Optimal timing and sequence of combining stereotactic radiosurgery with immune checkpoint inhibitors in treating brain metastases: clinical evidence and mechanistic basis

Abstract Recent evidence has shown that immune checkpoint inhibitors (ICIs) are efficacious for treating brain metastases of various primary tumors. However, the immunosuppressive tumor microenvironment and the blood–brain barrier (BBB) or blood-tumor barrier (BTB) essentially restrict the efficacy of ICIs. Stereotactic radiosurgery (SRS) can be a powerful ally to ICIs due to its trait of disrupting the BBB/BTB and increasing the immunogenicity of brain metastases. The combination of SRS + ICI has shown synergy in brain metastases in several retrospective studies. Nevertheless, the optimal schedule for the combination of SRS and ICI in brain metastases is yet to be determined. In this review, we summarized the current clinical and preclinical evidence on the timing and sequence of SRS + ICI to provide insight into the current state of knowledge about this important area in patient care

Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials

Abstract Over the past decade, immune checkpoint inhibitors (ICIs) have emerged as a revolutionary cancer treatment modality, offering long-lasting responses and survival benefits for a substantial number of cancer patients. However, the response rates to ICIs vary significantly among individuals and cancer types, with a notable proportion of patients exhibiting resistance or showing no response. Therefore, dual ICI combination therapy has been proposed as a potential strategy to address these challenges. One of the targets is TIGIT, an inhibitory receptor associated with T-cell exhaustion. TIGIT has diverse immunosuppressive effects on the cancer immunity cycle, including the inhibition of natural killer cell effector function, suppression of dendritic cell maturation, promotion of macrophage polarization to the M2 phenotype, and differentiation of T cells to regulatory T cells. Furthermore, TIGIT is linked with PD-1 expression, and it can synergize with PD-1/PD-L1 blockade to enhance tumor rejection. Preclinical studies have demonstrated the potential benefits of co-inhibition of TIGIT and PD-1/PD-L1 in enhancing anti-tumor immunity and improving treatment outcomes in several cancer types. Several clinical trials are underway to evaluate the safety and efficacy of TIGIT and PD-1/PD-L1 co-inhibition in various cancer types, and the results are awaited. This review provides an overview of the mechanisms of TIGIT and PD-1/PD-L1 co-inhibition in anti-tumor treatment, summarizes the latest clinical trials investigating this combination therapy, and discusses its prospects. Overall, co-inhibition of TIGIT and PD-1/PD-L1 represents a promising therapeutic approach for cancer treatment that has the potential to improve the outcomes of cancer patients treated with ICIs

Association of epidural analgesia during labor and early postpartum urinary incontinence among women delivered vaginally: a propensity score matched retrospective cohort study

Abstract Background Although epidural analgesia is considered the gold standard for pain relief during labor and is safe for maternity and fetus, the association between the epidural analgesia and pelvic floor disorders remains unclear. Thus we estimate the association between epidural analgesia and early postpartum urinary incontinence (UI). Methods A propensity score-matched retrospective cohort study was conducted at a university-affiliated hospital in Shanghai, China. Primiparous women with term, singleton, and vaginal delivery between December 2020 and February 2022 were included. UI was self-reported by maternity at 42 to 60 days postpartum and was classified by International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF). Using logistic regression models, the associations between epidural analgesia and early postpartum UI were assessed. Results Among 5190 participants, 3709 (71.5%) choose epidural anesthesia during labor. Analysis of the propensity-matched cohort (including 1447 maternal pairs) showed epidural anesthesia during labor was independently associated with UI in early postpartum period (aOR 1.50, 95% CI 1.24–1.81). This association was mainly contributed to stress UI (aOR 1.38, 95% CI 1.12–1.71) rather than urge UI (aOR 1.45, 95% CI 0.99–2.15) and mixed UI (aOR 1.52, 95% CI 0.95–2.45). Furthermore, we observed that the association between epidural anesthesia and UI was more pronounced among older women (≥ 35 y) and women with macrosomia (infant weight ≥ 4000 g), compared with their counterparts (both P for interaction < 0.01). After further analysis excluding the women with UI during pregnancy, the results remained largely consistent with the main analysis. Conclusions The findings support that epidural anesthesia was associated with SUI in the early postpartum period

Application of modified alveolar ridge augmentation technique for horizontal bone augmentation in posterior mandibular region: report of 3 cases

Three cases with severe horizontal bone deficiency on mandibular posterior region were committed by modified alveolar ridge augmentation. The therapeutic outcomes show that it is an effective methodology in cases with compromised horizontal bone

Association of cesarean delivery timing with pelvic floor muscle function and urine incontinence: A propensity score‐matched study

Abstract Pelvic floor dysfunction is a common gynecological disease that adversely affects women's quality of life and mental health. Delivery is considered a significant independent risk factor for pelvic floor dysfunction. Surface electromyography (sEMG) values for the pelvic floor muscles (PFM) have been shown to differ according to different delivery modes. This study aimed to compare sEMG results between intrapartum and antepartum cesarean delivery (CD), 42–60 days after delivery. Data of women who underwent CD at the International Peace Maternity and Child Health Hospital were collected from September 2021 to December 2021. Myotrac Infiniti System was used to measure the electromyographic activity of PFM after 42–60 days of parturition. Propensity score matching (1:1) was applied to achieve a balance in baseline data between the two groups (intrapartum and antepartum CD). A total of 200 paired cases were selected for statistical analysis. In the propensity score‐matched analysis, there were no statistically significant differences in PFM sEMG between women with antepartum or intrapartum CD (p > 0.05 for all). We observed similar results with postpartum urinary incontinence (24 [12.0] vs. 21 [10.5]; adjusted odds ratio (aOR), 1.12 [95% confidence interval (CI) 0.60–2.12]; p = 0.717) and stress urinary incontinence (12 [6.0] vs. 14 [7.0]; aOR, 0.80 [95% CI 0.35–1.80]; p = 0.596) as outcomes. After excluding participants with intrapartum CD when the cervix was dilated <6 cm, all sEMG of PFM had a comparable level of risk in both the antepartum and intrapartum CD groups. There were no significant differences in sEMG of the PFM and the incidence of urinary incontinence between patients undergoing intrapartum or antepartum CD. Excluding women who underwent intrapartum CD when the cervix was dilated to <6 cm produced little change in results. Thus, different opportunities for CD may not impact the sEMG of the PFM and the incidence of urinary incontinence

Physical, mechanical, and biological properties of collagen membranes for guided bone regeneration: a comparative in vitro study

Abstract Background To provide a reference for clinical selection of collagen membranes by analyzing the properties of three kinds of collagen membranes widely used in clinics: Bio-Gide membrane from porcine dermis (PD), Heal-All membrane from bovine dermis (BD), and Lyoplant membrane from bovine pericardium (BP). Methods The barrier function of three kinds of collagen membranes were evaluated by testing the surface morphology, mechanical properties, hydrophilicity, and degradation rate of collagen membranes in collagenase and artificial saliva. In addition, the bioactivity of each collagen membrane as well as the proliferation and osteogenesis of MC3T3-E1 cells were evaluated. Mass spectrometry was also used to analyze the degradation products. Results The BP membrane had the highest tensile strength and Young’s modulus as well as the largest water contact angle. The PD membrane exhibited the highest elongation at break, the smallest water contact angle, and the lowest degradation weight loss. The BD membrane had the highest degradation weight loss, the highest number of proteins in its degradation product, the strongest effect on the proliferation of MC3T3-E1 cells, and the highest expression level of osteogenic genes. Conclusions The PD membrane is the best choice for shaping and maintenance time, while the BD membrane is good for osteogenesis, and the BP membrane is suitable for spatial maintenance. To meet the clinical requirements of guided bone regeneration, using two different kinds of collagen membranes concurrently to exert their respective advantages is an option worth considering

Galphai1 and Galphai3 regulate macrophage polarization by forming a complex containing CD14 and Gab1

Heterotrimeric G proteins have been implicated in Toll-like receptor 4 (TLR4) signaling in macrophages and endothelial cells. However, whether guanine nucleotide-binding protein G(i) subunit alpha-1 and alpha-3 (Gαi1/3) are required for LPS responses remains unclear, and if so, the underlying mechanisms need to be studied. In this study, we demonstrated that, in response to LPS, Gαi1/3 form complexes containing the pattern recognition receptor (PRR) CD14 and growth factor receptor binding 2 (Grb2)-associated binding protein (Gab1), which are required for activation of PI3K-Akt signaling. Gαi1/3 deficiency decreased LPS-induced TLR4 endocytosis, which was associated with decreased phosphorylation of IFN regulatory factor 3 (IRF3). Gαi1/3 knockdown in bone marrow-derived macrophage cells (Gαi1/3 KD BMDMs) exhibited an M2-like phenotype with significantly suppressed production of TNF-α, IL-6, IL-12, and NO in response to LPS. The altered polarization coincidedwith decreased Akt activation. Further, Gαi1/3 deficiency caused LPS tolerance in mice. In vitro studies revealed that, in LPS-tolerant macrophages, Gαi1/3 were down-regulated partially by the proteasome pathway. Collectively, the present findings demonstrated that Gαi1/3 can interact with CD14/Gab1, which modulates macrophage polarization in vitro and in vivo.Fil: Li, Xiaolin. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; ChinaFil: Wang, Duowei. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; ChinaFil: Chen, Zen. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; ChinaFil: Lu, Ermei. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; ChinaFil: Wang, Zhuo. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; ChinaFil: Duan, Jingjing. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; ChinaFil: Tian, Wei. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; ChinaFil: Wang, Yun. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; ChinaFil: You, Linjun. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; ChinaFil: Zou, Yulian. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; ChinaFil: Cheng, Yan. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; ChinaFil: Zhu, Qingyi. Jiangsu Province Hospital of Traditional Chinese Medicine. Departament of Urology; ChinaFil: Wan, Xiaojian. Second Military Medical University. Department of Anesthesiology and Intensive Care Medicine, Changhai Hospita; ChinaFil: Xia, Tao. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; ChinaFil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. National Institute of Environmental Health Sciences. Laboratory of Neurobiology, ; Estados UnidosFil: Yang, Yong. China Pharmaceutical University. Center for New Drug Safety Evaluation and Research; Chin

CEPC Technical Design Report -- Accelerator

International audienceThe Circular Electron Positron Collider (CEPC) is a large scientific project initiated and hosted by China, fostered through extensive collaboration with international partners. The complex comprises four accelerators: a 30 GeV Linac, a 1.1 GeV Damping Ring, a Booster capable of achieving energies up to 180 GeV, and a Collider operating at varying energy modes (Z, W, H, and ttbar). The Linac and Damping Ring are situated on the surface, while the Booster and Collider are housed in a 100 km circumference underground tunnel, strategically accommodating future expansion with provisions for a Super Proton Proton Collider (SPPC). The CEPC primarily serves as a Higgs factory. In its baseline design with synchrotron radiation (SR) power of 30 MW per beam, it can achieve a luminosity of 5e34 /cm^2/s^1, resulting in an integrated luminosity of 13 /ab for two interaction points over a decade, producing 2.6 million Higgs bosons. Increasing the SR power to 50 MW per beam expands the CEPC's capability to generate 4.3 million Higgs bosons, facilitating precise measurements of Higgs coupling at sub-percent levels, exceeding the precision expected from the HL-LHC by an order of magnitude. This Technical Design Report (TDR) follows the Preliminary Conceptual Design Report (Pre-CDR, 2015) and the Conceptual Design Report (CDR, 2018), comprehensively detailing the machine's layout and performance, physical design and analysis, technical systems design, R&D and prototyping efforts, and associated civil engineering aspects. Additionally, it includes a cost estimate and a preliminary construction timeline, establishing a framework for forthcoming engineering design phase and site selection procedures. Construction is anticipated to begin around 2027-2028, pending government approval, with an estimated duration of 8 years. The commencement of experiments could potentially initiate in the mid-2030s

CEPC Technical Design Report -- Accelerator

International audienceThe Circular Electron Positron Collider (CEPC) is a large scientific project initiated and hosted by China, fostered through extensive collaboration with international partners. The complex comprises four accelerators: a 30 GeV Linac, a 1.1 GeV Damping Ring, a Booster capable of achieving energies up to 180 GeV, and a Collider operating at varying energy modes (Z, W, H, and ttbar). The Linac and Damping Ring are situated on the surface, while the Booster and Collider are housed in a 100 km circumference underground tunnel, strategically accommodating future expansion with provisions for a Super Proton Proton Collider (SPPC). The CEPC primarily serves as a Higgs factory. In its baseline design with synchrotron radiation (SR) power of 30 MW per beam, it can achieve a luminosity of 5e34 /cm^2/s^1, resulting in an integrated luminosity of 13 /ab for two interaction points over a decade, producing 2.6 million Higgs bosons. Increasing the SR power to 50 MW per beam expands the CEPC's capability to generate 4.3 million Higgs bosons, facilitating precise measurements of Higgs coupling at sub-percent levels, exceeding the precision expected from the HL-LHC by an order of magnitude. This Technical Design Report (TDR) follows the Preliminary Conceptual Design Report (Pre-CDR, 2015) and the Conceptual Design Report (CDR, 2018), comprehensively detailing the machine's layout and performance, physical design and analysis, technical systems design, R&D and prototyping efforts, and associated civil engineering aspects. Additionally, it includes a cost estimate and a preliminary construction timeline, establishing a framework for forthcoming engineering design phase and site selection procedures. Construction is anticipated to begin around 2027-2028, pending government approval, with an estimated duration of 8 years. The commencement of experiments could potentially initiate in the mid-2030s