Stimuli-sensitive biomimetic nanoparticles for the inhibition of breast cancer recurrence and pulmonary metastasis.

Biomimetic nanoparticles represent a promising avenue for mitigating rapid clearance by the reticuloendothelial system (RES); however, current challenges include insufficient tumour targeting, suboptimal adhesion, and inadequate localized drug release within tumour regions. These shortcomings contribute to persistent contests, such as recurrence and pulmonary metastasis, even with advanced breast cancer therapies. Stimuli-sensitive drug release can furbish the membrane coated nanoparticles for their efficiency against the stated problems. To enhance the efficacy of biomimetic nanoparticles in addressing these issues, we proposed a versatile, stimuli-responsive drug delivery system by encapsulating doxorubicin (Dox) and perfluorohexane (PFH) within poly (lactic-co-glycolic acid) (PLGA) nanoparticles, subsequently coated with macrophage-derived cell membranes. Within this framework, PFH serves as the mediator for ultrasonic (US)-irradiation-triggered drug release specifically within tumour microenvironment, while the macrophage-derived cell membrane coating enhances cell adhesion, enables immune evasion, and natural tumour-homing ability. The characterization assays and in vitro evaluations yielded encouraging results, indicating enhanced targeting and release efficiencies. In vivo studies demonstrated marked inhibitory effects on both breast cancer recurrence and pulmonary metastasis. The resulting data indicate that these engineered nanoparticles have notable potential for targeted delivery and controlled release upon US irradiation, thereby offering significant therapeutic efficacy against primary breast cancer, pulmonary metastasis, and recurrent malignancies. Our findings lay the groundwork for a novel clinical approach, representing an intriguing direction for ongoing investigation by oncologists.

Early administration of Wumei Wan inhibit myeloid-derived suppressor cells via PI3K/Akt pathway and amino acids metabolism to prevent Colitis-associated Colorectal Cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Wumei Wan (WMW), a traditional Chinese medicine prescription, has been proved to be effective in treating Colitis-associated colorectal cancer (CAC), but it has not been proven to be effective in different stages of CAC. AIM OF THE STUDY: The purpose of our study is to investigate the therapeutic effect and mechanism of WMW on the progression of CAC. MATERIALS AND METHODS: Azioximethane (AOM) and dextran sulfate sodium (DSS) were used to treat mice for the purpose of establishing CAC models. WMW was administered in different stages of CAC. The presentative chemical components in WMW were confirmed by UHPLCQTOF/MS under the optimized conditions. The detection of inflammatory cytokines in the serum and colon of mice were estimated by qRT-PCR and ELISA. The changes of T cells and myeloid-derived suppressor cells (MDSCs) in each group were detected by flow cytometry. The metabolic components in serum of mice were detected by UPLC-MS/MS. Expression of genes and proteins were detected by eukaryotic transcriptomics and western blot to explore the key pathway of WMW in preventing CAC. RESULTS: WMW had significant effect on inhibiting inflammatory responses and tumors during the early development stage of CAC when compared to other times. WMW increased the length of mice's colons, reduced the level of IL-1ß, IL-6, TNF-α in colon tissues, and effectively alleviated colonic inflammation, and improved the pathological damage of colon tissues. WMW could significantly reduce the infiltration of MDSCs in the spleen, increase CD4+ T cells and CD8+ T cells in the spleen of CAC mice, and effectively reform the immune microenvironment in CAC mice. Transcriptomics analysis revealed that 2204 genes had different patterns of overlap in the colon tissues of mice between control group, AOM+DSS group, and early administration of WMW group. And KEGG enrichment analysis showed that PI3K/Akt signaling pathway, ECM-receptor interaction, IL-17 signaling pathway, MAPK signaling pathway, pancreatic secretion, thermogenesis, and Rap1 signaling pathway were all involved. The serum metabolomics results of WMW showed that the metabolic compositions of the control group, AOM+DSS group and the early stage of WMW were different, and 42 differential metabolites with the opposite trends of changes were screened. The metabolic pathways mainly included pyrimidine metabolism, glycine, serine and threonine metabolism, tryptophan metabolism, and purine metabolism. And amino acids and related metabolites may play an important role in WMW prevention of CAC. CONCLUSION: WMW can effectively prevent the occurrence and development of CAC, especially in the initial stage. WMW can reduce the immune infiltration of MDSCs in the early stage. Early intervention of WMW can improve the metabolic disorder caused by AOM+DSS, especially correct the amino acid metabolism. PI3K/Akt signaling pathway was inhabited in early administration of WMW, which can regulate the amplification and function of MDSCs.

Establishment of an Experimental Mouse Model of Endometrioma to Study its Related Infertility.

Endometrioma (OMA), a subtype of endometriosis characterized by the formation of endometriotic cysts in the ovaries, affects 17-44% of individuals diagnosed with endometriosis. Women with OMA often experience compromised fertility, yet the exact mechanisms underlying OMA-associated infertility remain unclear. Notably, existing animal models simulate superficial peritoneal endometriosis (SUP) and deep infiltrating endometriosis (DIE), leaving a notable gap in research focused on OMA. In response to the gap of knowledge, this paper introduces a pioneering OMA-simulating mouse model and provides a comprehensive description of the techniques and procedures employed in the model. With a high success rate of 83% and ovarian lesion specificity, this model holds significant promise for advancing our understanding of OMA, particularly in the context of infertility. It offers a valuable platform for conducting targeted research into OMA-associated fertility challenges, potentially paving the way for improved diagnostic and therapeutic strategies in the field of reproductive medicine.

Elucidation of Spatial Cooperativity in Chemo-Immunotherapy by a Sequential Dual-pH-Responsive Drug Delivery System.

Combining immune checkpoint blockade with chemotherapy through nanotechnology is promising in terms of safety and efficacy. However, the distinct subcellular distribution of each ingredient's action site makes it challenging to acquire an optimal synergism. Herein, a dual-pH responsive hybrid polymeric micelle system, HNP(αPDL16.9, Dox5.3), is constructed as a proof-of-concept for the spatial cooperativity in chemo-immunotherapy. HNP retains the inherent pH-transition of each polymer, with stepwise disassembly under discrete pH thresholds. Within weakly acidic extracellular tumor environment, αPDL1 is first released to block the checkpoint on cell membranes. The remaining intact Doxorubicin-loaded micelle NP(Dox)5.3 displays significant tropism toward tumor cells and releases Dox upon lysosomal pH for efficient tumor immunogenic cell death without immune toxicity. This sequential-released pattern boosts DC activation and primes CD8+ T cells, leading to enhanced therapeutic performance than single agent or an inverse-ordered combination in multiple murine tumor models. Using HNP, the indispensable role of conventional type 1 DC (cDC1) is identified in chemo-immunotherapy. A co-signature of cDC1 and CD8 correlates with cancer patient survival after neoadjuvant Pembrolizumab plus chemotherapy in clinic. This study highlights spatial cooperativity of chemo- and immuno-agents in immunoregulation and provides insights into the rational design of drug combination for future nanotherapeutics development.

Healthy Lifestyle and the Risk of Metabolic Dysfunction-Associated Fatty Liver Disease: A Large Prospective Cohort Study.

Background: The incidence density of metabolic dysfunction-associated fatty liver disease (MAFLD) and the effect of a healthy lifestyle on the risk of MAFLD remain unknown. We evaluated the prevalence and incidence density of MAFLD and investigated the association between healthy lifestyle and the risk of MAFLD. Methods: A cross-sectional analysis was conducted on 37,422 participants to explore the prevalence of MAFLD. A cohort analysis of 18,964 individuals was conducted to identify the incidence of MAFLD, as well as the association between healthy lifestyle and MAFLD. Cox proportional hazards regression was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) with adjustments for confounding factors. Results: The prevalence of MAFLD, non-alcoholic fatty liver disease, and their comorbidities were 30.38%, 28.09%, and 26.13%, respectively. After approximately 70 thousand person-years of follow-up, the incidence densities of the three conditions were 61.03, 55.49, and 51.64 per 1,000 person-years, respectively. Adherence to an overall healthy lifestyle was associated with a 19% decreased risk of MAFLD (HR, 0.81; 95% CI, 0.72 to 0.92), and the effects were modified by baseline age, sex, and body mass index (BMI). Subgroup analyses revealed that younger participants, men, and those with a lower BMI experienced more significant beneficial effects from healthy lifestyle. Conclusion: Our results highlight the beneficial effect of adherence to a healthy lifestyle on the prevention of MAFLD. Health management for improving dietary intake, physical activity, and smoking and drinking habits are critical to improving MAFLD.

Cardiac Resolvin D2 ameliorates sepsis-induced cardiomyopathy via inhibiting Caspase-11/GSDMD dependent pyroptosis.

BACKGROUND: Sepsis-induced cardiomyopathy (SICM) is common complication in septic patients with a high mortality and is characterized by an abnormal inflammation response, which was precisely regulated by endogenous specialized pro-resolving mediators (SPMs). However, the metabolic changes of cardiac SPMs during SICM and the roles of SPMs subset in the development of SICM remain unknown. METHODS: In this work, the SPMs concentration was assessed using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) of SICM mice and SICM patients. The cardiac function was measured by echocardiography after the treatment of a SPMs subset, termed Resolvin D2 (RvD2). Caspase-11-/-, GSDMD-/- and double deficient (Caspase-11-/-GSDMD-/-) mice were used to clarify the mechanisms of RvD2 in SICM. RESULTS: We found that endogenous cardiac SPMs were disorders and RvD2 was decreased significantly and correlated with left ventricular ejection fraction (LVEF) and ß-BNP, cTnT in Lipopolysaccharide/Cecum ligation and puncture (CLP) induced SICM models. Treatment with RvD2 attenuated lethality, cardiac dysfunction and cardiomyocytes death during SICM. Mechanistically, RvD2 alleviated SICM via inhibiting Caspase-11/GSDMD-mediated cardiomyocytes pyroptosis. Finally, the plasma levels of RvD2 were also decreased and significantly correlated with IL-1ß, ß-BNP, cTnT and LVEF in patients with SICM. Of note, plasma RvD2 level is indicator of SICM patients from healthy controls or sepsis patients. CONCLUSION: These findings suggest that decreased cardiac RvD2 may involve in the pathogenesis of SICM. In addition, treatment with RvD2 represents a novel therapeutic strategy for SICM by inhibiting cardiomyocytes pyroptosis.

Accumulation of circulating myeloid-derived suppressor cell subsets: predicting poor clinical efficacy and prognosis through T cell suppression in non-Hodgkin's lymphoma.

Myeloid-derived suppressor cells (MDSC) are implicated in the regulation of immune responses closely associated with poor clinical outcomes in cancer. However, the MDSC subtypes in non-Hodgkin's Lymphoma (NHL) has not been systematically investigated. So we investigated the percentage of MDSC subsets in 78 newly diagnosed NHL patients by flow cytometry. The results showed that all MDSC subsets increased in NHL patients compared to healthy donors. Notably, MDSC, M-MDSC, and CD14+CD66b+MDSC significantly increased in NHL patients compared to those with lymphadenitis. PMN-MDSC, e-MDSC and IPI were independent risk factors for poor clinical efficacy and were involved in constructing the nomogram for predicting clinical efficacy. Progression-free survival (PFS) was significantly shorter in patients with high level of MDSC subsets, and PMN-MDSC emerged as an independent prognostic factor for PFS. PMN-MDSC, e-MDSC and IPI were involved in constructing the nomogram for predicting PFS. Patients with a higher percentage of MDSC, PMN-MDSC, e-MDSC, and CD14+CD66b+MDSC experienced a shorter OS compared to those with lower percentages. In addition, research on mechanisms found that T cell function was suppressed and mediated by the expansion of MDSC via involving Arg-1 and IL-10 in vitro and in vivo. In conclusion, our study demonstrates that the increased circulating MDSC subsets predict poor clinical efficacy and prognosis in NHL, potentially involving T cell suppression through MDSC subsets expansion. These findings indicate the potential of MDSC subsets as comprehensive diagnostic, prognostic biomarkers, and therapeutic targets for NHL.

ZMIZ2 facilitates hepatocellular carcinoma progression via LEF1 mediated activation of Wnt/ß-catenin pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies with a high lethality rate. ZMIZ2 is a transcriptional co-activator implicated in various human diseases. However, the role and molecular mechanism of ZMIZ2 in HCC remains to be elucidated. METHODS: The expression and prognostic value of ZMIZ2 in HCC was excavated from public databases and explored by bioinformatic analysis. Then the expression of ZMIZ2 and related genes was further validated by quantitative RT-PCR, western blotting, and immunohistochemistry. Loss and gain-of-function experiments were performed in vitro and in vivo to investigate the function of ZMIZ2 in HCC. In addition, transcriptome sequencing and immunoprecipitation was conducted to explore the potential molecular mechanisms of ZMIZ2. RESULTS: ZMIZ2 was highly expressed in HCC and associated with poor prognosis. Silencing ZMIZ2 significantly inhibited HCC cell proliferation, cell cycle process, migration, and invasion in vitro, and also inhibited the progression of HCC in vivo. Additionally, ZMIZ2 expression was correlated with immune cell infiltration in HCC samples. Somatic mutation analysis showed that ZMIZ2 and TP53 mutations jointly affected the progression of HCC. Mechanistically, ZMIZ2 interacted with LEF1 to regulate malignant progression of HCC by activating the Wnt/ß-catenin pathway. CONCLUSION: ZMIZ2 was overexpressed in HCC and associated with poor prognosis. The overexpression of ZMIZ2 was corelated with malignant phenotype, and it facilitated HCC progression via LEF1-mediated activation of the Wnt/ß-catenin pathway. Furthermore, ZMIZ2 could be served as a prognostic biomarker and a new therapeutic target for HCC.

Liposomal Bupivacaine Use During Orthognathic Surgery in Cleft Lip and Palate Patients.

INTRODUCTION: Effective pain management is crucial in cleft lip and palate (CLP) patients undergoing orthognathic surgery for earlier recovery and decreased opioid reliance. Liposomal bupivacaine (Exparel) is a local anesthetic that provides extended postoperative analgesia in adult patients; however, research on its use in adolescents is limited. This study explores the efficacy of liposomal bupivacaine for postoperative pain management in adolescent CLP patients undergoing orthognathic surgery. METHODS: The authors performed a retrospective chart review at their institution between July 2020 and December 2022 to identify patients who underwent LeFort I or mandibular osteotomy. Two cohorts were compared: patients who received liposomal bupivacaine and patients who received standard pain medications alone. Outcome measures included intraoperative pain medications, length of stay, breakthrough opioid use, time to first oral intake, volume of oral intake, and opioids prescribed at discharge. RESULTS: This study included 22 patients who underwent orthognathic surgery. The liposomal bupivacaine group (n=10) demonstrated earlier and greater oral intake during hospitalization compared with controls (n=12). The most significant difference was observed in total breakthrough opioid use, with an average of 8.60 morphine milligram equivalents for liposomal bupivacaine patients compared with 35.1 morphine milligram equivalents for controls (P=0.037). CONCLUSIONS: This study provides the first analysis of liposomal bupivacaine use in adolescent CLP patients undergoing orthognathic surgery, demonstrating a significant reduction in postoperative opioid consumption compared with controls. These results may guide future studies of liposomal bupivacaine within CLP patients, potentially as a component of enhanced recovery after surgery guidelines, as well as in cost-analysis studies.

Biomaterial-assisted strategies to improve islet graft revascularization and transplant outcomes.

Islet transplantation holds significant promise as a curative approach for type 1 diabetes (T1D). However, the transition of islet transplantation from the experimental phase to widespread clinical implementation has not occurred yet. One major hurdle in this field is the challenge of insufficient vascularization and subsequent early loss of transplanted islets, especially in non-intraportal transplantation sites. The establishment of a fully functional vascular system following transplantation is crucial for the survival and secretion function of islet grafts. This vascular network not only ensures the delivery of oxygen and nutrients, but also plays a critical role in insulin release and the timely removal of metabolic waste from the grafts. This review summarizes recent advances in effective strategies to improve graft revascularization and enhance islet survival. These advancements include the local release and regulation of angiogenic factors (e.g., vascular endothelial growth factor, VEGF), co-transplantation of vascular fragments, and pre-vascularization of the graft site. These innovative approaches pave the way for the development of effective islet transplantation therapies for individuals with T1D.

Gastric Ganglioneuroblastoma in an Elderly man: A Case Report and Literature Review.

Background. Ganglioneuroblastoma is a borderline tumor of sympathetic origin that is considered a childhood disease, with the majority of patients occurring in children less than five years old and few patients occurring in adults. There are no treatment guidelines for adult ganglioneuroblastoma. Here, we report a rare patient of adult gastric ganglioneuroblastoma that was completely resected by a laparoscopic approach. Case presentation. A 73-year-old man presented with dull pain in the upper abdomen along with abdominal distension for one month. Gastroscopy examination revealed chronic gastritis and submucosal tumors of the gastric antrum. Endoscopic ultrasonography showed a hypoechoic mass in the gastric antrum arising from the muscularis propria. An abdominal computed tomography scan revealed an irregular soft tissue mass in the gastric antrum with heterogeneous enhancement in the arterial phase. The mass was completely resected by laparoscopic surgery. Postoperative histopathology revealed that the mass contained differentiated neuroblasts, mature ganglion cells and ganglioneuroma components. The pathological diagnosis was ganglioneuroblastoma intermixed, and the patient was determined to be in stage I. The patient received no adjuvant chemotherapy or radiotherapy. At his two-year follow-up, the patient was doing well and showed no signs of recurrence. Conclusion. Despite the rarity of gastric ganglioneuroblastoma as a primary site of origin, it should be considered in the differential diagnosis of gastric masses in adults. Radical surgery is sufficient for the treatment of ganglioneuroblastoma intermixed, and long-term follow-up should be performed.

RBM45 reprograms lipid metabolism promoting hepatocellular carcinoma via Rictor and ACSL1/ACSL4.

Reprogramming of lipid metabolism during hepatocarcinogenesis is not well elucidated. Here, we aimed to explore pivotal RNA-binding motif proteins (RBMs) in lipid metabolism and their therapeutic potential in hepatocellular carcinoma (HCC). Through bioinformatic analysis, we identified RBM45 as a critical gene of interest among differentially expressed RBMs in HCC, with significant prognostic relevance. RBM45 influenced the malignant biological phenotype and lipid metabolism of HCC cells. Mechanically, RBM45 promotes de novo lipogenesis in HCC by directly targeting two key enzymes involved in long-chain fatty acid synthesis, ACSL1 and ACSL4. RBM45 also targets Rictor, which has been demonstrated to modulate lipid metabolism profoundly. RBM45 also aided lipid degradation through activating a key fatty acid ß oxidation enzyme, CPT1A. Thus, RBM45 boosted lipid synthesis and decomposition, indicating an enhanced utility of lipid fuels in HCC. Clinically, body mass index was positively correlated with RBM45 in human HCCs. The combination of a PI3K/AKT/mTOR pathway inhibitor in vitro or Sorafenib in orthotopic liver cancer mouse models with shRBM45 has a more significant therapeutic effect on liver cancer than the drug alone. In summary, our findings highlight the versatile roles of RBM45 in lipid metabolism reprogramming and its therapeutic potential in HCC. Lipids induced RBM45 expression. In turn, RBM45 promoted the utility of lipid in HCCs through accelerating both de novo lipogenesis and fatty acid ß oxidation, which required the participation of Rictor, a core component of mTORC2 that has been demonstrated to modulate lipid metabolism potently, as well as ACSL1/ACSL4, two key enzymes of long-chain fatty acid synthesis. When the first-line chemotherapy drug sorafenib is combined with a PI3K/AKT/mTOR pathway inhibitor (MK2206 is an AKT inhibitor, rapamycin is a mTOR inhibitor, and inhibiting RBM45 can significantly inhibit Rictor), cell cycle, proliferation, lipid metabolism reprogramming, and hepatocarcinogenesis can be significantly inhibited, while apoptosis can be significantly enhanced.

Selected pesticidal POPs and metabolites in the soil of five Vietnamese cities: Sources, fate, and health risk implications.

Large quantities of organochlorine pesticides (OCPs) have been used in tropical regions. The fate processes and risks of these legacy contaminants in the tropics are poorly understood. Herein, we investigated the occurrence of three classes of widely used OCPs and their metabolites in surface and core soil from five cities across Vietnam with a prevalent tropical monsoon climate and a long history of OCP application. We aimed to elucidate migration potentials, degradation conditions, and transformation pathways and assess current health risks of these contaminants. Generally, the concentrations of OCPs and metabolites in the soil core were slightly lower than those in surface soil except for hexachlorocyclohexane (HCH) isomers. 2,2-bis(4-chlorophenyl)-1,1,1-trichloroethane (p,p'-DDT), 2,2-bis(4-chlorophenyl)-1,1-dichloroethylene (p,p'-DDE), the sum of dicofol and 4,4'-dichlorobenzophenone (p,p'-DBP), and 2,2-bis(4-chlorophenyl)-1,1-dichloroethane (p,p'-DDD) were the most abundant compounds in both surface and core soils. A uniform distribution of HCHs (the sum of α-, ß-, γ-, and δ-HCH) at trace levels was found in almost all soils, serving as evidence of the lack of recent use of HCH pesticides. Higher concentrations of DDTs (the sum of DDT, DDD, and DDE) were observed in north-central Vietnamese soil, whereas appreciable concentrations of ENDs (the sum of α- and ß-endosulfan and endosulfan sulfate) were only found in southern Vietnamese soils. Empirical diagnostic ratios indicated residuals of DDTs were mainly from technical DDT rather than dicofol, whereas aged HCHs could be explained by the mixture of lindane and technical HCH. Both historical applications and recent input explain DDTs and ENDs in Vietnamese soil. Total organic carbon performs well in preventing vertical migration of more hydrophobic DDTs and ENDs. The dominant transformation pathway of DDT in surface soil followed p,p'-DDE→2,2-bis(4-chlorophenyl)-1-chloroethylene or p,p'-DDMU→1,1-bis(4-chlorophenyl)ethylene or p,p'-DDNU→p,p'-DBP, whereas the amount of p,p'-DDMU converted from p,p'-DDD and p,p'-DDE is similar in soil core. Non-cancer risks of OCPs and metabolites in all soils and cancer risks of those chemicals in core soils were below the safety threshold, whereas a small proportion of surface soil exhibited potential cancer risk after considering the exposure pathway of vegetable intake. This study implied that organic matter in non-rainforest tropical deep soils still could hinder the leaching of hydrophobic organic contaminants as in subtropical and temperate soils. When lands with a history of OCP application are used for agricultural purposes, dietary-related risks need to be carefully assessed.

Efficient pulmonary lymphatic drainage is necessary for inflammation resolution in ARDS.

The lymphatic vasculature is the natural pathway for the resolution of inflammation, yet the role of pulmonary lymphatic drainage function in sepsis-induced acute respiratory distress syndrome (ARDS) remains poorly characterized. In this study, indocyanine green-near infrared lymphatic living imaging was performed to examine pulmonary lymphatic drainage function in septic mouse models. We found that the pulmonary lymphatic drainage was impaired owing to the damaged lymphatic structure in sepsis-induced ARDS. Moreover, prior lymphatic defects by blocking vascular endothelial growth factor receptor-3 (VEGFR-3) worsened sepsis-induced lymphatic dysfunction and inflammation. Posttreatment with vascular endothelial growth factor-C (Cys156Ser) (VEGF-C156S), a ligand of VEGFR-3, ameliorated lymphatic drainage by rejuvenating lymphatics to reduce the pulmonary edema and promote draining of pulmonary macrophages and neutrophils to pretracheal lymph nodes. Meanwhile, VEGF-C156S posttreatment reversed sepsis-inhibited CC chemokine ligand 21 (CCL21), which colocalizes with pulmonary lymphatic vessels. Furthermore, the advantages of VEGF-C156S on the drainage of inflammatory cells and edema fluid were abolished by blocking VEGFR-3 or CCL21. These results suggest that efficient pulmonary lymphatic drainage is necessary for inflammation resolution in ARDS. Our findings offer a therapeutic approach to sepsis-induced ARDS by promoting lymphatic drainage function.

Pediatric Craniofacial Tumor Reconstruction.

Effective management of pediatric craniofacial tumors requires coordinated input from medical, oncologic, and surgical specialties. Reconstructive algorithms must consider limitations in pediatric donor tissue and account for future growth and development. Immediate reconstruction is often focused on filling dead space, protecting underlying structures, and ensuring skeletal symmetry. Staged reconstruction occurs after the patient has reached skeletal maturity and is focused on restoring permanent dentition. Reconstructive options vary depending on the location, size, and composition of resected tissue. Virtual surgical planning (VSP) reduces the complexity of pediatric craniofacial reconstruction and ensures more predictable outcomes.

Seminars in Plastic Surgery: Pediatric Ear Anomalies and Reconstruction.

Congenital ear anomalies affect 15 to 20% of neonates and can be categorized as either auricular deformations or malformations. Deformations involve a fully developed, albeit abnormally shaped, chondrocutaneous framework, which makes them amenable to correction with ear molding within the first few months of life. Malformations involve hypoplastic or fully absent auricular structures that require augmentation with alloplastic and/or autogenous reconstruction. The goal of this article is to outline the various auricular deformities and malformations, followed by a description of the latest clinical management options, both nonsurgical and surgical, by auricular anomaly.

miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor.

The activation of hepatic stellate cells (HSCs) is regarded as the primary driving factor of liver fibrosis. miR-192, a miRNA associated with hepatocellular carcinoma and enriched in HSCs, has an undisclosed role in HSC activation and liver fibrosis. In this study, a CCl4-induced rat liver fibrosis model and transforming growth factor-beta 1 (TGF-ß1)-treated HSC lines (LX-2 and HSC-T6) were used to detect miR-192 and Rictor levels in vivo and in vitro. Bioinformatic analysis and a dual luciferase assay were used to predict and confirm the interaction of Rictor with miR-192. Gain- and/or loss-of-function methods evaluated molecular changes and HSC activation phenotypes, detected by quantitative real-time PCR, western blotting, and immunofluorescence. We observed a gradual downregulation of miR-192 and upregulation of Rictor during CCl4-induced liver fibrosis/cirrhosis in rats. Enriched miR-192 was downregulated, while Rictor was upregulated in TGF-ß1-activated HSCs. miR-192 inhibited the activation of HSCs by directly targeting Rictor. High miR-192/low Rictor expression attenuated the fibrotic-related gene expression by AKT/mTORC2 signaling. In conclusion, miR-192 could inhibit the activation of HSCs by directly targeting Rictor in the AKT/mTORC2 signaling pathway. This study provides insights into potential therapeutic targets for liver fibrosis and cirrhosis.

Rictor mediates p53 deactivation to facilitate the malignant transformation of hepatocytes and promote hepatocarcinogenesis.

BACKGROUND: Mutations in TP53 gene is considered a main driver of hepatocellular carcinoma (HCC). While TP53 mutations are the leading cause of p53 dysfunction, their occurrence rates may drop to approximately 10% in cohorts without hepatitis B virus and aflatoxin exposure. This observation suggests that the deactivation of wild-type p53 (p53wt) may be a critical factor in the majority of HCC cases. However, the mechanism undermining p53wt activity in the liver remains unclear. METHODS: Microarray analysis and luciferase assay were utilized to confirm target associations. Gain- and/or loss-of-function methods were employed to assess alterations in signaling pathways. Protein interactions were analyzed by molecular immunological methods and further visualized by confocal microscopy. Bioinformatic analysis was performed to analyze clinical significance. Tumor xenograft nude mice were used to validate the findings in vivo. RESULTS: Our study highlights the oncogenic role of Rictor, a key component of the mammalian target of rapamycin complex 2 (mTORC2), in hepatocytes. Rictor exerts its oncogenic function by binding to p53wt and subsequently blocking p53wt activity based on p53 status, requiring the involvement of mTOR. Moreover, we observed a dynamic nucleocytoplasmic distribution pattern of Rictor, characterized by its translocation from the nucleus (in precancerous lesions) to the cytoplasm (in HCCs) during malignant transformation. Notably, Rictor is directly targeted by the liver-enriched microRNA miR-192, and the disruption of the miR-192-Rictor-p53-miR-192 signaling axis was consistently observed in both human and rat HCC models. Clinical analysis associated lower miR-192/higher Rictor with shorter overall survival and more advanced clinical stages (P < 0.05). In mice, xenograft tumors overexpressing miR-192 exhibited lower Rictor expression levels, leading to higher p53 activity, and these tumors displayed slower growth compared to untreated HCC cells. CONCLUSIONS: Rictor dynamically shuttles between the nucleus and cytoplasm during HCC development. Its pivotal oncogenic role involves binding and inhibiting p53wt activity within the nucleus in early hepatocarcinogenesis. Targeting Rictor presents a promising strategy for HCC based on p53 status.

Successful Treatment of Granulomatous Rosacea by JAK Inhibitor Abrocitinib: A Case Report.

Granulomatous rosacea (GR) is a rare inflammatory skin disease characterized by persistent, hard, yellow, brown, red, or flesh-colored papules, plaques, or nodules on the face. Limited data are available on patients treated for GR, with only case reports and case series published. Herein, we describe the case of a 53-year-old woman who presented to the hospital with persistent red to brown and pink patches on both cheeks accompanied by a burning sensation for one month. Histopathological examination of a cutaneous biopsy revealed granulomatous inflammation in focal areas. Both acid-fast and Periodic acid-Schiff staining were negative. The patient was diagnosed with GR based on her clinical presentation and laboratory test results. She was treated with abrocitinib, a JAK-1 inhibitor, for 20 weeks. This resulted in substantial improvement in her rash and the associated burning sensation. Subsequent follow-up visits indicated no adverse effects or relapses. Additionally, a literature review was conducted to compare with the current case, which concluded that abrocitinib is a viable treatment option for GR, exhibiting a relatively high safety profile with minimal side effects.

Enzyme-Silenced Nanosponges Prolong Intratumoral Lifetime to Facilitate Intercellular Relay Drug Delivery and Treatment Efficacy.

The clinical application of nanomedicines faces the dilemma of improved safety but restricted efficacy due to the poor intratumoral bioavailability of chemotherapeutics. We here design an enzyme-silenced nanosponge that shares a long-term lifespan to reversibly exhale/inhale doxorubicin (DOX) for continuous intercellular relay delivery and improved intratumoral retention. The nanosponge is composed of a cationic lipid overlaying a hyaluronic acid derivative polyampholyte core for enveloping of DOX and hyaluronidase-1-targeted siRNA (siHyal1), and a lipoprotein shell decorated with fusion peptide 4F-tLyP-1 that was fused with apolipoprotein A-I (apoA-I) mimetic peptide 4F and tLyP-1 for tumor homing and extravasation into the tumor interstitium. Triggered by the intra/intercellular pH variation, the nanosponge core could reversibly swell in endo/lysosome (pH 5.0) for DOX release. Owing to the deprotonation, the nanosponge core shrinks back in cytoplasm (pH 7.4) for DOX reloading and continues the behavior after being secreted to the extracellular matrix (pH 6.8) via Golgi apparatus, which dramatically improves intratumoral DOX retention and availability. Concurrently, the intratumoral lifespan of the nanosponge is prolonged by siHyal1-specific silencing, ensuring spatiotemporal consistency of carrier and drug when shuttling multilayer tumor cells. As a result, the nanosponge achieves efficient tumor inhibition in 99.1% of tumor spheroids and 80.1% of orthotopic tumor models. Collectively, this study provides an intelligent nanosponge design for active intercellular relay drug delivery, achieving improved intratumoral bioavailability of drugs and amplified chemotherapy on solid tumors.