Chronic Postsurgical Pain Following Lung Transplantation: Characteristics, Risk Factors, Treatment, and Prevention: A Narrative Review.

Chronic pain after lung transplantation (LTx) can substantially reduce quality of life (QoL), yet current consensus guidelines say little about how to prevent or manage it. Research on pain after LTx has tended to focus on acute rather than chronic pain, and it has not extensively examined the factors associated with onset or resolution of chronic pain, which differ from factors influencing chronic pain after general thoracic surgery. This narrative review explores what is known about the epidemiology and risk factors of chronic pain after LTx, as well as effective ways to treat or prevent it. The review identifies key questions and issues that should be the focus of future research.

Predictive modeling for identifying infection risk following spinal surgery: Optimizing patient management.

Infection is known to occur in a substantial proportion of patients following spinal surgery and predictive modeling may provide a useful means for identifying those at higher risk of complications and poor prognosis, which could help optimize pre- and postoperative management strategies. The outcome measure of the present study was to investigate the occurrence of all-cause infection during hospitalization following scoliosis surgery. To meet this aim, the present study retrospectively analyzed 370 patients who underwent surgery at the Second Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou, China) between January 2016 and October 2022, and patients who either experienced or did not experience all-cause infection while in hospital were compared in terms of their clinicodemographic characteristics, surgical variables and laboratory test results. Logistic regression was subsequently applied to data from a subset of patients in order to build a model to predict infection, which was validated using another subset of patients. All-cause, in-hospital postoperative infections were found to have occurred in 66/370 patients (17.8%). The following variables were included in a predictive model: Sex, American Society of Anesthesiologists (ASA) classification, body mass index (BMI), diabetes mellitus, hypertension, preoperative levels of white blood cells and preoperative C-reactive protein (CRP) and duration of surgery. The model exhibited an area under the curve of 0.776 against the internal validation set. In conclusion, dynamic nomograms based on sex, ASA classification, BMI, diabetes mellitus, hypertension, preoperative levels of white blood cells and CRP and duration of surgery may have the potential to be a clinically useful predictor of all-cause infection following scoliosis. The predictive model constructed in the present study may potentially facilitate the real-time visualization of risk factors associated with all-cause infection following surgical procedures.

Sonrotoclax overcomes BCL2 G101V mutation-induced venetoclax resistance in preclinical models of hematologic malignancy.

ABSTRACT: Venetoclax, the first-generation inhibitor of the apoptosis regulator B-cell lymphoma 2 (BCL2), disrupts the interaction between BCL2 and proapoptotic proteins, promoting the apoptosis in malignant cells. Venetoclax is the mainstay of therapy for relapsed chronic lymphocytic leukemia and is under investigation in multiple clinical trials for the treatment of various cancers. Although venetoclax treatment can result in high rates of durable remission, relapse has been widely observed, indicating the emergence of drug resistance. The G101V mutation in BCL2 is frequently observed in patients who relapsed treated with venetoclax and sufficient to confer resistance to venetoclax by interfering with compound binding. Therefore, the development of next-generation BCL2 inhibitors to overcome drug resistance is urgently needed. In this study, we discovered that sonrotoclax, a potent and selective BCL2 inhibitor, demonstrates stronger cytotoxic activity in various hematologic cancer cells and more profound tumor growth inhibition in multiple hematologic tumor models than venetoclax. Notably, sonrotoclax effectively inhibits venetoclax-resistant BCL2 variants, such as G101V. The crystal structures of wild-type BCL2/BCL2 G101V in complex with sonrotoclax revealed that sonrotoclax adopts a novel binding mode within the P2 pocket of BCL2 and could explain why sonrotoclax maintains stronger potency than venetoclax against the G101V mutant. In summary, sonrotoclax emerges as a potential second-generation BCL2 inhibitor for the treatment of hematologic malignancies with the potential to overcome BCL2 mutation-induced venetoclax resistance. Sonrotoclax is currently under investigation in multiple clinical trials.

Risk Factors for Hypocoagulability After Cardiac Surgery: A Retrospective Study.

Hemostatic disturbances after cardiac surgery can lead to excessive postoperative bleeding. Thromboelastography (TEG) was employed to evaluate perioperative coagulative alterations in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB), investigating the correlation between factors concomitant with cardiac surgery and modifications in coagulation. Coagulation index as determined by TEG correlated significantly with postoperative bleeding at 24-72 h after cardiac surgery (P < .001). Among patients with a normal preoperative coagulation index, those with postoperative hypocoagulability showed significantly lower nadir temperature (P = .003), larger infused fluid volume (P = .003), and longer CPB duration (P = .033) than those with normal coagulation index. Multivariate logistic regression showed that nadir intraoperative temperature was an independent predictor of postoperative hypocoagulability (adjusted OR: 0.772, 95% CI: 0.624-0.954, P = .017). Multivariate linear regression demonstrated linear associations of nadir intraoperative temperature (P = .017) and infused fluid volume (P = .005) with change in coagulation index as a result of cardiac surgery. Patients are susceptible to hypocoagulability after cardiac surgery, which can lead to increased postoperative bleeding. Ensuring appropriate temperature and fluid volume during cardiac surgery involving CPB may reduce risk of postoperative hypocoagulability and bleeding.

Nadir Hemoglobin Concentration After Spinal Tumor Surgery: Association With Risk of Composite Adverse Events.

STUDY DESIGN: Retrospective case-control study. OBJECTIVE: To explore the association of early postoperative nadir hemoglobin with risk of a composite outcome of anemia-related and other adverse events. METHODS: We retrospectively analyzed data from spinal tumor patients who received intraoperative blood transfusion between September 1, 2013 and December 31, 2020. Uni- and multivariate logistic regression was used to explore relationships of clinicodemographic and surgical factors with risk of composite in-hospital adverse events, including death. Subgroup analysis explored the relationship between early postoperative nadir hemoglobin and composite adverse events. RESULTS: Among the 345 patients, 331 (95.9%) experienced early postoperative anemia and 69 (20%) experienced postoperative composite adverse events. Multivariate logistic regression analysis showed that postoperative nadir Hb (OR = .818, 95% CI: .672-.995, P = .044), ASA ≥3 (OR = 2.007, 95% CI: 1.086-3.707, P = .026), intraoperative RBC infusion volume (OR = 1.133, 95% CI: 1.009-1.272, P = .035), abnormal hypertension (OR = 2.199, 95% CI: 1.085-4.457, P = .029) were correlated with composite adverse events. The lumbar spinal tumor was associated with composite adverse events with a decreased odds compared to thoracic spinal tumors (OR = .444, 95% CI: .226-.876, P = .019). Compared to patients with postoperative nadir hemoglobin ≥11.0 g/dL, those with nadir <9.0 g/dL were at significantly higher risk of postoperative composite adverse events (OR = 2.709, 95% CI: 1.087-6.754, P = .032). CONCLUSION: Nadir hemoglobin <9.0 g/dL after spinal tumor surgery is associated with greater risk of postoperative composite adverse events in patients who receive intraoperative blood transfusion.

Causal relationship between obesity and iron deficiency anemia: a two-sample Mendelian randomization study.

Background: Observational studies have suggested an association between obesity and iron deficiency anemia, but such studies are susceptible to reverse causation and residual confounding. Here we used Mendelian randomization to assess whether the association might be causal. Methods: Data on single-nucleotide polymorphisms that might be associated with various anthropometric indicators of obesity were extracted as instrumental variables from genome-wide association studies in the UK Biobank. Data on genetic variants in iron deficiency anemia were extracted from a genome-wide association study dataset within the Biobank. Heterogeneity in the data was assessed using inverse variance-weighted regression, Mendelian randomization Egger regression, and Cochran's Q statistic. Potential causality was assessed using inverse variance-weighted, Mendelian randomization Egger, weighted median, maximum likelihood and penalized weighted median methods. Outlier SNPs were identified using Mendelian randomization PRESSO analysis and "leave-one-out" analysis. Results: Inverse variance-weighted regression associated iron deficiency anemia with body mass index, waist circumference, trunk fat mass, body fat mass, trunk fat percentage, and body fat percentage (all odds ratios 1.003-1.004, P ≤ 0.001). Heterogeneity was minimal and no evidence of horizontal pleiotropy was found. Conclusion: Our Mendelian randomization analysis suggests that obesity can cause iron deficiency anemia.

A novel model for predicting a composite outcome of major complications after valve surgery.

Background: On-pump valve surgeries are associated with high morbidity and mortality. The present study aimed to reliably predict a composite outcome of postoperative complications using a minimum of easily accessible clinical parameters. Methods: A total of 7,441 patients who underwent valve surgery were retrospectively analyzed. Data for 6,220 patients at West China Hospital of Sichuan University were used to develop a predictive model, which was validated using data from 1,221 patients at the Second Affiliated Hospital of Zhejiang University School of Medicine. The primary outcome was a composite of major complications: all-cause death in hospital, stroke, myocardial infarction, and severe acute kidney injury. The predictive model was constructed using the least absolute shrinkage and selection operator as well as multivariable logistic regression. The model was assessed in terms of the areas under receiver operating characteristic curves, calibration, and decision curve analysis. Results: The primary outcome occurred in 129 patients (2.1%) in the development cohort and 71 (5.8%) in the validation cohort. Six variables were retained in the predictive model: New York Heart Association class, diabetes, glucose, blood urea nitrogen, operation time, and red blood cell transfusion during surgery. The C-statistics were 0.735 (95% CI, 0.686-0.784) in the development cohort and 0.761 (95% CI, 0.694-0.828) in the validation cohort. For both cohorts, calibration plots showed good agreement between predicted and actual observations, and ecision curve analysis showed clinical usefulness. In contrast, the well-established SinoSCORE did not accurately predict the primary outcome in either cohort. Conclusions: This predictive nomogram based on six easily accessible variables may serve as an "early warning" system to identify patients at high risk of major complications after valve surgery. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT04476134].

Discovery of BGB-8035, a Highly Selective Covalent Inhibitor of Bruton's Tyrosine Kinase for B-Cell Malignancies and Autoimmune Diseases.

Bruton's tyrosine kinase (BTK) plays an essential role in B-cell receptor (BCR)-mediated signaling as well as the downstream signaling pathway for Fc receptors (FcRs). Targeting BTK for B-cell malignancies by interfering with BCR signaling has been clinically validated by some covalent inhibitors, but suboptimal kinase selectivity may lead to some adverse effects, which also makes the clinical development of autoimmune disease therapy more challenging. The structure-activity relationship (SAR) starting from zanubrutinib (BGB-3111) leads to a series of highly selective BTK inhibitors, in which BGB-8035 is located in the ATP binding pocket and has similar hinge binding to ATP but exhibits high selectivity over other kinases (EGFR, Tec, etc.). With an excellent pharmacokinetic profile as well as demonstrated efficacy studies in oncology and autoimmune disease models, BGB-8035 has been declared a preclinical candidate. However, BGB-8035 showed an inferior toxicity profile compared to that of BGB-3111.

Large volume acute normovolemic hemodilution in patients undergoing cardiac surgery with intermediate-high risk of transfusion: A randomized controlled trial.

STUDY OBJECTIVE: To investigate whether large volume acute normovolemic hemodilution (L-ANH), compared with moderate acute normovolemic hemodilution (M-ANH), can reduce perioperative allogeneic blood transfusion in patients with intermediate-high risk of transfusion during cardiac surgery with cardiopulmonary bypass (CPB). DESIGN: Prospective randomized controlled trial. SETTING: University hospital. PATIENTS: Patients with transfusion risk understanding scoring tool ("TRUST") ≥2 points undergoing cardiac surgery with CPB in the Second Affiliated Hospital of Zhejiang University from May 2020 to January 2021 were included. INTERVENTIONS: The patients were randomly assigned with a 1:1 ratio to M-ANH (5 to 8 mL/kg) or L-ANH (12 to 15 mL/kg). MEASUREMENTS: The primary outcome was perioperative red blood cell (RBC) transfusion units. The composite outcome included new-onset atrial fibrillation, pulmonary infection, cardiac surgery associated acute kidney injury (CSA-AKI) class ≥2, surgical incision infection, postoperative excessive bleeding, and resternotomy. MAIN RESULTS: Total 159 patients were screened and 110 (55 L-ANH and 55 M-ANH) were included for final analysis. Removed blood volume of L-ANH is significantly higher than M-ANH (886 ± 152 vs. 395 ± 86 mL, P < 0.001). Perioperative RBC transfusion was median 0 unit ([25th, 75th] percentiles: 0-4.4) in M-ANH group vs. 0 unit ([25th, 75th] percentiles: 0-2.0) in L-ANH group (P = 0.012) and L-ANH was associated with lower incidence of transfusion (23.6% vs. 41.8%, P = 0.042, rate difference: 0.182, 95% confidence interval [0.007-0.343]). The incidence of postoperative excessive bleeding was significantly lower in L-ANH vs. M-ANH (3.6% vs. 18.2%, P = 0.029, rate difference: 0.146, 95% confidence interval [0.027-0.270]) without significant difference for other second outcomes. The volume of ANH was inversely related to perioperative RBC transfusion units (Spearman r = -0.483, 95% confidence interval [-0.708 to -0.168], P = 0.003), and L-ANH in cardiac surgery was associated with a significantly reduced risk of perioperative RBC transfusion (odds ratio: 0.43, 95% confidence interval: 0.19-0.98, P = 0.044). CONCLUSIONS: Compared with M-ANH, L-ANH during cardiac surgery inclined to be associated with reduced perioperative RBC transfusion and the volume of RBC transfusion was inversely proportional to the volume of ANH. In addition, LANH during cardiac surgery was associated with a lower incidence of postoperative excessive bleeding.

The Influence of Lactiplantibacillus plantarum and Oenococcus oeni Starters on the Volatile and Sensory Properties of Black Raspberry Wine.

Malolactic fermentation (MLF) by different lactic acid bacteria has a significantly influence on the aromatic and sensory properties of wines. In this study, four strains including two Oenococcus oeni (commercial O-Mega and native DS04) and two Lactiplantibacillus plantarum (commercial NoVA and native NV27) were tested for their performances over MLF and effects on the basic composition, volatile components and sensory property of black raspberry wine. Results of microbial growth kinetics showed Lactiplantibacillus strains had higher fermentation efficiency than Oenococcus. The volatile compounds were determined by GC-IMS; NoVA and NV27 had higher production of volatile esters, and DS04 synthesized more amounts of acetate esters and several alcohols. In terms of sensory evaluation, NV27 and DS04 showed great aroma properties due to the enhanced fruity and sweet aroma. Furthermore, PLS was used for the establishment of the relationship between volatiles and sensory odors and sensory data interpretation.

BTK kinase activity is dispensable for the survival of diffuse large B-cell lymphoma.

Inhibitors targeting Bruton's tyrosine kinase (BTK) have revolutionized the treatment for various B-cell malignancies but are limited by acquired resistance after prolonged treatment as a result of mutations in BTK. Here, by a combination of structural modeling, in vitro assays, and deep phospho-tyrosine proteomics, we demonstrated that four clinically observed BTK mutations-C481F, C481Y, C481R, and L528W-inactivated BTK kinase activity both in vitro and in diffused large B-cell lymphoma (DLBCL) cells. Paradoxically, we found that DLBCL cells harboring kinase-inactive BTK exhibited intact B cell receptor (BCR) signaling, unperturbed transcription, and optimal cellular growth. Moreover, we determined that DLBCL cells with kinase-inactive BTK remained addicted to BCR signaling and were thus sensitive to targeted BTK degradation by the proteolysis-targeting chimera. By performing parallel genome-wide CRISPR-Cas9 screening in DLBCL cells with WT or kinase-inactive BTK, we discovered that DLBCL cells with kinase-inactive BTK displayed increased dependence on Toll-like receptor 9 (TLR9) for their growth and/or survival. Our study demonstrates that the kinase activity of BTK is not essential for oncogenic BCR signaling and suggests that BTK's noncatalytic function is sufficient to sustain the survival of DLBCL.

Dimethyl Itaconate Attenuates CFA-Induced Inflammatory Pain via the NLRP3/ IL-1ß Signaling Pathway.

Itaconate plays a prominent role in anti-inflammatory effects and has gradually been ushered as a promising drug candidate for treating inflammatory diseases. However, its significance and underlying mechanism for inflammatory pain remain unexplored. In the current study, we investigated the effects and mechanisms of Dimethyl Itaconate (DI, a derivative of itaconate) on Complete Freund's adjuvant (CFA)-induced inflammatory pain in a rodent model. Here, we demonstrated that DI significantly reduced mechanical allodynia and thermal hyperalgesia. The DI-attenuated neuroinflammation was evident with the amelioration of infiltrative macrophages in peripheral sites of the hind paw and the dorsal root ganglion. Concurrently, DI hindered the central microglia activation in the spinal cord. Mechanistically, DI inhibited the expression of pro-inflammatory factors interleukin (IL)-1ß and tumor necrosis factor alpha (TNF-α) and upregulated anti-inflammatory factor IL-10. The analgesic mechanism of DI was related to the downregulation of the nod-like receptor protein 3 (NLRP3) inflammasome complex and IL-1ß secretion. This study suggested possible novel evidence for prospective itaconate utilization in the management of inflammatory pain.

Dimethyl itaconate inhibits neuroinflammation to alleviate chronic pain in mice.

The metabolite itaconate has both anti-inflammatory and immunomodulatory effects. However, its influence on chronic pain is unclear. Here, we demonstrated that intraperitoneal injection of the itaconate derivative dimethyl itaconate (DI) alleviated chronic pain symptoms, such as allodynia and hyperalgesia, in spinal nerve ligation (SNL) and inflammatory pain models. Moreover, intraperitoneal DI reduced the secretion of inflammatory cytokines (i.e., interleukin-1ß, tumour necrosis factor-alpha) in dorsal root ganglion (DRG), spinal cord and hind paw tissues, suppressed the activation of macrophages in the DRG and glial cells in the spinal dorsal horn and decreased the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the DRG and spinal cord. DI boosted nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) levels in the DRG and spinal cord of SNL mice. Intraperitoneal administration of the Nrf2 inhibitor ML385 abolished the analgesic effect of DI and decreased the expression of Nrf2 in the DRG and spinal cord. Similarly, administration of DI potently reversed the lipopolysaccharide (LPS)-induced inflammatory effect in microglia. Reduction of endogenous itaconate levels by pretreatment with immune-responsive gene 1 (IRG1) siRNA blocked Nrf2 expression, which impaired the analgesic and anti-inflammatory effects of DI in vitro. Therefore, our findings revealed for the first time that intraperitoneal DI elicited anti-inflammatory effect and sustained chronic pain relief, which may be regarded as a promising therapeutic agent for chronic pain treatment.

Reprogramming Escherichia coli Metabolism for Bioplastics Synthesis from Waste Cooking Oil.

The recycle and reutilization of food wastes is a promising alternative for supporting and facilitating circular economy. However, engineering industrially relevant model organisms to use food wastes as their sole carbon source has remained an outstanding challenge so far. Here, we reprogrammed Escherichia coli metabolism using modular pathway engineering followed by laboratory adaptive evolution to establish a strain that can efficiently utilize waste cooking oil (WCO) as the sole carbon source to produce monomers of bioplastics, namely, medium-chain α,ω-dicarboxylic acids (MCDCAs). First, the biosynthetic pathway of MCDCAs was designed and rewired by modifying the ß-oxidation pathway and introducing an ω-oxidation pathway. Then, metabolic engineering and laboratory adaptive evolution were applied for improving the pathway efficiency of fatty acids utilization. Finally, the engineered strain E. coli AA0306 was able to produce 15.26 g/L MCDCAs with WCO as the sole carbon source. This study provides an economically attractive strategy for biomanufacturing bioplastics from food wastes, which has a great potentiality to be developed as a wide range of enabling biotechnologies for achieving green revolution.

The correlation between tumor-associated macrophage infiltration and progression in cervical carcinoma.

Tumor microenvironment (TME) plays a particularly important role in the progression, invasion and metastasis of cervical carcinoma (CC). Tumor-associated macrophages (TAMs) are significant components of the tumor microenvironment in CC. However, the results of studies on the correlation between TAMs and progression in CC are still controversial. This research aimed to investigate the relationship between TAMs infiltration and progression in CC. A total of 100 patients with CC were included in the study. The correlation between TAMs and clinicopathologic features was studied. Besides, a systematic literature search was conducted from legitimate electronic databases to specifically evaluate the role of TAMs in TME of cervical carcinoma. In the meta-analysis, high stromal CD68+ TAMs density was relevant to lymph node metastasis (WMD = 11.89, 95% CI: 5.30-18.47). At the same time, CD163+ M2 TAM density was associated with lymph node metastasis (OR = 2.42, 95% CI: 1.09-5.37; WMD = 39.37, 95% CI: 28.25-50.49) and FIGO stage (WMD = -33.60, 95% CI: -45.04 to -22.16). This was further confirmed in the experimental study of 100 tissues of cervical cancer. It supported a critical role of TAMs as a prospective predictor of cervical cancer. In conclusion, CD68+ TAM and CD163+ M2 TAM infiltration in CC were associated with tumor progression. And CD163+ M2 TAM infiltration was associated with more advanced FIGO stage and lymph node metastasis in CC.

Effect of Hydroxyapatite Composite Nano-Artificial Bone on Treatment and Rehabilitation of Patients with Ankle Joint Injury.

The formation of natural bone tissue is the result of the joint regulation of multiple template molecules. Although its complex hierarchical structure has been studied for many years, the mechanism of biomineralization of hard bone tissue has not been fully clarified. In this paper, the nanocomposites obtained by mineralization were characterized and analyzed, and the effect of the template on the crystal formation of hydroxyapatite was studied. The characterization results show that the main phase of the inorganic mineral obtained by template mineralization is the hydroxyapatite phase. The nano-apatite composite particles with an inorganic component content of 90.2% have the highest loading efficiency, reaching 67.9 mg/g. By statistical analysis of the pain scores at 5 days, 10 days, and 15 days after ankle injury, it was found that the average pain score of the treatment group was smaller than that of the control group. Two weeks later, the clinical efficacy judgment standard statistics show that the treatment group has a 22.5% improvement in healing rate, a significant increase in 3.18%, and a total effective rate of 8.71%, which is significantly better than the control group.

miR-148a Regulates the Stem Cell-Like Side Populations Distribution by Affecting the Expression of ACVR1 in Esophageal Squamous Cell Carcinoma.

INTRODUCTION: Esophageal squamous cell carcinoma (ESCC) is a malignant tumor disease with high mortality and morbidity rates, especially for a terminal cancer. At present, the prognosis and treatment of ESCC cannot effectively control or inhibit the spread and proliferation of tumor cells. microRNAs, a class of small spliced RNAs, are essential in the regulation of tumorigenesis and tumor cell migration and proliferation. microRNAs interact with target mRNA to silence gene expression and degrade mRNA, thereby inhibiting the expression of tumor genes or impairing the expression of tumor suppressor genes. METHODS: A total of 20 human ESCC samples were collected from the Affiliated Tumor Hospital of Xinjiang Medical University. Eca109 and Kyse510 cells, which are ESCC cell lines, were subjected to FACS analysis to get side population (SP) cells and non-SP cells. Cell cycle and cell proliferation were analyzed by flow cytometry. Cell migration and invasion were detected using a transwell assay. Quantitative PCR and Western blot were performed to analyze the expression levels of ABCG2, KLF4, OCT4, and ACVR1, which are related to the stemness of stem cells. The target genes of hsa-miR-148a were predicted using TargetScan (version 7.2) and verified by a dual luciferase reporter assay. A chromatin immunoprecipitation (ChIP) assay was carried out to demonstrate direct interaction between miR-148a and ACVR1. RESULTS: The expression of miR-148a was significantly down-regulated in ESCC cells and significantly decreased in SP esophageal squamous cells when compared to the tumor cells. By analyzing the stem cell stemness of ESCC, overexpression of miR-148a decreased the expression of ABCG2, KLF4, SOX2, OCT4, and Nanog, indicating that miR-148a may regulate stem cell function. Target gene prediction and functional annotation of miR-148a suggested that miR-148a is involved in stem cell stemness of ESCC via ACVR1. Expression of the dual luciferase-labeled gene indicates that overexpression of miR-148a inhibits the expression of ACVR1, thereby affecting stem cell stemness. CONCLUSION: miR-148a regulates the stem cell-like side populations distribution by inhibiting the expression of ACVR1 in ESCC. miR-148a may be a promising targeted therapy for ESCC.

Tumor-Associated CD163+ M2 Macrophage Infiltration is Highly Associated with PD-L1 Expression in Cervical Cancer.

BACKGROUND: Programmed death-ligand 1 (PD-L1) is a negative costimulatory molecule, and its main function is widely considered to be in the regulation of T cells. Tumor-associated macrophages (TAMs) are an important part of the tumor microenvironment, and they also play an important role in immunosuppression. However, the relationship between the expression of PD-L1 and TAMs in cervical carcinoma (CC) remains unclear. We detected the expression of PD-L1 and TAMs in tumor tissue to study the correlation between them. METHODS: Immunohistochemical staining of PD-L1, CD68 (pan-macrophage), and CD163 (M2-like macrophage) was performed in 120 cases of cervical squamous cell carcinoma. Logistic regression analysis was used to evaluate the predictors related to positive PD-L1 expression. We also apply the Kaplan-Meier method to study the recurrence-free and overall survival rate of CC patients. RESULTS: The increase in PD-L1 expression in tumor cells (TC) was significantly correlated with the increase in CD163 density (r=0.8550, p<0.0001), while PD-L1 in the stroma was also significantly associated with the intratumoral density of CD68- or CD163-positive cells (CD68 p<0.0001; CD163 p=0.0009). The mean infiltration rates of CD68- and CD163-positive cells in PD-L1-positive TC were significantly higher than in PD-L1-negative TC (CD68 p=0.0095; CD163 p<0.0001). In multivariate logistic regression analyses, only the density of CD163-positive cells was correlated with the expression of PD-L1 in TC cells (OR 1.52; p=0.032). In prognostic analysis, PD-L1 more than 10% was significantly correlated with short RFS (HR=2.66; p=0.028). For CD163+ macrophage evaluation, the density above the median was also significantly correlated with RFS (HR=2.48; p=0.021). CONCLUSION: CD163+ M2-like macrophage infiltration is highly associated with PD-L1 expression in CC, suggesting that macrophage infiltration can serve as a potential therapeutic target.

Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase.

Aberrant activation of Bruton's tyrosine kinase (BTK) plays an important role in pathogenesis of B-cell lymphomas, suggesting that inhibition of BTK is useful in the treatment of hematological malignancies. The discovery of a more selective on-target covalent BTK inhibitor is of high value. Herein, we disclose the discovery and preclinical characterization of a potent, selective, and irreversible BTK inhibitor as our clinical candidate by using in vitro potency, selectivity, pharmacokinetics (PK), and in vivo pharmacodynamic for prioritizing compounds. Compound BGB-3111 (31a, Zanubrutinib) demonstrates (i) potent activity against BTK and excellent selectivity over other TEC, EGFR and Src family kinases, (ii) desirable ADME, excellent in vivo pharmacodynamic in mice and efficacy in OCI-LY10 xenograft models.