Non-invasive visualization of liver fibrosis with [68Ga]Ga-DOTA-FAPI-04 PET from preclinical insights to clinical translation.

PURPOSE: The reversibility of early liver fibrosis highlights the need for improved early detection and monitoring techniques. Fibroblast activation protein (FAP) is a promising theranostics target significantly upregulated during fibrosis. This preclinical and preliminary clinical study investigated a FAP-targeted probe, gallium-68-labeled FAP inhibitor 04 ([68Ga]Ga-DOTA-FAPI-04), for its capability to visualize liver fibrosis. METHODS: The preclinical study employed [68Ga]Ga-DOTA-FAPI-04 micro-positron emission tomography (PET)/computed tomography (CT) on carbon tetrachloride-induced mice model (n = 34) and olive oil-treated control group (n = 26), followed by validation of the probe's biodistribution. Hepatic uptake was correlated with fibrosis and inflammation levels, quantified through histology and serum assays. FAP and α-smooth muscle actin expression were determined by immunohistochemistry, as well as immunofluorescence. The subsequent clinical trial enrolled 26 patients with suspected or confirmed liver fibrosis to undergo [68Ga]Ga-DOTA-FAPI-04 PET/magnetic resonance imaging or PET/CT. Key endpoints included correlating [68Ga]Ga-DOTA-FAPI-04 uptake with histological inflammation grades and fibrosis stages, and evaluating its diagnostic and differential efficacy compared to established serum markers and liver stiffness measurement (LSM). RESULTS: [68Ga]Ga-DOTA-FAPI-04 mean uptake in mice livers was notably higher than in control mice, increasing from week 6 [0.70 ± 0.11 percentage injected dose per cubic centimeter (%ID/cc)], peaking at week 10 (0.97 ± 0.15%ID/cc) and slightly reducing at week 12 (0.89 ± 0.28%ID/cc). The hepatic biodistribution and FAP expression showed a consistent trend. In the patient cohort, hepatic [68Ga]Ga-DOTA-FAPI-04 uptake presented moderate correlations with inflammation grades (r = 0.517 to 0.584, all P < 0.05) and fibrosis stages (r = 0.653 to 0.698, all P < 0.01). The average SUVmax to background ratio in the liver showed superior discriminative ability, especially between stage 0 and stage 1, outperforming LSM (area under curve 0.984 vs. 0.865). CONCLUSION: [68Ga]Ga-DOTA-FAPI-04 PET shows significant potential for non-invasive visualization and dynamic monitoring of liver fibrosis in both preclinical experiment and preliminary clinical trial, especially outperforming other common clinical indicators in the early stage. TRIAL REGISTRATION: NCT04605939. Registered October 25, 2020, https://clinicaltrials.gov/study/NCT04605939.

Development and evaluation of albumin binder-conjugated heterodimeric radiopharmaceuticals targeting integrin αvß3 and CD13 for cancer therapy.

PURPOSE: The advancement of heterodimeric tracers, renowned for their high sensitivity, marks a significant trend in the development of radiotracers for cancer diagnosis. Our prior work on [68Ga]Ga-HX01, a heterodimeric tracer targeting CD13 and integrin αvß3, led to its approval for phase I clinical trials by the China National Medical Production Administration (NMPA). However, its fast clearance and limited tumor retention pose challenges for broader clinical application in cancer treatment. This study aims to develop a new radiopharmaceutical with increased tumor uptake and prolonged retention, rendering it a potential therapeutic candidate. METHODS: New albumin binder-conjugated compounds were synthesized based on the structure of HX01. In vitro and in vivo evaluation of these new compounds were performed after labelling with 68Ga. Small-animal PET/CT imaging were conducted at different time points at 0.5-6 h post injection (p.i.) using BxPC-3 xenograft mice models. The one with the best imaging performance was further radiolabeled with 177Lu for small-animal SPECT/CT and ex vivo biodistribution investigation. RESULTS: We have synthesized novel albumin binder-conjugated compounds, building upon the structure of HX01. When radiolabeled with 68Ga, all compounds demonstrated improved pharmacokinetics (PK). Small-animal PET/CT studies revealed that these new albumin binder-conjugated compounds, particularly [68Ga]Ga-L6, exhibited significantly enhanced tumor accumulation and retention compared with [68Ga]Ga-L0 without an albumin binder. [68Ga]Ga-L6 outperformed [68Ga]Ga-L7, a compound developed using a previously reported albumin binder. Furthermore, [177Lu]Lu-L6 demonstrated rapid clearance from normal tissues, high tumor uptake, and prolonged retention in small-animal SPECT/CT and biodistribution studies, positioning it as an ideal candidate for radiotherapeutic applications. CONCLUSION: A new integrin αvß3 and CD13 targeting compound was screened out. This compound bears a novel albumin binder and exhibits increased tumor uptake and prolonged tumor retention in BxPC-3 tumors and low background in normal organs, making it a perfect candidate for radiotherapy when radiolabeled with 177Lu.

Efficacy of sensory-based static balance training on the balance ability, aging attitude, and perceived stress of older adults in the community: a randomized controlled trial.

BACKGROUND: This study explores the effect of sensory-based static balance training on the balance ability, aging attitude, and perceived stress of older adults in the community. It provides a practical basis for the in-depth implementation and revision of the community health management model. METHODS: A randomized controlled intervention study was conducted from 2022 to 2023. A total of 72 older adults were recruited and randomly divided into an intervention group (36 individuals) and a control group (36 individuals). Balance ability (measured by the Short Physical Performance Battery and One Leg Stand Test), aging attitudes, and perceived stress were assessed at baseline and at the 12-week and 24-week follow-ups. Repeated-measures ANOVA and generalized estimating equations were used to compare outcome measures. RESULTS: Sensory-based static balance training was beneficial for balance ability and aging attitude among participants in the intervention group. At the end of the intervention, participants in the intervention group showed significant improvements in SPPB scores and OLST scores compared with the control group (FSPPB = 12.347, P = 0.001, Waldχ2OLST = 45.530, P < 0.001), as well as significant differences in aging attitudes (FAAQ = 18.549, P < 0.001). Multiple comparisons at different time points in the intervention group reveal a significant intervention effect (FSPPB = 29.211, Waldχ2OLST = 80.428, FAAQ = 45.981, all P < 0.05). However, the difference in perceived stress before and after the intervention was not significant (FCPSS = 2.876, P = 0.095). CONCLUSIONS: Sensory-based static balance training significantly improved balance ability and aging attitudes among older adults in the community. The effect on perceived stress among older adults in the community was not significant. TRIAL REGISTRATION: Registered in the Chinese Clinic on 04/06/2022. The registration number is ChiCTR2200060541.

Noninvasive longitudinal PET/CT imaging of CAR T cells using PSMA reporter gene.

PURPOSE: Chimeric antigen receptor (CAR) T cell therapy has achieved great success in treating hematologic malignancies. However, it is yet to prove effective in the treatment of solid tumors. Thus, it is necessary to develop appropriate methodology for the long-term, accurate, and quantitative evaluation of the distribution and activities of CAR T cells in solid tumors. In the present study, we engineered TfR ΔPSMA CAR (CAR-ΔPSMA) T cells, which targeted the transferrin receptor (TfR) expressed by tumor cells and could be tracked in vivo via a reporter gene encoding the truncated prostate specific membrane antigen (ΔPSMA). We then quantitatively monitored these CAR T cells in vitro and in vivo using [68Ga]Ga-PSMA-617 positron emission tomography (PET)/computed tomography (CT). METHODS: The CAR-ΔPSMA T cells were genetically engineered by transducing T cells with a lentiviral vector encoding TfR41BBζ-T2A-ΔPSMA. Firstly, the target expression, activation, and cytotoxicity of CAR-ΔPSMA T cells were validated in vitro. Secondly, the minimum thresholds of CAR-ΔPSMA T cells detection for [68Ga]Ga-PSMA-617 PET/CT were also determined in vitro and in vivo respectively. Lastly, the feasibility of monitoring the biodistribution and infiltration of CAR-ΔPSMA T cells after systematic administration was evaluated in the breast cancer subcutaneous xenograft model. RESULTS: The CAR-ΔPSMA T cells retained activation and tumor killing capacity after transduction of the ΔPSMA-encoding reporter gene. Next, the CAR-ΔPSMA T cells could be reliably tracked by [68Ga]Ga-PSMA-617 PET/CT, the detection sensitivity of which was 250 cells/mm3 in vitro and 100 cells/mm3 in vivo. Next, the sequential imaging assays revealed that [68Ga]Ga-PSMA-617 PET/CT could be used to specifically visualize ΔPSMA+ CAR T cells at the tumor site. The increase in the [68Ga]Ga-PSMA-617 signal intensity over time allowed us to effectively detect CAR T cells in vivo. CONCLUSION: Our findings preliminarily confirmed that [68Ga]Ga-PSMA-617 PET/CT could reliably detect CAR-ΔPSMA T cells in vitro and in vivo in solid tumors, laying the foundation for the monitoring CAR T cell therapy in the future.

Detection and phenotype analysis of a novel Ael blood group allele.

BACKGROUND AND OBJECTIVES: The presence of blood subtypes may lead to difficulties in blood group identification; however, third-generation sequencing (TGS) can help in accurately identifying difficult blood groups, and study the serological characteristics and molecular mechanism of Ael subtypes. MATERIALS AND METHODS: ABO blood group was identified by the standard serological technique, weak blood group antigen was identified by adsorption-elution experiments, ABH substance in the saliva was determined and glycosyltransferase activity of A and B was detected. The ABO gene full-length sequence and promoter region were amplified by specific primers using single-molecule real-time sequencing, with the amplified products being sequenced directly and analysed in real time. RESULTS: The patient was serologically identified as Ael subtype, and TGS analysis revealed new intron mutations in Ael patients (c.467C>T; c.29-10T>A). CONCLUSION: The discovery of the new allele and the identification of ABO subtypes can be combined with serological characterization and molecular biological methods.

Drug Repositioning for Amyloid Transthyretin Amyloidosis by Interactome Network Corrected by Graph Neural Networks and Transcriptome Analysis.

Amyloid transthyretin (ATTR) amyloidosis caused by transthyretin misfolded into amyloid deposits in nerve and heart is a progressive rare disease. The unknown pathogenesis and the lack of therapy make the 5-year survival prognosis extremely poor. Currently available ATTR drugs can only relieve symptoms and slow down progression, but no drug has demonstrated curable effect for this disease. The growing volume of pharmacological data and large-scale genome and transcriptome data bring new opportunities to find potential new ATTR drugs through computational drug repositioning. We collected the ATTR-related in the disease pathogenesis and differentially expressed (DE) genes from five public databases and Gene Expression Omnibus expression profiles, respectively, then screened drug candidates by a corrected protein-protein network analysis of the ATTR-related genes as well as the drug targets from DrugBank database, and then filtered the drug candidates on the basis of gene expression data perturbed by compounds. We collected 139 and 56 ATTR-related genes from five public databases and transcriptome data, respectively, and performed functional enrichment analysis. We screened out 355 drug candidates based on the proximity to ATTR-related genes in the corrected interactome network, refined by graph neural networks. An Inverted Gene Set Enrichment analysis was further applied to estimate the effect of perturbations on ATTR-related and DE genes. High probability drug candidates were discussed. Drug repositioning using systematic computational processes on an interactome network with transcriptome data were performed to screen out several potential new drug candidates for ATTR.

Construction of truncated PSMA as a PET reporter gene for CAR T cell trafficking.

In solid tumors, there are multiple barriers for a chimeric antigen receptor (CAR) T cell to surmount in order to reach the tumor site. For better understanding whether CAR T cells effectively infiltrate into tumor site, and simultaneously, whether there are off-target effects, real-time monitoring technologies need to be established. Cell-based positron emission tomography reporter genes have been developed to monitor engineered cells in living subjects. In this study, we reported the construction of a novel reporter gene truncated prostate-specific membrane antigen (ΔPSMA) pending for monitoring CAR T cells using 68Ga-PSMA-617 and a method for tracking the distribution of CAR T cells in vivo was developed. Data were provided to demonstrate that ΔPSMA was predominantly localized on the plasma membrane and could take up 68Ga-PSMA-617 in vitro in a time-dependent manner. And the expression of ΔPSMA did not affect CAR expression and cytolytic capacity of CAR T cells. CAR-ΔPSMA T cell xenografts in nude mice were clearly imaged by positron emission tomography 60 min after injection of 68Ga-PSMA-617. PSMA paired with 68Ga-PSMA-617 was capable of identifying approximately 1 × 104 engineered CAR T cells. The ability to image small numbers of CAR T cells in vivo would be helpful to accelerate the translation of cell-based therapies into the clinic, and it may reinforce our understanding of treatment success, failure, and toxicity.

Causal effects of gut microbiome on hypertension: a Mendelian randomization study.

Background: Previous observational studies have shown that there is an important relationship between gut microbiota and hypertension, we performed a two-sample Mendelian randomization analysis to examine whether the gut microbiota is causally related to hypertension in order to find a basis for potential diagnostic or intervention approaches for hypertension. Methods: We obtained significant single nucleotide polymorphisms related to gut microbiota and hypertension from publicly available genome-wide association studies for a two-sample Mendelian randomization study. A total of 18,340 individual genome-wide genotype data were included from 24 population-based cohorts. The inverse-variance weighted meta-analysis is the main analytical method for evaluating causal relationships, and the Mendelian randomization research results have been validated through a series of sensitivity analyses. Results: The inverse-variance weighted analysis results indicated that phylum Verrucomicrobia (OR:0.831, 95%CI: 0.710-0.972; p = 0.021), family BacteroidalesS24.7group (OR:0.672, 95%CI: 0.496-0.911; p = 0.01), family Bifidobacteriaceae (OR:0.709, 95%CI:0.569-0.884, p = 0.002), genus Adlercreutzia (OR: 0.991, 95%CI: 0.982-0.999, p = 0.035), genus Phascolarctacterium (OR:0.819, 95%CI:0.685-0.981; p = 0.03), genus LachnospiraceaeNK4A136group (OR:0.990, 95%CI:0.981-0.999; p = 0.025), and genus Ruminococcus2 (OR:0.988, 95%CI: 0.979-0.997; p = 0.008) had protective causal effects on hypertension. The Family Alcaliginaceae (OR:1.011, 95%CI:1.000-1.021, p = 0.04), Genus Anaerostipes (OR:1.375, 95%CI:1.096-1.653; p = 0.025), Genus Collinsella (OR:1.899, 95%CI:1.361-2.348; p = 0.02), and Genus Lachnospiraceae_UCG_010 (OR:1.536, 95%CI:1.072-2.202; p = 0.019) were associated with a higher risk of HTN. The reverse Mendelian randomization analysis results showed no reverse causal relationship between HTN and these bacterial taxa. Conclusion: Our Mendelian randomization analysis results indicate a potential causal relationship between these bacterial taxa and hypertension, providing a new perspective for the treatment and prevention of hypertension.

First complete mitogenome of Massarineae and its contribution to phylogenetic implications in Pleosporales.

Endophytic fungi play an important role in the growth and development of traditional Chinese medicine plants. We isolated a strain of Acrocalymma vagum from the endophytic fungi of the traditional Chinese plants Paris. To accurately identify this endophytic fungal species of interest, we sequenced the mitochondrial genome of A. vagum, which is the first discovered mitochondrial genome in Massarineae. The A. vagum mitochondrial genome consists of a 35,079-bp closed circular DNA molecule containing 36 genes. Then, we compared the general sequence characteristics of A. vagum with those of Pleosporales, and the second structure of the 22 tRNAs was predicted. The phylogenetic relationship of A. vagum was constructed using two different data sets (protein-coding genes and amino acids). The phylogenetic tree shows that A. vagum is located at the root of Pleosporales. The analysis of introns shows that the number of introns increases with the increase in branch length. The results showed that monophyly was confirmed for all families in Pleosporales except for Pleosporaceae. A. vagum is an ancient species in the Pleosporales, and Pleosporaceae may require further revision. In Pleosporales, the number of introns is positively correlated with branch length, providing data for further study on the origin of introns.

Heat-stone massage for patients with chronic musculoskeletal pain: a protocol for multicenter randomized controlled trial.

Introduction: Chronic musculoskeletal pain bothers the quality of life for approximately 1.71 billion people worldwide. Although pharmacological therapies play an important role in controlling chronic pain, overuse of opioids, persistent or recurrent symptoms, and pain-related disability burden still need to be addressed. Heat-stone massage is using the heated stone to stimulate muscles and ligaments followed by massage for relax, which can potentially treat the chronic musculoskeletal pain. To determine the efficacy and safety of heat-stone massage for patients with chronic musculoskeletal pain is needed. Methods and analysis: This multicenter, 2-arm, randomized, positive drug-controlled trial will include a total of 120 patients with chronic musculoskeletal pain. The intervention group will receive a 2 week heat-stone massage, 3 times per week, whereas the control group will receive the flurbiprofen plaster twice per day for 2 weeks. The primary end point is the change in Global Pain Scale from baseline to the end of the 2 week intervention. The secondary outcomes include the pain severity (Numerical Rating Scale), pain acceptance (Chronic Pain Acceptance Questionnaire), self-management (Health Education Impact Questionnaire), self-efficacy (Pain Self-Efficacy Questionnaire), anxiety and depression (Hospital Anxiety and Depression Scale), quality of life (Short Form-36). The intention-to-treat dataset will be used for analysis. Discussion: The pain management remains the research topic that patients always pay close attention to. This will be the first randomized clinical trial to evaluate whether heat-stone massage, a non-pharmacological therapy, is effective in the chronic musculoskeletal pain management. The results will provide evidence for new option of daily practice. Clinical trial registration: World Health Organization Chinese Clinical Trial Registry [ChiCTR2200065654; https://www.chictr.org.cn/showproj.html?proj=185403]; International Traditional Medicine Clinical Trial Registry [ITMCTR2022000104; http://itmctr.ccebtcm.org.cn/en-US/Home/ProjectView?pid=51776b6f-77b8-4811-9b5a-a0fec10f2cee].

Preclinical evaluation of a dual-receptor targeted tracer [68Ga]Ga-HX01 in 10 different subcutaneous and orthotopic tumor models.

PURPOSE: The integrin αvß3 and aminopeptidase N (APN/CD13) play vital roles in the tumor angiogenesis process. They are highly expressed in a variety of tumor cells and proliferating endothelial cells during angiogenesis, which have been considered as highly promising targets for tumor imaging. Arginine-glycine-aspartic (RGD) and asparagine-glycine-arginine (NGR) are two peptides specifically binding to the integrin αvß3 and CD13, respectively. In this study, we optimized our previously developed probe and preclinically evaluated the new integrin αvß3 and CD13 dual-targeted probe, NOTA-RGD-NGR (denoted as HX01) radiolabeled with 68Ga, in 10 different subcutaneous and orthotopic tumor models. METHODS: The specific activity and radiochemical purity of [68Ga]Ga-HX01 were identified. The dual-receptor targeting ability was confirmed by a series of blocking studies and partly muted tracers using BxPC-3 xenograft model. The dynamic imaging study and dose escalation study were explored to determine the optimal imaging time point and dosage in the BxPC-3 xenograft model. Next, we established a variety of subcutaneous and orthotopic tumor models including pancreas (BxPC-3), breast (MCF-7), gallbladder (NOZ), lung (HCC827), ovary (SK-OV-3), colorectal (HCT-8), liver (HuH-7), stomach (NUGC-4), and glioma (U87) cancers. All models underwent [68Ga]Ga-HX01 PET/CT imaging about 2 weeks post-inoculation, with a subset of them undergoing [18F]FDG PET/CT scan performed concurrently, and their results were compared. In addition, ex vivo biodistribution studies were also performed for verifying the semi-quantitative results of the non-invasive PET images. RESULTS: [68Ga]Ga-HX01 significantly outperformed single target probes in the BxPC-3 xenograft model. All blocking and single target groups exhibited significantly descending tumor uptake. The high tumor uptakes were found in BxPC-3, MCF-7, and NOZ subcutaneous tumors (%ID/g > 1.1), while middle uptakes were observed in HCC827, SK-OV-3, HCT-8, and HuH-7 subcutaneous tumor (%ID/g 0.7-1.0). Due to the low background, the tumor-to-muscle and tumor-to-blood ratios of [68Ga]Ga-HX01 were higher than that of [18F]FDG. CONCLUSIONS: [68Ga]Ga-HX01, as a dual target imaging agent, exhibited superior in vivo performance in different subcutaneous and orthotopic mice models of human tumors over [18F]FDG and its respectively mono-receptor targeted agents, which warrants the future clinical translation for tumor imaging.

Undifferentially Expressed CXXC5 as a Transcriptionally Regulatory Biomarker of Breast Cancer.

This work hypothesizes that some genes undergo radically changed transcription regulations (TRs) in breast cancer (BC), but don't show differential expressions for unknown reasons. The TR of a gene is quantitatively formulated by a regression model between the expression of this gene and multiple transcription factors (TFs). The difference between the predicted and real expression levels of a gene in a query sample is defined as the mqTrans value of this gene, which quantitatively reflects its regulatory changes. This work systematically screens the undifferentially expressed genes with differentially expressed mqTrans values in 1036 samples across five datasets and three ethnic groups. This study calls the 25 genes satisfying the above hypothesis in at least four datasets as dark biomarkers, and the strong dark biomarker gene CXXC5 (CXXC Finger Protein 5) is even supported by all the five independent BC datasets. Although CXXC5 does not show differential expressions in BC, its transcription regulations show quantitative associations with BCs in diversified cohorts. The overlapping long noncoding RNAs (lncRNAs) may have contributed their transcripts to the expression miscalculations of dark biomarkers. The mqTrans analysis serves as a complementary view of the transcriptome-based detections of biomarkers that are ignored by many existing studies.

Transcriptional Dysregulations of Seven Non-Differentially Expressed Genes as Biomarkers of Metastatic Colon Cancer.

Background: Colon cancer (CC) is common, and the mortality rate greatly increases as the disease progresses to the metastatic stage. Early detection of metastatic colon cancer (mCC) is crucial for reducing the mortality rate. Most previous studies have focused on the top-ranked differentially expressed transcriptomic biomarkers between mCC and primary CC while ignoring non-differentially expressed genes. Results: This study proposed that the complicated inter-feature correlations could be quantitatively formulated as a complementary transcriptomic view. We used a regression model to formulate the correlation between the expression levels of a messenger RNA (mRNA) and its regulatory transcription factors (TFs). The change between the predicted and real expression levels of a query mRNA was defined as the mqTrans value in the given sample, reflecting transcription regulatory changes compared with the model-training samples. A dark biomarker in mCC is defined as an mRNA gene that is non-differentially expressed in mCC but demonstrates mqTrans values significantly associated with mCC. This study detected seven dark biomarkers using 805 samples from three independent datasets. Evidence from the literature supports the role of some of these dark biomarkers. Conclusions: This study presented a complementary high-dimensional analysis procedure for transcriptome-based biomarker investigations with a case study on mCC.

Data-independent acquisition mass spectrometry reveals comprehensive plasma protein profiles in the natural history of patients with hereditary transthyretin amyloidosis (ATTRv).

OBJECTIVES: Hereditary transthyretin amyloidosis (ATTRv) is a rare, fatal, autosomal dominant disease with more than 140 mutations discovered. Three phenotypes of amyloid infiltration are neuropathy (ATTRv-PN), cardiopathy (ATTRv-CM), and neuropathy + cardiopathy (ATTRv-MIX). The lack of ATTR-specific biomarkers, difficulties in biopsy evidence, and limited known pathogenic mechanisms have made diagnosis difficult. Newly emerging noninvasive measures for monitoring progression and disease-modifying therapies have improved early diagnosis and patient management. METHODS: Our research applies the latest technology, Data-Independent Acquisition-Based Quantitative Proteomics (DIA), to reveal comprehensive plasma protein profiles in the natural history of Chinese patients with hereditary transthyretin amyloidosis (ATTRv). We analyzed differentially expressed proteins (DEPs) in three phenotypes (ATTRv-PN, ATTRv-CM, and ATTRv-MIX). RESULTS: Serum samples were collected from a total of 18 patients (6 ATTRv-PN, 5 ATTRv-CM, and 7 ATTRv-MIX patients) and 20 healthy participants as a control group. Combined with the results of the proteomic and bioinformatic analyses, we found 30 DEPs and protein interaction networks clustered in KRT family proteins and DSC3 between ATTRv-PN and the control, which were rich in the estrogen signaling pathway and the cell adhesion molecule (CAM) pathway. CONCLUSION: This study demonstrates a global and significant proteomic profile in different stages of ATTRv.

Postmarketing Reevaluation of Chinese Traditional Therapy Kangbingdu Oral Liquid in the Treatment of the Common Cold.

Background: Observational studies from China suggest that Kangbingdu oral liquid (KBD) may be effective in treating the common cold. Objective: Reevaluation of efficacy and safety of Kangbingdu oral liquid after marketing and expanding population. Design: Prospective, Pragmatic randomized controlled trial (Chictr.org.cn registration number: chiCTR-TRC-12002399). Setting. Eleven hospitals from 3 provinces in China. Patients were recruited through 11 centers, including 7 teaching hospitals, 2 University health services, one military clinic, and one community hospital. Patients. 2647 persons aged 18 to 75 years with Common cold. Intervention. Patients were randomly allocated to 2 groups: the treatment group Kangbingdu oral liquid (composed of 9 Chinese herbal medicines and honey) and the placebo group were divided into a standard-dose group of 10 ml every time, a middle dose group of 20 ml every time, high dose group of 30 ml every time, 3 times daily. Interventions and control were given for 5 days. Measurements. The primary outcome is the mean amount of total scores measured by the 11-primary symptoms: to observe the change of main symptoms from severe to disappear and to calculate and compare the mean amount of total scores after the periods of observation. Secondary outcomes are the disappearance rate of each symptom and the median time of body temperature returned to normal. Results: On day 5, the Kangbingdu liquid group had significant reductions in the mean amount of total scores measured by the 11-primary symptoms (7.39 [95% CI 7.26 to 7.51] compared to the placebo group (6.43 [95%: CI 6.24 to 6.62]). The Kangbingdu liquid can improve the remission rate of accompanying symptoms on day 5 including aversion to wind, aversion to cold, fever, cough, stuffy, runny nose, sore throat, muscular aches, headache, fatigue, and sweat (P < 0.0001). Significant reductions in time of body temperature to return to normal in the Kangbingdu liquid group (P50, 48.33 [95% CI 46.00 to 52.50] compared with the control group (P50, 64.59 [95% CI 51.08 to 70.50] (P=0.0022). 13 (0.7%) participants in the Kangbingdu liquid group and 1(0.2%) participants in the placebo group (P > 0.05) had treatment-related AEs, which mainly include diarrhea and dyspepsia in the Kangbingdu liquid group and constipation in the placebo group. Conclusion: The study's conclusion in this paper was based on the placebo, Kangbingdu oral liquid two groups which clinically diagnosed the common cold and flu. (1) Kangbingdu oral liquid can effectively improve the comprehensive clinical symptoms of common adult cold, also improved main symptoms, including sore throat, muscle aches, headache, and so on. (2) Kangbingdu oral liquid effectively shortens the time of body temperature to return to normal.

Visualizing γδ T cells by very late antigen-4-targeted positron emission tomography.

PURPOSE: γδ T cell-based immunotherapy has been rolled out as a promising treatment strategy for malignant tumors due to their potent anti-tumor cytotoxicity, ease of expansion, and unrestricted MHC feature. However, the dynamics and outcomes of γδ T cells in tumor sites are poorly understood. Reported strategies rely on ex vivo biolabeling, significantly limiting the application of γδ T cell molecular imaging. Herein, we investigated whether VLA-4 (very late antigen-4), a crucial component in the effective trafficking of lymphocytes, could serve as a biomarker to non-invasively visualize γδ T cells. METHODS: VLA-4-targeted tracer, 68 Ga-LLP2A, was evaluated in MDA-MB-231- and A549-bearing mice with adoptive transfer of γδ T cells by longitudinal PET/CT imaging. Imaging data were verified by ex vivo biodistribution studies, and the co-localization of CD3 and VLA-4 was validated by immunohistochemistry studies. RESULTS: 68 Ga-LLP2A showed high specificity to VLA-4-expressing γδ T cells in both in vitro and tumor-bearing mice with adoptive transfer of γδ T cells. Longitudinal PET imaging of 68 Ga-LLP2A in tumor-bearing mice with adoptive transfer of γδ T cells showed an increasing tumor tracer uptake, revealing the tumor-specific homing of γδ T cells. The presence of VLA-4-expressing γδ T cells in tumors was confirmed via histological analysis. CONCLUSION: To the best of our knowledge, we reported the first molecular probe, 68 Ga-LLP2A, for in vivo imaging of γδ T cells in live tumors, which advances PET imaging of γδ T cells and supports the translation of imaging agents for immunotherapeutic monitoring.

Effects of corticosteroid treatment in patients with severe fever with thrombocytopenia syndrome: A single-center retrospective cohort study.

OBJECTIVES: To evaluate the effect and safety of corticosteroid (CS) treatment in patients with severe fever with thrombocytopenia syndrome (SFTS). METHODS: Patients with and without CS were retrospectively compared by Cox regression and 1:1 propensity score matching analysis to evaluate the effects of CS on mortality and secondary infections in patients with SFTS. RESULTS: A total of 467 patients with SFTS were enrolled in the cohort study, there were 52 fatal cases and 415 nonfatal cases, the overall fatality rate was 11.1%. The mortality was observed in 36/144 (25%) and 16/323 (5%) patients in the CS-treated and non-CS-treated groups, respectively (P < 0.001). Multi variate Cox regression analysis showed that the difference was not statistically significant for CS treatment in fatality (P > 0.05, aHR 0.767, 95% CI 0.360-1.634). Difference in survival time between the CS-treated and non-CS-treated groups after propensity score matching had no statistical significance (Log-rank test P = 0.390), whereas there was a significant difference in secondary infections between the CS-treated and non-CS-treated groups (P = 0.007). CONCLUSION: Although the CS treatment had no impact on fatality in patients with SFTS, it increased the risk of secondary infections. Administration of CS in patients with SFTS should be carefully considered and evaluated the balance between therapeutic efficacy and adverse effects.

Evaluation of a CD13 and Integrin αvß3 Dual-Receptor Targeted Tracer 68Ga-NGR-RGD for Ovarian Tumor Imaging: Comparison With 18F-FDG.

Ovarian cancer has the highest mortality rate of gynecologic malignancy. 18F-FDG positron emission tomography (PET) adds an important superiority over traditional anatomic imaging modalities in oncological imaging but has drawbacks including false negative results at the early stage of ovarian cancer, and false positives when inflammatory comorbidities are present. Aminopeptidase N (APN, also known as CD13) and integrin αvß3 are two important targets overexpressed on tumor neo-vessels and frequently on ovarian cancerous cells. In this study, we used subcutaneous and metastatic models of ovarian cancer and muscular inflammation models to identify 68Ga-NGR-RGD, a heterodimeric tracer consisting of NGR and RGD peptides targeting CD13 and integrin αvß3, respectively, and compared it with 18F-FDG. We found that 68Ga-NGR-RGD showed greater contrast in SKOV3 and ES-2 tumors than 18F-FDG. Low accumulation of 68Ga-NGR-RGD but avid uptake of 18F-FDG were observed in inflammatory muscle. In abdominal metastasis models, PET imaging with 68Ga-NGR-RGD allowed for rapid and clear delineation of both peritoneal and liver metastases (3-6 mm), whereas, 18F-FDG could not distinguish the metastasis lesions due to the relatively low metabolic activity in tumors and the interference of intestinal physiological 18F-FDG uptake. Due to the high tumor-targeting efficacy, low inflammatory uptake, and higher tumor-to-background ratios compared to that of 18F-FDG, 68Ga-NGR-RGD presents a promising imaging agent for diagnosis, staging, and follow-up of ovarian tumors.