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Abstract Background Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients. Methods This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded. Results Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217). Conclusions Sirolimus’s long-term administration is not associated with adverse effects on children’s physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration. Trial registration Pediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892.

Abstract Background Tyrosine phosphorylation of intracellular proteins is a post‐translational modification that plays a regulatory role in signal transduction during cellular events. Dephosphorylation of signal transduction proteins caused by protein tyrosine phosphatases (PTPs) contributed their role as a convergent node to mediate cross‐talk between signaling pathways. In the context of cancer, PTP‐mediated pathways have been identified as signaling hubs that enabled cancer cells to mitigate stress induced by clinical therapy. This is achieved by the promotion of constitutive activation of growth‐stimulatory signaling pathways or modulation of the immune‐suppressive tumor microenvironment. Preclinical evidences suggested that anticancer drugs will release their greatest therapeutic potency when combined with PTP inhibitors, reversing drug resistance that was responsible for clinical failures during cancer therapy. Areas covered This review aimed to elaborate recent insights that supported the involvement of PTP‐mediated pathways in the development of resistance to targeted therapy and immune‐checkpoint therapy. Expert opinion This review proposed the notion of PTP inhibition in anticancer combination therapy as a potential strategy in clinic to achieve long‐term tumor regression. Ongoing clinical trials are currently underway to assess the safety and efficacy of combination therapy in advanced‐stage tumors.

Abstract As the most common form of epigenetic regulation by RNA, N6 methyladenosine (m6A) modification is closely involved in physiological processes, such as growth and development, stem cell renewal and differentiation, and DNA damage response. Meanwhile, its aberrant expression in cancer tissues promotes the development of malignant tumors, as well as plays important roles in proliferation, metastasis, drug resistance, immunity and prognosis. This close association between m6A and cancers has garnered substantial attention in recent years. An increasing number of small molecules have emerged as potential agents to target m6A regulators for cancer treatment. These molecules target the epigenetic level, enabling precise intervention in RNA modifications and efficiently disrupting the survival mechanisms of tumor cells, thus paving the way for novel approaches in cancer treatment. However, there is currently a lack of a comprehensive review on small molecules targeting m6A regulators for anti-tumor. Here, we have comprehensively summarized the classification and functions of m6A regulators, elucidating their interactions with the proliferation, metastasis, drug resistance, and immune responses in common cancers. Furthermore, we have provided a comprehensive overview on the development, mode of action, pharmacology and structure–activity relationships of small molecules targeting m6A regulators. Our aim is to offer insights for subsequent drug design and optimization, while also providing an outlook on future prospects for small molecule development targeting m6A.

IntroductionBody dissatisfaction significantly impacts depression among adolescents with polycystic ovary syndrome (PCOS). This relationship is compounded by various factors. Our study aims to explore the roles of self-esteem and self-compassion in the relationship between body dissatisfaction and depression in adolescent with PCOS.MethodsA cross-sectional study was conducted at the Shanghai First Maternity and Infant Hospital, involving 287 adolescents diagnosed with PCOS from January 2020 to December 2021. Participants completed validated questionnaires covering body dissatisfaction, self-esteem, self-compassion and depression. We utilized correlation and mediation analyses to examine the relationships and mediating effects among these variables.ResultsBody dissatisfaction had a significant positive effect on depression (β = 4.254, p < 0.001). Conversely, self-esteem (β = −0.944, p < 0.001) and self-compassion (β = −0.318, p < 0.001) were negative predictors of depression. Both self-esteem [β = 3.405, 95% CI = (0.151, 0.305)] and self-compassion [β = 1.525, 95% CI = (0.045, 0.165)] were shown to partially mediate the relationship between body dissatisfaction and depression, explaining 37.07% and 16.61% of the total effect, respectively.ConclusionThis study highlights the importance of fostering self-esteem and self-compassion among adolescents with PCOS to buffer the depressive effects of body dissatisfaction. Interventions aimed at promoting accurate and positive body perceptions, enhancing self-esteem, fostering a supportive attitude toward personal challenges, and maintaining positive emotional states are recommended to decrease the incidence of depression.

Abstract Adipocytes are the primary sites for fatty acid storage, but the synthesis rate of fatty acids is very low. The physiological significance of this phenomenon remains unclear. Here, we show that surplus fatty acid synthesis in adipocytes induces necroptosis and lipodystrophy. Transcriptional activation of FASN elevates fatty acid synthesis, but decreases NADPH level and increases ROS production, which ultimately leads to adipocyte necroptosis. We identify MED20, a subunit of the Mediator complex, as a negative regulator of FASN transcription. Adipocyte-specific male Med20 knockout mice progressively develop lipodystrophy, which is reversed by scavenging ROS. Further, in a murine model of HIV-associated lipodystrophy and a human patient with acquired lipodystrophy, ROS neutralization significantly improves metabolic disorders, indicating a causal role of ROS in disease onset. Our study well explains the low fatty acid synthesis rate in adipocytes, and sheds light on the management of acquired lipodystrophy.

Abstract Clinical studies have found 14-3-3η to be associated with osteoporosis through undefined mechanisms. We aimed to investigate the role of 14-3-3η in osteoporosis and its potential associations with miRNAs. The Gene Expression Omnibus(GEO) and Human Protein Atlas 1 databases were analyzed to examine both the mRNA and protein expression of 14-3-3η in OP. Gene enrichment analyses were performed to explore the underlying mechanism of 14-3-3η based on DAVID. miRWalk was used to predict the associated miRNAs. The statistics were analysed by R software and SPSS software. 14-3-3η was overexpressed and knock down expressed in BMSCs by lentiviral vector transfecting. And BMSCs were induced by hypoxia. qRT-PCR and Western-Blot verified the expression of mRNA and protein. Scratch assay detected the migration of osteocytes. Co-immunoprecipitation and luciferase assay studied the 14-3-3η targeted protein and miRNA. overexpression and knock down of miRNA to verify the relationship of 14-3-3η and target genes. The 14-3-3η mRNA expression level was low in patients with osteoporosis, as corroborated by immunohistochemical staining images. Functional analyses revealed enrichment of the MAPK-associated cascade. 14-3-3η was correlated with MAPK family proteins and five key miRNAs, including mir-142-3p. In addition, 14-3-3η knockdown in BMSCs increased the mRNA and protein expression levels of Hif-α, VEGF, BMP-2, OPN, OST, and Runx2, and enhanced the cells migration ability. Under hypoxic conditions, Hif-α and BMP-2 protein expression levels were upregulated, whereas those of 14-3-3η and MAPK3 were downregulated. Co-immunoprecipitation experiments showed decreased binding of 14-3-3η to MAPK3. 14-3-3η knockdown produced the same results as hypoxia induction. Adding caspase3 inhibitor and knocking down 14-3-3η again prevented MAPK3 cleavage by caspase3 and inhibited BMP-2 expression. Moreover, under hypoxic conditions, miR-142-3P expression was upregulated and luciferase assays revealed 14-3-3η as its target gene. miR-142-3P overexpression decreased mRNA and protein levels of 14-3-3η and MAPK3, while increasing BMP-2 expression. miR-142-3P knockdown reversed these results. BMSC osteogenesis was suppressed by 14-3-3η, whereas miRNA-142-3p promoted it through the inhibition of 14-3-3η.

Due to the complexity of marine environment, underwater acoustic signal will be affected by complex background noise during transmission. Underwater acoustic signal denoising is always a difficult problem in underwater acoustic signal processing. To obtain a better denoising effect, a new denoising method of underwater acoustic signal based on optimized variational mode decomposition by black widow optimization algorithm (BVMD), fluctuation-based dispersion entropy threshold improved by Otsu method (OFDE), cosine similarity stationary threshold (CSST), BVMD, fluctuation-based dispersion entropy (FDE), named BVMD-OFDE-CSST-BVMD-FDE, is proposed. In the first place, decompose the original signal into a series of intrinsic mode functions (IMFs) by BVMD. Afterwards, distinguish pure IMFs, mixed IMFs and noise IMFs by OFDE and CSST, and reconstruct pure IMFs and mixed IMFs to obtain primary denoised signal. In the end, decompose primary denoising signal into IMFs by BVMD again, use the FDE value to distinguish noise IMFs and pure IMFs, and reconstruct pure IMFs to obtain the final denoised signal. The proposed mothod has three advantages: (i) BVMD can adaptively select the decomposition layer and penalty factor of VMD. (ii) FDE and CS are used as double criteria to distinguish noise IMFs from useful IMFs, and Otsu algorithm and CSST algorithm can effectively avoid the error caused by manually selecting thresholds. (iii) Secondary decomposition can make up for the deficiency of primary decomposition and further remove a small amount of noise. The chaotic signal and real ship signal are denoised. The experiment result shows that the proposed method can effectively denoise. It improves the denoising effect after primary decomposition, and has good practical value.

Mitogen-activated protein kinases (MAPKs) are a group of serine-threonine protein kinases that can be activated by extracellular stimuli. MAPK14 (p38α) affects major disease processes, while inhibition of p38α has been shown to have potential therapeutic effects. Many inhibitors targeting p38α have entered clinical trials but have a long development cycle and severe side effects. We developed a multi-step receptor structure-based virtual screening method to screen potential bioactive molecules from SPECS and our MCDB libraries. Compound 10 was identified as a promising p38α inhibitor that may be used in the treatment of p38αMAPK pathway-related diseases, but corollary studies are warranted.

Abstract BACKGROUND Mutations in the RAS‐MAPK pathway, such as KRAS, NRAS, and BRAF, are known as high‐risk factors associated with poor prognosis in patients with various cancers, but studies in myeloma have yielded mixed results. METHODS We describe the clinicopathologic, cytogenetic, molecular features, and outcomes of 68 patients with RAS/BRAF‐mutated myeloma, and compare with 79 patients without any mutations. RESULTS We show that KRAS, NRAS, and BRAF were mutated in 16%, 11%, and 5% of cases, respectively. RAS/BRAF‐mutated patients had lower hemoglobin and platelet counts, higher levels of serum lactate dehydrogenase and calcium, higher percentage of bone marrow plasma cells, and more advanced R‐ISS stage. RAS/BRAF mutations were associated with complex karyotype and gain/amplification of CKS1B. The median overall survival and progression‐free survival were significantly shorter for RAS/BRAF‐mutated patients (69.0 vs. 220.7 months, p = 0.0023 and 46.0 vs. 60.6 months, p = 0.0311, respectively). Univariate analysis revealed that KRAS mutation, NRAS mutation, lower hemoglobin, elevated lactate dehydrogenase, higher R‐ISS stage, complex karyotype, gain/amplification of CKS1B, monosomy 13/RB1 deletion and lack of autologous stem cell transplantation were associated with poorer prognosis. Multivariate analysis showed that KRAS mutation, lower hemoglobin level, higher level of serum calcium, higher ISS stage, and lack of autologous stem cell transplantation predict inferior outcome. CONCLUSIONS RAS/BRAF mutations occur in 30%–40% of myeloma cases and are associated with higher tumor burden, higher R‐ISS stage, complex karyotype, and shorter overall survival and progression‐free survival. These findings support testing for RAS/BRAF mutations in myeloma patients and underscore the potential therapeutic benefits of RAS/BRAF inhibitors.

IntroductionOur previous studies have demonstrated that tumor-infiltrating lymphocytes (TILs), including normal B cells, T cells, and natural killer (NK) cells, in diffuse large B-cell lymphoma (DLBCL) have a significantly favorable impact on the clinical outcomes of patients treated with standard chemoimmunotherapy. In this study, to gain a full overview of the tumor immune microenvironment (TIME), we assembled a flow cytometry cohort of 102 patients diagnosed with DLBCL at the Duke University Medical Center.MethodsWe collected diagnostic flow cytometry data, including the proportion of T cells, abnormal B cells, normal B cells, plasma cells, NK cells, monocytes, and granulocytes in fresh biopsy tissues at clinical presentation, and analyzed the correlations with patient survival and between different cell populations.ResultsWe found that low T cell percentages in all viable cells and low ratios of T cells to abnormal B cells correlated with significantly poorer survival, whereas higher percentages of normal B cells among total B cells (or high ratios of normal B cells to abnormal B cells) and high percentages of NK cells among all viable cells correlated with significantly better survival in patients with DLBCL. After excluding a small number of patients with low T cell percentages, the normal B cell percentage among all B cells, but not T cell percentage among all cells, continued to show a remarkable prognostic effect. Data showed significant positive correlations between T cells and normal B cells, and between granulocytes and monocytes. Furthermore, we constructed a prognostic model based on clinical and flow cytometry factors, which divided the DLBCL cohort into two equal groups with remarkable differences in patient survival and treatment response.SummaryTILs, including normal B cells, T cells, and NK cells, are associated with favorable clinical outcomes in DLBCL, and flow cytometry capable of quantifying the TIME may have additional clinical utility for prognostication.

AIM: To investigate the clinical efficacy of pars plana vitrectomy(PPV)combined with inverted internal limiting membrane flap technique in the treatment of macular hole retinal detachment(MHRD)in high myopia.METHODS: A retrospective clinical study was conducted. A total of 63 patients(64 eyes)with high myopia and MHRD who treated at our hospital from October 2017 to October 2021 were selected as research subjects. They were divided into two groups according to different surgery, with 34 cases(35 eyes)who received PPV combined with inverted internal limiting membrane flap technique in group A, and 29 cases(29 eyes)received PPV combined with internal limiting membrane peeling in group B. The patients were followed up for 6mo. The two groups were compared in terms of the hole closure rate, the reduction rate of retinal detachment and best corrected visual acuity(BCVA)before operation and at 1wk, 1, 3 and 6mo after operation, and the postoperative complications were recorded.RESULTS: The hole closure rate within 6mo after operation was significantly higher in group A than in group B(P0.05). The BCVA of the two groups was significantly improved over time after operation(P0.05). Complications were observed in the two groups, but there was no statistically significant difference in the incidence of complications between the two groups(P

Obesity has become a global pandemic. WDTC1 is a WD40-containing protein that functions as an anti-obesity factor. WDTC1 inhibits adipogenesis by working as an adaptor of the CUL4-DDB1 E3 ligase complex. It remains unclear about how WDTC1 is regulated. Here, we show that the TRiC/CCT functions as a chaperone to facilitate the protein folding of WDTC1 and proper function in adipogenesis. Through tandem purification, we identified the molecular chaperone TRiC/CCT as WDTC1-interacting proteins. WDTC1 bound the TRiC/CCT through its ADP domain, and the TRiC/CCT recognized WDTC1 through the CCT5 subunit. Disruption of the TRiC/CCT by knocking down CCT1 or CCT5 led to misfolding and lysosomal degradation of WDTC1. Furthermore, the knockdown of CCT1 or CCT5 eliminated the inhibitory effect of WDTC1 on adipogenesis. Our studies uncovered a critical role of the TRiC/CCT in the folding of WDTC1 and expanded our knowledge on the regulation of adipogenesis.