Developing a Prediction Model for Radiation Pneumonitis in Lung Cancer Patients Treated With Stereotactic Body Radiation Therapy Combined With Clinical, Dosimetric Factors, and Laboratory Biomarkers.

BACKGROUND: The study aims to identify the risk factors and develop a model for predicting grade ≥2 radiation pneumonitis (RP) for lung cancer patients treated with stereotactic body radiation therapy (SBRT). MATERIALS AND METHODS: Clinical data, dosimetric data, and laboratory biomarkers from 186 patients treated with lung SBRT were collected. Univariate and multivariate logistic regression were performed to determine the predictive factors for grade ≥2 RP. Three models were developed by using the clinical, dosimetric, and combined factors, respectively. RESULTS: With a median follow-up of 36 months, grade ≥2 RP was recorded in 13.4% of patients. On univariate logistic regression analysis, clinical factors of age and lung volume, dosimetric factors of treatment durations, fractional dose and V10, and laboratory biomarkers of neutrophil, PLT, PLR, and Hb levels were significantly associated with grade ≥2 RP. However, on multivariate analysis, only age, lung volume, fractional dose, V10, and Hb levels were independent factors. AUC values for the clinical, dosimetric, and combined models were 0.730 (95% CI, 0.660-0.793), 0.711 (95% CI, 0.641-0.775) and 0.830 (95% CI, 0.768-0.881), respectively. The combined model provided superior discriminative ability than the clinical and dosimetric models (P < .05). CONCLUSION: Age, lung volume, fractional dose, V10, and Hb levels were demonstrated to be significant factors associated with grade ≥2 RP for lung cancer patients after SBRT. A novel model combining clinical, dosimetric factors, and laboratory biomarkers improved predictive performance compared with the clinical and dosimetric model alone.

The Clinical Outcomes, Prognostic Factors and Nomogram Models for Primary Lung Cancer Patients Treated With Stereotactic Body Radiation Therapy.

Purpose: Stereotactic body radiation therapy (SBRT) is a standard treatment for early primary lung cancer patients. However, there are few simple models for predicting the clinical outcomes of these patients. Our study analyzed the clinical outcomes, identified the prognostic factors, and developed prediction nomogram models for these patients. Materials and Methods: We retrospectively analyzed 114 patients with primary lung cancer treated with SBRT from 2012 to 2020 at our institutions and assessed patient's clinical outcomes and levels of toxicity. Kaplan-Meier analysis with a log-rank test was used to generate the survival curve. The cut-off values of continuous factors were calculated with the X-tile tool. Potential independent prognostic factors for clinical outcomes were explored using cox regression analysis. Nomograms for clinical outcomes prediction were established with identified factors and assessed by calibration curves. Results: The median overall survival (OS) was 40.6 months, with 3-year OS, local recurrence free survival (LRFS), distant disease-free survival (DDFS) and progression free survival (PFS) of 56.3%, 61.3%, 72.9% and 35.8%, respectively, with grade 3 or higher toxicity rate of 7%. The cox regression analysis revealed that the clinical stage, immobilization device, and the prescription dose covering 95% of the target area (D95) were independent prognostic factors associated with OS. Moreover, the clinical stage, and immobilization device were independent prognostic factors of LRFS and PFS. The smoking status, hemoglobin (Hb) and immobilization device were significant prognostic factors for DDFS. The nomograms and calibration curves incorporating the above factors indicated good predictive accuracy. Conclusions: SBRT is effective and safe for primary lung cancer. The prognostic factors associated with OS, LRFS, DDFS and PFS are proposed, and the nomograms we proposed are suitable for clinical outcomes prediction.

[Course Design and Discussions of Integrating Ideological and Political Theories Education in Medical Laboratory Pathways and Their Clinical Application].

Specialty courses are an important carrier for driving forward the education reform of integrating ideological and political theories education in all courses and implementing the philosophy of fostering character through moral education. Medical Laboratory Pathways and Their Clinical Applicationis an undergraduate specialty course offered by the Department of Laboratory Medicine, West China Hospital, Sichuan University. The paper is based on the campaign of Integrating Ideological and Political Theories Education in All Courses and takes into consideration the features of the medical laboratory technology specialty. The paper proposes the organic unity of knowledge and skills teaching objectives and emotions and value-guided teaching objectives. In regard to the teaching content, horizontal integration was carried out, transforming the design of the course content from being laboratory test-centered to being disease-centered. Ideological and political theories education was organically incorporated in the content of the specialty course, assigning to the course the important task of values guidance. In addition, we made discussions on course design and instruction of Medical Laboratory Pathways and Their Clinical Application mainly in regard to the instruction, teaching methodology, and the form of classroom instruction of the course. We hope that the paper will provide useful information and reference for the ongoing education reform of the medical laboratory technology specialty under the new circumstances.

Role of serum CXCL9 and CXCL13 in predicting infection after kidney transplant: A STROBE study.

ABSTRACT: Chemokines are majorly involved in inflammatory and immune responses. The interferon-γ-inducible chemokines C-X-C motif chemokines 9 and 10 (CXCL9 and CXCL10) are considerably associated with Th1 cells and monocytes, and their expression levels rapidly increase during the early episodes of renal allograft rejection and various infectious diseases. CXCL13 is one of the most potent B-cell and T follicular helper-cell chemoattractants. The expression of CXCL13 in the presence of infection indicates an important chemotactic activity in multiple infectious diseases. C-C motif chemokine ligand 2 (CCL2) can attract monocytes and macrophages during inflammatory responses. However, there are no studies on the role of these chemokines in posttransplant infection in kidney transplant recipients.In this study, CXCL9, CXCL10, CXCL13, and CCL2 were analyzed using the Bio-Plex suspension array system before transplant and 30 days after transplant.The serum levels of CXCL9 and CXCL13 30 days after kidney transplant were associated with infection within 1 year after transplant (P = .021 and P = .002, respectively). The serum levels of CXCL9 and CXCL13 before surgery and those of CCL2 and CXCL10 before and after surgery were not associated with infection within 1 year after transplant (P > .05). The combination of postoperative day (POD) 30 CXCL9 and postoperative day 30 CXCL13 provided the best results with an area under the curve of 0.721 (95% confidence interval, 0.591-0.852), with a sensitivity of 71.4% and specificity of 68.5% at the optimal cutoff value of 52.72 pg/mL.As important chemokines, CXCL9 and CXCL13 could be used to predict the occurrence of infection after kidney transplant.

A Combined Model to Improve the Prediction of Local Control for Lung Cancer Patients Undergoing Stereotactic Body Radiotherapy Based on Radiomic Signature Plus Clinical and Dosimetric Parameters.

PURPOSE: Stereotactic body radiotherapy (SBRT) is an important treatment modality for lung cancer patients, however, tumor local recurrence rate remains some challenge and there is no reliable prediction tool. This study aims to develop a prediction model of local control for lung cancer patients undergoing SBRT based on radiomics signature combining with clinical and dosimetric parameters. METHODS: The radiomics model, clinical model and combined model were developed by radiomics features, incorporating clinical and dosimetric parameters and radiomics signatures plus clinical and dosimetric parameters, respectively. Three models were established by logistic regression (LR), decision tree (DT) or support vector machine (SVM). The performance of models was assessed by receiver operating characteristic curve (ROC) and DeLong test. Furthermore, a nomogram was built and was assessed by calibration curve, Hosmer-Lemeshow and decision curve. RESULTS: The LR method was selected for model establishment. The radiomics model, clinical model and combined model showed favorite performance and calibration (Area under the ROC curve (AUC) 0.811, 0.845 and 0.911 in the training group, 0.702, 0.786 and 0.818 in the validation group, respectively). The performance of combined model was significantly superior than the other two models. In addition, Calibration curve and Hosmer-Lemeshow (training group: P = 0.898, validation group: P = 0.891) showed good calibration of combined nomogram and decision curve proved its clinical utility. CONCLUSIONS: The combined model based on radiomics features plus clinical and dosimetric parameters can improve the prediction of 1-year local control for lung cancer patients undergoing SBRT.

Annexin A2 regulates unfolded protein response via IRE1-XBP1 axis in macrophages during P. aeruginosa infection.

Pseudomonas aeruginosa is a severe Gram-negative opportunistic bacterium that causes a spectrum of organ system diseases, particularly in immunocompromised patients. This bacterium has been shown to induce unfolded protein response (UPR) during mammalian infection. Annexin A2 (AnxA2) is a multicompartmental protein relating to a number of cellular processes; however, it remains unknown whether AnxA2 coordinates a UPR pathway under bacterial infection conditions. Here, we report that the endoplasmic reticulum stress inositol-requiring enzyme 1 (IRE1)-X-box binding protein 1 (XBP1) pathway was up-regulated by AnxA2 through p38 MAPK signaling following P. aeruginosa infection in macrophages, whereas ATF4 and ATF6 not. In addition, XBP1 was found as a positive regulator of innate immunity to tame P. aeruginosa challenges by enhancing autophagy and bacterial clearance. XBP1 also facilitated NF-κB activation to elicit the release of proinflammatory cytokines predominantly in macrophages. Together, our findings identify AnxA2 as a regulator for XBP1-mediated UPR pathway.

Effects of Wuzhi Capsules on Blood Concentration of Tacrolimus in Renal Transplant Recipients.

BACKGROUND Tacrolimus is a widely used immunosuppressant in renal transplant recipients. It was demonstrated in rats and healthy volunteers that Wuzhi capsules could inhibit metabolism and maintain blood concentration of tacrolimus. However, there are no clinical studies of Wuzhi capsules in renal transplant recipients. This research aimed to assess the effect of Wuzhi capsules on the blood concentration of tacrolimus in renal transplant recipients. MATERIAL AND METHODS A total of 158 Chinese renal transplant recipients receiving tacrolimus with or without Wuzhi capsules were included in this retrospective study. The cohort study included 126 recipients, with 86 recipients receiving Wuzhi capsules (WZCs) and the other 40 recipients not receiving WZCs. Another 32 recipients were involved in a self-control study. RESULTS Dose- and body weight-adjusted trough concentrations (C0/D/W) of tacrolimus in the WZC group were found to be significantly higher than that in the non-WZC group (P<0.05). The improvement of C0/D/W by administration of Wuzhi capsules was more significant in CYP3A5 expressers than in non-expressers following subgroup analysis. Furthermore, the WZC group had a remarkably higher proportion of subjects who reached target tacrolimus concentration than in the non-WZC group, both in CYP3A5 expressers (P=0.01) and non-expressers (P<0.001). Multiple linear regression analysis and self-control analysis confirmed the positive impact of Wuzhi capsules on tacrolimus concentration (P<0.001). CONCLUSIONS Wuzhi capsules can increase tacrolimus trough concentration without adverse effects on allograft function, especially in CYP3A5 expressers. Efficient and convenient immunosuppressive effects on renal transplant recipients can be achieved by treatment including administration of Wuzhi capsules.

Expression Level of MiRNA-126 in Serum Exosomes of Allergic Asthma Patients and Lung Tissues of Asthmatic Mice.

BACKGROUND: To investigate MiRNA-126 amounts in serum exosomes from allergic asthma patients as well as lung tissues of asthmatic mice, evaluating the expression of its target gene DNMT1 in mouse specimens. METHODS: MiRNA-126 amounts in serum exosomes from asthmatic patients were detected by real-time PCR. The mouse model of allergic asthma was established by OVA-sensitization, and allergic symptoms were recorded; serum IL-4 and sIgE level evaluation (ELISA), broncho alveolar lavage fluid (BALF) cell count and H&E staining were performed to assess airway inflammation. MiRNA-126 and DNMT1 levels in the lung of asthmatic and control mice were detected by real-time PCR; DNMT1 protein levels were detected by immunoblot. RESULTS: MiRNA-126 amounts in peripheral blood exosomes from patients with allergic asthma were significantly higher than that of healthy volunteers (P<0.05). The frequencies of scratching of both sides of the nose and sneezing were elevated within 10 min of excitation in asthmatic rats compared with controls. Meanwhile, OVA-sIgE and IL-4 levels were significantly higher in asthmatic animals than controls (P<0.05). In the asthma group, narrowed bronchial lumen and thickened wall were observed, and bronchial and peripheral vessels showed overt inflammatory cell infiltration. Eosinophil, neutrophil and mast cell amounts in the BALF of asthmatic mice were significantly higher than control values. Furthermore, lung miRNA-126 expression in asthmatic mice was significantly higher than that of controls. Finally, DNMT1 mRNA and protein levels were significantly lower in asthmatic animals compared with controls (P < 0.01). CONCLUSION: MiRNA-126 is highly expressed in serum exosomes from allergic asthma patients and lung tissues of asthmatic mice, suggesting that it may be involved in the pathogenesis of bronchial asthma.

Trypanosoma dionisii in insectivorous bats from northern China.

Although bats were considered as a major host of trypanosomatid flagellates, information of trypanosomes in bats is unknown in China. We collected bats in 2015 from Shandong Province of China and used PCR to amplify the Trypanosoma glycosomal glyceraldehyde phosphate dehydrogenase (gGAPDH) gene and 18S rRNA gene from the bat blood samples and heart tissues. The results showed that 10.3% (13/126) of bats (Eptesicus serotinus and Myotis pequinius) were positive for trypanosomatid DNA and DNA sequencing showed that all PCR amplified Trypanosoma DNA belonged to T. dionisii. We concluded that T. dionisii had a infection rate in bats from China. For the first time, Trypanosoma infections were detected in bats from China, providing valuable information on the prevalence of these parasites in Asia. This is also the first report of Trypanosoma dionisii in Myotis pequinius, suggesting that Trypanosoma dionisii has a broad host species.

Pathogenic Leptospira Species in Insectivorous Bats, China, 2015.

PCR amplification of the rrs2 gene indicated that 50% (62/124) of insectivorous bats from eastern China were infected with Leptospira borgpetersenii, L. kirschneri, and several potentially new Leptospira species. Multilocus sequence typing defined 3 novel sequence types in L. kirschneri, suggesting that bats are major carriers of Leptospira.

Anaplasma species detected in Haemaphysalis longicornis tick from China.

Anaplasma are tick-borne obligatory intracellular bacteria, which infect humans and other animals. The Anaplasma species carried by ticks in China are not well studied. We collected 3145 questing Haemaphysalis longicornis ticks including 120 larvae, 2460 nymphs and 565 adults from vegetation in Jiaonan County, Shandong Province, China from 2013 to 2015. All ticks were examined for the presence of Anaplasma species by nested PCR amplification of the 16S rRNA gene. For further differentiation of A. capra from A. centrale, gltA and msp2 genes were sequenced for A. capra. Three Anaplasma species were detected in the nymph and/or adult ticks with the minimum infection rate of ticks as follows: 1.55% for A. bovis, 0.10% for A. phagocytophilum, and 0.03% for A. capra. These results indicated that the H. longicornis tick in Jiaonan County carried multiple Anaplasma species, which may be a challenge for public health in the studying area.

Detection of Imjin Virus and Seoul Virus in Crocidurine Shrews in Shandong Province, China.

INTRODUCTION: Recently, hantaviruses have been discovered in insectivores in Europe, Asia, Africa, and North America. Imjin virus (MJNV) was first isolated from the lung tissues of Ussuri white-toothed shrew (Crocidura lasiura) from South Korea in 2009. We aim to detect the species and prevalence of insectivore- and rodent-borne hantaviruses in shrews and rodents. MATERIALS AND METHODS: Shrews and rodents were captured in Jiaonan County of Shandong Province, China, in 2014. RT-PCR was used to amplify viral RNA of Hantavirus species, including insectivore-borne Imjin virus (MJNV), rodent-borne Hantaan virus (HTNV), and Seoul virus (SEOV) from shrews and rodents. RESULTS AND DISCUSSION: We found that MJNV infected 10.7% (19/178) of Crocidura shrews, but it infected none of rodents (0/475); we also found that 2 of 178 (1.1%) Crocidura shrews were PCR positive to SEOV. This study indicated that the major animal hosts of Imjin virus are shrews, and rodent-borne SEOV can infect shrews.

Seroprevalence of Severe Fever with Thrombocytopenia Syndrome Virus in Hedgehog from China.

Severe fever with thrombocytopenia syndrome, an emerging hemorrhagic fever, is caused by severe fever with thrombocytopenia syndrome virus (SFTSV), a tick-borne bunyavirus. Information regarding SFTSV animal hosts is very limited. In this study, we showed that 64% (9/14) of hedgehogs in Shandong Province, China were seropositive to SFTSV antibody, suggesting that hedgehog could be a vertebrate parasitifer for SFTSV.

Novel Bartonella Species in Insectivorous Bats, Northern China.

Bartonella species are emerging human pathogens. Bats are known to carry diverse Bartonella species, some of which are capable of infecting humans. However, as the second largest mammalian group by a number of species, the role of bats as the reservoirs of Bartonella species is not fully explored, in term of their species diversity and worldwide distribution. China, especially Northern China, harbors a number of endemic insectivorous bat species; however, to our knowledge, there are not yet studies about Bartonella in bats in China. The aim of the study was to investigate the prevalence and genetic diversity of Bartonella species in bats in Northern China. Bartonella species were detected by PCR amplification of gltA gene in 25.2% (27/107) bats in Mengyin County, Shandong Province of China, including 1/3 Rhinolophus ferrumequinum, 2/10 Rhinolophus pusillus, 9/16 Myotis fimbriatus, 1/5 Myotis ricketti, 14/58 Myotis pequinius. Phylogenetic analysis showed that Bartonella species detected in bats in this study clustered into ten groups, and some might be novel Bartonella species. An association between Bartonella species and bat species was demonstrated and co-infection with different Bartonella species in a single bat was also observed. Our findings expanded our knowledge on the genetic diversity of Bartonella in bats, and shed light on the ecology of bat-borne Bartonella species.

The influence of living donor SHROOM3 and ABCB1 genetic variants on renal function after kidney transplantation.

OBJECTIVE: A genome-wide association study has identified several gene polymorphisms associated with loss of renal function. The effect of these variants on renal function in kidney transplant recipients receiving immunosuppressive treatment is unknown. MATERIALS AND METHODS: A cohort of 189 kidney transplant recipients and their living donors were recruited from West China Hospital of Sichuan University, on whom we assessed the association of five single nucleotide polymorphisms with renal function after kidney transplantation. RESULTS: Glomerular filtration rate estimated by serum creatinine was significantly higher in recipients carrying allograft with the A allele at rs17319721 in SHROOM3 (shroom family member 3) than those in the group with the GG genotype from month 1 to month 6 after transplantation (P=0.020). Covariate adjustment analysis showed that the variant at rs17319721 in SHROOM3 was an independent risk factor for renal dysfunction after the first month after transplantation (P=0.022). The estimated glomerular filtration rate was the lowest in recipients with allograft carrying both the A allele at rs17319721 in SHROOM3 and the CC genotype at rs1045642 in ABCB1 (P<0.05). CONCLUSION: The genetic variants in SHROOM3 and ABCB1 in donors were associated closely with renal function after kidney transplantation.

[Plasma from patients with systemic lupus erythematosus inhibits suppressive activity of mesenchymal stem cells against lupus B lymphocytes].

OBJECTIVE: To investigate whether plasma from patients with systemic lupus erythematosus (SLE) inhibits the suppressive effects of mesenchymal stem cells (MSCs) on lupus B lymphocytes. METHODS: MSCs isolated and expanded from the bone marrow of healthy donors were co-cultured with B cells purified from the peripheral blood of SLE patients in the presence of fetal bovine serum or pooled plasma from SLE patients, and the proliferation and maturation of the B lymphocytes were analyzed. RESULTS: s Co-culture with normal MSCs obviously inhibited the proliferation of lupus B cells and suppressed the maturation of B lymphocytes, which showed lowered expressions of CD27 and CD38. The pooled plasma from SLE patients significantly inhibited the suppressive effects of normal MSCs on B cell proliferation and maturation. CONCLUSION: Plasma from SLE patients negatively modulates the effects of normal MSCs in suppressing lupus B cell proliferation and maturation to affect the therapeutic effect of MSC transplantation for treatment of SLE. Double filtration plasmapheresis may therefore prove beneficial to enhance the therapeutic effects of MSC transplantation for SLE.

Molecular Evolution and Spatial Transmission of Severe Fever with Thrombocytopenia Syndrome Virus Based on Complete Genome Sequences.

Severe fever with thrombocytopenia syndrome virus (SFTSV) was a novel tick-borne bunyavirus that caused hemorrhagic fever with a high fatality rate in East Asia. In this study we analyzed the complete genome sequences of 122 SFTSV strains to determine the phylogeny, evolution and reassortment of the virus. We revealed that the evolutionary rate of three genome segments were different, with highest in the S segment and lowest in the L segment. The SFTSV strains were phylogenetically classified into 5 lineages (A, B, C, D and E) with each genome segment. SFTSV strains from China were classified in all 5 lineages, strains from South Korea were classified into 3 lineages (A, D, and E), and all strains from Japan were classified in only linage E. Using the average evolutionary rate of the three genome segments, we found that the extant SFTSV originated 20-87 years ago in the Dabie Mountain area in central China. The viruses were then transmitted to other areas of China, Japan and South Korea. We also found that six SFTSV strains were reassortants. Selection pressure analysis suggested that SFTSV was under purifying selection according to the four genes (RNA-dependent RNA polymerase, glycoprotein, nucleocapsid protein, non-structural protein), and two sites (37, 1033) of glycoproteins were identified as being under strong positive selection. We concluded that SFTSV originated in central China and spread to other places recently and the virus was under purifying selection with high frequency of reassortment.

Haemaphysalis longicornis Ticks as Reservoir and Vector of Severe Fever with Thrombocytopenia Syndrome Virus in China.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever in East Asia caused by SFTS virus (SFTSV), a newly discovered phlebovirus. The Haemaphysalis longicornis tick has been suspected to be the vector of SFTSV. To determine whether SFTSV can be transmitted among ticks, from ticks to animals, and from animals to ticks, we conducted transmission studies between developmental stages of H. longicornis ticks and between ticks and mice. Using reverse transcription PCR, we also analyzed the prevalence of SFTSV infection among H. longicornis ticks collected from vegetation in Shandong Province, China. Our results showed a low prevalence of SFTSV among collected ticks (0.2%, 8/3,300 ticks), and we showed that ticks fed on SFTSV-infected mice could acquire the virus and transstadially and transovarially transmit it to other developmental stages of ticks. Furthermore, SFTSV-infected ticks could transmit the virus to mice during feeding. Our findings indicate ticks could serve as a vector and reservoir of SFTSV.

Bats as reservoirs of severe emerging infectious diseases.

In recent years severe infectious diseases have been constantly emerging, causing panic in the world. Now we know that many of these terrible diseases are caused by viruses originated from bats (Table 1), such as Ebola virus, Marburg, SARS coronavirus (SARS-CoV), MERS coronavirus (MERS-CoV), Nipah virus (NiV) and Hendra virus (HeV). These viruses have co-evolved with bats due to bats' special social, biological and immunological features. Although bats are not in close contact with humans, spillover of viruses from bats to intermediate animal hosts, such as horses, pigs, civets, or non-human primates, is thought to be the most likely mode to cause human infection. Humans may also become infected with viruses through aerosol by intruding into bat roosting caves or via direct contact with bats, such as catching bats or been bitten by bats.