Clinical chemotherapy for prostate cancer is still compromised by high treatment thresholds and severe off-target toxicity of drugs. Given the limited progress in improving therapeutic outcomes and reducing toxicity with the existing toolbox, efforts to broaden the chemotherapeutic window are highly desired. Here, we discover that gossypol (GSP, a natural compound) dramatically enhances the chemosensitivity of cabazitaxel (CTX), even at previously ineffective concentrations. Based on this interesting finding, we exploit a carrier-free chemotherapeutic nano-booster for prostate cancer treatment, which is molecularly co-assembled by GSP and cabazitaxel (CTX). GSP not only readily forms nanoassembly with CTX, but also functions as a chemotherapeutic enhancer that unlocks an ultra-low-dose chemotherapeutic window. Not only that, precise dual-drug nanoassembly confers CTX a significantly larger maximum tolerable dose. As expected, the nano-booster exerts striking therapeutic benefits in mouse prostate tumor xenograft models. This study advances chemotherapeutic window expansion and self-sensitized chemotherapy toward clinical applicability.

Periodontal bone defects, primarily caused by periodontitis, are highly prevalent in clinical settings and manifest as bone fenestration, dehiscence, or attachment loss, presenting a significant challenge to oral health. In regenerative medicine, harnessing developmental principles for tissue repair offers promising therapeutic potential. Of particular interest is the condensation of progenitor cells, an essential event in organogenesis that has inspired clinically effective cell aggregation approaches in dental regeneration. However, the precise cellular coordination mechanisms during condensation and regeneration remain elusive. Here, taking the tooth as a model organ, we employed single-cell RNA sequencing to dissect the cellular composition and heterogeneity of human dental follicle and dental papilla, revealing a distinct Platelet-derived growth factor receptor alpha (PDGFRA) mesenchymal stem/stromal cell (MSC) population with remarkable odontogenic potential. Interestingly, a reciprocal paracrine interaction between PDGFRA⁺ dental follicle stem cells (DFSCs) and CD31⁺ Endomucin⁺ endothelial cells (ECs) was mediated by Vascular endothelial growth factor A (VEGFA) and Platelet-derived growth factor subunit BB (PDGFBB). This crosstalk not only maintains the functionality of PDGFRA⁺ DFSCs but also drives specialized angiogenesis. In vivo periodontal bone regeneration experiments further reveal that communication between PDGFRA⁺ DFSC aggregates and recipient ECs is essential for effective angiogenic-osteogenic coupling and rapid tissue repair. Collectively, our results unravel the importance of MSC-EC crosstalk mediated by the VEGFA and PDGFBB-PDGFRA reciprocal signaling in orchestrating angiogenesis and osteogenesis. These findings not only establish a framework for deciphering and promoting periodontal bone regeneration in potential clinical applications but also offer insights for future therapeutic strategies in dental or broader regenerative medicine.
Receptor, Platelet-Derived Growth Factor alpha/metabolism* ; Humans ; Neovascularization, Physiologic/physiology* ; Dental Sac/cytology* ; Single-Cell Analysis ; Transcriptome ; Mesenchymal Stem Cells/metabolism* ; Bone Regeneration ; Animals ; Dental Papilla/cytology* ; Periodontium/physiology* ; Stem Cells/metabolism* ; Regeneration ; Angiogenesis

Melasma is an acquired pigmentation disorder with complex pathogenesis. In addition to the dysfunction of melanocytes, the imbalance of the microenvironment, particularly the multicellular interactions among keratinocytes, fibroblasts, vascular endothelial cells, mast cells, and sebocytes, also contributes to the progression of melasma. This review summarizes relevant research progress on melanocytes and their microenvironment in the pathogenesis of melasma, as well as advances in the treatment of melasma.

Objective To investigate the current situation of off-label use of immune checkpoint inhibitors(ICIs)in China and the cognition of medical staff.Methods From August 31 to September 9,2022,a nationwide survey questionnaire was sent to medical staff in the form of electronic questionnaire.The questionnaire included 13 questions,covering four dimensions:Drug allocation,current situation of medication beyond the instructions,cognition of medication beyond the instructions and current situation of medication beyond the instructions.Results A total of 745 questionnaires were collected.75.70％of respondents reported off-label use of ICIs in their hospitals,with the most common type being off-label indications.The primary reasons for such practices included support from authoritative domestic and international guidelines,clinical research data validation,and approved indications in foreign regulatory documents.85.37％of respondents believed off-label use could offer new hope for patients,while 68.86％considered it unlikely to increase adverse reactions.44.97％of respondents' hospitals had not established off-label use registration systems for ICIs.88.86％of respondents emphasized the need for stricter regulations governing off-label use of immunotherapeutic agents.Conclusion Off-label use of ICIs is common,and there is a lack of unified guidance in clinical practice.It is urgent to form norms and consensus on the management of off-label use of ICIs.

The diagnosis rate of early breast cancer has significantly increased with the proliferation of tumor screening and heightened health awareness.Clinical research,as the evidence base for guidelines and consensus,provides optimized treatment plans for breast cancer.This article summarized and classified several pivotal clinical studies that changed the clinical practice of early breast cancer,according to updates in domestic and international guidelines and consensus from 2023 to 2024.These included the optimization of neoadjuvant and adjuvant therapies,the escalation of adjuvant endocrine therapy,the optimization of local treatment,and attention to quality of life,etc.In the optimization of neoadjuvant and adjuvant therapies,the KEYNOTE-522 study established the therapeutic role of pembrolizumab combined with chemotherapy in early high-risk triple-negative breast cancer(TNBC).The FDChina study confirmed the non-inferiority of the subcutaneous formulation of trastuzumab combined with pertuzumab(H+P)in neoadjuvant treatment of human epidermal growth factor receptor 2(HER2)-positive breast cancer,offering a more convenient administration method.The KATHERINE study clarified the adjuvant role of trastuzumab emtansine(T-DM1)in HER2-positive breast cancer patients who did not achieve a pathologic complete response(pCR)after neoadjuvant therapy.In the escalation of adjuvant endocrine therapy,the MonarchE and NATALEE studies confirmed the efficacy of abemaciclib and ribociclib combined with endocrine therapy in high-risk hormone receptor(HR)-positive HER2-negative early breast cancer patients,promoting the application of cyclin-dependent kinase(CDK)4/6 inhibitors in early breast cancer treatment.In the optimization of local treatment,the ACOSOG Z11102 study supported the feasibility of breast-conserving surgery for multicentric breast cancer,the SENOMAC study provided evidence for exempting sentinel lymph node(SLN)low-burden breast cancer patients from axillary lymph node dissection(ALND),the SOUND study supported the exemption of sentinel lymph node biopsy(SLNB)for T1 and cN0 breast cancer patients,and the ICARO study suggested the feasibility of exempting ALND for patients with isolated tumor cells(ITCs)found after neoadjuvant chemotherapy with SLNB or targeted axillary dissection(TAD).The NSABP B-51/RTOG 1304 study provided a basis for the de-escalation of regional lymph node irradiation(RNI)and local treatment in ypN0 breast cancer after neoadjuvant therapy.In terms of quality of life and chemoprevention,the POSITIVE study proposed a protocol for pausing endocrine therapy for breast cancer patients with fertility needs,and the TAM-01 and IBIS-Ⅱ studies provided strong evidence-based medical evidence for chemoprevention in high-risk breast cancer patients.These pivotal clinical studies have profoundly impacted the clinical practice of early-stage breast cancer,not only optimizing treatment plans but also focusing on the quality of life and disease prevention of breast cancer patients.This article discussed the impact of the aforementioned clinical studies on the clinical practice of early breast cancer,centered on updates to various domestic and international breast cancer diagnosis and treatment guidelines and consensus.

The diagnosis rate of early breast cancer has significantly increased with the proliferation of tumor screening and heightened health awareness.Clinical research,as the evidence base for guidelines and consensus,provides optimized treatment plans for breast cancer.This article summarized and classified several pivotal clinical studies that changed the clinical practice of early breast cancer,according to updates in domestic and international guidelines and consensus from 2023 to 2024.These included the optimization of neoadjuvant and adjuvant therapies,the escalation of adjuvant endocrine therapy,the optimization of local treatment,and attention to quality of life,etc.In the optimization of neoadjuvant and adjuvant therapies,the KEYNOTE-522 study established the therapeutic role of pembrolizumab combined with chemotherapy in early high-risk triple-negative breast cancer(TNBC).The FDChina study confirmed the non-inferiority of the subcutaneous formulation of trastuzumab combined with pertuzumab(H+P)in neoadjuvant treatment of human epidermal growth factor receptor 2(HER2)-positive breast cancer,offering a more convenient administration method.The KATHERINE study clarified the adjuvant role of trastuzumab emtansine(T-DM1)in HER2-positive breast cancer patients who did not achieve a pathologic complete response(pCR)after neoadjuvant therapy.In the escalation of adjuvant endocrine therapy,the MonarchE and NATALEE studies confirmed the efficacy of abemaciclib and ribociclib combined with endocrine therapy in high-risk hormone receptor(HR)-positive HER2-negative early breast cancer patients,promoting the application of cyclin-dependent kinase(CDK)4/6 inhibitors in early breast cancer treatment.In the optimization of local treatment,the ACOSOG Z11102 study supported the feasibility of breast-conserving surgery for multicentric breast cancer,the SENOMAC study provided evidence for exempting sentinel lymph node(SLN)low-burden breast cancer patients from axillary lymph node dissection(ALND),the SOUND study supported the exemption of sentinel lymph node biopsy(SLNB)for T1 and cN0 breast cancer patients,and the ICARO study suggested the feasibility of exempting ALND for patients with isolated tumor cells(ITCs)found after neoadjuvant chemotherapy with SLNB or targeted axillary dissection(TAD).The NSABP B-51/RTOG 1304 study provided a basis for the de-escalation of regional lymph node irradiation(RNI)and local treatment in ypN0 breast cancer after neoadjuvant therapy.In terms of quality of life and chemoprevention,the POSITIVE study proposed a protocol for pausing endocrine therapy for breast cancer patients with fertility needs,and the TAM-01 and IBIS-Ⅱ studies provided strong evidence-based medical evidence for chemoprevention in high-risk breast cancer patients.These pivotal clinical studies have profoundly impacted the clinical practice of early-stage breast cancer,not only optimizing treatment plans but also focusing on the quality of life and disease prevention of breast cancer patients.This article discussed the impact of the aforementioned clinical studies on the clinical practice of early breast cancer,centered on updates to various domestic and international breast cancer diagnosis and treatment guidelines and consensus.

Objective To investigate the early dynamic changes of biomarkers associated with capillary leak syndrome(CLS)in patients with severe acute pancreatitis(SAP)and their correlation with multiple organ failure(MOF).Methods A total of 171 SAP patients admitted to the West China Centre of Excellence for Pancreatitis,West China Hospital,Sichuan University between September 1,2019 and December 31,2020 were enrolled for this study.The patients were divided into MOF and non-MOF groups based on the occurrence of MOF in the first 5 days of hospitalization,and were further divided into subgroups based on the presence of moderate-to-severe intra-abdominal hypertension(IAH).We performed dynamic monitoring of the blood biomarkers(hematocrit[HCT].blood urea nitrogen[BUN].and creatinine[Cr]),plasma proteins(albumin[Alb].total protein[TP].and non-albumin plasma proteins[NAPP]),and intra-abdominal pressure.Trends in these indicators across groups were analyzed comprehensively.Results No significant differences in baseline data between the two groups were observed.The baseline data of the 2 groups were comparable.The MOF group had significantly higher rates of persistent systemic inflammatory response syndrome(SIRS)lasting 48 hours(91.3％vs.71.8％),ICU admission(70.4％vs.17.6％),and length-of-stay([32±17.7]days vs.[19.0±12.2]days)compared to those of the non-MOF group(P＜0.05).The incidences of respiratory,circulatory,and renal failures were higher in the MOF group than those in the non-MOF group,showing significant differences in circulatory failure(69％vs.3.5％)and renal failure(65.5％vs.3.5％)(P＜0.05).In the first 5 days of hospitalization,the MOF group showed significantly elevated BUN and Cr levels,while Alb and TP levels dropped rapidly upon admission and then gradually recovered.The NAPP level of the MOF group continued to decrease after admission,and on the third day after admission,the NAPP level was lower than that of the Non-MOF group,showing statistically significant difference(P＜0.001).The Alb/NAPP ratio of the MOF group decreased significantly on day 1 and then rapidly increased,showing significant differences between the groups on days 3 and 4(P=0.001).Subgroup analysis of MOF patients with moderate-to-severe IAH revealed similar trends in the dynamic changes and the overall changes in the indicators,and the difference was even more pronounced.The mixed linear model showed that the average levels of HCT,BUN,Alb/NAPP,and Alb/TP were higher and increased over time in the MOF combined with IAP subgroup(P＜0.001).Conclusion The CLS model of SAP patients is validated,confirming that CLS is a key factor in the progression from SIRS to MOF.The loss of NAPP is an early and important indicator of CLS persistence and progression to MOF.Additionally,moderate-to-severe IAH accelerates the deterioration of MOF.These findings provide valuable insights into the potential mechanisms of MOF and warrant further validation through large-scale prospective studies.

Melasma is an acquired pigmentation disorder with complex pathogenesis. In addition to the dysfunction of melanocytes, the imbalance of the microenvironment, particularly the multicellular interactions among keratinocytes, fibroblasts, vascular endothelial cells, mast cells, and sebocytes, also contributes to the progression of melasma. This review summarizes relevant research progress on melanocytes and their microenvironment in the pathogenesis of melasma, as well as advances in the treatment of melasma.

Objective To investigate the current situation of off-label use of immune checkpoint inhibitors(ICIs)in China and the cognition of medical staff.Methods From August 31 to September 9,2022,a nationwide survey questionnaire was sent to medical staff in the form of electronic questionnaire.The questionnaire included 13 questions,covering four dimensions:Drug allocation,current situation of medication beyond the instructions,cognition of medication beyond the instructions and current situation of medication beyond the instructions.Results A total of 745 questionnaires were collected.75.70％of respondents reported off-label use of ICIs in their hospitals,with the most common type being off-label indications.The primary reasons for such practices included support from authoritative domestic and international guidelines,clinical research data validation,and approved indications in foreign regulatory documents.85.37％of respondents believed off-label use could offer new hope for patients,while 68.86％considered it unlikely to increase adverse reactions.44.97％of respondents' hospitals had not established off-label use registration systems for ICIs.88.86％of respondents emphasized the need for stricter regulations governing off-label use of immunotherapeutic agents.Conclusion Off-label use of ICIs is common,and there is a lack of unified guidance in clinical practice.It is urgent to form norms and consensus on the management of off-label use of ICIs.

OBJECTIVES: To investigate the inhibitory effect of GSK484, a PAD4 inhibitor, on H3Cit expression following sepsis and its effects for improving sepsis-induced endothelial dysfunction. METHODS: Eighteen C57BL/6 mice were randomized into sham-operated group, sepsis model group and GSK484 treatment group (n=6), and in the latter two groups, models of sepsis were established by cecal ligation and puncture (CLP). The mice in GSK484 treatment group were given an intraperitoneal injection of GSK484 (4 mg/kg) on the second day following the surgery. Twenty-four hours after the injection, the mice were euthanized for measurement of serum levels of VEGF, ESM-1, IL-6 and IL-1β using ELISA. Lung tissue pathology was observed with HE staining, and pulmonary expressions of F-actin, VE-cadherin, ZO-1 and H3Cit proteins were detected using immunofluorescence staining and Western blotting. In primary cultured of mouse lung microvascular endothelial cells, the effect of stimulation with LPS (10 μg/mL) for 24 h on tube formation, proliferation, apoptosis and expressions of VEGF, ESM-1, IL-6 and IL-1β were assessed using CCK-8 assay, flow cytometry and ELISA. RESULTS: Compared to the sham-operated mice, the septic mice exhibited significant lung tissue pathologies characterized by vascular congestion, alveolar rupture, edema, and neutrophil infiltration. Serum levels of IL-6, IL-1β, VEGF, and ESM-1 were elevated, pulmonary expressions of F-actin, VE-cadherin, and ZO-1 were decreased, and H3Cit expression was increased significantly in the septic mice. GSK484 treatment effectively mitigated these changes in the septic mice. The LPS-stimulated endothelial cells showed increased productions of IL-6, IL-1β, VEGF and ESM-1, which were significantly reduced after treatment with 2.5 μmol/L GSK484. CONCLUSIONS GSK484 treatment effectively suppresses H3Cit expression in septic mice to ameliorate sepsis-induced endothelial dysfunction.
Animals ; Sepsis/drug therapy* ; Mice ; Mice, Inbred C57BL ; Lung Injury/drug therapy* ; Endothelial Cells/drug effects* ; Interleukin-6/metabolism* ; Protein-Arginine Deiminase Type 4/metabolism* ; Lung/metabolism* ; Vascular Endothelial Growth Factor A/metabolism* ; Interleukin-1beta/metabolism* ; Disease Models, Animal ; Cadherins/metabolism* ; Apoptosis/drug effects* ; Imidazoles ; Antigens, CD