXCR5-CD4+ T cells outside lymphoid aggregates was found in NPs. Nasal PD-1highCXCR5-CD4+ T cells were characterized by a unique phenotype that was related to B-cell help and tissue residency and distinct from PD-1-/intCXCR5- and CXCR5+ CD4+ T cells in NPs as well as PD-1highCXCR5highCD4+ follicular helper T cells in tonsils. Compared with the frequencies of PD-1highCXCR5-CD4+ T cells and their IFN-γ+, IL-17A+, and IL-21+ subsets in the control inferior turbinate tissues, the frequencies of these cells and their subsets were increased in both eosinophilic and noneosinophilic NPs, whereas the frequencies of the IL-4+ and IL-4+IL-21+ subsets were increased only in eosinophilic NPs. Nasal PD-1highCXCR5-CD4+ T cells induced immunoglobulin production from B cells in a potency comparable to that induced by tonsillar follicular helper T cells. PD-1highCXCR5-CD4+ T-cell frequencies were correlated with IgE levels in eosinophilic NPs. PD-L1 and PD-L2 suppressed the function of PD-1highCXCR5-CD4+ T cells, and their levels were reduced in NPs. PD-1highCXCR5-CD4+ T-cell abundance was associated with the postsurgical relapse of NPs. CONCLUSION: PD-1highCXCR5-CD4+ T cells participate in local immunoglobulin production independent of eLTs in NPs.

Combined Cyclin-Dependent Kinase Inhibition Overcomes MAPK/Extracellular Signal-Regulated Kinase Kinase Inhibitor Resistance in Plexiform Neurofibroma of Neurofibromatosis Type I.

MAPK/extracellular signal-regulated kinase kinase (MEK) 1/2 inhibitors (MEKis) have recently achieved surprising success in treating unresectable plexiform neurofibromas (PNFs). However, few studies have investigated the mechanisms of MEKi resistance in patients with PNF. We determined the efficacy of six different MEKis for treating PNFs, explored drug resistance mechanisms, and identified potential combination therapies to overcome resistance. By screening drug efficacy among six MEKis in human NF1-deficient PNF cell lines, TAK-733 was found to reduce PNF cell viability the most. We then cultured the TAK-733‒resistant cells and explored the potential targets for further treatment. Both high-throughput drug screening and RNA sequencing analyses of MEKi-resistant PNF cells identified cyclin-dependent kinase inhibitors as potential agents for PNFs. Dinaciclib, a cyclin-dependent kinase inhibitor, showed synergistic effects on MEKi-resistant cells. Coadministration of dinaciclib and TAK-733 significantly reduced cell viability and inhibited sphere formation and colony formation. Dinaciclib did not affect MEK signaling but decreased the expression of several prosurvival proteins, including survivin and cyclin-dependent kinase 1, to induce apoptosis and inhibit mitosis. TAK-733/dinaciclib combination therapy induced tumor reduction in PNF patient‒derived xenografts mouse models. Therefore, the combination of MEKi and cyclin-dependent kinase inhibitor may be promising for treating inoperable PNFs, especially when drug resistance exists. Our findings provide evidence for future clinical trials with MEKi-resistant patients with PNF.

Impacts of NF1 Gene Mutations and Genetic Modifiers in Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a tumor predisposition genetic disorder that directly affects more than 1 in 3,000 individuals worldwide. It results from mutations of the NF1 gene and shows almost complete penetrance. NF1 patients show high phenotypic variabilities, including cafe-au-lait macules, freckling, or other neoplastic or non-neoplastic features. Understanding the underlying mechanisms of the diversities of clinical symptoms might contribute to the development of personalized healthcare for NF1 patients. Currently, studies have shown that the different types of mutations in the NF1 gene might correlate with this phenomenon. In addition, genetic modifiers are responsible for the different clinical features. In this review, we summarize different genetic mutations of the NF1 gene and related genetic modifiers. More importantly, we focus on the genotype-phenotype correlation. This review suggests a novel aspect to explain the underlying mechanisms of phenotypic heterogeneity of NF1 and provides suggestions for possible novel therapeutic targets to prevent or delay the onset and development of different manifestations of NF1.