Tumor suppressor FRMD3 controls mammary epithelial cell fate determination via notch signaling pathway.

The luminal-to-basal transition in mammary epithelial cells (MECs) is accompanied by changes in epithelial cell lineage plasticity; however, the underlying mechanism remains elusive. Here, we report that deficiency of Frmd3 inhibits mammary gland lineage development and induces stemness of MECs, subsequently leading to the occurrence of triple-negative breast cancer. Loss of Frmd3 in PyMT mice results in a luminal-to-basal transition phenotype. Single-cell RNA sequencing of MECs indicated that knockout of Frmd3 inhibits the Notch signaling pathway. Mechanistically, FERM domain-containing protein 3 (FRMD3) promotes the degradation of Disheveled-2 by disrupting its interaction with deubiquitinase USP9x. FRMD3 also interrupts the interaction of Disheveled-2 with CK1, FOXK1/2, and NICD and decreases Disheveled-2 phosphorylation and nuclear localization, thereby impairing Notch-dependent luminal epithelial lineage plasticity in MECs. A low level of FRMD3 predicts poor outcomes for breast cancer patients. Together, we demonstrated that FRMD3 is a tumor suppressor that functions as an endogenous activator of the Notch signaling pathway, facilitating the basal-to-luminal transformation in MECs.

Effects of a semi-interpenetrating network hydrogel loaded with oridonin and DNase-I on the healing of chemoradiotherapy-induced oral mucositis.

The aim of this study was to develop a semi-interpenetrating network (IPN) hydrogel system suitable for the oral environment, capable of controlled release of DNase-I and oridonin (ORI), to exert antimicrobial, anti-inflammatory, and reparative effects on chemoradiotherapy-induced oral mucositis (OM). This IPN was based on the combination of ε-polylysine (PLL) and hetastarch (HES), loaded with DNase-I and ORI (ORI/DNase-I/IPN) for OM treatment. In vitro studies were conducted to evaluate degradation, adhesion, release analysis, and bioactivity including cell proliferation and wound healing assays using epidermal keratinocyte and fibroblast cell lines. Furthermore, the therapeutic effects of ORI/DNase-I/IPN were investigated in vivo using Sprague-Dawley (SD) rats with chemoradiotherapy-induced OM. The results demonstrated that the IPN exhibited excellent adhesion to wet mucous membranes, and the two drugs co-encapsulated in the hydrogel were released in a controlled manner, exerting inhibitory effects on bacteria and degrading NETs in wound tissues. The in vivo wound repair effect, microbiological assays, H&E and Masson staining supported the non-toxicity of ORI/DNase-I/IPN, as well as its ability to accelerate the healing of oral ulcers and reduce inflammation. Overall, ORI/DNase-I/IPN demonstrated a therapeutic effect on OM in rats by significantly accelerating the healing process. These findings provide new insights into possible therapies for OM.

Limbal stem cells carried by a four-dimensional -printed chitosan-based scaffold for corneal epithelium injury in diabetic rabbits.

Methods: Herein, we obtained and characterized deltaN p63- and adenosine triphosphate-binding cassette subfamily G member 2-expressing limbal stem cells (LSCs). Chitosan and carboxymethyl chitosan (CTH) were cross-linked to be an in situ thermosensitive hydrogel (ACH), which was printed through four-dimensional (4D) printing to obtain a porous carrier with uniform pore diameter (4D-CTH). Rabbits were injected with alloxan to induce diabetes mellitus (DM). Following this, the LSC-carrying hydrogel was spread on the surface of the cornea of the diabetic rabbits to cure corneal epithelium injury. Results: Compared with the control group (LSCs only), rapid wound healing was observed in rabbits treated with LSC-carrying 4D-CTH. Furthermore, the test group also showed better corneal nerve repair ability. The results indicated the potential of LSC-carrying 4D-CTH in curing corneal epithelium injury. Conclusion: 4D-CTH holds potential as a useful tool for studying regenerative processes occurring during the treatment of various diabetic corneal epithelium pathologies with the use of stem cell-based technologies.

Delineating abnormal individual structural covariance brain network organization in pediatric epilepsy with unilateral resection of visual cortex.

Although several previous studies have used resting-state functional magnetic resonance imaging and diffusion tensor imaging to report topological changes in the brain in epilepsy, it remains unclear whether the individual structural covariance network (SCN) changes in epilepsy, especially in pediatric epilepsy with visual cortex resection but with normal functions. Herein, individual SCNs were mapped and analyzed for seven pediatric patients with epilepsy after surgery and 15 age-matched healthy controls. A whole-brain individual SCN was constructed based on an automated anatomical labeling template, and global and nodal network metrics were calculated for statistical analyses. Small-world properties were exhibited by pediatric patients after brain surgery and by healthy controls. After brain surgery, pediatric patients with epilepsy exhibited a higher shortest path length, lower global efficiency, and higher nodal efficiency in the cuneus than those in healthy controls. These results revealed that pediatric epilepsy after brain surgery, even with normal functions, showed altered topological organization of the individual SCNs, which revealed residual network topological abnormalities and may provide initial evidence for the underlying functional impairments in the brain of pediatric patients with epilepsy after surgery that can occur in the future.

PiR-hsa-23533 promotes malignancy in head and neck squamous cell carcinoma via USP7.

BACKGROUND: With regard to head and neck squamous cell carcinoma (HNSCC), its occurrence and advancement are controlled by genetic and epigenetic anomalies. PIWI-interacting RNAs (piRNAs) are recognized with significance in tumor, but the precise molecular mechanisms of piRNAs in HNSCC largely remain undisclosed. METHODS: Differentially expressed piRNAs were identified by RNA sequencing. The expression of piR-hsa-23533 was evaluated using quantitative real-time PCR and RNA in situ hybridization. The impacts of piR-hsa-23533 on the proliferation and apoptosis of HNSCC cells were investigated by a series of in vitro and in vivo assays. RESULTS: piR-hsa-23533 exhibits upregulation within HNSCC cells and tissues. Besides, piR-hsa-23533 overexpression promotes proliferation while inhibiting apoptosis in vitro and in vivo, while piR-hsa-23533 silencing has an opposite function. From the mechanistic perspective, piR-hsa-23533 can bind to Ubiquitin-specific protease 7 (USP7), as shown through RNA pull-down and RNA immunoprecipitation assays, promoting USP7 mRNA and protein expression. CONCLUSIONS: These findings highlight the functional importance of piR-hsa-23533 in HNSCC and may assist in the development of anti-HNSCC therapeutic target.

Helicobacter pylori Treatment and Gastric Cancer Risk Among Individuals With High Genetic Risk for Gastric Cancer.

Importance: Helicobacter pylori treatment and nutrition supplementation may protect against gastric cancer (GC), but whether the beneficial effects only apply to potential genetic subgroups and whether high genetic risk may be counteracted by these chemoprevention strategies remains unknown. Objective: To examine genetic variants associated with the progression of gastric lesions and GC risk and to assess the benefits of H pylori treatment and nutrition supplementation by levels of genetic risk. Design, Setting, and Participants: This cohort study used follow-up data of the Shandong Intervention Trial (SIT, 1989-2022) and China Kadoorie Biobank (CKB, 2004-2018) in China. Based on the SIT, a longitudinal genome-wide association study was conducted to identify genetic variants for gastric lesion progression. Significant variants were examined for incident GC in a randomly sampled set of CKB participants (set 1). Polygenic risk scores (PRSs) combining independent variants were assessed for GC risk in the remaining CKB participants (set 2) and in an independent case-control study in Linqu. Exposures: H pylori treatment and nutrition supplementation. Main Outcomes and Measures: Primary outcomes were the progression of gastric lesions (in SIT only) and the risk of GC. The associations of H pylori treatment and nutrition supplementation with GC were evaluated among SIT participants with different levels of genetic risk. Results: Our analyses included 2816 participants (mean [SD] age, 46.95 [9.12] years; 1429 [50.75%] women) in SIT and 100 228 participants (mean [SD] age, 53.69 [11.00] years; 57 357 [57.23%] women) in CKB, with 147 GC cases in SIT and 825 GC cases in CKB identified during follow-up. A PRS integrating 12 genomic loci associated with gastric lesion progression and incident GC risk was derived, which was associated with GC risk in CKB (highest vs lowest decile of PRS: hazard ratio [HR], 2.54; 95% CI, 1.80-3.57) and further validated in the analysis of 702 case participants and 692 control participants (mean [SD] age, 54.54 [7.66] years; 527 [37.80%] women; odds ratio, 1.83; 95% CI, 1.11-3.05). H pylori treatment was associated with reduced GC risk only for individuals with high genetic risk (top 25% of PRS: HR, 0.45; 95% CI, 0.25-0.82) but not for those with low genetic risk (HR, 0.81; 95% CI, 0.50-1.34; P for interaction = .03). Such effect modification was not found for vitamin (P for interaction = .93) or garlic (P for interaction = .41) supplementation. Conclusions and Relevance: The findings of this cohort study indicate that a high genetic risk of GC may be counteracted by H pylori treatment, suggesting primary prevention could be tailored to genetic risk for more effective prevention.

Flavonoid Compounds in Hippophae rhamnoides L. Protect Endothelial Cells from Oxidative Damage Through the PI3K/AKT-eNOS Pathway.

Sea buckthorn, a traditional medicinal plant, has been used for several years in China for the prevention and treatment of various diseases, a practice closely associated with its significant antioxidant activity. The aim of this study was to investigate the protective effects of sea buckthorn flavonoids on vascular endothelial cells in an oxidative stress environment. We isolated and extracted active compounds from sea buckthorn and investigated their impact on endothelial nitric oxide synthase (eNOS) activity through the PI3K/AKT-eNOS signaling pathway through a combination of network pharmacology and cellular experiments, elucidating the regulatory effects of these compounds on endothelial cell functions. Three flavonoids, named Fr.4-2-1, Fr.4-2-2 and Fr.4-2-3, were obtained from sea buckthorn. The results of network pharmacology indicated that they might exert their effects by regulating the PI3K-AKT signaling pathway. In vitro results showed that all three flavonoids were effective in alleviating the degree of oxidative stress in cells, among which Fr.4-2-1 exerted its antioxidant effects by modulating the PI3K/AKT-eNOS pathway. Flavonoids in sea buckthorn can effectively inhibit oxidative stress-induced cellular damage, preserving the integrity and functionality of endothelial cells, which is crucial for maintaining vascular health and function.

Ageing on the impact of distribution about preformed anti-HLA and anti-MICA antibody specificities in recipients prior to initial HSCT from East China.

BACKGROUND: With the development of Hematopoietic Stem Cell Transplantation (HSCT) technology, increasing numbers of elderly patients were undergoing allogeneic HSCT and elderly patients with hematologic malignancies could benefit most from it. Preformed donor-specific human leukocyte antigen (HLA) antibodies (DSA) were associated with graft failure in HLA-mismatched allogeneic HSCT and the absence of DSA was the main criterion of selecting the donor. Except for sensitization events such as transfusion, pregnancy or previous transplantation, ageing affects the humoral immune response both quantitatively and qualitatively. To evaluate the prevalence and distribution of anti-HLA and antibodies of MHC class I chain related antigens A (MICA) specificities in different age groups before initial HSCT would provide HLA and MICA specific antibody profiles under the impact of ageing, which could provide meaningful information in the process of selecting suitable HLA-mismatched donors by avoiding preformed DSA. RESULTS: There were no significant differences in the distribution of anti-HLA class I, class II and anti-MICA antibodies among the three age groups in this study except that a significant lower negative ratio of anti-HLA class I, class II antibodies and higher positive rate of MICA antibodies with maximum mean fluorescent intensity (MFI) > 5000 in the elderly than in young age group. The distribution of antibody specificities against HLA -A, -B, -C, -DR, -DQ, -DP and MICA antigens in the three age groups were generally consistent. The anti-HLA class I antibody specificities with higher frequencies were A80,A68;B76,B45;Cw17, which were unlikely to become DSA in Chinese. Anti-HLA class II antibody specificities were more likely to become potential DSA than class I.DR7, DR9, DQ7, DQ8 and DQ9 were most likely to become potential DSA. CONCLUSIONS: The prevalence of anti-HLA and anti-MICA antibodies increased slightly as age increased. While ageing had a small impact on the distribution of antibody specificity frequencies against HLA-A, -B, -C, -DR,-DQ, -DP and MICA antigens in recipients awaiting initial HSCT from East China. The risk of developing preformed DSA was basically consistent in the three age groups and the elderly group might be more favorable in HLA-mismatched HSCT due to higher positive rate of anti-MICA antibody.

RAB27B-regulated exosomes mediate LSC maintenance via resistance to senescence and crosstalk with the microenvironment.

The fate of leukaemia stem cells (LSCs) is determined by both their inherent mechanisms and crosstalk with their niches. Although LSCs were confirmed to be eradicated by restarting senescence, the specific key regulators of LSC resistance to senescence and remodelling of the niche to obtain a microenvironment suitable for stemness remain unknown. Here, we found that RAB27B, a gene regulating exosome secretion, was overexpressed in LSCs and associated with the poor prognosis of acute myeloid leukaemia (AML) patients. The increased RAB27B in LSCs prevented their senescence and maintained their stemness in vitro and in vivo. Mechanically, the increased RAB27B expression in LSCs selectively promoted the loading and release of exosomes rich in senescence-inducing proteins by direct combination. Furthermore, RAB27B-regulated LSC-derived exosomes remodelled the niche and induced senescence of mesenchymal stem cells (MSCs) with increased RAB27B expression ex vivo and in vivo. The increased RAB27B in the senescent MSCs conversely promoted LSC maintenance ex vivo and in vivo via selective excretion of exosomes rich in stemness-promoting proteins. Therefore, we identified the specifically increased RAB27B in LSCs and their educated senescent MSCs as a hub molecule for LSC resistance to senescence and maintenance through crosstalk with its niche via selective exosome excretion.

Ozone exposure affects corneal epithelial fate by promoting mtDNA leakage and cGAS/STING activation.

Ozone is a common air pollutant associated with various human diseases. The human ocular surface is frequently exposed to ozone in the troposphere, but the mechanisms by which ozone affects the ocular surface health remain unclear. This study aimed to establish a mouse model to investigate the effects of ozone exposure on the ocular surface and the corneal epithelium. The findings revealed that ozone exposure disrupted corneal epithelial homeostasis and differentiation, resulting in corneal squamous metaplasia. Further, ozone exposure induced oxidative damage and cytoplasmic leakage of mitochondrial DNA (mtDNA), thereby activating the cGAS/STING signaling pathway. The activation of the cGAS/STING signaling pathway triggered the activation of downstream NF-κB and TRAF6 signaling pathways, causing corneal inflammation, thereby promoting corneal inflammation and squamous metaplasia. Finally, C-176, a selective STING inhibitor, effectively prevented and treated corneal inflammation and squamous metaplasia caused by ozone exposure. This study revealed the role of mtDNA leakage-mediated cGAS/STING activation in corneal squamous epithelial metaplasia caused by ozone exposure. It also depicted the abnormal expression pattern of corneal epithelial keratin using three-dimensional images, providing new targets and strategies for preventing and treating corneal squamous metaplasia and other ocular surface diseases.

A multicenter single-arm trial of neoadjuvant pyrotinib and trastuzumab plus chemotherapy for HER2-positive breast cancer.

The objective of this multicenter, single-arm trial (ChiCTR1900022293) was to explore the efficacy and safety of neoadjuvant therapy with epirubicin, cyclophosphamide, and pyrotinib followed by docetaxel, trastuzumab, and pyrotinib (ECPy-THPy) in the treatment of patients with stage II-III HER2-positive breast cancer. The present study enrolled patients with stage II-III HER2-positive breast cancer. Epirubicin and cyclophosphamide were administrated for four 21-day cycles, followed by four cycles of docetaxel and trastuzumab. Pyrotinib was taken orally once per day throughout the treatment period. The primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0) rate in the modified intention-to-treat (mITT) population. In total, 175 patients were included. The tpCR rate was 68.6% (95% CI, 60.7-75.8%), while the objective response rate was 89.1%. In the post-hoc subgroup analysis, no association between clinical characteristics and the tpCR rate was observed. The most common grade ≥3 adverse events were diarrhea (54.3%), followed by white blood cell count decreased (5.1%), and neutrophil count decreased (4.6%). In conclusion, the neoadjuvant regimen with ECPy-THPy showed promising pathological response and clinical benefits with an acceptable safety profile in patients with stage II-III HER2-positive breast cancer.

Engineered mesenchymal stem cell exosomes loaded with miR-34c-5p selectively promote eradication of acute myeloid leukemia stem cells.

Most patients with acute myeloid leukemia (AML) relapse eventually because of the inability to effectively eliminate leukemia stem cells (LSCs), prompting the search of new therapies to eradicate LSCs. Our previous study demonstrated that miR-34c-5p promotes the clearance of LSCs in an AML mouse model, highlighting its potential as a therapeutic target for eradicating LSCs, but the effective delivery of miR-34c-5p to LSCs remains a great challenge. Here, we employed simultaneous two-step modifications to engineer mesenchymal stem cells (MSCs) and MSC-derived exosomes to create exosomes overexpressing the fused protein lysosome-associated membrane protein 2-interleukin 3 (Lamp2b-IL3) and hematopoietic cell E-selectin/L-selectin ligand (HCELL), and demonstrated that the engineered exosomes exhibited an enhanced ability for bone marrow homing and selective targeting of LSCs. Additionally, using a humanized AML mouse model, we confirmed that the engineered exosomes, loaded with miR-34c-5p, could selectively promote eradication of LSCs and impede the AML development in vivo. In summary, we successfully designed an effective delivery system and provided new insights into the development of novel therapies for delivering miRNA or other molecules to LSCs with greater cellular targeting specificity.

Black Carbon in Deep-Sea Seamount Sediment Cores: Vertical Variation and Non-negligible Char Black Carbon.

Deep-sea sediments (>1000 m) are often considered to be the ultimate sink for black carbon (BC), and the long-term buried BC in these sediments is believed to potentially provide a negative feedback effect on climate warming. The burial flux of BC in marine sediments is predominantly estimated based on soot BC (SBC) in most studies, frequently ignoring the contribution of char BC (CBC). While this methodology may result in an underestimation of the BC burial flux, the precise extent of this underestimation is yet to be determined. This study used the benzene poly(carboxylic acid) (BPCA) method and chemothermal oxidation (CTO) method to analyze CBC and SBC in four deep-sea sediment cores from the Zhongnan seamount in the South China Sea, respectively. The CBC content increased from 0.026 ± 0.010% at the seamount upper part (1432 m) to 0.039 ± 0.012% at the seamount foot (4278 m), constituting approximately 25 to 42% of the SBC content. The content disparity between CBC and SBC diminishes as depth increases. In deep-sea sediments, biogeochemical factors influence the variation of CBC molecules with depth. In the seamount middle-upper part (1432 and 2465 m), highly condensed CBC gradually accumulated along the core downward profile. In the sediment core profile of the seamount middle-lower part (3497 m), benzenetricarboxylic acid and benzenetetracarboxylic acid content decreased while the BC condensation degree rose, i.e., less condensed CBC was preferentially consumed. Afterward, CBC molecules reached a relatively stable state at the seamount foot. This study reveals that CBC possesses the capacity for long-term carbon sequestration in deep-sea sediments, and its content is not negligible.

Is Sliding Compression Necessary for Intramedullary Nailing Fixation of AO/OTA Type A3.3 Intertrochanteric Fracture?

OBJECTIVES: The intramedullary nail is considered the gold standard for treating AO/OTA type A3.3 intertrochanteric fractures. However, it still faces a significant rate of failure, mainly due to the critical factor of comminuted lateral wall defects leading to inadequate proximal sliding compression. The primary objective of this study is to investigate the requirement of sliding compression in the treatment of unstable AO/OTA type A3.3 intertrochanteric fractures. To achieve this, we conduct a comparative analysis between two approaches: InterTAN alone and proximal femoral anti-rotation blade nailing (PFNA) combined with lateral wall reconstruction for treating AO/OTA type A3.3 intertrochanteric fractures with lateral wall damage. METHODS: A retrospective analysis was conducted on the clinical data of patients who underwent intramedullary nailing fixation for AO/OTA type A3.3 intertrochanteric fractures at our hospital from January 2012 to January 2022. Patient characteristics as well as treatment details, including operative time, intraoperative blood loss, weight-bearing time, fracture healing time, tip apex distance (TAD) loss, Harris hip scores (HHS), Parker-Palmer mobility score (PPMS), and postoperative complications, were collected and analyzed. Continuous variables were analyzed using independent sample t-tests, while categorical variables were examined using the chi-square test. For group comparisons, variance analysis was applied, and pairwise comparisons were conducted using the LSD-t test. RESULTS: These patients were divided into PFNA combined with lateral wall reconstruction group (sliding compression group) and InterTAN fixation group (static fixation group) based on surgical methods. The operation time, intraoperative bleeding loss, HHS at 12 months and PPMS at 12 months in the sliding compression group were significantly higher than those in the static fixation group, and time to weight-bearing and fracture healing time were significantly lower than those in the static fixation group (p < 0.05). There were no significant differences between two groups in terms of the TAD at 2 days, 2, and 12 months postoperatively, the incidence of complications (p > 0.05). At 6 months postoperatively, femoral neck length was shortened compared to 2 days postoperatively in both groups, and the sliding compression group had a significantly greater degree of femoral neck shortening than the static fixation group (p < 0.05). CONCLUSION: The use of PFNA with lateral wall reconstruction for A3.3 intertrochanteric fractures demonstrated superior mobility, efficiency, and reduced internal fixation failure rates compared to InterTAN. These findings suggest that sliding compression may be required for intramedullary nailing treatment.

Association between probiotic consumption and periodontitis: Evidence from NHANES 2009-2014.

AIM: The study aimed to provide evidence of the relationship between probiotics consumption and periodontitis. MATERIALS AND METHODS: A total of 4577 adults who participated in the National Health and Nutrition Examination Survey (NHANES) during 2009-2014 were included in the study. The weighted prevalence of periodontitis was compared among different groups, and a weighted binary logistic regression analysis was conducted to explore the relationship between probiotic consumption and periodontitis. Receiver operating characteristic (ROC) curves were used to assess the role of probiotic consumption in the periodontitis prediction model. RESULTS: Participants who consumed probiotics had a significantly lower prevalence of periodontitis than those who did not (41.08% vs. 27.83%, p < .001). After fully adjusting for all factors, the odds ratio associated with periodontitis for consuming probiotics was 0.70 (95% confidence interval 0.54-0.92, p = .01) when compared with those who did not consume probiotics. A predictive model including age, sex, ethnicity, poverty income ratio, smoking status and probiotics had 77.0% sensitivity and 60.3% specificity in detecting periodontitis in US adults and achieved an area under the ROC curve of 0.749. CONCLUSIONS: These results indicate that consuming probiotics is associated with a reduced risk of periodontitis.

FRMD8 targets both CDK4 activation and RB degradation to suppress colon cancer growth.

Cyclin-dependent kinase 4 (CDK4) and retinoblastoma protein (RB) are both important cell-cycle regulators that function in different scenarios. Here, we report that FERM domain-containing 8 (FRMD8) inhibits CDK4 activation and stabilizes RB, thereby causing cell-cycle arrest and inhibiting colorectal cancer (CRC) cell growth. FRMD8 interacts separately with CDK7 and CDK4, and it disrupts the interaction of CDK7 with CDK4, subsequently inhibiting CDK4 activation. FRMD8 competes with MDM2 to bind RB and attenuates MDM2-mediated RB degradation. Frmd8 deficiency in mice accelerates azoxymethane/dextran-sodium-sulfate-induced colorectal adenoma formation. The FRMD8 promoter is hypermethylated, and low expression of FRMD8 predicts poor prognosis in CRC patients. Further, we identify an LKCHE-containing FRMD8 peptide that blocks MDM2 binding to RB and stabilizes RB. Combined application of the CDK4 inhibitor and FRMD8 peptide leads to marked suppression of CRC cell growth. Therefore, using an LKCHE-containing peptide to interfere with the MDM2-RB interaction may have therapeutic value in CDK4/6 inhibitor-resistant patients.

Controllable hypoxia-activated chemotherapy as a dual enhancer for synergistic cancer photodynamic immunotherapy.

The efficacy of photodynamic therapy (PDT) is severely limited by the hypoxic tumor microenvironment (TME), while the performance of PDT-aroused antitumor immunity is frustrated by the immunosuppressive TME and deficient immunogenic cell death (ICD) induction. To simultaneously tackle these pivotal problems, we herein create an albumin-based nanoplatform co-delivering IR780, NLG919 dimer and a hypoxia-activated prodrug tirapazamine (TPZ) as the dual enhancer for synergistic cancer therapy. Under NIR irradiation, IR780 generates 1O2 for PDT, which simultaneously cleaves the ROS-sensitive linker for triggered TPZ release, and activates its chemotherapy via exacerbated tumor hypoxia. Meanwhile, firstly found by us, TPZ-mediated chemotherapy boosts PDT-induced tumor ICD to evoke stronger antitumor immunity including the development of tumor-specific cytotoxic T lymphocytes (CTLs). Eventually, enriched intratumoral GSH triggers the activation of NLG919 to mitigate the immunosuppressive TME via specific indoleamine 2,3-dioxygenase 1 (IDO-1) inhibition, consequently promoting the intratumoral infiltration of CTLs and the killing of both primary and distant tumors, while the resultant memory T cells allows nearly 100% suppression of tumor recurrence and metastasis. This nanoplatform sets up an example for dully enhanced photodynamic immunotherapy of breast cancer via hypoxia-activated chemotherapy, and paves a solid way for the treatment of other hypoxic and immunosuppressive malignant tumors.

Molecular and biochemical investigations of the anti-fatigue effects of tea polyphenols and fruit extracts of Lycium ruthenicum Murr. on mice with exercise-induced fatigue.

Background: The molecular mechanisms regulating the therapeutic effects of plant-based ingredients on the exercise-induced fatigue (EIF) remain unclear. The therapeutic effects of both tea polyphenols (TP) and fruit extracts of Lycium ruthenicum (LR) on mouse model of EIF were investigated. Methods: The variations in the fatigue-related biochemical factors, i.e., lactate dehydrogenase (LDH), superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-2 (IL-2), and interleukin-6 (IL-6), in mouse models of EIF treated with TP and LR were determined. The microRNAs involved in the therapeutic effects of TP and LR on the treatment of mice with EIF were identified using the next-generation sequencing technology. Results: Our results revealed that both TP and LR showed evident anti-inflammatory effect and reduced oxidative stress. In comparison with the control groups, the contents of LDH, TNF-α, IL-6, IL-1ß, and IL-2 were significantly decreased and the contents of SOD were significantly increased in the experimental groups treated with either TP or LR. A total of 23 microRNAs (21 upregulated and 2 downregulated) identified for the first time by the high-throughput RNA sequencing were involved in the molecular response to EIF in mice treated with TP and LR. The regulatory functions of these microRNAs in the pathogenesis of EIF in mice were further explored based on Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses with a total of over 20,000-30,000 target genes annotated and 44 metabolic pathways enriched in the experimental groups based on GO and KEGG databases, respectively. Conclusion: Our study revealed the therapeutic effects of TP and LR and identified the microRNAs involved in the molecular mechanisms regulating the EIF in mice, providing strong experimental evidence to support further agricultural development of LR as well as the investigations and applications of TP and LR in the treatment of EIF in humans, including the professional athletes.

Corneal regeneration strategies: From stem cell therapy to tissue engineered stem cell scaffolds.

Corneal epithelial defects and excessive wound healing might lead to severe complications. As stem cells can self-renew infinitely, they are a promising solution for regenerating the corneal epithelium and treating severe corneal epithelial injury. The chemical and biophysical properties of biological scaffolds, such as the amniotic membrane, fibrin, and hydrogels, can provide the necessary signals for stem cell proliferation and differentiation. Multiple researchers have conducted investigations on these scaffolds and evaluated them as potential therapeutic interventions for corneal disorders. These studies have identified various inherent benefits and drawbacks associated with these scaffolds. In this study, we provided a comprehensive overview of the history and use of various stem cells in corneal repair. We mainly discussed biological scaffolds that are used in stem cell transplantation and innovative materials that are under investigation.

Evaluation of artificial intelligent breast ultrasound on lesion detection and characterization compared with hand-held ultrasound in asymptomatic women.

Introduction: To compare the accuracy of Artificial Intelligent Breast Ultrasound (AIBUS) with hand-held breast ultrasound (HHUS) in asymptomatic women and to offer recommendations for screening in regions with limited medical resources. Methods: 852 participants who underwent both HHUS and AIBUS were enrolled between December 2020 and June 2021. Two radiologists, who were unaware of the HHUS results, reviewed the AIBUS data and scored the image quality on a separate workstation. Breast imaging reporting and data system (BI-RADS) final recall assessment, breast density category, quantified lesion features, and examination time were evaluated for both devices. The statistical analysis included McNemar's test, paired t-test, and Wilcoxon test. The kappa coefficient and consistency rate were calculated in different subgroups. Results: Subjective satisfaction with AIBUS image quality reached 70%. Moderate agreements were found between AIBUS with good quality images and HHUS for the BI-RADS final recall assessment (κ = 0.47, consistency rate = 73.9%) and breast density category (κ = 0.50, consistency rate = 74.8%). The lesions measured by AIBUS were statistically smaller and deeper than those measured by HHUS (P < 0.001), though they were not significant in clinical diagnosis (all < 3 mm). The total time required for the AIBUS examination and image interpretation was 1.03 (95% CI (0.57, 1.50)) minutes shorter than that of HHUS per case. Conclusion: Moderate agreement was obtained for the description of the BI-RADS final recall assessment and breast density category. With image quality comparable to that of HHUS, AIBUS was superior for the efficiency of primary screening.