Citations

Promoting immune tolerance to transplanted organs can minimize the amount of immunosuppressive drugs that patients need to take, reducing lifetime risks of mortality and morbidity. Regulatory T cells (T regs ) are essential for immune tolerance, and preclinical studies have shown their therapeutic efficacy in inducing transplantation tolerance. Here, we report the results of a phase 1/2 trial (ARTEMIS, NCT02474199) of autologous donor alloantigen–reactive T reg (darT reg ) therapy in individuals 2 to 6 years after receiving a living donor liver transplant. The primary efficacy endpoint was calcineurin inhibitor dose reduction by 75% with stable liver function tests for at least 12 weeks. Among 10 individuals who initiated immunosuppression withdrawal, 1 experienced rejection before planned darT reg infusion, 5 received darT regs , and 4 were not infused because of failure to manufacture the minimal infusible dose of 100 × 10 6 cells. darT reg infusion was not associated with adverse events. Two darT reg -infused participants reached the primary endpoint, but an insufficient number of recipients were treated for assessing the efficacy of darT regs . Mechanistic studies revealed generalized T reg activation, senescence, and selective reduction of donor reactivity after liver transplantation. Overall, the ARTEMIS trial features a design concept for evaluating the efficacy of T reg therapy in transplantation. The mechanistic insight gained from the study may help guide the design of future trials.

There are four solid tumors with common screening options in the average-risk population aged 21 to 75 years (breast, cervical, colorectal, and, based on personalized risk assessment, prostate), but many cancers lack recommended population screening and are often detected at advanced stages when mortality is high. Blood-based multi-cancer early detection tests have the potential to improve cancer mortality through additional population screening. Reported here is a post-hoc analysis from the third Circulating Cell-free Genome Atlas substudy to examine multi-cancer early detection test performance in solid tumors with and without population screening recommendations and in hematologic malignancies. Participants with cancer in the third Circulating Cell-free Genome Atlas substudy analysis were split into three subgroups: solid screened tumors (breast, cervical, colorectal, prostate), solid unscreened tumors, and hematologic malignancies. In this post hoc analysis, sensitivity is reported for each subgroup across all ages and those aged ⩾50 years overall, by cancer, and by clinical cancer stage. Aggregate sensitivity in the solid screened, solid unscreened, and hematologic malignancy subgroups was 34%, 66%, and 55% across all cancer stages, respectively; restricting to participants aged ⩾50 years showed similar aggregate sensitivity. Aggregate sensitivity was 27%, 53%, and 60% across stages I to III, respectively. Within the solid unscreened subgroup, aggregate sensitivity was >75% in 8/18 cancers (44%) and >50% in 13/18 (72%). This multi-cancer early detection test detected cancer signals at high (>75%) sensitivity for multiple cancers without existing population screening recommendations, suggesting its potential to complement recommended screening programs. Clinical trial identifier: NCT02889978.

Background Our goal was to compare the updated European Society of Gastrointestinal Endoscopy (ESGE) and United States Multi-Society Task Force on Colorectal Cancer (USMSTF) high risk groups in predicting metachronous advanced neoplasia on first follow-up colonoscopy and long-term colorectal cancer (CRC). Methods We compared advanced metachronous neoplasia risk (serrated polyps ≥ 1 cm or with dysplasia, advanced adenomas [≥ 1 cm, villous, high grade dysplasia], CRC) on first surveillance colonoscopy in patients with high risk findings according to ESGE versus USMSTF guidelines. We also compared the positive and negative predictive values (PPV, NPV) of both guidelines for metachronous neoplasia. Results The risk for metachronous neoplasia in our sample (n = 20 458) was higher in the high risk USMSTF (3 year) (13.6 %; 95 %CI 12.3–14.9) and ESGE groups (13.6 %; 95 %CI 12.3–15.0) compared with the lowest risk USMSTF (5.1 %; 95 %CI 4.7–5.5; P < 0.001) and ESGE categories (6.3 %; 95 %CI 6.0–6.7; P < 0.001), respectively. Adding other groups such as USMSTF 5–10-year and 3–5-year groups to the 3-year category resulted in minimal change in the PPV and NPV for metachronous advanced neoplasia. High risk ESGE (hazard ratio [HR] 3.03, 95 %CI 1.97–4.65) and USMSTF (HR 3.07, 95 %CI 2.03–4.66) designations were associated with similar long-term CRC risk (CRC per 100 000 person-years: USMSTF 3-year group 3.54, 95 %CI 2.68–4.68; ESGE high risk group: 3.43, 95 %CI 2.57–4.59). Conclusion Performance characteristics for the ESGE and USMSTF recommendations are similar in predicting metachronous advanced neoplasia and long-term CRC. The addition of risk groups, such as the USMSTF 5–10-year and 3–5-year groups to the USMSTF 3-year category did not alter the PPV or NPV significantly.

AbstractBackgroundWeight loss (WL) has been associated with shorter survival in patients with advanced cancer, while obesity has been associated with longer survival. Integrating body mass index (BMI) and WL provides a powerful prognostic tool but has not been well‐studied in lung cancer patients, particularly in the setting of clinical trials.MethodsWe analysed patient data (n = 10 128) from 63 National Cancer Institute sponsored advanced non‐small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) trials. Risk matrices were created using BMI and WL percentage, which were divided into ‘grades’ based on median survival. Relationships between survival, BMI and WL percentage were examined using Kaplan–Meier estimators and Cox proportional hazards (PH) models with restricted cubic splines.ResultsFor NSCLC, a twofold difference was noted in median survival between the BMI > 28 and WL ≤ 5% group (13.5 months) compared with the BMI < 20 and WL > 5% group (6.6 months). These associations were less pronounced in SCLC. Kaplan–Meier curves showed significant survival differences between grades for both NSCLC and SCLC (log‐rank, P < 0.0001). In Stage IV NSCLC, Cox PH analyses with restricted cubic splines demonstrated significant associations between BMI and survival in both WL ≤ 5% (P = 0.0004) and >5% (P = 0.0129) groups, as well as in WL > 5% in Stage III (P = 0.0306). In SCLC, these relationships were more complex.ConclusionsBMI and WL have strong associations with overall survival in patients with advanced lung cancer, with a greater impact seen in NSCLC compared with SCLC. The integration of a BMI/WL grading scale may provide additional prognostic information and should be included in the evaluation of therapeutic interventions in future clinical trials in advanced lung cancer.

Abstract Objective. Measuring waves induced with acoustic radiation force (ARF) in arteries has been studied over the last decade. To date, it remains a challenge to quantitatively assess the local arterial biomechanical properties. The cylindrical shape and waveguide behavior of waves propagating in the arterial wall pose complexities to determining the mechanical properties of the artery. Approach . In this paper, an artery-mimicking tube in water is examined utilizing three-dimensional measurements. The cross-section of the tube is measured while a transducer is translated over 41 different positions along the length of the tube. Motion in the radial direction is calculated using two components of motion which are measured from the two orthogonal views of the cross-section. This enables more accurate estimation of motion along the circumference of tube. Main results . The results provide more information to categorize the motion in tube wall into two types of responses: a transient response and a steady state response. The transient response is caused by ARF application and the waves travel along the length of the tube for a relatively short period of time. This corresponds to the axial and circumferential propagating waves. The two circumferential waves travel along the circumference of tube in CW (clockwise) and CCW (counter-clockwise) direction and result in a standing wave. By using a directional filter, the two waves were successfully separated, and their propagation was more clearly visualized. As a steady state response, a circumferential mode is generated showing a symmetric motion (i.e. the proximal and distal walls move in the opposite direction) following the transient response. Significance. This study provides a more comprehensive understanding of the waves produced in an artery-mimicking tube with ARF application, which will provide opportunities for improving measurement of arterial mechanical properties.

Background Wake-up stroke represents a significant challenge in acute treatment and care. Thrombolysis has been extensively studied in the wake-up stroke population. However, mechanical thrombectomy in wake-up stroke exclusively has not been well studied. We performed a systematic review and meta-analysis to assess the clinical and functional outcomes of patients undergoing mechanical thrombectomy for wake-up stroke. Methods We performed a systematic review of the literature using publically accessible databases. Data extraction was completed using Nested Knowledge AutoLit software. Outcomes of interest included modified Rankin Scale (mRS) 0–2, mortality, symptomatic intracerebral hemorrhage (sICH), and thrombolysis in cerebral infarction (TICI) score 2b/3. Statistical analysis was performed using R software version 4.1.2. Results A total of 12 studies were included in our study with a total of 510 patients included. Patients with wake-up stroke were found to have good functional outcome (mRS 0–2) in 46.2% of patients and successful reperfusion (TICI 2b/3) was seen in 83.5% of patients. Mortality was observed in 20.4% of patients with sICH seen in 8.3%. Conclusion Mechanical thrombectomy for patients with wake-up stroke was found to have favorable rates of good functional outcomes and relatively low rates of adverse events.

Background. Danlou tablet (DLT), the traditional Chinese medicine has been commonly used for dyslipidemia, atherosclerosis, and coronary heart disease. Whether it was effective against vascular injury caused by CIH has remained unknown. The aim of the current study was to observe the effects of DLT on chronic intermittent hypoxia (CIH)-induced vascular injury via regulation of blood lipids and to explore potential mechanisms. Methods. Sixteen 12-week-old male ApoE−/− mice were randomly divided into four groups. The sham group was exposed to normal room air, whereas the other three groups were exposed to CIH. Mice in the CIH + normal saline (NS) group were gavaged with NS. Mice in the CIH + Angptl4-ab group were intraperitoneally injected with Angptl4-antibody. Mice in the CIH + DLT group were gavaged with DLT. After four weeks of intervention, serum lipid concentrations, and serum lipoprotein lipase (LPL) activity were detected. The changes in atherosclerosis in vascular tissue were detected by hematoxylin and eosin (H&E) staining. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis were applied to detect the expression levels of hypoxia-induciblefactor-1 (HIF-1), factor-inhibiting HIF-1 (FIH-1), angiopoietin-like 4 (Angptl4), and LPL in different tissues. Results. CIH exposure increases serum lipid levels, decreases serum LPL activity, and exacerbates atherosclerosis. Both Angptl4-ab and DLT treatment reversed the changes in lipid concentration, LPL activity, and atherosclerosis caused by CIH. In the epididymal fat pad, CIH exposure decreased the expression of FIH-1 and increased the expression of HIF-1, whereas DLT treatment increased the expression of FIH-1 and LPL and inhibited the expression of HIF-1 and Angptl4. In heart tissue, the expression levels of LPL and Angptl4 were not affected by modeling or treatment. Conclusions. DLT improved vascular damage by improving the increase in blood lipids induced by CIH, potentially by upregulating FIH-1 and downregulating HIF-1 and Angptl4 in adipose tissue. Therefore, DLT may be a promising agent for the prevention and treatment of CIH-induced vascular injury.

Abstract Background A genome-wide association study (GWAS) assessing change in left ventricular ejection fraction (LVEF) in dilated cardiomyopathy (DCM), a surrogate marker of morbidity and mortality in heart failure (HF), had not been performed previously and could provide insight into novel biological pathways that could lead to the development of new drugs that might target myocardial recovery. The presence and extent of cardiac fibrosis in DCM is independently associated with myocardial recovery and cardiovascular mortality. Purpose To identify the biological relevance of genetic targets that are associated with change in LVEF in patients with DCM. Methods A GWAS was performed using DNA from 686 patients with recent onset DCM who were on standard HF therapy using change in LVEF at a median of 6 months after initial diagnosis. Cultured human cardiac fibroblasts (HCFs) were used as an in vitro model to study the functional and biological relevance of the gene target identified in the GWAS. Specifically, HCFs were transfected with siRNA by using the Lipofectamine™ RNAiMAX Transfection Reagent for gene knockdown (KD). RNA-seq was performed using the Illumina TruSeq protocol with expression analysis conducted with the EdgeR package. Ingenuity Pathway Analysis was used. Results A single-nucleotide polymorphism, rs11105445(G&gt;A), mapping to the neuron navigator 3 (NAV3) gene (rs11105445, p=2.37E-07; beta 2.74±0.53) was associated with improvement in LVEF. We performed a phenome-wide association study using data from the UK Biobank and demonstrated that genetic variation in NAV3 was significantly associated with HF mortality (p=3.2E-28), highlighting the potential importance of this gene in HF. Using GTEx data we demonstrated that in LV tissue the minor allele A was associated with ↓NAV3 expression (p=0.03) suggesting that ↓NAV3 expression might be associated with improvement in LVEF. We demonstrated that NAV3 KD significantly ↓TGF-β1 mediated HCF transdifferentiation into myofibroblasts, ↓α-smooth muscle actin (ACTA2) and ↓collagen I (COL1A1), therefore NAV3 KD was anti-fibrotic (see Figure 1), 1a. HCFs treated by vehicle/TGF-β1 after KD of NAV3/ctrl, and ACTA2 and COL1A1 were analyzed by qPCR; 1b. Representative immunofluorescence staining for α-SMA (in green), RNA-seq after NAV3 KD followed by pathway analysis suggested that NAV3 exerted its effect by regulating cell cycle related proteins (Figure 2), 2a. Volcano plot shows significant differentially expressed genes identified by RNA-seq analysis (down-regulated in blue, up-regulated in red); 2b. NAV3 KD significantly increased expression of cell cycle related proteins, which was validated by Western blot. Conclusions Decreased expression of NAV3 is associated with myocardial recovery in DCM, most likely due to its anti-fibrotic effect via direct regulation of cell cycle proteins. The role of NAV3 as a novel therapeutic target in DCM needs to be explored. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Mayo Clinic Center for Individualized MedicineMayo Clinic Department of Cardiovascular Medicine

PURPOSE Diagnosis of Mismatch Repair Deficiency (MMRD) is crucial for tumor management and early detection in patients with the cancer predisposition syndrome constitutional mismatch repair deficiency (CMMRD). Current diagnostic tools are cumbersome and inconsistent both in childhood cancers and in determining germline MMRD. PATIENTS AND METHODS We developed and analyzed a functional Low-pass Genomic Instability Characterization (LOGIC) assay to detect MMRD. The diagnostic performance of LOGIC was compared with that of current established assays including tumor mutational burden, immunohistochemistry, and the microsatellite instability panel. LOGIC was then applied to various normal tissues of patients with CMMRD with comprehensive clinical data including age of cancer presentation. RESULTS Overall, LOGIC was 100% sensitive and specific in detecting MMRD in childhood cancers (N = 376). It was more sensitive than the microsatellite instability panel (14%, P = 4.3 × 10 −12 ), immunohistochemistry (86%, P = 4.6 × 10 −3 ), or tumor mutational burden (80%, P = 9.1 × 10 −4 ). LOGIC was able to distinguish CMMRD from other cancer predisposition syndromes using blood and saliva DNA ( P < .0001, n = 277). In normal cells, MMRDness scores differed between tissues (GI > blood > brain), increased over time in the same individual, and revealed genotype-phenotype associations within the mismatch repair genes. Importantly, increased MMRDness score was associated with younger age of first cancer presentation in individuals with CMMRD ( P = 2.2 × 10 −5 ). CONCLUSION LOGIC was a robust tool for the diagnosis of MMRD in multiple cancer types and in normal tissues. LOGIC may inform therapeutic cancer decisions, provide rapid diagnosis of germline MMRD, and support tailored surveillance for individuals with CMMRD.

Précis: Surgical and clinical success rates were similar among Ahmed FP7, and Baerveldt 250 and 350 glaucoma drainage devices at three years. Purpose: To compare rates of surgical and clinical success in patients with Ahmed FP7 (FP7), Baerveldt 250 (B250), or Baerveldt 350 (B350) glaucoma drainage devices (GDDs). Design: A retrospective cohort study. Methods: A total of 157 eyes of 129 adult patients with FP7, B250, B350 GDDs, and 190 eyes of 99 medically controlled glaucoma patients were enrolled at a tertiary care institution from August 2017 through July 2019. They were followed through April 2020. The main outcome measures included surgical and clinical failure. Surgical failure was defined as intraocular pressure (IOP) outside 5–21 mm Hg, IOP reduced <20% below baseline, additional glaucoma surgery, GDD removal, or no light perception. Eyes that did not meet their goal IOP ranges or required secondary glaucoma interventions were deemed clinical failures. Results: A total of 43 (12.4%) FP7, 36 (10.4%) B250, 78 (22.5%) B350, and 190 (54.8%) medically treated control eyes were enrolled. By the postoperative year 3 visit, 10 (23.2%) FP7, 11 (30.6%) B250, and 32 (41.0%) B350 eyes had met a surgical failure criterion (P=0.127). There were no significant differences in the numbers of eyes meeting their IOP target ranges (P=0.510), and rates of secondary glaucoma surgeries (P=0.270). Overall clinical success was attained among 83.3% FP7, 81.8% B250, and 68.0% B350 eyes (P=0.447). Conclusions: The GDD groups were similar in their rates of success, based on both the surgical and clinical success definitions.