Pre-encoded responsiveness to type I interferon in the peripheral immune system defines outcome of PD1 blockade therapy.

Type I interferons (IFN-Is) are central regulators of anti-tumor immunity and responses to immunotherapy, but they also drive the feedback inhibition underlying therapeutic resistance. In the present study, we developed a mass cytometry approach to quantify IFN-I-stimulated protein expression across immune cells and used multi-omics to uncover pre-therapy cellular states encoding responsiveness to inflammation. Analyzing peripheral blood cells from multiple cancer types revealed that differential responsiveness to IFN-Is before anti-programmed cell death protein 1 (PD1) treatment was highly predictive of long-term survival after therapy. Unexpectedly, IFN-I hyporesponsiveness efficiently predicted long-term survival, whereas high responsiveness to IFN-I was strongly associated with treatment failure and diminished survival time. Peripheral IFN-I responsive states were not associated with tumor inflammation, identifying a disconnect between systemic immune potential and 'cold' or 'hot' tumor states. Mechanistically, IFN-I responsiveness was epigenetically imprinted before therapy, poising cells for differential inflammatory responses and dysfunctional T cell effector programs. Thus, we identify physiological cell states with clinical importance that can predict success and long-term survival of PD1-blocking immunotherapy.

Generation of an Inhibitory NK Cell Subset by TGF-ß1/IL-15 Polarization.

NK cells have been shown to exhibit inflammatory and immunoregulatory functions in a variety of healthy and diseased settings. In the context of chronic viral infection and cancer, distinct NK cell populations that inhibit adaptive immune responses have been observed. To understand how these cells arise and further characterize their immunosuppressive role, we examined in vitro conditions that could polarize human NK cells into an inhibitory subset. TGF-ß1 has been shown to induce regulatory T cells in vitro and in vivo; we therefore investigated if TGF-ß1 could also induce immunosuppressive NK-like cells. First, we found that TGF-ß1/IL-15, but not IL-15 alone, induced CD103+CD49a+ NK-like cells from peripheral blood NK cells, which expressed markers previously associated with inhibitory CD56+ innate lymphoid cells, including high expression of GITR and CD101. Moreover, supernatant from ascites collected from patients with ovarian carcinoma also induced CD103+CD49a+ NK-like cells in vitro in a TGF-ß-dependent manner. Interestingly, TGF-ß1/IL-15-induced CD103+CD56+ NK-like cells suppressed autologous CD4+ T cells in vitro by reducing absolute number, proliferation, and expression of activation marker CD25. Collectively, these findings provide new insight into how NK cells may acquire an inhibitory phenotype in TGF-ß1-rich environments.

Targeted glycan degradation potentiates cellular immunotherapy for solid tumors.

Immune cell-based cancer therapies, such as chimeric antigen receptor T (CAR-T)-cell immunotherapy, have demonstrated impressive potency against hematological tumors. However, the efficacy of CAR-T cells against solid tumors remains limited. Herein, we designed tumor-targeting molecule-sialidase conjugates that potently and selectively stripped different sialoglycans from a variety of cancer cells. Desialylation enhanced induced pluripotent stem cell-derived chimeric antigen receptor-macrophage (CAR-iMac) infiltration and activation. Furthermore, the combination of cancer cell desialylation and CAR-iMac adoptive cellular therapy exerted a dramatic therapeutic effect on solid tumors and significantly prolonged the survival of tumor-bearing mice; these effects were mainly dependent on blockade of the checkpoint composed of sialic acid-binding immunoglobulin-like lectin (Siglec)-5 and Siglec-10 on the macrophages, and knockout of the glycoimmune checkpoint receptors could construct a CAR-iMac cell with stronger anticancer activity. This strategy that reverts the immune escape state ("cold tumor") to a sensitive recognition state ("hot tumor") has great significance for enhancing the effect of cellular immunotherapy on solid tumors. Therefore, desialylation combined with CAR-iMac cellular immunotherapy is a promising approach to enhance treatment with cellular immunotherapy and expand the valid indications among solid tumors, which provides inspiration for the development of cellular immunotherapies with glycoimmune checkpoint inhibition for the treatment of human cancer.

All is not lost: learning from 9p21 loss in cancer.

The cancer research community continues to search for additional biomarkers of response and resistance to immune checkpoint treatment (ICT). The ultimate goal is to direct the use of ICT in patients whose tumors are most likely to benefit to achieve a refinement that is equivalent to that of a genotype-matched targeted treatment. Dissecting the mechanisms of ICT resistance can help us characterize ICT nonresponders more efficiently. In this opinion, we argue that there may be additional knowledge gained about immune evasion in cancer by analyzing the loss of the human 9p21.3 locus; as an example, we highlight findings of 9p21.3 loss from the investigator-initiated, pan-cancer INSPIRE study, in which patients were treated with pembrolizumab (anti-PD-1 antibody) ICT.

ASC-expressing pyroptotic extracellular vesicles alleviate sepsis by protecting B cells.

Pyroptosis is an inflammatory programmed cell death process characterized by membrane rupture. Interestingly, pyroptotic cells can generate plenty of nanosized vesicles. Non-inflammatory apoptotic cell death-derived apoptotic vesicles (apoVs) were systemically characterized and displayed multiple physiological functions and therapeutic potentials. However, the characteristics of pyroptotic cell-generated extracellular vesicles (EVs) are largely unknown. Here, we identified a group of pyroptotic EVs (pyroEVs) from in vitro cultured pyroptotic mesenchymal stem cells (MSCs), as well as from septic mouse blood. Compared with apoVs, pyroEVs express similar levels of annexin V, calreticulin, and common EV markers, but express a decreased level of apoptotic marker cleave caspase-3. PyroEVs, but not apoVs and exosomes, specifically express pyroptotic maker apoptosis-associated speck-like protein containing CARD (ASC). More importantly, MSC-derived pyroEVs protect B cells in the spleen and bone marrow to relieve inflammatory responses and enhance the survival rate of the septic mice. Mechanistically, pyroEV membrane-expressed ASC binds to B cells to repress cell death by repressing Toll-like receptor 4. This study uncovered the characteristics of pyroEVs and their therapeutic role in sepsis and B cell-mediated immune response.

The role of Interleukin-22 in severe acute pancreatitis.

Severe acute pancreatitis (SAP) begins with premature activation of enzymes, promoted by the immune system, triggering a potential systemic inflammatory response that leads to organ failure with increased mortality and a bleak prognosis. Interleukin-22 (IL-22) is a cytokine that may have a significant role in SAP. IL-22, a member of the IL-10 cytokine family, has garnered growing interest owing to its potential tissue-protective properties. Recently, emerging research has revealed its specific effects on pancreatic diseases, particularly SAP. This paper provides a review of the latest knowledge on the role of IL-22 and its viability as a therapeutic target in SAP.

Advancing autologous CAR T-cell therapy through real-time patient health data integration: a simulation-based approach.

Autologous chimeric antigen receptor T-cell therapy presents promising treatment outcomes for various cancers. However, its potential is restrained by unique supply chain challenges, including dynamic patient health conditions and extended turnaround time. These challenges often lead to missed optimal treatment windows, impeding the effective delivery of life-saving treatments. This article presents SimPAC (simulation-based decision support for Patient-centric manufacturing of autologous cell therapies). SimPAC is designed to model and incorporate real-time patient health conditions into the supply chain decisions of autologous chimeric antigen receptor T-cell therapy. SimPAC integrates system dynamics and agent-based simulation techniques, facilitating the adaptation of manufacturing processes and production schedules based on real-time patient health conditions. SimPAC can model various patient disease progressions using parametric functions, nonparametric functions, or tabular data. Additionally, SimPAC offers easy configuration options to model various cell therapy supply chains. We provide two case studies to demonstrate the capabilities of SimPAC and highlight the benefits of patient-centric manufacturing, including improved survival rates and potential economic advantages. However, while the benefits are significant, our study also emphasizes the importance of balancing improved patient outcomes, economic viability and ethical considerations in the context of personalized medicine. SimPAC can be used to explore applications of this approach to diverse therapeutic contexts and supply chain configurations.

Resource-Efficient Direct Characterization of General Density Matrix.

Sequential weak measurements allow for the direct extraction of individual density-matrix elements, rather than relying on global reconstruction of the entire density matrix, which opens a new avenue for the characterization of quantum systems. Nevertheless, extending the sequential scheme to multiqudit quantum systems is challenging due to the requirement of multiple coupling processes for each qudit and the lack of appropriate precision evaluation. To address these issues, we propose a resource-efficient scheme (RES) that directly characterizes the density matrix of general multiqudit systems while optimizing measurements and establishing a feasible estimation analysis. In the RES, an efficient observable of the quantum system is constructed such that a single meter state coupled to each qudit is sufficient to extract the corresponding density-matrix element. An appropriate model based on the statistical distribution of errors is utilized to evaluate the precision and feasibility of the scheme. We have experimentally applied the RES to the direct characterization of general single-photon qutrit states and two-photon entangled states. The results show that the RES outperforms sequential schemes in terms of efficiency and precision in both weak- and strong-coupling scenarios. This Letter sheds new light on the practical characterization of large-scale quantum systems and the investigation of their nonclassical properties.

Predictive Value of the Diffusion Magnetic Resonance Imaging Technique for the Postoperative Outcome of Cervical Spondylotic Myelopathy.

BACKGROUND: Diffusion magnetic resonsance imaging (dMRI) can potentially predict the postoperative outcome of cervical spondylotic myelopathy (CSM). PURPOSE: To explore preoperative dMRI parameters to predict the postoperative outcome of CSM through multifactor correlation analysis. STUDY TYPE: Prospective. POPULATION: Post-surgery CSM patients; 102 total, 73 male (52.42 ± 10.60 years old) and 29 female (52.0 ± 11.45 years old). FIELD STRENGTH/SEQUENCE: 3.0 T/Turbo spin echo T1/T2-weighted, T2*-weighted multiecho gradient echo and dMRI. ASSESSMENT: Spinal cord function was evaluated using modified Japanese Orthopedic Association (mJOA) scoring at different time points: preoperative and 3, 6, and 12 months postoperative. Single-factor correlation and t test analyses were conducted based on fractional anisotropy (FA), mean diffusivity, intracellular volume fraction, isotropic volume fraction, orientation division index, increased signal intensity, compression ratio, age, sex, symptom duration and operation method, and multicollinearity was calculated. The linear quantile mixed model (LQMM) and the linear mixed-effects regression model (LMER) were used for multifactor correlation analysis using the combinations of the above variables. STATISTICAL TESTS: Distance correlation, Pearson's correlation, multiscale graph correlation and t tests were used for the single-factor correlation analyses. The variance inflation factor (VIF) was used to calculate multicollinearity. LQMM and LMER were used for multifactor correlation analyses. P < 0.05 was considered statistically significant. RESULTS: The single-factor correlation between all variables and the postoperative mJOA score was weak (all r < 0.3). The linear relationship was stronger than the nonlinear relationship, and there was no significant multicollinearity (VIF = 1.10-1.94). FA values in the LQMM and LMER models had a significant positive correlation with the mJOA score (r = 5.27-6.04), which was stronger than the other variables. DATA CONCLUSION: The FA value based on dMRI significantly positively correlated with CSM patient postoperative outcomes, helping to predict the surgical outcome and formulate a treatment plan before surgery. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Purification, crystallization and preliminary crystallographic analysis of Chlamydophila pneumoniae AP endonuclease IV.

Base excision is a crucial DNA repair process mediated by endonuclease IV in nucleotide excision. In Chlamydia pneumoniae, CpendoIV is the exclusive AP endonuclease IV, exhibiting DNA replication error-proofreading capabilities, making it a promising target for anti-chlamydial drug development. Predicting the structure of CpendoIV, molecular docking with DNA was performed, analyzing complex binding sites and protein surface electrostatic potential. Comparative structural studies were conducted with E. coli EndoIV and DNA complex containing AP sites.CpendoIV was cloned, expressed in E. coli, and purified via Ni-NTA chelation and size-exclusion chromatography. Low NaCl concentrations induced aggregation during purification, while high concentrations enhanced purity.CpendoIV recognizes and cleaving AP sites on dsDNA, and Zn2+ influences the activity. Crystallization was achieved under 8% (v/v) Tacsimate pH 5.2, 25% (w/v) polyethylene glycol 3350, and 1.91 Å resolution X-ray diffraction data was obtained at 100 K. This research is significant for provides a deeper understanding of CpendoIV involvement in the base excision repair process, offering insights into Chlamydia pneumoniae.

Leptomeningeal carcinomatosis and brain metastases in gastroesophageal carcinoma: a real-world analysis of clinical and pathologic characteristics and outcomes.

BACKGROUND: Brain metastasis (BrM) and Leptomeningeal Carcinomatosis (LMC) are uncommon complications in gastroesophageal carcinoma (GEC) patients. These patients have a poor prognosis and are challenging to treat. We described the clinicopathologic features and outcomes in the largest cohort of Central Nervous System (CNS) metastasis in GEC patients. METHODS: single-center retrospective study of GEC treated from 2007 to 2021. Clinicopathologic characteristics and treatment modalities were reviewed. Survival was calculated from the date of CNS diagnosis until date of death/last follow-up using the Kaplan-Meier method. A multivariable Cox proportional hazards regression model was used. RESULTS: Of 3283 GEC patients, 100 (3.04%) were diagnosed with BrM and 20 with LMC (0.61%). Patients with known human epidermal growth factor receptor 2 (HER2) status (N = 48), 60% were HER2 positive (defined as IHC 3 + or IHC 2+/FISH+). Among LMC patients most were signet-ring subtype (85%), and only 15% (2/13) were HER2 positive. Median survival was 0.7; 3.8; and 7.7 months in BrM patients treated with best supportive care, radiation, and surgery, respectively (p < 0.001). In LMC, median survival was 0.7 month in patients who had best supportive care (7/19) and 2.8 months for those who had whole brain radiation therapy (p = 0.015). Multivariate analysis showed worse outcomes in ECOG ≥ 2 (p = 0.002), number of BrM ≥ 4 (p < 0.001) and number of metastatic sites (p = 0.009). CONCLUSION: HER2 expression were enriched in patients with BrM, while it is uncommon in LMC. Patients treated with surgery followed by radiation had an improved OS in BrM and WBRT benefited patients with LMC.

Rational control of the typical surface defects of hybrid perovskite using tetrahexylammonium iodide.

There are numerous defects existing on the surface and grain boundary of perovskite, which adversely affect the performance and stability of perovskite solar cell devices. Systematic first-principles calculations show that the I vacancy (VI), Pb vacancy (VPb), Pb-I antisite (PbI), and I-Pb antisite (IPb) defects can significantly affect the electronic properties of the surface of formamidinium lead triiodide (FAPbI3); in particular the VPb, PbI and IPb surface defects can introduce defect energy levels in the band gap. Tetrahexylammonium iodide (THAI) that is strongly adsorbed on the (1 0 0) surface of FAPbI3 by forming Pb-I coordination bonds and I⋯H hydrogen bonds could eliminate or reduce the defect states near the band edge or in the band gap by transferring electrons between THAI and the surface of FAPbI3. In particular, the defect states introduced by VPb could be completely eliminated after the adsorption of THAI. This study shows an in-depth understanding of the influence of defects on the electronic properties of the surface of FAPbI3, as well as the passivation mechanism of organic salts on the surface defects of perovskite.

Realization of hydrogenation-induced superconductivity in two-dimensional Ti2N MXene.

Two-dimensional (2D) MXene superconductors have been currently attracting considerable interest due to their unique electronic properties and diverse applicability. Utilizing first-principles computational methods, we have designed two distinct configurations of hydrogenated 2D Ti2N MXene materials, namely Ti2NH2 and Ti2NH4, and have conducted an exhaustive analysis of their structural stability, electronic characteristics, and superconductivity. Hydrogenation endows monolayer Ti2N with inherent metallic characteristics, as evidenced by an elevated density of states (DOS) at the Fermi level (Ef). Notably, Ti2NH4 exhibits a superconducting critical temperature (Tc) of 15.8 K, which is predominantly ascribed to the electronic contributions stemming from the Ti 3d orbitals. Analysis of phonon dispersion underscores the pivotal role that diverse lattice vibrational modes play in electron-phonon coupling (EPC), particularly the significance of low-frequency vibrations for facilitating electron pairing and the emergence of superconductivity. Furthermore, strain engineering can effectively modulate the superconducting properties of Ti2NH4, with a 2% tensile strain enhancing the EPC strength (λ) to 0.857 and increasing Tc to 18.7 K. This research elucidates the superconducting mechanisms of hydrogenated Ti2N structures, offering valuable insights for the development of novel 2D superconducting materials.

Repair spinal cord injury with a versatile anti-oxidant and neural regenerative nanoplatform.

Spinal cord injury (SCI) often results in motor and sensory deficits, or even paralysis. Due to the role of the cascade reaction, the effect of excessive reactive oxygen species (ROS) in the early and middle stages of SCI severely damage neurons, and most antioxidants cannot consistently eliminate ROS at non-toxic doses, which leads to a huge compromise in antioxidant treatment of SCI. Selenium nanoparticles (SeNPs) have excellent ROS scavenging bioactivity, but the toxicity control problem limits the therapeutic window. Here, we propose a synergistic therapeutic strategy of SeNPs encapsulated by ZIF-8 (SeNPs@ZIF-8) to obtain synergistic ROS scavenging activity. Three different spatial structures of SeNPs@ZIF-8 were synthesized and coated with ferrostatin-1, a ferroptosis inhibitor (FSZ NPs), to achieve enhanced anti-oxidant and anti-ferroptosis activity without toxicity. FSZ NPs promoted the maintenance of mitochondrial homeostasis, thereby regulating the expression of inflammatory factors and promoting the polarization of macrophages into M2 phenotype. In addition, the FSZ NPs presented strong abilities to promote neuronal maturation and axon growth through activating the WNT4-dependent pathways, while prevented glial scar formation. The current study demonstrates the powerful and versatile bioactive functions of FSZ NPs for SCI treatment and offers inspiration for other neural injury diseases.

Revealing an association between HPV and systemic lupus erythematosus: A bidirectional two-sample Mendelian randomization study.

BACKGROUND: An increasing number of studies have focused on the association between Human papillomavirus (HPV) infection and systemic lupus erythematosus (SLE). However, current evidence is largely based on retrospective studies, which are susceptible to confounding factors and cannot establish causation. METHODS: A bidirectional two-sample Mendelian randomization (MR) design was used to evaluate the causal relationship between HPV and SLE. Mononucleoside polymers (SNPS) with strong evidence for genome-wide association studies (GWAS) were selected from the HPV exposure dataset and used as an instrumental variable (IV) for this study. For the MR Analysis results, the MR-Egger intercept P test, MR-Presso global test, CochranQ test and leave-one test were used for sensitivity analysis. RESULTS: Based on the evidence of MR Analysis, this study finally determined that there was no causal association between HPV16 and HPV18 and SLE. CONCLUSIONS: Possible regulation of HPV infection is not significantly associated with regulation of SLE. These findings provide new insights into the underlying mechanisms of HPV and SLE and need to be validated by further studies.

Would the one-stage combined approach lead to better long-term neurological outcomes than the posterior approach alone in multilevel degenerative cervical myelopathy patients with T2-Weighted increased signal intensity? An 8-year follow-up results and propensity score matching analysis.

BACKGROUND: T2-weighted increased signal intensity (ISI) is commonly recognized as a sign of more severe spinal cord lesions, usually accompanied by worse neurological deficits and possibly worse postoperative neurological recovery. The combined approach could achieve better decompression and better neurological recovery for multilevel degenerative cervical myelopathy (MDCM). The choice of surgical approach for MDCM with intramedullary T2-weighted ISI remains disputed. This study aimed to compare the neurological outcomes of posterior and one-stage combined posteroanterior approaches for MDCM with T2-weighted ISI. METHODS: A total of 83 consecutive MDCM patients with confirmed ISI with at least three intervertebral segments operated between 2012 and 2014 were retrospectively enrolled. Preoperative demographic, radiological and clinical condition variables were collected, and neurological conditions were evaluated by the Japanese Orthopedic Assessment score (JOA) and Neck Disability Index (NDI). Propensity score matching analysis was conducted to produce pairs of patients with comparable preoperative conditions from the posterior-alone and combined groups. Both short-term and mid-term surgical outcomes were evaluated, including the JOA recovery rate (JOARR), NDI improvements, complications, and reoperations. RESULTS: A total of 83 patients were enrolled, of which 38 and 45 patients underwent posterior surgery alone and one-stage posteroanterior surgery, respectively. After propensity score matching, 38 pairs of comparable patients from the posterior and combined groups were matched. The matched groups presented similar preoperative clinical and radiological features and the mean follow-up duration were 111.6 ± 8.9 months. The preoperative JOA scores of the posterior and combined groups were 11.5 ± 2.2 and 11.1 ± 2.3, respectively (p = 0.613). The combined group presented with prolonged surgery duration(108.8 ± 28.0 and 186.1 ± 47.3 min, p = 0.028) and greater blood loss(276.3 ± 139.1 and 382.1 ± 283.1 ml, p<0.001). At short-term follow-up, the combined group presented a higher JOARR than the posterior group (posterior group: 50.7%±46.6%, combined group: 70.4%±20.3%, p = 0.024), while no significant difference in JOARR was observed between the groups at long-term follow-up (posterior group: 49.2%±48.5%, combined group: 59.6%±47.6%, p = 0.136). No significant difference was found in the overall complication and reoperation rates. CONCLUSIONS: For MDCM patients with ISI, both posterior and one-stage posteroanterior approaches could achieve considerable neurological alleviations in short-term and long-term follow-up. With greater surgical trauma, the combined group presented better short-term JOARR but did not show higher efficacy in long-term neurological function preservation in patients with comparable preoperative conditions.

Multiple cell death modalities and immune response in pulpitis.

AIM: To investigate the level and distribution of apoptosis, pyroptosis, necroptosis, and NETosis in pulpitis with or without necrosis on a basis of histological classification. Additionally, to examine the effect of pulpitis with necrosis (PWN) on the number and activation of peripheral and bone marrow (BM) neutrophils, as well as spleen lymphocytes, in a mouse model of pulpitis. METHODOLOGY: The material comprised 20 permanent teeth, with or without caries, which were classified into three histological categories based on the distribution of inflammatory cells and the presence or absence of necrosis: (i) healthy pulp (HP), (ii) pulpitis without necrosis (PWON), and (iii) PWN. The levels of the four regulated cell death (RCD) pathways were detected by immunohistochemical and immunofluorescent staining with specific markers: apoptosis (caspase-8, cleaved caspase-3), pyroptosis (cleaved caspase-1, membrane-binding gasdermin D), necroptosis (receptor-interacting kinase 3, phosphorylated MLKL), and NETosis (myeloperoxidase, citrullinated histone H3). Acute pulpitis was induced in C57BL/6J mice via pulp exposure, and the mice were divided into four groups: (i) control (no tooth preparation, n = 6), (ii) Day 1 (sacrificed at 1 day after pulp exposure, n = 3), (iii) Day 3 (n = 3), and (iv) Day 5 (n = 7). The control and Day 5 groups were used for further immunofluorescent analysis to assess the levels of RCD and flow cytometry to monitor the changes in peripheral and BM neutrophils, as well as spleen lymphocytes. Human dental pulp stem cells (hDPSCs) were isolated and cultured from extracted healthy third molars. Apoptosis and necroptosis in hDPSCs were induced by staurosporine, whilst pyroptosis was induced by lipopolysaccharide and nigericin. One-way analysis of variance (ANOVA) with Tukey's test, Welch's ANOVA with Tamhane's test, and Student's t-tests were used to compare immunohistochemical labelling and flow cytometric data amongst groups (p < .05). RESULTS: The pulpal tissue of PWN can be divided into the abscess core (PWN-AC) and fibrous tissue (PWN-FT). The ratio of total necrotic cells (TUNEL-positive) in PWN-AC was significantly higher than in PWN-FT and PWON (both p < .01). Compared with HP, the expression levels of markers for apoptosis and pyroptosis were increased in PWON, whilst the expression levels of markers for apoptosis, pyroptosis, and NETosis were elevated in PWN, primarily detected in PWN-AC. Interestingly, myeloperoxidase (MPO) was exclusively observed in PWN-AC, with minimal detection in PWN-FT and PWON. Additionally, the frequency of MPO+ cells was significantly higher than that of MB-GSDMD+ cells and Cl-cas3+ cells in PWN-AC (both p < .01). Histological observation and TUNEL staining showed abundant necrotic cells in mouse pulpal tissue after pulp exposure, indicating a simulation of human PWN. In mouse pulpitis tissue, markers of apoptosis, pyroptosis, and NETosis were detected. In vitro, various cell deaths including apoptosis, pyroptosis, and necroptosis were also triggered in hDPSCs under various cell death treatments. Furthermore, in terms of systemic changes, pulp exposure-induced pulpitis could increase the number (p < .05) and cellular activity (p < .01) of neutrophils from BM in a mouse model. No significant changes in peripheral blood neutrophils, spleen T cells, B cells, or the CD4/CD8 ratio were detected between the control and pulpitis mice. CONCLUSIONS: Our findings uncover distinct patterns of mixed cell death at different histological stages of human pulpitis and the impact of pulpitis on the number and activity of BM neutrophils. Notably, NETosis occurs specifically and predominates in the abscess area of pulpitis, suggesting a potential effect of neutrophil extracellular traps (NETs) on pulpitis progression and NETs-targeted diagnostic strategy may play a role in decision making for vital pulp therapy.

A modified method for precise anastomosis during laparoscopic low anterior resection for rectal cancer: the first clinical experience and application.

BACKGROUND: There is no criterion to guide and evaluate the anastomosis of laparoscopic low anterior resection (LAR). We developed a new technique for precise anastomosis. This study endeavored to evaluate the effectiveness and safety of this new technology. METHODS: Patients with mid-low rectal cancer who underwent laparoscopic LAR in our department were enrolled retrospectively between January 1, 2021 and July 1, 2023. During the LAR, the distance between the sacral promontory and the rectal stump was measured and used to determine the length of the sigmoid colon, which was preserved for anastomose. The demographic characteristics and short-term outcomes were analyzed. RESULTS: Forty-nine patients (26 men, 23 women) with low and middle rectal cancer were retrospectively enrolled in the study. The distance of the tumor from the anal verge was 6.4 ± 2.7 cm. The operative time was 193 ± 42 min. All patients underwent precise anastomosis, among which 12 patients underwent freeing of the splenic flexure of the colon. According to our criteria, there was no redundant or tense state of the colon anterior to the sacrum after the anastomosis. Only one patient had a postoperative anastomotic leak (Grade B). All 15 patients receiving neoadjuvant chemoradiotherapy underwent terminal ileostomy. No postoperative death occurred within 30 days of the surgery. The median follow-up time in our study was 12 months. One patient developed a single metastasis in the right lobe of the liver in the eighth month after surgery and underwent microwave radiofrequency ablation, which did not recur in the four months of postoperative follow-up, and the rest of the patients survived disease-free without recurrence of metastasis. CONCLUSIONS: Precise measurement of the proximal colon of the anastomosis can ensure accurate and convenient colorectal anastomosis and this may be a technique worthy of clinical application. However, its effectiveness needs to be further verified in a multicenter clinical trial.

Conversion Total Hip Arthroplasty After Pedicled Peri-Hip Bone Flap Grafting: The Chinese Experience.

BACKGROUND: This study investigated the perioperative outcomes of patients undergoing conversion total hip arthroplasty (THA) after failed peri-hip bone flap grafting (PBFG) and compared them with those patients undergoing primary THA for osteonecrosis of the femoral head (ONFH). METHODS: From January 2010 to December 2021, 163 Chinese patients (163 hips) were treated by conversion THA after failed PBFG (containing 94 patients who had pedicled vascularized iliac bone flap grafting and 69 patients who had pedicled vascularized greater trochanter bone flap grafting), and 178 Chinese patients were treated by primary THA. The preoperative baseline data and perioperative indicators in both groups were compared. RESULTS: In the conversion group, patients had significantly greater blood loss, a longer length of stay, and greater changes in serum hemoglobin than those in the primary THA group (P < 0.05). The operative room time, transfusion volume, calculated blood loss, changes in serum hematocrit, and increased superficial infection (P > 0.05) in the conversion group were greater compared with the primary cohort; however, the difference was not statistically significant. The mean postoperative Harris Hip Scoring system (HHS) of the PBFG group at the 1-month follow-up was 81, and the control group had a score of 82. Importantly, subgroup analysis of the PBFG group indicated that there was no significant difference between patients who had prior pedicled vascularized iliac bone flap grafting and pedicled vascularized greater trochanter bone flap grafting (P > 0.05), except for the operative room time (P = 0.032). CONCLUSIONS: Hip-sparing surgery of ONFH did not make THA more difficult or lead to more perioperative complications, but increased blood loss and extended hospital stay from a prior PBFG are still notable problems in clinical practice. Thus, it is necessary for surgeons to focus attention on the improvement of the preoperative condition and prepare for any specific intraoperative challenges.

Poly(lactic acid hydroxyacetic acid)-poly(ethylene glycol)-modified ginsenoside Rg3 nanomedicine enhances anti-tumor effect in hepatocellular carcinoma.

OBJECTIVE: This research aims to improve the bioavailability and anti-hepatocellular carcinoma (HCC) efficacy of Ginsenoside Rg3 by modification with poly (lactic acid hydroxyacetic acid)-poly(ethylene glycol) (PLGA-PEG). METHODS: PLGA-PEG-Rg3 was obtained by emulsification and evaluated it physiochemical characterization by FTIR, SEM, laser particle-size analyzer and HPLC. The effect of the PLGA-PEG-Rg3 and Rg3 on HepG2 cells was compared in vitro studies, including cell proliferation, transwell and a series of apoptosis detection, and in-situ HCC model. RESULTS: The PLGA-PEG-Rg3 were 122 nm in size and 0.112 in polydispersity index with sustained release profile in vitro. Compared to Rg3, PLGA-PEG-Rg3 was more effective in suppressing HepG2 growth and inducing apoptosis by the mitochondrial apoptosis pathway in vitro. And PLGA-PEG modification enhanced the liver-targeting ability and drug circulation time of Rg3 in vivo, resulting in PLGA-PEG-Rg3 possessing superior performance in inhibiting tumor growth and prolonging the survival time of tumor-bearing mice than Rg3. CONCLUSIONS: Overall, these results showed PLGA-PEG-Rg3 enhanced the anti-tumor effect of Rg3 in HCC.