The Clinical Efficacy of Platelet-Rich Plasma Injection Therapy versus Different Control Groups for Chronic Low Back Pain: A Network Meta-Analysis of Randomized Controlled Trials.

Objective: Low back pain is one of the main causes of disability in the world. Although regenerative medicine may represent breakthroughs in the management of low back pain, its use remains controversial. Therefore, we conducted a meta-analysis to evaluate the clinical efficacy of platelet-rich plasma (PRP) injection therapy versus different control groups for chronic low back pain during 4 weeks, 3 months, and 6 months. Methods: Different electronic databases were searched for randomized controlled trials up to August 2023. Mean changes from baseline in pain and Oswestry Disability Index (ODI) scores at 4 weeks, 3 months, and 6 months and standard deviations of outcome were recorded. Results: Four articles with 154 cases were finally included in this meta-analysis. After 4 weeks, corticosteroid (CS) was the optimal treatment option for chronic low back pain in terms of improvement in pain and disability index (surface under the cumulative ranking curve [SUCRA]=71.3%, SUCRA=57.8%, respectively). After 3 months, radiofrequency (RF) emerged as the best therapy in pain (SUCRA=100%) and disability index (SUCRA=98.5%), followed by PRP (SUCRA=62.3%, SUCRA=64.3%, respectively), CS (SUCRA=24.6%, SUCRA=25.9%, respectively) and lidocaine (SUCRA=13.1%, SUCRA=11.3%, respectively). At 6 months, RF was most likely to be the best treatment in pain (SUCRA=94.9%) and disability index (SUCRA=77.3%), followed by PRP (SUCRA=71.2%, SUCRA=79.6%, respectively). However, compared with the last follow-up, there was a slight downward trend in improvement pain and disability index with RF, while PRP was still an upward trend. Conclusion: This study demonstrated better short-term improvement of chronic low back pain with CS after 4 weeks. PRP and RF improvement effects matched, but follow-up of at least 6 months showed that PRP seemed to be more advantageous in improvement in disability indices. Considering the limitations of this study, these conclusions still need to be verified by more comparative RCTs and a longer follow-up period.

Abnormal circulating steroids refine risk of progression to heart failure in ischemic heart disease.

BACKGROUND: Patients with ischemic heart disease (IHD) experience a high incidence of progression to heart failure (HF) despite current therapies. We speculated that steroid hormone metabolic disorders distinct adverse phenotypes and contribute to HF. METHODS: We measured 18 steroids using liquid chromatography with tandem mass spectrometry in 2023 patients from the Registry Study of Biomarkers in Ischemic Heart Disease (BIOMS-IHD), including 1091 patients with IHD in a retrospective discovery set and 932 patients with IHD in a multicentre validation set. Our outcomes included incident HF after a median follow-up of 4 years. RESULTS: We demonstrated steroid-based signatures of inflammation, coronary microvascular dysfunction and left ventricular hypertrophy that were associated with subsequent HF events in patients with IHD. In both cohorts, patients with a high steroid-heart failure score (SHFS) (>1) exhibited a greater risk of incident HF than patients with a low SHFS (≤1). The SHFS further improved the prognostic accuracy beyond clinical variables (net reclassification improvement of 0.628 in the discovery set and 0.299 in the validation set) and demonstrated the maximal effect of steroid signatures in patients with IHD who had lower B-type natriuretic peptide levels (pinteraction = 0.038). CONCLUSIONS: A steroid-based strategy can simply and effectively identify individuals at higher HF risk who may derive benefit from more intensive follow-ups.

Current Progress and Challenges in Large-Scale 3D Mitochondria Instance Segmentation.

In this paper, we present the results of the MitoEM challenge on mitochondria 3D instance segmentation from electron microscopy images, organized in conjunction with the IEEE-ISBI 2021 conference. Our benchmark dataset consists of two large-scale 3D volumes, one from human and one from rat cortex tissue, which are 1,986 times larger than previously used datasets. At the time of paper submission, 257 participants had registered for the challenge, 14 teams had submitted their results, and six teams participated in the challenge workshop. Here, we present eight top-performing approaches from the challenge participants, along with our own baseline strategies. Posterior to the challenge, annotation errors in the ground truth were corrected without altering the final ranking. Additionally, we present a retrospective evaluation of the scoring system which revealed that: 1) challenge metric was permissive with the false positive predictions; and 2) size-based grouping of instances did not correctly categorize mitochondria of interest. Thus, we propose a new scoring system that better reflects the correctness of the segmentation results. Although several of the top methods are compared favorably to our own baselines, substantial errors remain unsolved for mitochondria with challenging morphologies. Thus, the challenge remains open for submission and automatic evaluation, with all volumes available for download.

Epigenetic regulation in the commitment of progenitor cells during retinal development and regeneration.

Retinal development is initiated by multipotent retinal progenitor cells, which undergo several rounds of cell divisions and subsequently terminal differentiation. Retinal regeneration is usually considered as the recapitulation of retinal development, which share common mechanisms underlying the cell cycle re-entry of adult retinal stem cells and the differentiation of retinal neurons. However, how proliferative retinal progenitor cells perform a precise transition to postmitotic retinal cell types during the process of development and regeneration remains elusive. It is proposed that both the intrinsic and extrinsic programming are involved in the transcriptional regulation of the spatio-temporal fate commitment. Epigenetic modifications and the regulatory mechanisms at both DNA and chromatin levels are also postulated to play an important role in the timing of differentiation of specific retinal cells. In the present review, we have summarized recent knowledge of epigenetic regulation that underlies the commitment of retinal progenitor cells in the settings of retinal development and regeneration.

Using GRACE to Detect Groundwater Variation in North China Plain after South-North Water Diversion.

The gravity recovery and climate experiment (GRACE) and its Follow-On mission provide a versatile tool for monitoring groundwater depletion in North China Plain (NCP). However, intermittent data gaps and inherent coarse spatial resolution have restricted the continuous detection of regional groundwater storage anomaly (GWSA) after 2014, the period of interest during the implementation of the south-to-north water diversion middle route project (SNWDP). Here, we investigated the spatiotemporal changes of GWSA in the NCP during 2004 to 2020 based on continuous downscaled GRACE data. First, we derived the continuous terrestrial water storage anomaly from six GRACE and Follow-On solutions (i.e., spherical harmonics (SH) and mass concentration [mascon] solutions). Second, we employed a long short-term memory (LSTM) model and water balance equation to downscale GWSA (i.e., 0.25° × 0.25°). Lastly, we investigated its spatiotemporal characteristics before (2004 to 2014) and after (2015 to 2020) the SNWDP operation. We show the applicability of the continuous downscaled GWSA to capture the characteristics of in situ measurements. The GWSA detects groundwater depletion at a significant (p < 0.05) rate of -17.09 ± 1.80 (SH) and -17.87 ± 1.65 (mascon) mm/a during 2004 to 2014, but a recovering trend of 7.18 ± 3.98 (SH) and 8.23 ± 4.99 (mascon) during 2015 to 2018. The subsequent groundwater extraction and precipitation reduction from 2019 to 2020, resulted in the decreasing trend of GWSA from 2015 to 2020, which is -19.11 ± 8.75 (SH) and -19.72 ± 9.08 mm/a (mascon), respectively. Spatially, the overall depletion trends become nonsignificant along the canals of SNWDP compared to the period 2004 to 2014, and groundwater recovering with trends <6 mm/a near Beijing and Tianjin are detected by the mascon solution during 2015 to 2020.

The Role of Adaptive Immunity in Diabetic Retinopathy.

Diabetic retinopathy (DR) is currently one of the common causes of vision loss in working-age adults. It is clinically diagnosed and classified according to the vascular changes in the fundus. However, the activation of immune cells occurs before these vascular changes become detectable. These, together with molecular studies and the positive clinical outcomes of anti-inflammatory treatment, highlight the pivotal involvement of the immune system. The role of innate immunity in DR pathophysiology has been studied in depth, but the contribution of adaptive immunity remains largely elusive. This review aims to summarize our current understanding of the activation mechanism of adaptive immunity in DR microenvironments and to discuss the relationship between adaptive immunity and local vascular units or innate immunity, which opens new avenues for clinical applications in DR treatment.

Efficacy of Trastuzumab + Cisplatin Combined with Irinotecan on the Quality of Life of Patients with Advanced Her-2 Positive Gastric Cancer.

Objective: To observe the effect of trastuzumab and cisplatin combined with irinotecan in the treatment of advanced Her-2 positive gastric cancer and its influence on disease control rate. Methods: From January 2018 to January 2021, 120 patients with advanced Her-2 positive gastric cancer admitted to our hospital were selected as the research subjects. According to the treatment plan of the patients, they were divided into a control group and a joint group, with 60 cases in each group; the control group was given trastuzumab + cisplatin, the joint group was treated with irinotecan on this basis, and the clinical effects and disease control rate of the two groups were observed. Results: After treatment, there were 4 patients with CR in the joint group and 0 patients with CR in the control group. The ORR and DCR of the joint group were significantly higher than those of the control group (P < 0.05). The expression levels of CA199, CEA, and CA724 after treatment in the two groups were significantly reduced (P < 0.05), and the reduction in the joint group after treatment was more evident as compared with the control group (P < 0.05). The joint group witnessed better memory function, physical function, behavioral function, emotional function, and communication function than the control group (P < 0.05), and the scores of all dimensions of the two groups of patients after treatment were superior to those before treatment (P < 0.05). The occurrence of side effects was not statistically different between the two groups of patients (P > 0.05). The 1-year survival rate of the control group was 41.67%, the PFS was 6.33 ± 1.02 months, and the OS was 15.51 ± 2.16 months; the 1-year survival rate of the joint group was 43.33%, and the PFS was 8.05 ± 1.07 months, and OS was 16.03 ± 2.44 months; there was no significant difference in the 1-year survival rate between the two groups (P > 0.05), the difference in PFS between the groups was significant (t = 9.013, P < 0.001), and the difference in OS between the groups was not significant (t = 1.236, P=0.219). Conclusion: Trastuzumab + cisplatin combined with irinotecan yields a promising result in the treatment of advanced gastric cancer. It can effectively regulate the expression level of tumor markers, delay disease progression, and improve the quality of life of patients. Moreover, irinotecan will not bring more toxic side effects.

Next-day manufacture of a novel anti-CD19 CAR-T therapy for B-cell acute lymphoblastic leukemia: first-in-human clinical study.

To improve clinical outcomes and shorten the vein-to-vein time of chimeric antigen receptor T (CAR-T) cells, we developed the FasT CAR-T (F-CAR-T) next-day manufacturing platform. We report the preclinical and first-in-human clinical studies evaluating the safety, feasibility, and preliminary efficacy of CD19 F-CAR-T in B-cell acute lymphoblastic leukemia (B-ALL). CD19 F-CAR-T cells demonstrated excellent proliferation with a younger cellular phenotype, less exhaustion, and more effective tumor elimination compared to conventional CAR-T cells in the preclinical study. In our phase I study (NCT03825718), F-CAR-T cells were successfully manufactured and infused in all of the 25 enrolled pediatric and adult patients with B-ALL. CD19 F-CAR-T safety profile was manageable with 24% grade 3 cytokine release syndrome (CRS) and 28% grade 3/4 neurotoxicity occurring predominantly in pediatric patients. On day 14, 23/25 patients achieved minimal residual disease (MRD)-negative complete remission (CR), and 20 subsequently underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) within 3 months post F-CAR-T therapy. Fifteen of 20 patients were disease-free with a median remission duration of 734 days. One patient relapsed and 4/20 died from transplant-related mortality. Of the three patients who did not undergo allo-HSCT, two remained in CR until 10 months post-F-CAR-T. Our data indicate that anti-CD19 FasT CAR-T shows promising early efficacy for B-ALL. Further evaluations in larger clinical studies are needed.

Novel CD19 chimeric antigen receptor T cells manufactured next-day for acute lymphoblastic leukemia.

Chimeric antigen receptor-engineered T (CAR-T) cells have shown promising efficacy in patients with relapsed/refractory B cell acute lymphoblastic leukemia (R/R B-ALL). However, challenges remain including long manufacturing processes that need to be overcome. We presented the CD19-targeting CAR-T cell product GC007F manufactured next-day (FasTCAR-T cells) and administered to patients with R/R B-ALL. A total of 21 patients over 14 years of age with CD19+ R/R B-ALL were screened, enrolled and infused with a single infusion of GC007F CAR-T at three different dose levels. The primary objective of the study was to assess safety, secondary objectives included pharmacokinetics of GC007F cells in patients with R/R B-ALL and preliminary efficacy. We were able to demonstrate in preclinical studies that GC007F cells exhibited better proliferation and tumor killing than conventional CAR-T (C-CAR-T) cells. In this investigator-initiated study all 18 efficacy-evaluable patients achieved a complete remission (CR) (18/18, 100.00%) by day 28, with 17 of the patients (94.4%) achieving CR with minimal residual disease (MRD) negative. Fifteen (83.3%) remained disease free at the 3-month assessment, 14 patients (77.8%) maintaining MRD negative at month 3. Among all 21 enrolled patients, the median peak of CAR-T cell was on day 10, with a median peak copy number of 104899.5/µg DNA and a median persistence period of 56 days (range: 7-327 days). The incidence of cytokine release syndrome (CRS) was 95.2% (n = 20), with severe CRS occurring in 52.4% (n = 11) of the patients. Six patients (28.6%) developed neurotoxicity of any grade. GC007F demonstrated superior expansion capacity and a less exhausted phenotype as compared to (C-CAR-T) cells. Moreover, this first-in-human clinical study showed that the novel, next-day manufacturing FasTCAR-T cells was feasible with a manageable toxicity profile in patients with R/R B-ALL.

Somatostatin signalling promotes the differentiation of rod photoreceptors in human pluripotent stem cell-derived retinal organoid.

OBJECTIVES: Stem cell-derived photoreceptor replacement therapy is a promising strategy for the treatment of retinal degenerative disease. The development of 3D retinal organoids has permitted the production of photoreceptors. However, there is no strategy to enrich a specific photoreceptor subtype due to inadequate knowledge of the molecular mechanism underlying the photoreceptor fate determination. Hence, our aim is to explore the uncharacterized function of somatostatin signalling in human pluripotent stem cell-derived photoreceptor differentiation. MATERIALS AND METHODS: 3D retinal organoids were achieved from human embryonic stem cell. The published single-cell RNA-sequencing datasets of human retinal development were utilized to further investigate the transcriptional regulation of photoreceptor differentiation. The assays of immunofluorescence staining, lentivirus transfection, real-time quantitative polymerase chain reaction and western blotting were performed. RESULTS: We identified that the somatostatin receptor 2 (SSTR2)-mediated signalling was essential for rod photoreceptor differentiation at the precursor stage. The addition of the cognate ligand somatostatin in human 3D retinal organoids promoted rod photoreceptor differentiation and inhibited cone photoreceptor production. Furthermore, we found that the genesis of rod photoreceptors was modulated by endogenous somatostatin specifically secreted by developing retinal ganglion cells. CONCLUSIONS: Our study identified SSTR2 signalling as a novel extrinsic regulator for rod photoreceptor fate determination in photoreceptor precursors, which expands the repertoire of functional signalling pathways in photoreceptor development and sheds light on the optimization of the photoreceptor enrichment strategy.

Plasma Ceramides and Cardiovascular Events in Hypertensive Patients at High Cardiovascular Risk.

BACKGROUND: Plasma ceramides (Cer) have been used to evaluate risk of cardiovascular (CV) events in patients with coronary heart disease. We investigated the performance of ceramides and ceramide score (CERT) in hypertensive patients at high CV risk. METHODS: Seven ceramides were analyzed using ultra-performance liquid chromatography-tandem mass spectrometry in 920 essential hypertension patients at high CV risk, who visited Beijing Anzhen Hospital from September 2016 to September 2018 (median age: 49 years, 562 males). All patients were followed up for major adverse cardiovascular events (MACE), which included incident acute coronary syndrome, heart failure, stroke, and CV death. RESULTS: During mean 2.3-year follow-up, 71 patients experienced MACE. Cer(d18:1/16:0), Cer(d18:1/22:0), and Cer(d18:1/24:0) were highly significant in predicting MACE [multiadjusted hazard ratios (95% confidence interval, CI) per SD were 1.76 (1.34-2.30), 0.55 (0.41-0.73), and 0.66 (0.47-0.92), respectively]. Compared with traditional variables (comprising presence of CV risk factors, hypertension-mediated organ damage, and comorbidities), a novel CERT for hypertensive patients (CERT-HBP), composed of Cer(d18:1/16:0), Cer(d18:1/24:1), and their ratios to Cer(d18:1/24:0) and Cer(d18:1/22:0), respectively, increased the C-statistic from 0.751 (95% CI, 0.697-0.806) to 0.791 (95% CI, 0.737-0.845), P = 0.010. Net reclassification improvement and integrated discrimination improvement were 0.648 (95% CI, 0.421-0.885, P < 0.001) and 0.046 (95% CI, 0.025-0.068, P < 0.001), respectively. CONCLUSIONS: A ceramide-based CERT-HBP was established to evaluate risk of MACE in hypertensive patients at high CV risk. This may improve identification of high-risk patients requiring increased attention and aggressive therapy. CLINICAL TRIALS REGISTRATION: Trial Number NCT03708601.

Towards generalisable hate speech detection: a review on obstacles and solutions.

Hate speech is one type of harmful online content which directly attacks or promotes hate towards a group or an individual member based on their actual or perceived aspects of identity, such as ethnicity, religion, and sexual orientation. With online hate speech on the rise, its automatic detection as a natural language processing task is gaining increasing interest. However, it is only recently that it has been shown that existing models generalise poorly to unseen data. This survey paper attempts to summarise how generalisable existing hate speech detection models are and the reasons why hate speech models struggle to generalise, sums up existing attempts at addressing the main obstacles, and then proposes directions of future research to improve generalisation in hate speech detection.

Treatment of mustard tuber wastewater (MTWW) using a pilot-scale packed cage rotating biological contactor system: process modeling and optimization.

The water quality range for wastewater treatment projects in the food processing industry changes constantly. To fully understand the threshold for pollutant removal with the lowest possible energy consumption, the relationship between pollutant removal and wastewater treatment conditions was established using response surface methodology (RSM). The optimum conditions for total COD, TN, and NH3-N removal from saline mustard tuber wastewater (MTWW) with a packed cage rotating biological contactor (RBC) system were investigated by experiments based on a Box-Behnken design (BBD). The independent variables were organic load (ORL), rotational disk velocity (RDV), and immersion rate (IR). Parameters of COD, TN, and NH3-N removal efficiency were selected as responses. The optimal conditions for the best COD, TN, and NH3-N removal efficiency with the lowest energy consumption were found to be at an ORL of 26.71 kg/day, a RDV of 1.62 rpm (7.62 m/s), and an IR of 46%. After the optimization, the energy cost was evaluated by coupling energy performance indicators with organic pollution efficiencies to be the highest class of performance. This research demonstrates that the suggested models have a good predicting and fitting ability in interrelations between the pollutant removal and process parameters of the packed cage RBC system treating saline MTWW.

Improving the Resolution and Accuracy of Groundwater Level Anomalies Using the Machine Learning-Based Fusion Model in the North China Plain.

The launch of GRACE satellites has provided a new avenue for studying the terrestrial water storage anomalies (TWSA) with unprecedented accuracy. However, the coarse spatial resolution greatly limits its application in hydrology researches on local scales. To overcome this limitation, this study develops a machine learning-based fusion model to obtain high-resolution (0.25°) groundwater level anomalies (GWLA) by integrating GRACE observations in the North China Plain. Specifically, the fusion model consists of three modules, namely the downscaling module, the data fusion module, and the prediction module, respectively. In terms of the downscaling module, the GRACE-Noah model outperforms traditional data-driven models (multiple linear regression and gradient boosting decision tree (GBDT)) with the correlation coefficient (CC) values from 0.24 to 0.78. With respect to the data fusion module, the groundwater level from 12 monitoring wells is incorporated with climate variables (precipitation, runoff, and evapotranspiration) using the GBDT algorithm, achieving satisfactory performance (mean values: CC: 0.97, RMSE: 1.10 m, and MAE: 0.87 m). By merging the downscaled TWSA and fused groundwater level based on the GBDT algorithm, the prediction module can predict the water level in specified pixels. The predicted groundwater level is validated against 6 in-situ groundwater level data sets in the study area. Compare to the downscaling module, there is a significant improvement in terms of CC metrics, on average, from 0.43 to 0.71. This study provides a feasible and accurate fusion model for downscaling GRACE observations and predicting groundwater level with improved accuracy.

MitoEM Dataset: Large-scale 3D Mitochondria Instance Segmentation from EM Images.

Electron microscopy (EM) allows the identification of intracellular organelles such as mitochondria, providing insights for clinical and scientific studies. However, public mitochondria segmentation datasets only contain hundreds of instances with simple shapes. It is unclear if existing methods achieving human-level accuracy on these small datasets are robust in practice. To this end, we introduce the MitoEM dataset, a 3D mitochondria instance segmentation dataset with two (30µm)3 volumes from human and rat cortices respectively, 3, 600× larger than previous benchmarks. With around 40K instances, we find a great diversity of mitochondria in terms of shape and density. For evaluation, we tailor the implementation of the average precision (AP) metric for 3D data with a 45× speedup. On MitoEM, we find existing instance segmentation methods often fail to correctly segment mitochondria with complex shapes or close contacts with other instances. Thus, our MitoEM dataset poses new challenges to the field. We release our code and data: https://donglaiw.github.io/page/mitoEM/index.html.

Glycyrrhizic Acid Inhibits Proliferation of Gastric Cancer Cells by Inducing Cell Cycle Arrest and Apoptosis.

PURPOSE: Glycyrrhizic acid (GA) is the main active ingredient extracted from Chinese herb licorice root, and it shows anti-tumor effects in many cancer types, while its role in gastric cancer (GC) is still unknown. In this study, we evaluated the effects of GA on GC cells and explored the underlying mechanisms. METHODS: The anti-proliferation effect of GA on GC cells was assessed by CCK-8, colony formation, and EdU assay. The effects of GA on cell cycle and apoptosis were detected by flow cytometer. Western blotting was performed to explore the underlying mechanisms. RESULTS: Our results showed that GA had a time- and dose-dependent inhibitory effect on proliferation of GC cells. Flow cytometer analysis demonstrated that GA would lead to G1/S-phase arrest and apoptosis. GA treatment down-regulated the levels of G1 phase-related proteins, including cyclin D1, D2, D3, E1, and E2. In terms of apoptosis, GA treatment up-regulated the levels of Bax, cleaved PARP, and pro-caspase-3, -8, -9, but did not influence their cleavage patterns. The expression of Bcl-2, survivin and p65 was attenuated after treatment. Besides, GA would down-regulate the phosphorylation of PI3K/AKT pathway. CONCLUSION: This study focused on inhibitory effect of GA on GC cells by inducing cell cycle arrest and apoptosis. Several important cyclins- and apoptosis-related proteins were involved in the regulation of GA to GC cells, and phosphorylated PI3K and AKT were attenuated. The results of this study indicated that GA is a potential and promising anti-cancer drug for GC.

Bioinformatics analysis of the prognosis and biological significance of HMGB1, HMGB2, and HMGB3 in gastric cancer.

High mobility group box (HMGB) consists primarily of HMGB1, HMGB2, and HMGB3 proteins. Although abnormal HMGB expression is associated with various tumors, the relationship with gastric cancer (GC) remains unclear. In this study, HMGB1, HMGB2, and HMGB3 expression was analyzed using the Oncomine and TCGA databases. Correlations between HMGB1, HMGB2, and HMGB3 and clinicopathological factors were analyzed. cBioPortal was used to analyze HMGB1, HMGB2, and HMGB3 genetic alterations and its gene regulation network in GC tissue. HMGB1, HMGB2, and HMGB3 expression was higher in tumor tissues than in normal tissues, especially in GC. High HMGB1, HMGB2, and HMGB3 expression may predict a poor prognosis among patients with GC (hazard ratios [HR] = 1.90; 95% confidence interval [CI]: [1.30-2.78]) and human digestive system neoplasm (HR = 1.85; 95% CI [1.64-2.10]). These findings suggest that HMGB1, HMGB2, and HMGB3 may be useful prognostic indicators for patients with GC.

Central Roles of OX40L-OX40 Interaction in the Induction and Progression of Human T Cell-Driven Acute Graft-versus-Host Disease.

Graft-versus-host disease (GVHD) is one of the major obstacles for the success of allogeneic hematopoietic stem cell transplantation. Here, we report that the interaction between OX40L and OX40 is of critical importance for both induction and progression of acute GVHD (aGVHD) driven by human T cells. Anti-human OX40L monoclonal antibody (hOX40L) treatment could thus effectively reduce the disease severity in a xenogeneic-aGVHD (x-aGVHD) model in both preventative and therapeutic modes. Mechanistically, blocking OX40L-OX40 interaction with an anti-hOX40L antibody reduces infiltration of human T cells in target organs, including liver, gut, lung, and skin. It also decreases IL-21- and TNF-producing T cell responses, while promoting regulatory T cell (Treg) responses without compromising the cytolytic activity of CD8+ T cells. Single blockade of hOX40L was thus more effective than dual blockade of IL-21 and TNF in reducing the severity of aGVHD as well as mortality. Data from this study indicate that OX40L-OX40 interactions play a central role in the pathogenesis of aGVHD induced by human T cells. Therapeutic strategies that can efficiently interrupt OX40L-OX40 interaction in patients might have potential to provide patients with an improved clinical benefit.

The Value of COX-2, NF-κB, and Blood Routine Indexes in the Prognosis of Malignant Peritoneal Mesothelioma.

BACKGROUND/AIMS: To investigate differences in blood routine indexes and the expression of cyclooxygenase-2 (COX-2) and nuclear factor-kappa B (NF-κB) in malignant peritoneal mesothelioma (MPeM) and their relationship with clinical prognosis. METHODS: We investigated changes in blood routine indexes between the MPeM patients and healthy subjects and detected the expression of COX-2 and NF-κB in peritoneal tissues by a streptavidin-peroxidase immunohistochemistry method. Potential prognostic factors were analyzed including age, gender, white blood cell count (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute platelet count (APC), absolute monocyte count (AMC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), COX-2, and NF-κB. Cox regression model analysis established independent factors for the survival prognosis of the patients. RESULTS: Compared with the control group, AMC, MXD%, ANC, neutrophilic granulocyte percentage (NEUT%), APC, NLR, MLR, and PLR were markedly increased (p < 0.05) in the MPeM group. The positivity rates for COX-2 and NF-κB expression were 59.4 and 44.9%, respectively. Single factor analyses indicated that PLR, NLR, MLR, COX-2, and NF-κB were factors that affected the overall survival of MPeM patients, but multivariate analyses identified MLR and COX-2 as independent prognostic factors. CONCLUSIONS: High blood levels of MLR and COX-2 are adverse prognostic factors for patients with MPeM.

Analysis of B-ultrasound and contrast-enhanced ultrasound characteristics of different hepatic neuroendocrine neoplasm.

BACKGROUND: Hepatic neuroendocrine neoplasm (hNEN) is a highly heterogeneous tumor. The exact identification of the source and malignant degree of hNEN is important. However, there is a lack of information regarding diagnosis of hNEN with imaging. In addition, no studies have compared the imaging between hNEN and hepatocellular carcinoma (HCC) and among different sources and malignant degrees of hNEN. AIM: To compare the ultrasound characteristics between hNEN and HCC and among different sources and malignant degrees of hNEN. METHODS: A total of 55 patients with hNEN were recruited and defined as the hNEN group. Among them, 35 cases of hNET were defined as the hNET group. Twenty cases of hepatic neuroendocrine carcinoma (hNEC) were defined as the hNEC group. Among the 55 lesions, 29 were transferred from the pancreas, 20 were from the gastrointestinal tract, and six were from other sites. In total, 55 patients with HCC were recruited and defined as the HCC group. The characteristic differences of B-mode ultrasound and contrast-enhanced ultrasound (CEUS) between hNEN and HCC and among different sources and malignant degrees of hNEN were compared. RESULTS: In the hNEN group, the proportions of multiple liver lesions, unclear borders, and high echo lesions were higher than those in the HCC group. The proportions of non-uniform echo and peripheral acoustic halo were lower than those in the HCC group (P < 0.05). The washout to iso-enhancement time and washout to hypo-enhancement time were lower than those in the HCC group (P < 0.05). The characteristics of B-ultrasound and CEUS among different sources of hNEN were similar, and the differences were not statistically significant (P > 0.05). B-mode ultrasound characteristics of hNET and hNEC were similar. The proportions of low enhancement at portal venous phase, non-uniform enhancement forms, and combined tumor vasculature in the hNEC group were larger than those in the hNEN group (P < 0.05). CONCLUSION: Compared with HCC, hNEN showed multiple intrahepatic lesions, uniform high echo, uniform high enhancement at arterial phase, and rapid washout. Low enhancement at portal venous phase, overall non-uniform enhancement form, and the proportion of combined tumor vasculature in hNEC were larger than those in hNET.