Clinical Pharmacology Strategies for Bispecific Antibody Development: Learnings from FDA-Approved Bispecific Antibodies in Oncology.

Bispecific antibodies, by enabling the targeting of more than one disease-associated antigen or engaging immune effector cells, have both advantages and challenges compared with a combination of two different biological products. As of December 2023, there are 11 U.S. Food and Drug Administration-approved BsAb products on the market. Among these, 9 have been approved for oncology indications, and 8 of these are CD3 T-cell engagers. Clinical pharmacology strategies, including dose-related strategies, are critical for bispecific antibody development. This analysis reviewed clinical studies of all approved bispecific antibodies in oncology and identified dose-related perspectives to support clinical dose optimization and regulatory approvals, particularly in the context of the Food and Drug Administration's Project Optimus: (1) starting doses and dose ranges in first-in-human studies; (2) dose strategies including step-up doses or full doses for recommended phase 2 doses or dose level(s) used for registrational intent; (3) restarting therapy after dose delay; (4) considerations for the introduction of subcutaneous doses; (5) body weight vs. flat dosing strategy; and (6) management of immunogenicity. The learnings arising from this review are intended to inform successful strategies for future bispecific antibody development.

Artificial intelligence technology and ultrasound-guided nerve block for analgesia in total knee arthroplasty.

BACKGROUND: Knee diseases are more common in middle-aged and elderly people, so artificial knee replacement is also more used in middle-aged and elderly people. Although the patient's pain can be reduced through surgery, often accompanied by moderate pain after surgery and neutralization, which not only increases the psychological burden of the patient, but also greatly reduces the postoperative recovery effect, and may also lead to the occurrence of postoperative adverse events in severe cases. AIM: To investigate the analgesic effect of artificial intelligence (AI) and ultrasound-guided nerve block in total knee arthroplasty (TKA). METHODS: A total of 92 patients with TKA admitted to our hospital from January 2021 to January 2022 were opted and divided into two groups according to the treatment regimen. The control group received combined spinal-epidural anesthesia. The research group received AI technique combined with ultrasound-guided nerve block anesthesia. The sensory block time, motor block time, visual analogue scale (VAS) at different time points and complications were contrasted between the two groups. RESULTS: The time of sensory block onset and sensory block perfection in the research group was shorter than those in the control group, but the results had no significant difference (P > 0.05). Duration of sensory block in the research group was significantly longer than those in the control group (P < 0.05). The time of motor block onset and motor block perfection in the research group was shorter than those in the control group, but the results had no significant difference (P > 0.05). Duration of motor block in the research group was significantly longer than those in the control group. The VAS scales of the research group were significantly lower than that of the control group at different time points (P < 0.05). The postoperative hip flexion and abduction range of motion in the research group were significantly better than those in the control group at different time points (P < 0.05). The incidence of complications was significantly lower in the research group than in the control group (P = 0.049). CONCLUSION: In TKA, the combination of AI technology and ultrasound-guided nerve block has a significantly effect, with fewer postoperative complications and significantly analgesic effect, which is worthy of application.

Population Pharmacokinetics and Exposure-Response Analysis for the CTLA-4 Inhibitor Tremelimumab in Metastatic NSCLC Patients in the Phase III POSEIDON Study.

Blockade of CTLA-4 by tremelimumab combined with anti-PD-L1 durvalumab and chemotherapy provided increased antitumor activity and long-term survival benefits in first-line metastatic non-small cell lung cancer (mNSCLC) in the phase III POSEIDON study. We performed population pharmacokinetic modeling for tremelimumab using data from 1,605 patients across 6 studies (including POSEIDON) in multiple tumors (lung cancer, bladder cancer, malignant mesothelioma, and other solid tumors), and identified a 2-compartment model with linear and time-varying clearance for tremelimumab. Cox proportional hazard regression models were applied to 326 patients with mNSCLC from POSEIDON to evaluate the association between exposure metrics and efficacy end points, adjusting for baseline prognostic covariates. Improved progression-free survival (PFS) and overall survival (OS) in the tremelimumab arm (in combination with durvalumab and chemotherapy) was associated with higher tremelimumab exposure (e.g., minimum concentration at 5th dose (Cmin,dose5 ) and area under the curve at 5th dose (AUCdose5 )). However, further case-matching analyses yielded hazard ratios for the comparison of tremelimumab-treated patients in the Cmin,dose5 quartile 1 (Q1) subgroup with matched chemotherapy-treated patients of 1.04 (95% confidence interval (CI): 0.76-1.44) for OS and 0.99 (95% CI: 0.72-1.36) for PFS, suggesting that the observed apparent exposure-response relationship might be confounded. No relationship between tremelimumab exposure and safety (grade ≥3 treatment-emergent adverse events [AEs], AEs of special interest, or discontinuation due to AEs) was identified. These results support the consistent benefit observed with tremelimumab 75 mg every 3 weeks for up to 5 doses in combination with durvalumab and chemotherapy in POSEIDON as first-line therapy for mNSCLC.

Could extracellular vesicles derived from mesenchymal stem cells be a potential therapy for acute pancreatitis-induced cardiac injury?

Acute pancreatitis (AP) often leads to a high incidence of cardiac injury, posing significant challenges in the treatment of severe AP and contributing to increased mortality rates. Mesenchymal stem cells (MSCs) release bioactive molecules that participate in various inflammatory diseases. Similarly, extracellular vesicles (EVs) secreted by MSCs have garnered extensive attention due to their comparable anti-inflammatory effects to MSCs and their potential to avoid risks associated with cell transplantation. Recently, the therapeutic potential of MSCs-EVs in various inflammatory diseases, including sepsis and AP, has gained increasing recognition. Although preclinical research on the utilization of MSCs-EVs in AP-induced cardiac injury is limited, several studies have demonstrated the positive effects of MSCs-EVs in regulating inflammation and immunity in sepsis-induced cardiac injury and cardiovascular diseases. Furthermore, clinical studies have been conducted on the therapeutic application of MSCs-EVs for some other diseases, wherein the contents of these EVs could be deliberately modified through prior modulation of MSCs. Consequently, we hypothesize that MSCs-EVs hold promise as a potential therapy for AP-induced cardiac injury. This paper aims to discuss this topic. However, additional research is essential to comprehensively elucidate the underlying mechanisms of MSCs-EVs in treating AP-induced cardiac injury, as well as to ascertain their safety and efficacy.

Modeling of Proliferating CD4 and CD8 T-Cell Changes to Tremelimumab Exposure in Patients with Unresectable Hepatocellular Carcinoma.

The STRIDE (Single Tremelimumab Regular Interval Durvalumab) regimen of single-dose tremelimumab 300 mg, plus durvalumab 1,500 mg every 4 weeks demonstrated potential for long-term survival in studies of unresectable hepatocellular carcinoma (uHCC; Study 22 and HIMALAYA). The aim of this analysis was to investigate changes in proliferating CD4+ Ki67+ and CD8+ Ki67+ T cells and their relationship with tremelimumab exposure in patients with uHCC. Median cell count, change from baseline, and percent change from baseline in CD4+ and CD8+ T cells peaked around 14 days after STRIDE. A model of CD4+ and CD8+ T cell response to tremelimumab exposure was developed. Patients with lower baseline T cell counts had a greater percent change from baseline in T cell response to tremelimumab, and baseline T-cell count was included in the final model. With the full covariate model, the half-maximal effective concentration (EC50 ) of tremelimumab was 6.10 µg/mL (standard error = 1.07 µg/mL); > 98.0% of patients were predicted to have a minimum plasma concentration greater than EC50 with tremelimumab 300 or 750 mg. For EC75 (9.82 µg/mL), 69.5% and 98.2% of patients were predicted to exceed the EC75 with tremelimumab 300 and 750 mg, respectively. This analysis supports the clinical hypothesis that combination anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) and anti-programmed cell death ligand-1 (anti-PD-L1) therapy primes an immune response that may then be sustained by anti-PD-L1 monotherapy and supports the clinical utility of the STRIDE regimen in patients with uHCC. These insights may also help inform dose selection of anti-CTLA-4 plus anti-PD-L1 combination strategies.

Population Pharmacokinetics and Exposure-Response Analysis of Tremelimumab 300 mg Single Dose Combined with Durvalumab 1500 mg Q4W (STRIDE) in Patients with Unresectable Hepatocellular Carcinoma.

A novel single-dose regimen of 300 mg tremelimumab in combination with durvalumab (STRIDE) has demonstrated a favorable benefit-risk profile in the phase 1/2 Study 22 trial (in patients with unresectable hepatocellular carcinoma, uHCC) and in the phase 3 HIMALAYA study. The current analysis evaluated the population pharmacokinetics (PopPK) of tremelimumab and durvalumab, and the exposure-response (ER) relationship for efficacy and safety of STRIDE in patients with uHCC. Previous PopPK models for tremelimumab and durvalumab were updated using data from previous studies in various cancers combined with data from Study 22 and HIMALAYA. Typical population mean parameters and associated inter- and intra-individual variability were assessed, as was the influence of covariates. Individual exposure metrics were derived from the individual empirical Bayes estimates as drivers for ER analysis related to efficacy and safety from HIMALAYA. The observed pharmacokinetics of tremelimumab in uHCC were well described by a 2-compartment model with both linear and time-dependent clearance. All identified covariates changed tremelimumab PK parameters by <25%, and thus had minimal clinical relevance; similar results were obtained from durvalumab PopPK analysis. None of tremelimumab or durvalumab exposure metrics were significantly associated with overall survival (OS), progression-free survival (PFS), or adverse events. Baseline aspartate aminotransferase and neutrophil-to-lymphocyte ratio (NLR) were associated with OS (P < .001) by the Cox proportional hazards model. No covariate was identified as a significant factor for PFS. No dose adjustment for tremelimumab or durvalumab is needed based on PopPK covariate analyses or ER analyses. Our findings support the novel STRIDE dosing regimen in patients with uHCC.

Associate factors for endoscopic submucosal dissection operation time and postoperative delayed hemorrhage of early gastric cancer.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a treatment for early gastric cancer with the advantages of small invasion, fewer complications, and a low local recurrence rate. However, there is a high risk of complications such as bleeding and perforation, and the operation time is also longer. ESD operation time is closely related to bleeding and perforation. AIM: To investigate the influencing factors associated with ESD operation time and postoperative delayed hemorrhage to provide a reference for early planning, early identification, and prevention of complications. METHODS: We conducted a retrospective study based on the clinical data of 520 patients with early gastric cancer in the Second Affiliated Hospital of Hainan Medical University from January 2019 to December 2021. The baseline data, clinical features, and endoscopic and pathological characteristics of patients were collected. The multivariate linear regression model was used to investigate the influencing factors of ESD operation time. Logistic regression analysis was carried out to evaluate the influencing factors of postoperative delayed hemorrhage. RESULTS: The multivariate analysis of ESD operation time showed that the maximum lesion diameter could affect 8.815% of ESD operation time when other influencing factors remained unchanged. The operation time increased by 3.766% or 10.247% if the lesion was mixed or concave. The operation time increased by 4.417% if combined with an ulcer or scar. The operation time increased by 3.692% if combined with perforation. If infiltrated into the submucosa, it increased by 2.536%. Multivariate analysis of delayed hemorrhage after ESD showed that the maximum diameter of the lesion, lesion morphology, and ESD operation time were independent influencing factors for delayed hemorrhage after ESD. Patients with lesion ≥ 3.0 cm (OR = 3.785, 95%CI: 1.165-4.277), lesion morphology-concave (OR = 10.985, 95%CI: 2.133-35.381), and ESD operation time ≥ 60 min (OR = 2.958, 95%CI: 1.117-3.526) were prone to delayed hemorrhage after ESD. CONCLUSION: If the maximum diameter of the lesion in patients with early gastric cancer is ≥ 3.0 cm, and the shape of the lesion is concave, or accompanied by an ulcer or scar, combined with perforation, and infiltrates into the submucosa, the ESD operation will take a longer time. When the maximum diameter of the lesion is ≥ 3.0 cm, the shape of the lesion is concave in patients and the operation time of ESD takes longer time, the risk of delayed hemorrhage after ESD is higher.

[Role of NLRP3 inflammasome in diabetic neuropathy and prevention and treatment with traditional Chinese medicine].

As one of the most frequent complications of diabetes, diabetic neuropathy often involves peripheral and central nervous systems. Neuroinflammation is the key pathogenic factor of secondary nerve injury in diabetes. NOD-like receptor pyrin domain-containing 3(NLRP3) inflammasome is a group of subcellular multiprotein complexes, including NLRP3, apoptosis associated speck-like protein(ASC), and pro-cysteinyl aspartate specific proteinase 1(pro-caspase-1). NLRP3 inflammasome is an inducer of innate immune responses. Its activation stimulates the inflammatory cascade reaction, promotes the release of inflammatory mediators, triggers cell death and uncontrolled autophagy, activates glial cells, facilitates peripheral immune cell infiltration, and initiates amyoid ß(Aß)-tau cascade reactions. As a result, it contributes to the central nerve, somatic nerve, autonomic nerve, and retinal nerve cell damage secondary to diabetes. Therefore, due to its key role in the neuroinflammation responses of the body, NLRP3 inflammasome may provide new targets for the treatment of diabetic neuropathy. With multi-target and low-toxicity advantages, traditional Chinese medicine plays a vital role in the treatment of diabetic neuropathy. Accumulating evidence has shown that traditional Chinese medicine exerts curative effects on diabetic neuropathy possibly through regulating NLRP3 inflammasome. Although the role of NLRP3 inflammasome in diabetes and related complications has been investigated in the literature, systematical studies on drugs and mechanism analysis for secondary neuropathy are still lacking. In this article, the role of NLRP3 inflammasome in diabetic neuropathy was explored, and the research progress on traditional Chinese medicine in the treatment of diabetic neuropathy through NLRP3 inflammasome was reviewed.

Population Pharmacokinetics of Monalizumab in Patients With Advanced Solid Tumors.

Monalizumab is a novel, first-in-class humanized immunoglobulin G4 monoclonal antibody immune checkpoint inhibitor that targets the inhibitory CD94/NKG2A receptors. The objectives of this analysis were to develop a population pharmacokinetic (PK) model of monalizumab, evaluate the impact of clinically relevant covariates on monalizumab PK, and provide dose justification for clinical trials. We developed a monalizumab population PK model to characterize the PK properties of monalizumab in patients with advanced solid tumors or head and neck squamous cell carcinoma. Data from clinical studies D419NC00001 (NCT02671435) and IPH2201-203 (NCT02643550) were pooled for the analysis, resulting in a data set of 3066 PK samples derived from 507 subjects. The PK of monalizumab were reasonably described by a 2-compartment model with first-order elimination. Monalizumab generally exhibited linear PK over a dose range of 22.5-750 mg or 10 mg/kg every 2 weeks. The estimate of clearance was ≈0.255 L/day, and apparent volume of distribution was 6.36 L for a typical individual, consistent with previous findings for endogenous immunoglobulin Gs and other therapeutic monoclonal antibodies. Baseline albumin and body weight were identified as significant covariates of clearance; body weight, sex, and smoking status had a significant impact on volume of distribution; and none of these covariates had impact on peripheral volume of distribution. Although these covariates were identified as statistically significant, they are considered to be not clinically meaningful, as changes in monalizumab exposure were <30%. Therefore, no dose adjustments of monalizumab based on patient or disease characteristics are recommended.

Osimertinib + Savolitinib to Overcome Acquired MET-Mediated Resistance in Epidermal Growth Factor Receptor-Mutated, MET-Amplified Non-Small Cell Lung Cancer: TATTON.

MET-inhibitor and EGFR tyrosine kinase inhibitor (EGFR-TKI) combination therapy could overcome acquired MET-mediated osimertinib resistance. We present the final phase Ib TATTON (NCT02143466) analysis (Part B, n = 138/Part D, n = 42) assessing oral savolitinib 600 mg/300 mg once daily (q.d.) + osimertinib 80 mg q.d. in patients with MET-amplified, EGFR-mutated (EGFRm) advanced non-small cell lung cancer (NSCLC) and progression on prior EGFR-TKI. An acceptable safety profile was observed. In Parts B and D, respectively, objective response rates were 33% to 67% and 62%, and median progression-free survival (PFS) was 5.5 to 11.1 months and 9.0 months. Increased antitumor activity may occur with MET copy number ≥10. EGFRm circulating tumor DNA clearance on treatment predicted longer PFS in patients with detectable baseline ctDNA, while acquired resistance mechanisms to osimertinib + savolitinib were mediated by MET, EGFR, or KRAS alterations. SIGNIFICANCE: The savolitinib + osimertinib combination represents a promising therapy in patients with MET-amplified/overexpressed, EGFRm advanced NSCLC with disease progression on a prior EGFR-TKI. Acquired resistance mechanisms to this combination include those via MET, EGFR, and KRAS. On-treatment ctDNA dynamics can predict clinical outcomes and may provide an opportunity to inform earlier decision-making. This article is highlighted in the In This Issue feature, p. 1.

Circ_0001535 Facilitates Tumor Malignant Progression by miR-485-5p/LASP1 Axis in Colorectal Cancer

Background: Increasing evidence revealed that circular RNAs (circRNAs) are involved in colorectal cancer progression. However, the potential function of circ_0001535 in colorectal cancer remains unclear. Aims: To investigate the mechanism of circ_0001535 by silencing circ_0001535 in colorectal cancer cells and nude mice. Study Design: A cell study. Methods: Expressions of circ_0001535, LIM and SH3 protein 1 (LASP1) mRNA, and miR-485-5p were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Western blot analyses of LASP1, PCNA, cleaved caspase 3, snail 1, and OCT4 protein expression were performed. CCK-8, EdU, flow cytometry, transwell assays, and sphere formation were conducted to evaluate colorectal cancer cell proliferation, apoptosis, invasion, and stemness. Luciferase reporter assays, RNA pull-down, and RIP validated binding. A nude mice xenograft model was constructed. Results: Circ_0001535 was significantly upregulated in colorectal tissues and cells. Circ_0001535 knockdown suppressed the malignant behavior of colorectal cells such as proliferation, invasion, stemness, and tumor growth in vivo. This knockdown also induced apoptosis by sponging miR-485-5p and upregulating LASP1 expression. Conclusion: Circ_0001535 promotes colorectal cancer cell development by absorbing miR-485-5p and upregulating LASP1.

Pharmacokinetics and pharmacodynamics of MEDI0680, a fully human anti-PD-1 monoclonal antibody, in patients with advanced malignancies.

MEDI0680 is a humanized immunoglobulin monoclonal antibody that targets human programmed cell death protein 1 (PD-1) for the treatment of cancer. A population two-compartmental pharmacokinetic (PK) model and a sequential direct maximal effective drug concentration receptor occupancy (RO) model with baseline parameters were developed to quantify PK variability, identify significant covariates, and characterize the relationship between the PK and the RO of MEDI0680. A total of 58 patients with advanced malignancies received MEDI0680 by intravenous infusion at a dose of 0.1-20 mg/kg in a phase 1 study. The clearance was 0.27 L per day and the central volume of distribution (V1) was 3.14 L, with a modest between-subject variability of 30 and 19%, respectively. None of the evaluated covariates showed any impact on PK parameters except for a nonclinically meaningful relevant impact of body weight on V1. The estimated half-maximal effective concentration for MEDI0680 binding to the PD-1 antigen was approximately 1.88 µg/mL. Visual predictive check results demonstrated good predictability of the final population PK-RO model. PK-RO simulations demonstrated that > 90% RO could be maintained in all subjects after a 20-mg/kg dose every 2 weeks (Q2W). Therefore, 20 mg/kg Q2W and an equivalently fixed dose of 1500 mg was recommended for phase 2 studies.

Osimertinib Plus Durvalumab in Patients With EGFR-Mutated, Advanced NSCLC: A Phase 1b, Open-Label, Multicenter Trial.

INTRODUCTION: EGFR tyrosine kinase inhibitors (TKIs) are recommended for EGFR-mutated NSCLC treatment. EGFR activation up-regulates programmed death-ligand 1 expression and other immunosuppressive factors in NSCLC, causing immune microenvironment remodeling. Osimertinib (an EGFR TKI) plus durvalumab (programmed death-ligand 1 blockade) was evaluated in the TATTON study (NCT02143466). METHODS: This open-label, phase 1b study enrolled patients with advanced EGFR-mutated NSCLC. In part A, patients who had progressed on a previous EGFR TKI received osimertinib (80 mg once daily) plus durvalumab 3 or 10 mg/kg every 2 weeks. In part B, patients received first-line osimertinib plus durvalumab 10 mg/kg every 2 weeks. However, part B enrollment was terminated early owing to an increased incidence of interstitial lung disease (ILD)-related adverse events (AEs). Safety (primary objective) and preliminary anti-tumor activity determined by objective response rate (ORR), best overall response, duration of response (DOR), and progression-free survival were evaluated. RESULTS: Before enrollment termination, 23 and 11 patients received treatment across parts A and B, respectively. The most common AEs across parts A and B were as follows: diarrhea (50%), nausea (41%), and decreased appetite (35%). A total of 12 patients (35%) reported ILD-related AEs (lung disorder, ILD or pneumonitis). In part A, ORR was 43% (95% confidence interval [CI]: 23-66); median DOR was 20.4 months. In part B, ORR was 82% (95% CI: 48-98), median DOR was 7.1 months, and median progression-free survival was 9.0 months (95% CI: 3.5-12.3). CONCLUSIONS: This study highlighted a potential risk of ILD-related AEs when combining osimertinib with durvalumab. Further research looking to combine EGFR TKIs with immune checkpoint inhibitors should be approached with caution.

Circular noncoding RNA circ_0007334 sequestrates miR-577 to derepress KLF12 and accelerate colorectal cancer progression.

Colorectal cancer (CRC) is a prevalent malignant tumor with a poor prognosis. Circular RNA (circRNA) circ_0007334 is related to cell proliferation in CRC. This study is designed to explore the role and mechanism of circ_0007334 in CRC progression. Circ_0007334, microRNA-577 (miR-577) and kruppel-like factor 12 (KLF12) levels were measured by real-time quantitative PCR (RT-qPCR). Exosomes were detected by a transmission electron microscope and nanoparticle tracking analysis (NTA). CD63, TSG101, matrix metallopeptidase-2 (MMP-2), MMP-9, VEGFA and KLF12 protein levels were examined by western blot assay. The binding relationship between miR-577 and circ_0007334 or KLF12 was predicted by circRNA interactome or Starbase and verified by a dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Cell viability, colony number, migration, invasion and angiogenesis were detected by cell counting kit-8 (CCK-8), colony formation, wound healing, transwell and tube formation assays. The biological role of circ_0007334 was examined by the xenograft tumor model in vivo. Circ_0007334 and KLF12 were increased, and miR-577 was decreased in CRC tissues and cells. Also, circ_0007334 expression was upregulated in CRC cell-derived exosomes. Circ_0007334 deficiency repressed cell viability, colony formation, migration, invasion, and angiogenesis in CRC cells. Mechanically, circ_0007334 could regulate KLF12 expression by sponging miR-577. Circ_0007334 downregulation or exosomal circ_0007334 silencing blocked CRC tumor growth in vivo. These results presented that circ_0007334 deficiency exerts a tumor-suppressor by the miR-577/KLF12 axis in CRC, and indicated that exosomal circ_0007334 could hinder CRC tumor growth and angiogenesis in vivo. Our findings provided a novel therapeutic strategy for CRC.

circ_0101802 functions as a sponge of miR-1236-3p to facilitate the proliferation, migration and invasion of colorectal cancer via regulating MACC1.

Circular RNAs (circRNAs) have been shown to be involved in the progression of many diseases, including cancer. However, the role of circ_0101802 in the proliferation, migration and invasion of colorectal cancer (CRC) has not been studied. Our results showed that circ_0101802 was highly expressed in CRC tumor tissues and cells. Functional experiments suggested that circ_0101802 knockdown could inhibit the proliferation, migration and invasion of CRC cells in vitro and CRC tumorigenesis in vivo. In the terms of mechanism, we discovered that circ_0101802 could act as a sponge of miR-1236-3p, and miR-1236-3p could target MACC1. The rescue experiments revealed that miR-1236-3p inhibitor could reverse the inhibition effect of circ_0101802 silencing on CRC proliferation, migration and invasion, and MACC1 overexpression also could abolish the negative regulation of miR-1236-3p on CRC proliferation, migration and invasion. More important, our data confirmed that circ_0101802 sponged miR-1236-3p to positively regulate MACC1. In summary, our results revealed that circ_0101802 functioned as a tumor promoter in CRC, which could facilitate CRC proliferation, migration and invasion via regulating the miR-1236-3p/MACC1 axis.

Nomogram for Predicting the Probability of Permanent Stoma after Laparoscopic Intersphincteric Resection.

PURPOSE: The purpose of this study was to determine the risk factors for the development of a permanent stoma in laparoscopic intersphincteric resection (LS-ISR) for ultralow rectal adenocarcinoma and to develop and validate a prediction model to predict the probability of permanent stoma after surgery. METHODS: A primary cohort consisting of 301 consecutive patients who underwent LS-ISR was enrolled in this study. Multivariable logistic regression analysis was used to identify risk factors and develop the nomogram. The performance of the nomogram was assessed with respect to its calibration, discrimination, and clinical usefulness. An independent validation cohort contained 91 consecutive patients from January 2012 to January 2019. RESULTS: The permanent stoma rate was 11.3% (34/301) in the primary cohort and 18.7% (17/91) in the validation cohort. Multivariable analysis revealed that nCRT (OR, 3.195; 95% CI, 1.169-8.733; P=0.024), ASA score of 3 (OR, 5.062; 95% CI, 1.877-13.646; P=0.001), distant metastasis (OR, 14.645; 95% CI, 3.186-67.315; P=0.001), and anastomotic leakage (OR, 11.308; 95% CI, 3.650-35.035; P<0.001) were independent risk factors for permanent stoma, and a nomogram was established. The AUCs of the nomogram were 0.842 and 0.858 in the primary and validation cohorts, respectively. The calibration curves showed good calibration in both cohorts. Decision curve analysis demonstrated that the nomogram was clinically useful. CONCLUSION: We developed and validated a nomogram for ultralow rectal adenocarcinoma patients who underwent LS-ISR, and the nomogram could help surgeons identify which patients are at a higher risk of a permanent stoma after surgery.

miR-29a-3p transferred by mesenchymal stem cells-derived extracellular vesicles protects against myocardial injury after severe acute pancreatitis.

AIMS: Acute pancreatitis (AP) is an inflammatory disease of the pancreas that may affect local tissues or remote organ systems, while severe acute pancreatitis (SAP) is a life-threatening disorder associated with multiple organ failure. In this investigation, we set about to determine whether microRNA-29a-3p (miR-29a-3p) carried by mesenchymal stem cell (MSCs)-derived extracellular vesicles (EVs) affects the myocardial injury during SAP. MAIN METHODS: EVs were isolated from MSCs of rat bone marrow by differential centrifugation. An SAP rat model was developed and treated with MSCs-EVs and/or alteration of miR-29a-3p and HMGB1 expression, followed by assessment of the rats' cardiac function and inflammation. Next, cardiomyocytes H9C2 were co-cultured with MSC-EVs and internalization of EVs was evaluated, followed by evaluation of whether EVs could transmit miR-29a-3p cargos into H9C2 cells and affect their biological functions. KEY FINDINGS: EVs derived from MSCs were observed to protect against SAP-induced myocardial injury. In SAP-induced rats, miR-29a-3p was under-expressed in myocardial tissues. In addition, we also confirmed that miR-29a-3p could be transferred into the H9C2 cardiomyocytes by MSC-derived EVs, which downregulated the expression of inflammatory markers and improve cardiac function to attenuate myocardial injury. Furthermore, miR-29a-3p inhibited the expression of HMGB1 to downregulate TLR4 expression and further inactivate the Akt signaling pathway. SIGNIFICANCE: These findings support the cardioprotective action of miR-29a-3p transmitted by MSCs-derived EVs in SAP-induced myocardial injury via downregulation of the HMGB1/TLR4/Akt axis, highlighting a promising target for the EV-based therapy for SAP.

Comparison of the efficacy and safety of tacrolimus monotherapy and cyclophosphamide combined with glucocorticoid in the treatment of adult primary membranous nephropathy: protocol of a multicenter, randomized, controlled, open study.

BACKGROUND: Idiopathic membranous nephropathy (IMN) remains the leading cause of adult nephrotic syndrome. Immunosuppressive therapy with cyclophosphamide (CTX) is often successful in reducing proteinuria, but its use is associated with severe side effects. Tacrolimus (TAC) is effective in achieving complete remission (CR) in patients with IMN. However, whether it is as effective as CTX in inducing and maintaining complete or partial remission in these patients is unknown. This trial aims to test TAC monotherapy for its non-inferiority to CTX in inducing long-term remission of proteinuria. METHODS: Patients with biopsy-proven IMN with nephrotic syndrome will be randomized into a 12-month treatment period with oral TAC of 0.05-0.1 mg/kg/day for 6 months or with CTX + glucocorticoid. The efficacy of the treatment will be assessed by the remission status (based on changes in proteinuria) and relapse rate. DISCUSSION: This study will test whether treatment with TAC monotherapy is superior to CTX with glucocorticoid in inducing long-term remission of proteinuria in patients with adult IMN. The role of serum anti-PLA2R antibodies in the early assessment of the response to therapy using different therapeutic regimens will also be clarified. TRIAL REGISTRATION: ClinicalTrials.gov ChiCTR1800016140. Registered 12 June 2017. http://www.chictr.org.cn.