Comparative efficacy and safety of targeted therapy and immunotherapy for HER2-positive breast cancer: a systematic review and network meta-analyses.

Background: In recent years, novel therapies targeting specific molecular pathways and immunotherapies have exhibited promising outcomes for treating human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Our work aimed to assess the effectiveness and safety of these emerging treatment regimens for this disease. Material and methods: We systematically searched databases including PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials their inception to August 2023 to identify relevant randomized controlled trials (RCTs). The quality of eligible RCTs was evaluated with the Cochrane risk-of-bias tool, version 2 (RoB2). Investigated outcomes encompassed progression-free survival (PFS), overall survival (OS), disease-free survival (DFS), pathologic complete remission (pCR), and adverse events (AEs). They were expressed as hazard ratio (HR) with 95% conference intervals (CI) or risk ratio (RR) with 95% CI. Results: Our analysis identified a total of 28 RCTs suitable for inclusion in the NMA. Regarding the PFS, all these treatment regimens exhibited comparable effectiveness. In terms of OS, Capecitabine+Trastuzumab, Lapatinib+Trastuzumab and Pyrotinib+Capecitabine exhibited better effect compared to other treatments. Regarding pCR and AEs, all these treatment regimens exhibited comparable effectiveness, especially Lapatinib+Trastuzumab and Pyrotinib+Capecitabine. Conclusion: Our study highlights the prominent role of targeted therapies and immunotherapies in treating HER2-positive breast cancer. The efficacy of trastuzumab-containing regimens was superior to other treatment options, while maintaining a comparable safety profile. Based on these findings, trastuzumab-containing regimens emerge as a preferable and recommended choice in clinical practice for managing HER2-positive breast cancer. Systematic Review Registration: PROSPERO, identifier CRD42023414348.

Rescuing Nucleus Pulposus Cells from ROS Toxic Microenvironment via Mitochondria-Targeted Carbon Dot-Supported Prussian Blue to Alleviate Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) is invariably accompanied by excessive accumulation of reactive oxygen species (ROS), resulting in progressive deterioration of mitochondrial function and senescence in nucleus pulposus cells (NPCs). Significantly, the main ROS production site in non-immune cells is mitochondria, suggesting mitochondria is a feasible therapeutic target to reverse IVDD. Triphenylphosphine (TPP), which is known as mitochondrial-tropic ligands, is utilized to modify carbon dot-supported Prussian blue (CD-PB) to scavenge superfluous intro-cellular ROS and maintain NPCs at normal redox levels. CD-PB-TPP can effectively escape from lysosomal phagocytosis, permitting efficient mitochondrial targeting. After strikingly lessening the ROS in mitochondria via exerting antioxidant enzyme-like activities, such as superoxide dismutase, and catalase, CD-PB-TPP rescues damaged mitochondrial function and NPCs from senescence, catabolism, and inflammatory reaction in vitro. Imaging evaluation and tissue morphology assessment in vivo suggest that disc height index, mean grey values of nucleus pulposus tissue, and histological morphology are significantly improved in the IVDD model after CD-PB-TPP is locally performed. In conclusion, this study demonstrates that ROS-induced mitochondrial dysfunction and senescence of NPCs leads to IVDD and the CD-PB-TPP possesses enormous potential to rescue this pathological process through efficient removal of ROS via targeting mitochondria, supplying a neoteric strategy for IVDD treatment.

Manganese Amplifies Photoinduced ROS in Toluidine Blue Carbon Dots to Boost MRI Guided Chemo/Photodynamic Therapy.

The contrast agents and tumor treatments currently used in clinical practice are far from satisfactory, due to the specificity of the tumor microenvironment (TME). Identification of diagnostic and therapeutic reagents with strong contrast and therapeutic effect remains a great challenge. Herein, a novel carbon dot nanozyme (Mn-CD) is synthesized for the first time using toluidine blue (TB) and manganese as raw materials. As expected, the enhanced magnetic resonance (MR) imaging capability of Mn-CDs is realized in response to the TME (acidity and glutathione), and r1 and r2 relaxation rates are enhanced by 224% and 249%, respectively. In addition, the photostability of Mn-CDs is also improved, and show an efficient singlet oxygen (1 O2 ) yield of 1.68. Moreover, Mn-CDs can also perform high-efficiency peroxidase (POD)-like activity and catalyze hydrogen peroxide to hydroxyl radicals, which is greatly improved under the light condition. The results both in vitro and in vivo demonstrate that the Mn-CDs are able to achieve real-time MR imaging of TME responsiveness through aggregation of the enhanced permeability and retention effect at tumor sites and facilitate light-enhanced chemodynamic and photodynamic combination therapies. This work opens a new perspective in terms of the role of carbon nanomaterials in integrated diagnosis and treatment of diseases.

Breaking Osteoclast-Acid Vicious Cycle to Rescue Osteoporosis via an Acid Responsive Organic Framework-Based Neutralizing and Gene Editing Platform.

In the osteoporotic microenvironment, the acidic microenvironment generated by excessive osteoclasts not only causes irreversible bone mineral dissolution, but also promotes reactive oxygen species (ROS) production to induce osteoblast senescence and excessive receptor activator of nuclear factor kappa-B ligand (RANKL) production, which help to generate more osteoclasts. Hence, targeting the acidic microenvironment and RANKL production may break this vicious cycle to rescue osteoporosis. To achieve this, an acid-responsive and neutralizing system with high in vivo gene editing capacity is developed by loading sodium bicarbonate (NaHCO3) and RANKL-CRISPR/Cas9 (RC) plasmid in a metal-organic framework. This results showed ZIF8-NaHCO3@Cas9 (ZNC) effective neutralized acidic microenvironment and inhibited ROS production . Surprisingly, nanoparticles loaded with NaHCO3 and plasmids show higher transfection efficiency in the acidic environments as compared to the ones loaded with plasmid only. Finally, micro-CT proves complete reversal of bone volume in ovariectomized mice after ZNC injection into the bone remodeling site. Overall, the newly developed nanoparticles show strong effect in neutralizing the acidic microenvironment to achieve bone protection through promoting osteogenesis and inhibiting osteolysis in a bidirectional manner. This study provides new insights into the treatment of osteoporosis for biomedical and clinical therapies.

The relationship of negative life events, trait-anxiety and depression among Chinese university students: A moderated effect of self-esteem.

BACKGROUND: Negative life events are major triggers for depression. How individual physical qualities and psychological resources affect the relationship between negative life events and depression in college students remains to be studied. Therefore, we constructed a structural equation model to explore the mediating effect of trait anxiety and the moderating effect of self-esteem in the relationship between negative life events and depression among college students. METHODS: A total of 6224 Chinese college students (aged 16-25) in Jiangxi Province in the central area of China completed the online survey. A moderated mediation model was tested to verify the hypothesis. RESULTS: The mediation analysis showed a significant indirect effect of negative life events on depression through trait-anxiety. Mediation was moderated by self-esteem, which significantly interacted with negative life events to reduce their effect on both anxiety and depression. LIMITATIONS: All measures were self-reported. The cross-sectional design only provides evidence of correlation. CONCLUSIONS: The results in this study revealed that self-esteem as a component of psychological defense mechanism to reduce the harm of environmental threats to individuals. Low self-esteem college students are more likely to have adverse effects when experiencing low-level life events. University mental health education reduces the effects of negative life events on trait anxiety and depression of college students by raising their self-esteem levels.

11ß-Hydroxysteroid Dehydrogenase Type 1 Facilitates Osteoporosis by Turning on Osteoclastogenesis through Hippo Signaling.

11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a key enzyme that transform cortisone to cortisol, which activates the endogenous glucocorticoid function. 11ß-HSD1 has been observed to regulate skeletal metabolism, specifically within osteoblasts. However, the function of 11ß-HSD1 in osteoclasts has not been elucidated. In this study, we observed increased 11ß-HSD1 expression in osteoclasts within an osteoporotic mice model (ovariectomized mice). Then, 11ß-HSD1 global knock-out or knock-in mice were employed to demonstrate its function in manipulating bone metabolism, showing significant bone volume decrease in 11ß-HSD1 knock-in mice. Furthermore, specifically knock out 11ß-HSD1 in osteoclasts, by crossing cathepsin-cre mice with 11ß-HSD1flox/flox mice, presented significant protecting effect of skeleton when they underwent ovariectomy surgery. In vitro experiments showed the endogenous high expression of 11ß-HSD1 lead to osteoclast formation and maturation. Meanwhile, we found 11ß-HSD1 facilitated mature osteoclasts formation inhibited bone formation coupled H type vessel (CD31hiEmcnhi) growth through reduction of PDFG-BB secretion. Finally, transcriptome sequencing of 11ß-HSD1 knock in osteoclast progenitor cells indicated the Hippo pathway1 was mostly enriched. Then, by suppression of YAP expression in Hippo signaling, we observed the redundant of osteoclasts formation even in 11ß-HSD1 high expression conditions. In conclusion, our study demonstrated the role of 11ß-HSD1 in facilitating osteoclasts formation and maturation through the Hippo signaling, which is a new therapeutic target to manage osteoporosis.

Rescuing Nucleus Pulposus Cells From Senescence via Dual-Functional Greigite Nanozyme to Alleviate Intervertebral Disc Degeneration.

High levels of reactive oxygen species (ROS) lead to progressive deterioration of mitochondrial function, resulting in tissue degeneration. In this study, ROS accumulation induced nucleus pulposus cells (NPCs) senescence is observed in degenerative human and rat intervertebral disc, suggesting senescence as a new therapeutic target to reverse intervertebral disc degeneration (IVDD). By targeting this, dual-functional greigite nanozyme is successfully constructed, which shows the ability to release abundant polysulfides and presents strong superoxide dismutase and catalase activities, both of which function to scavenge ROS and maintain the tissue at physical redox level. By significantly lowering the ROS level, greigite nanozyme rescues damaged mitochondrial function in IVDD models both in vitro and in vivo, rescues NPCs from senescence and alleviated the inflammatory response. Furthermore, RNA-sequencing reveals ROS-p53-p21 axis is responsible for cellular senescence-induced IVDD. Activation of the axis abolishes greigite nanozyme rescued NPCs senescence phenotype, as well as the alleviated inflammatory response to greigite nanozyme, which confirms the role of ROS-p53-p21 axis in greigite nanozyme's function to reverse IVDD. In conclusion, this study demonstrates that ROS-induced NPCs senescence leads to IVDD and the dual-functional greigite nanozyme holds strong potential to reverse this process, providing a novel strategy for IVDD management.

N-Acetylcysteine-Derived Carbon Dots for Free Radical Scavenging in Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) is associated with oxidative stress induced reactive oxygen species (ROS) dynamic equilibrium disturbance. Nanozymes, as nanomaterials with enzyme-like activity, can regulate intro-cellular ROS levels. In this study, a new carbon dots nanozyme, N-acetylcysteine-derived carbon dots (NAC-CDs), is developed and proved to be an ideal antioxidant and anti-senescent agent in IVDD management. The results confirmed the NAC-CDs have satisfactory biocompatibility and strong superoxide dismutase (250 U mg-1 ), catalase, glutathioneperoxidase-like activity, and total antioxidant capacity. Then, the powerful free radical scavenging and antioxidant ability of NAC-CDs are demonstrated in vitro as observing the reduced ROS in H2 O2 induced senescent nucleus pulposus cells (NPCs), in which the elimination efficiency of toxic ROS is more than 90%. NAC-CDs also maintained mitochondrial homeostasis and suppressed cellular senescence, subsequently inhibited the expression of inflammatory factors in NPCs. In vivo, evaluations of imaging and tissue morphology assessments suggested that disc height index, magnetic resonance imaging grade and histological score are significantly improved from the degenerative models when NAC-CDs is applied. In conclusion, the study developed a novel carbon dots nanozyme, which efficiently rescues IVDD from ROS induced NPCs senescence and provides a potential strategy in management of IVDD in clinic.

Controlled-release of apatinib for targeted inhibition of osteosarcoma by supramolecular nanovalve-modified mesoporous silica.

Targeted delivery of antitumor drugs has been recognized as a promising therapeutic modality to improve treatment efficacy, reduce the toxic side effects and inhibit tumor recurrence. In this study, based on the high biocompatibility, large specific surface area, and easy surface modification of small-sized hollow mesoporous silica nanoparticles ß-cyclodextrin (ß-CD)-benzimidazole (BM) supramolecular nanovalve, together with bone-targeted alendronate sodium (ALN) were constructed on the surface of small-sized HMSNs. The drug loading capacity and efficiency of apatinib (Apa) in HMSNs/BM-Apa-CD-PEG-ALN (HACA) were 65% and 25%, respectively. More importantly, HACA nanoparticles can release the antitumor drug Apa efficiently compared with non-targeted HMSNs nanoparticles in the acidic microenvironment of the tumor. In vitro studies showed that HACA nanoparticles exhibited the most potent cytotoxicity in osteosarcoma cells (143B cells) and significantly reduced cell proliferation, migration and invasion. Therefore, the drug-efficient release of antitumor effect of HACA nanoparticles is a promising way to treat osteosarcoma.

Polystyrene microplastics arrest skeletal growth in puberty through accelerating osteoblast senescence.

Polystyrene microplastics (PS-MPs) have attracted worldwide attention to their massive accumulation in terrestrial and aquatic ecosystems. It has been demonstrated that MPs are easily to accumulate in organs and exert toxic effects. However, their exposure risk to the skeleton remains unknown. In this study, we observed PS-MPs accumulation in both the long bones and axial bones, leading to reduced body length, as well as femur and tibia length. PS-MPs treated mice exhibited redundant skeletal growth and impaired trabecular bone micro-architecture, which is due to the suppressed osteogenic ability as the number of osteoblasts decreased significantly in PS-MPs treated mice. In histological analysis, we observed the accumulation of senescent osteoblasts in the bone trabecula of PS-MPs treated mice, as well as the impaired autophagy with decreased autophagosome and reduced autophagy-related proteins in the senescent osteoblasts. Re-establishing autophagy effectively reversed the senescent phenotype in osteoblasts and ameliorated PS-MPs induced skeletal growth arrest. Hence, our study reveals the detrimental role of PS-MPs in skeletal growth in puberty through accelerating osteoblast senescence, which may be alleviated by reactivating the autophagy. This study provides new evidence of the PS-MPs on health threats and the potential therapeutic targets to reverse it.

How social support predicts anxiety among university students during COVID-19 control phase: Mediating roles of self-esteem and resilience.

Public health emergency, such as COVID-19 pandemic, generally has severe impacts on mental health in public. One of the often-neglected negative consequences is that the control and prevention measures of COVID-19 in the post-epidemic can pose psychological threats to public mental health. This study aimed to seek the factors and mechanisms to alleviate this mental health threat based on a sample of university students in China. Accordingly, this study proposed an environmental-individual interaction model examining the multiple mediating effects of self-esteem and resilience in the association between social support and anxiety among university students during COVID-19 control phase. A questionnaire containing multiple scales were administered on the sample of 2734 Chinese university students. Results indicated that social support negatively predicted anxiety through the serial mediating effects of self-esteem and resilience sequentially. Our results highlight the impact of social support and the internal factors on relieving anxiety among university students in COVID-19 control phase. Findings suggest that effective psychological intervention tools should be designed and offered to college students to reduce anxiety distress and improve mental health in the post-epidemic era or the similar situations in the future.

Does tourniquet use affect the periprosthetic bone cement penetration in total knee arthroplasty? A meta-analysis.

BACKGROUND: A tourniquet is a device commonly used to control massive hemorrhage during knee replacement surgery. However, the question remains whether the use of tourniquets affects the permeability of the bone cement around the knee prosthesis. Moreover, the long-term effects and stability of the knee prosthesis are still debatable. The aim of this study was to examine whether the use of a tourniquet increases the thickness of the cement mantle and affects the postoperative blood loss and pain during primary total knee arthroplasty (TKA) using meta-analysis. METHODS: We searched the Cochrane Central Library, MEDLINE, Embase, PubMed, CNKI, and Wang Fang databases for randomized controlled trials (RCTs) on primary TKA, from inception to November 2019. All RCTs in primary TKA with and without a tourniquet were included. The meta-analysis was conducted using RevMan 5.2 software. RESULTS: A total of eight RCTs (677 knees) were analyzed. We found no significant difference in the age and sex of the patients. The results showed that the application of tourniquet affects the thickness of the bone cement around the tibial prosthesis (WMD = 0.16, 95%CI = 0.11 to 0.21, p < 0.00001). However, in our study, there was no significant difference in postoperative blood loss between the two groups was observed (WMD = 12.07, 95%CI = - 78.63 to 102.77, p = 0.79). The use of an intraoperative tourniquet can increase the intensity of postoperative pain (WMD = 1.34, 95%, CI = 0.32 to 2.36, p = 0.01). CONCLUSIONS: Tourniquet application increases the thickness of the bone cement around the prosthesis and may thus increase the stability and durability of the prosthesis after TKA. The application of an intraoperative tourniquet can increase the intensity of postoperative pain.

The procrastinators want it now: Behavioral and event-related potential evidence of the procrastination of intertemporal choices.

Much past research has focused on the correlation between procrastination and personality traits (e.g., impulsivity). According to the temporal motivation theory, procrastinators are impulsive and sensitive to delays in time. However, there is still a lack of direct evidence of the tendency of procrastinators to prefer immediate over future rewards. To investigate this question, we recorded event-related potentials (ERPs) in the brain while participants performed an intertemporal choice task involving both time delay and reward processing. The participants were assigned to a high procrastination group and a low procrastination group according to their scores on self-report measures. We found that high procrastination participants preferred immediate rewards compared to future ones whereas low procrastination participants did not. High procrastinators also exhibited a larger and delayed P2 component, indicating delay time processing and abnormal reward processing. No significant effect associated with procrastination was found on the P300 component. Taken together, these findings suggest that high procrastinators are more impulsive and encode the information of delay time more slowly but with a higher level of motivation-driven attention. The current study substantiates higher impulsivity in procrastination and verifies that a difference exists in the sensitivity to time delay between high and low procrastinators.