Retained or altered expression of major histocompatibility complex class I in patient-derived xenograft models in breast cancer

Immunologic Research - The expression of major histocompatibility complex class I (MHC I) in tumor cells is regulated by interferon signaling, and it is an important factor in the efficacy of...     

Enhanced Anti-Leukemic Effects through Induction of Immunomodulating Microenvironment by Blocking CXCR4 and PD-L1 in an AML Mouse Model

Previously, we found that dual therapy by the CXCR4 inhibitor Plerixafor and cytosine arabinoside (Ara-C) effectively eradicated leukemia cells and concurrently activated immune cells in acute myeloid leukemia (AML). To reveal the significance of programmed death-ligand1 (PD-L1) in AML and as a strategic approach, we investigated the anti-leukemic effect of a triple combinational therapy by utilizing Plerixafor and anti-PD-L1 in combination with chemotherapy in an AML mouse model. We examined leukemic myeloid blast cells in multiple organs after the successive treatment with Ara-C, Plerixafor, and anti-PD-L1. The results showed that noticeable benefits of triple combinational therapy for eradication of myeloid blast cells in vivo with prolonged survival rates. The frequencies of regulatory T cells (Tregs), monocytic-myeloid-derived suppressor cells (M-MDSCs), and granulocytic-myeloid-derived suppressor cells (G-MDSCs), in the peripheral blood of leukemic mice were consistently decreased, even when mice were sacrificed alive at D + 26 after completion of the triple combinational therapy, compared to the other subgroups. These findings imply that the modulation by the triple combinational therapy may lead to more efficient leukemic myeloid blast cell ablation through the suppression of Tregs or M-MDSCs and G-MDSCs in AML. Although Plerixafor and PD-L1 antagonist do not have a direct anti-leukemic role, our results provide some clues and guidelines to develop clinically therapeutic strategies for chemotherapy-resistant patients by the modulation of leukemic microenvironments.     

Chinese liver fluke Clonorchis sinensis infection changes the gut microbiome and increases probiotic Lactobacillus in mice

Chinese liver fluke Clonorchis sinensis changes the host’s immune system. Recently, it has been reported that helminths including C. sinensis can ameliorate immune-related diseases such as allergy. In addition, recent studies showed that helminth infection can alleviate immune-mediated disorders by altering the gut microbiome. However, changes in the gut microbiome due to C. sinensis have not been reported yet. In this study, changes in the gut microbiome of C57BL/6 mice infected with C. sinensis metacercariae were evaluated over time. Stool was analyzed by 16S rRNA amplicon analysis using high-throughput sequencing technology. There was no apparent difference in species richness and diversity between the infected and control groups. However, the composition of the microbiome was different between the infected and control groups at 20 days and 30 days post-infection, and the difference disappeared at 50 days post-infection. In particular, this microbiome alteration was associated with a change in the relative abundance of genus Lactobacillus and the probiotic Lactobacillus species that are known to have an immune-modulation role in immune-mediated diseases.

     

Residual varus alignment after total knee arthroplasty increases knee adduction moment without improving patient function: A propensity score-matched cohort study

BackgroundTargeting residual varus alignment in total knee arthroplasty may be functionally beneficial to preoperative varus patients.MethodsBilateral TKA patients were enrolled. According to the postoperative hip-knee-ankle axis, patients were allocated into residual varus (3° ± 1°) alignment group or neutral (0° ± 1°) alignment group. Then, 1:2 propensity score matching was used to match preoperative variables. Finally, matched neutral (n = 45) and varus groups (n = 32) were followed-up for two years and compared. The primary outcome was the Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC). Secondary outcomes were range of motion (ROM), Knee Society knee score and function score, spatiotemporal gait parameters, dynamic alignment, knee flexion angle, knee adduction moment (KAM) and internal knee extension moment.ResultsAt two years after surgery, the mean difference of WOMAC score was 0.3 (95% CI, [? 3.1, 3.7]) between the two groups. All secondary outcomes, except KAM and dynamic alignment, showed no significant difference between the two groups. Residual varus alignment group showed increased KAM and maximum KAM was 19% higher (P = 0.006).ConclusionsResidual varus alignment showed no clinical benefits, and both groups of patients had a functionally identical knee gait biomechanics, except for increased KAM and varus alignment. The authors consider that even in patients with varus alignment, the first principle is still achieving neutral alignment, which is helpful for reducing the KAM.Level of evidenceIII, retrospective cohort study.     

Referencing the trochlear groove based on three-dimensional computed tomography imaging improves the reliability of the measurement of the tibial tuberosity–trochlear groove distance in patients with higher grades of trochlea dysplasia

BackgroundTo determine whether 3D-CT imaging technique is valid and reproducible compared to conventional CT measurement technique (CCT) for the detection of a femoropatellar instability.MethodsPatients who had undergone surgery for femoropatellar instability (patellar instability group) between 2010 and 2016 (n = 37 knees of 35 patients) were retrospectively enrolled. For the matched control group, patients who had acute anterior cruciate ligament injury (< 4 weeks previously; n = 30) were recruited. Preoperative CT data had been obtained in all patients. Inter-rater reliability was calculated for both measurement protocols, and inter-method reliability was calculated between the two imaging modalities. The results are reported using intraclass correlation coefficients (ICCs) and Bland–Altman 95% limits of agreement.ResultsAll patients in the patellar instability group had femoral trochlear dysplasia (Dejour types A: four, B: 19, C: seven, and D: six), but no dysplasia was noted in the control group. In the patellar instability group, the CCT technique showed a poor inter-rater agreement (ICC = 0.74), and the 3D-CT technique still showed excellent inter-rater agreement (ICCs = 0.91). In the sub-analysis of the patellar instability group according to the trochlear dysplasia grade, ICCs were markedly decreased with severe trochlear dysplasia when using CCT technique; however, the 3D-CT technique could provide excellent reliability even with severe trochlear dysplasia.ConclusionThe 3D-CT imaging technique for the measurement of the TT–TG distance can be suggested as a better measurement technique for patellar instability patients with bone abnormality.     

The midterm results of a cohort study of patellofemoral arthroplasty from a non-designer centre using an asymmetric trochlear prosthesis

PurposePatellofemoral arthroplasty (PFA) prosthesis with asymmetric trochlear component was introduced as an improvement from existing designs for surgical treatment of symptomatic isolated patellofemoral arthritis. The purpose of this study was to evaluate midterm results in patients who underwent PFA procedure using such prosthesis.MethodsOur study involved a continuous retrospective cohort of patients who underwent PFA using Journey PFA prosthesis with an asymmetric trochlear component, performed between June 2007 and July 2016 at a non-designer centre. The Patient Reported Outcome Measures and patient satisfaction questionnaires were collected for final evaluation.ResultsA total of 103 PFA performed on 79 patients were evaluated. Median age at the time of surgery was 58 years (range 42 to 78 years); the mean follow-up period was 6 years (range 2 to 11 years). Four knees were revised to Total Knee Arthroplasty for reasons not related to the implant. The cumulative survival estimated by the Kaplan–Meier method was 94.3% (95% confidence interval: 88.4%–100%). There were statistically significant improvements in functional outcome scores.ConclusionThis series of patients who underwent PFA with the asymmetric trochlear component has shown promising mid-term results with no implant-related complications.     

Aligned Tubular Conjugated Microporous Polymer Films for the Aggregation‐Induced Emission‐Based Sensing of Explosives

This work shows the sensing performance of conjugated microporous polymer (CMP) tubes. Aligned tubular CMP films (CMP‐AT) are synthesized by a template method. The Sonogashira coupling of tetra(4‐ethynyl)phenylethylene with 1,4‐diiodobenzene in the cylindrical pores of anodic aluminum oxide (AAO) plates and the etching of templates result in the CMP‐AT films. Due to the tetraphenylethylene moieties in the materials, the CMP‐AT films show aggregation‐induced emission (AIE). Based on emission‐quenching behavior, the sensing performance of CMP‐AT films toward model explosives, nitrotoluenes, is studied. The CMP‐AT films having longer CMP tubes with thinner wall thickness show better sensing performance with the Stern–Volmer constant (K_sv) values up to 92 400 M^?1 toward 2,4‐dinitrotoluene. The reduced diffusion pathway of substrates by the thin wall of the CMP tubes is critical for the AIE quenching‐based sensing of nitrotoluenes. These observations indicate that the functionality of CMP materials can be further enhanced by their morphological engineering. Due to the chemical stability of CMP materials, the CMP‐AT‐5 film can be recycled at least five times, maintaining the original sensing performance and tubular morphology.     

Population pharmacokinetics of theophylline in adult Chinese patients with asthma and chronic obstructive pulmonary disease

Background Theophylline has a narrow therapeutic range and large interindividual variability in blood levels, so a thorough understanding of its pharmacokinetic characteristics is essential. Population pharmacokinetic (PPK) approaches could achieve it and many PPK studies of theophylline have been reported in infants. However, none was conducted in Chinese adults and none has explored the effect of CYP1A2 genotypes on the PPK characteristics of theophylline in adults. Objective To evaluate the PPK characteristics of theophylline and to assess the possible influence of covariates, including CYP1A2 genotypes, on theophylline clearance in Chinese adult patients. Setting The study is conducted at the department of respiration in Zhujiang Hospital, Guangzhou, China. Methods Theophylline concentrations were obtained from eligible patients and were measured by high performance liquid chromatography. The polymorphisms of ??3860G?>?A, ??163C?>?A, C5347T (CYP1A2*1B) and G-3113A were genotyped using a direct sequencing method. Then, CYP1A2 genotypes, age, fat-free mass (FFM) and other covariates were used to develop a PPK model by NONMEM software. Bootstrap analysis was used to asses the accuracy and prediction of the PPK model. Main outcome measure The concentration and clearance of theophylline. Results A total of 134 theophylline concentrations from 95 patients were obtained. The final model was as follows: CL/F(L/h)?=?4.530?×?(FFM/56.1)^0.75 ×?0.713^CYP1A2*1B, the inter-individual variability in clearance/bioavailability (CL/F) was 44.0%, and the residual variability was 9.8%. The final model was proved to be reliable by bootstrap analysis. Conclusion Theophylline clearance was significantly associated with FFM and CYP1A2*1B genotypes in Chinese adult patients.