l-2-Hydroxyglutarate contributes to tumor radioresistance through regulating the hypoxia-inducible factor-1α signaling pathway.

l-2-Hydroxyglutarate (l-2-HG) has been regarded as a tumor metabolite, and it plays a crucial role in adaptation of tumor cells to hypoxic conditions. However, the role of l-2-HG in tumor radioresistance and the underlying mechanism have not yet been revealed. Here, we found that l-2-HG exhibited to have radioresistance effect on U87 human glioblastoma cells, which could reduce DNA damage and apoptosis caused by irradiation, promote cell proliferation and migration, and impair G2/M phase arrest. Mechanistically, l-2-HG upregulated the protein level of hypoxia-inducible factor-1α (HIF-1α) and the expression levels of HIF-1α downstream target genes. The knockdown of l-2-hydroxyglutarate dehydrogenase (L2HGDH) gene promoted the tumor growth and proliferation of U87 cells in nude mice by increasing HIF-1α expression level in vivo. In addition, the low expression level of L2HGDH gene was correlated with the short survival of patients with glioma or kidney cancer. In conclusion, our study revealed the role and mechanism of l-2-HG in tumor radioresistance and may provide a new perspective for overcoming tumor radioresistance and broaden our comprehension of the role of metabolites in tumor microenvironment.

Comparing the broth enrichment-multiplex lateral flow immunochromatographic assay with real time quantitative PCR for the rapid detection of carbapenemase-producing organisms in rectal swabs.

BACKGROUND: Rapid and accurate identification of carbapenemase-producing organism (CPO) intestinal carriers is essential for infection prevention and control. Molecular diagnostic methods can produce results in as little as 1 h, but require special instrumentation and are expensive. Therefore, it is urgent to find an alternative method. The broth enrichment-multiplex lateral flow immunochromatographic assay was recently reported, but using it to directly detect CPO intestinal carriers in rectal swabs still requires the evaluation of many samples. The aim of this study was to compare the performance of these two methods, and to explore the control measures of CPO infection. METHODS: Through CPO selective culture, PCR and DNA sequencing, 100 rectal swabs confirmed to be CPO-positive and 100 rectal swabs with negative results were collected continuously. After eluting the rectal swabs with saline, three aliquots were used: one for counting, one for detection by Xpert Carba-R, and one for culture in broth for 0 h, 1 h, 2 h, 3 h and 4 h, followed by NG-Test CARBA 5 assessment. The sensitivity and specificity of the NG-Test CARBA 5 method after different incubation times were calculated. The limit of detection (LoD) of this assay after 4 h broth incubation was estimated by examining the bacterial suspensions and simulated faecal suspensions prepared with CPOs producing different types of carbapenemases. RESULTS: Xpert Carba-R demonstrated a combined sensitivity of 99.0% and specificity of 98.0%. The sensitivity and specificity were higher than 90.0% for the different enzyme types. The specificities of five common carbapenemases detected by the broth enrichment NG-Test CARBA 5 combined method after different incubation times were 100%. The sensitivities increased with increasing incubation time. At 4 h, the Klebsiella pneumoniae carbapenemase (KPC), New Delhi metallo-beta-lactamase (NDM), imipenemase (IMP), Verona integron-encoded metallo-beta-lactamase (VIM), and oxacillinase (OXA) -48 detection sensitivities were 93.0%, 96.3%, 100%, 100% and 85.7%, respectively. The LoDs were between 102 and 104 CFU/mL for all five enzymes after 4 h of incubation. CONCLUSIONS: This investigation highlighted that the broth enrichment-multiplex lateral flow immunochromatographic assay can be used as a new method for screening CPOs in rectal swabs.

Association of low-dose ionising radiation with site-specific solid cancers: Chinese medical X-ray workers cohort study, 1950-1995.

BACKGROUND: The dose-response relationship between cancers and protracted low-dose rate exposure to ionising radiation is still uncertain. This study aims to estimate quantified relationships between low-dose radiation exposures and site-specific solid cancers among Chinese medical X-ray workers. METHODS: This cohort study included 27 011 individuals who were employed at major hospitals in 24 provinces in China from 1950 to 1980 and had been exposed to X-ray equipment, and a control group of 25 782 physicians who were not exposed to X-ray equipment. Person-years of follow-up were calculated from the year of employment to the date of the first diagnosis of cancer or the end of follow-up, whichever occurred first. All cancers were obtained from medical records during 1950-1995. This study used Poisson regression models to estimate the excess relative risk (ERR) and excess absolute risk (EAR) for incidence of site-specific solid cancers associated with cumulative dose. RESULTS: 1643 solid cancers were developed, the most common being lung, liver and stomach cancer. Among X-ray workers, the average cumulative colon dose was 0.084 Gy. We found a positive relationship between cumulative organ-specific dose and liver (ERR/Gy=1.48; 95% CI 0.40 to 2.83), oesophagus (ERR/Gy=18.1; 95% CI 6.25 to 39.1), thyroid (ERR/Gy=2.96; 95% CI 0.44 to 8.18) and non-melanoma skin cancers (ERR/Gy=7.96; 95% CI 2.13 to 23.12). We found no significant relationship between cumulative organ-specific doses and other cancers. Moreover, the results showed a statistically significant EAR for liver, stomach, breast cancer (female), thyroid and non-melanoma skin cancers. CONCLUSIONS: These findings provided more useful insights into the risks of site-specific cancers from protracted low-dose rate exposure to ionising radiation.

CD39 pathway inhibits Th1 cell function in tuberculosis.

The role of CD39 pathway in Th1 cell function in tuberculosis (TB) is rarely elucidated. The present study aims to investigate the modulating mechanism of CD39 pathway during Mycobacterium tuberculosis (MTB) infection. CD39 expression was examined on host immune cells among patients with TB. The relationship between CD39 expression and Th1 cell function was analysed. Patients with TB displayed dramatically higher CD39 expression on Th1 cells than healthy controls, and a significantly increased expression of surface markers, including activation, exhaustion and apoptosis markers, were noted in CD39+ Th1 cells in comparison with CD39- Th1 cells. Conversely, CD39 expression on Th1 cells was associated with diminished number of polyfunctional cells producing Th1-type cytokines, and CD39+ Th1 cells showed obviously lower proliferation potential. Notably, tetramer analysis demonstrated a predominant CD39 expression on TB-specific CD4+ cells, which was associated with higher apoptosis and lower cytokine-producing ability. Transcriptome sequencing identified 27 genes that were differentially expressed between CD39+ and CD39- Th1 cells, such as IL32, DUSP4 and RGS1. Inhibition of CD39 pathway could enhance the activation, proliferation and cytokine-producing ability of Th1 cells. Furthermore, there was a significantly negative correlation between CD39 expression on Th1 cells and nutritional status indicators such as lymphocyte count and albumin levels, and we observed a significant decline in CD39 expression on Th1 cells after anti-TB treatment. CD39 is predominantly expressed on TB-specific Th1 cells and correlated with their exhausted function, which suggests that CD39 could serve as a prominent target for TB therapy.

Prediction models of treatment response in lupus nephritis.

In order to develop prediction models of one-year treatment response in lupus nephritis, an approach using machine learning to combine traditional clinical data and novel urine biomarkers was undertaken. Contemporary lupus nephritis biomarkers were identified through an unbiased PubMed search. Thirteen novel urine proteins contributed to the top 50% of ranked biomarkers and were selected for measurement at the time of lupus nephritis flare. These novel markers along with traditional clinical data were incorporated into a variety of machine learning algorithms to develop prediction models of one-year proteinuria and estimated glomerular filtration rate (eGFR). Models were trained on 246 individuals from four different sub-cohorts and validated on an independent cohort of 30 patients with lupus nephritis. Seven models were considered for each outcome. Three-quarters of these models demonstrated good predictive value with areas under the receiver operating characteristic curve over 0.7. Overall, prediction performance was the best for models of eGFR response to treatment. Furthermore, the best performing models contained both traditional clinical data and novel urine biomarkers, including cytokines, chemokines, and markers of kidney damage. Thus, our study provides further evidence that a machine learning approach can predict lupus nephritis outcomes at one year using a set of traditional and novel biomarkers. However, further validation of the utility of machine learning as a clinical decision aid to improve outcomes will be necessary before it can be routinely used in clinical practice to guide therapy.

Molecular profiling of kidney compartments from serial biopsies differentiate treatment responders from non-responders in lupus nephritis.

The immune pathways that define treatment response and non-response in lupus nephritis (LN) are unknown. To characterize these intra-kidney pathways, transcriptomic analysis was done on protocol kidney biopsies obtained at flare (initial biopsy (Bx1)) and after treatment (second biopsy (Bx2)) in 58 patients with LN. Glomeruli and tubulointerstitial compartments were isolated using laser microdissection. RNA was extracted and analyzed by nanostring technology with transcript expression from clinically complete responders, partial responders and non-responders compared at Bx1 and Bx2 and to the healthy controls. Top transcripts that differentiate clinically complete responders from non-responders were validated at the protein level by confocal microscopy and urine ELISA. At Bx1, cluster analysis determined that glomerular integrin, neutrophil, chemokines/cytokines and tubulointerstitial chemokines, T cell and leukocyte adhesion genes were able to differentiate non-responders from clinically complete responders. At Bx2, glomerular monocyte, extracellular matrix, and interferon, and tubulointerstitial interferon, complement, and T cell transcripts differentiated non-responders from clinically complete responders. Protein analysis identified several protein products of overexpressed glomerular and tubulointerstitial transcripts at LN flare, recapitulating top transcript findings. Urine complement component 5a and fibronectin-1 protein levels reflected complement and fibronectin expression at flare and after treatment. Thus, transcript analysis of serial LN kidney biopsies demonstrated how gene expression in the kidney changes with clinically successful and unsuccessful therapy. Hence, these insights into the molecular landscape of response and non-response may help align LN management with the pathogenesis of kidney injury.

Development of diagnostic algorithm using machine learning for distinguishing between active tuberculosis and latent tuberculosis infection.

BACKGROUND: The discrimination between active tuberculosis (ATB) and latent tuberculosis infection (LTBI) remains challenging. The present study aims to investigate the value of diagnostic models established by machine learning based on multiple laboratory data for distinguishing Mycobacterium tuberculosis (Mtb) infection status. METHODS: T-SPOT, lymphocyte characteristic detection, and routine laboratory tests were performed on participants. Diagnostic models were built according to various algorithms. RESULTS: A total of 892 participants (468 ATB and 424 LTBI) and another 263 participants (125 ATB and 138 LTBI), were respectively enrolled at Tongji Hospital (discovery cohort) and Sino-French New City Hospital (validation cohort). Receiver operating characteristic (ROC) curve analysis showed that the value of individual indicator for differentiating ATB from LTBI was limited (area under the ROC curve (AUC) < 0.8). A total of 28 models were successfully established using machine learning. Among them, the AUCs of 25 models were more than 0.9 in test set. It was found that conditional random forests (cforest) model, based on the implementation of the random forest and bagging ensemble algorithms utilizing conditional inference trees as base learners, presented best discriminative power in segregating ATB from LTBI. Specially, cforest model presented an AUC of 0.978, with the sensitivity of 93.39% and the specificity of 91.18%. Mtb-specific response represented by early secreted antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10) spot-forming cell (SFC) in T-SPOT assay, as well as global adaptive immunity assessed by CD4 cell IFN-γ secretion, CD8 cell IFN-γ secretion, and CD4 cell number, were found to contribute greatly to the cforest model. Superior performance obtained in the discovery cohort was further confirmed in the validation cohort. The sensitivity and specificity of cforest model in validation set were 92.80% and 89.86%, respectively. CONCLUSIONS: Cforest model developed upon machine learning could serve as a valuable and prospective tool for identifying Mtb infection status. The present study provided a novel and viable idea for realizing the clinical diagnostic application of the combination of machine learning and laboratory findings.

Therapy-Related Acute Myeloid Leukemia Mimicking Lymphoma: a Diagnostic Dilemma.

BACKGROUND: Based on the 2017 revision of the World Health Organization Classification, therapy-related myeloid neoplasms consist of therapy-related acute myeloid leukemia, therapy-related myelodysplastic syndromes, and therapy-related myelodysplastic/myeloproliferative neoplasms, which exist as a late-occurring complication of radiation and/or chemotherapy treatment due to previous application of iatrogenic mutagenic agents. METHODS: Here we present the first described case of therapy-related acute monocytic leukemia mimicking lym-phoma after chemotherapy and radiotherapy for breast cancer. RESULTS: Based on immunophenotypic analysis and biopsy of the BM, the patient was diagnosed with acute monocytic leukemia (AML FAB M5b) according to WHO classification. Due to short interval of development, a diagnosis of therapy-related acute monocytic leukemia was made. CONCLUSIONS: The atypical morphology of the patient, a diagnostic mistake, resulted in an initial diagnosis of secondary lymphoma. Recognizing the atypical morphology is vital in distinguishing it from lymphoma, which is closely related to the treatment and prognosis of the patient.

AGuIX nanoparticles enhance ionizing radiation-induced ferroptosis on tumor cells by targeting the NRF2-GPX4 signaling pathway.

In the frame of radiotherapy treatment of cancer, radioresistance remains a major issue that still needs solutions to be overcome. To effectively improve the radiosensitivity of tumors and reduce the damage of radiation to neighboring normal tissues, radiosensitizers have been given increasing attention in recent years. As nanoparticles based on the metal element gadolinium, AGuIX nanoparticles have been shown to increase the radiosensitivity of cancers. Although it is a rare nanomaterial that has entered preclinical trials, the unclear biological mechanism hinders its further clinical application. In this study, we demonstrated the effectiveness of AGuIX nanoparticles in the radiosensitization of triple-negative breast cancer. We found that AGuIX nanoparticles increased the level of DNA damage by compromising the homologous recombination repair pathway instead of the non-homologous end joining pathway. Moreover, the results showed that AGuIX nanoparticles induced apoptosis, but the degree of apoptosis ability was very low, which cannot fully explain their strong radiosensitizing effect. Ferroptosis, the other mode of cell death, was also discovered to play a significant role in radiation sensitization, and AGuIX nanoparticles may regulate the anti-ferroptosis system by inhibiting the NRF2-GSH-GPX4 signaling pathway.

An H3K4me3 reader, BAP18 as an adaptor of COMPASS-like core subunits co-activates ERα action and associates with the sensitivity of antiestrogen in breast cancer.

Estrogen receptor alpha (ERα) signaling pathway is essential for ERα-positive breast cancer progression and endocrine therapy resistance. Bromodomain PHD Finger Transcription Factor (BPTF) associated protein of 18kDa (BAP18) has been recognized as a crucial H3K4me3 reader. However, the whole genomic occupation of BAP18 and its biological function in breast cancer is still elusive. Here, we found that higher expression of BAP18 in ERα-positive breast cancer is positively correlated with poor prognosis. ChIP-seq analysis further demonstrated that the half estrogen response elements (EREs) and the CCCTC binding factor (CTCF) binding sites are the significant enrichment sites found in estrogen-induced BAP18 binding sites. Also, we provide the evidence to demonstrate that BAP18 as a novel co-activator of ERα is required for the recruitment of COMPASS-like core subunits to the cis-regulatory element of ERα target genes in breast cancer cells. BAP18 is recruited to the promoter regions of estrogen-induced genes, accompanied with the enrichment of the lysine 4-trimethylated histone H3 tail (H3K4me3) in the presence of E2. Furthermore, BAP18 promotes cell growth and associates the sensitivity of antiestrogen in ERα-positive breast cancer. Our data suggest that BAP18 facilitates the association between ERα and COMPASS-like core subunits, which might be an essential epigenetic therapeutic target for breast cancer.

MOF upregulates the estrogen receptor α signaling pathway by its acetylase activity in hepatocellular carcinoma.

The histone acetyltransferase MOF (KAT8) is mainly involved in the acetylation of histone H4 at lysine 16 (H4K16) and some non-histone proteins. The MOF expression level is significantly reduced in many cancers, however the biological function of MOF and its underlying mechanism are still elusive in hepatocellular carcinoma (HCC). Estrogen receptor α (ERα) has been considered as a tumor suppressor in HCC. Here, we demonstrated that MOF expression is significantly reduced in HCC samples, and is positively correlated with that of ERα. MOF interacts with ERα, and participates in acetylation of ERα at K266, K268, K299, thereby inhibiting ERα ubiquitination to maintain the stability of ERα. In addition, MOF participates in the upregulation of ERα-mediated transactivation. Depletion of MOF significantly promotes cell growth, migration, and invasion in HCC cell lines. Taken together, our results provide new insights to understand the mechanism underlying the modulation function of MOF on ERα action in HCC, suggesting that MOF might be a potential therapeutic target for HCC.

Combination of prealbumin and tuberculosis-specific antigen/phytohemagglutinin ratio for discriminating active tuberculosis from latent tuberculosis infection.

BACKGROUND: Given that there is no rapid and effective method for distinguishing active tuberculosis (ATB) from latent tuberculosis infection (LTBI), the discrimination between these two statuses remains challenging. This study sought to investigate the value of nutritional indexes and tuberculosis-specific antigen/phytohemagglutinin ratio (TBAg/PHA ratio) for distinguishing ATB from LTBI. METHODS: Participants were consecutively recruited based on positive T-SPOT.TB results between January 2018 and January 2020. ATB was diagnosed by positive mycobacterial culture and/or positive GeneXpert MTB/RIF, with clinical symptoms and radiological characteristics suggestive of ATB. Individuals with positive T-SPOT.TB but without the evidence of ATB were defined as LTBI. Patients younger than 17 years and undergoing anti-TB treatment were excluded. RESULTS: A total of 709 (312 ATB and 397 LTBI) and another 309 (120 ATB and 189 LTBI) subjects were respectively recruited from Tongji Hospital (Qiaokou cohort) and Sino-French New City Hospital (Caidian cohort). The level of prealbumin was significantly lower in ATB than in LTBI. With a cut-off value of 139 mg/L, the sensitivity and specificity of prealbumin in distinguishing ATB from LTBI were 50.96% (45.41%-56.51%) and 91.69% (88.97%-94.40%). Meanwhile, TBAg/PHA ratio was found statistically higher in ATB compared with LTBI. If using the threshold of 0.29, the sensitivity and specificity of TBAg/PHA ratio were 65.71% (60.44%-70.97%) and 90.93% (88.11%-93.76%), respectively. Moreover, the combination of prealbumin and TBAg/PHA ratio (obtaining by diagnostic model) yielded better specificity (90.18%, [87.25%-93.10%]) and sensitivity (87.18%, [83.47%-90.89%]), while the clinical utility index (CUI) positive and CUI negative were respectively 0.76 and 0.81. After anti-TB treatment, TBAg/PHA ratio was declined while the level of prealbumin was restored (Wilcoxon test, P < 0.001). Furthermore, the performance of diagnostic model obtained in Qiaokou cohort was confirmed in Caidian cohort. CONCLUSIONS: The diagnostic model based on combination of prealbumin and TBAg/PHA ratio is a rapid and accurate tool for discriminating ATB from LTBI.

Splicing factor PRPF6 upregulates oncogenic androgen receptor signaling pathway in hepatocellular carcinoma.

Androgen receptor (AR) signaling is considered to be crucial for the pathogenesis of hepatocellular carcinoma (HCC) with obvious sexual dimorphism. Pre-mRNA processing factor 6 (PRPF6) was identified as a coactivator of AR. However, the molecular mechanism underlying the modulation function of PRPF6 on AR-mediated transcriptional activity in HCC needs to be further clarified. In this study, we analyzed data from The Cancer Genome Atlas to show that PRPF6 is highly expressed in HCC. . Our data indicated that PRPF6 interacts with AR/AR splice variants (AR-Vs) and upregulates AR/AR splice variant 7-mediated transcriptional activity even without dihydrotestosterone treatment. We observed that AR is obviously induced by androgen treatment and is mainly expressed in the nucleus in HCC-derived cell lines. Moreover, overexpression of PRPF6 enhances AR expression accompanied with the increase of AR-Vs expression. We provided evidence that PRPF6 participates in upregulating AR self-transcription. PRPF6 facilitates the recruitment of AR to the androgen responsive element region of the AR gene. Finally, PRPF6 depletion inhibits cell proliferation in HCC cells and mouse xenografts. Taken together, our results suggest that PRPF6 as a splicing factor enhances AR self-transcription, thereby coactivating oncogenic AR/AR-Vs actions in HCC.

ASH2L is involved in promotion of endometrial cancer progression via upregulation of PAX2 transcription.

Absent, small or homeotic 2-like protein (ASH2L) is a core component of a multimeric histone methyltransferase complex that is involved in the maintenance of active transcription, participating in several cancers, however the biological function and molecular mechanism of ASH2L in endometrial cancer (ECa) are largely unknown. Endometrial cancer is a common malignant tumor in women and the incidence of this cancer is on the rise. Estrogen-ERα signaling, as an oncogenic pathway, plays a crucial role in endometrial carcinogenesis. Therefore, further exploration of the molecular mechanisms around ERα-mediated gene transcription in ECa would be helpful to the understanding of tumor development and to finding a new therapeutic target for ECa. Here, our study demonstrated that ASH2L was highly expressed in ECa samples, and higher expression of ASH2L was positively correlated with a poor prognosis. Moreover, we identified that ASH2L associated with ERα and that knockdown of ASH2L resulted in decreased expression of a subset of the estrogen-induced target genes, including paired box 2 (PAX2), an oncogenic gene in ECa. ASH2L was recruited to cis-regulatory elements in PAX2, thereby altering histone H3K4me3 and H3K27me3 levels, to enhance ERα-mediated transactivation. Finally, depletion of ASH2L suppressed endometrial cancer cell proliferation and migration. Our findings suggest that ASH2L participates in the promotion of ECa progression, if not totally at least partially, via upregulation of PAX2 transcription.

Prediction Model Based on the Combination of Cytokines and Lymphocyte Subsets for Prognosis of SARS-CoV-2 Infection.

BACKGROUND: There are currently rare satisfactory markers for predicting the death of patients with coronavirus disease 2019 (COVID-19). The aim of this study is to establish a model based on the combination of serum cytokines and lymphocyte subsets for predicting the prognosis of the disease. METHODS: A total of 739 participants with COVID-19 were enrolled at Tongji Hospital from February to April 2020 and classified into fatal (n = 51) and survived (n = 688) groups according to the patient's outcome. Cytokine profile and lymphocyte subset analysis was performed simultaneously. RESULTS: The fatal patients exhibited a significant lower number of lymphocytes including B cells, CD4+ T cells, CD8+ T cells, and NK cells and remarkably higher concentrations of cytokines including interleukin-2 receptor, interleukin-6, interleukin-8, and tumor necrosis factor-α on admission compared with the survived subjects. A model based on the combination of interleukin-8 and the numbers of CD4+ T cells and NK cells showed a good performance in predicting the death of patients with COVID-19. When the threshold of 0.075 was used, the sensitivity and specificity of the prediction model were 90.20% and 90.26%, respectively. Meanwhile, interleukin-8 was found to have a potential value in predicting the length of hospital stay until death. CONCLUSIONS: Significant increase of cytokines and decrease of lymphocyte subsets are found positively correlated with in-hospital death. A model based on the combination of three markers provides an attractive approach to predict the prognosis of COVID-19.

Mediating effects of nursing organizational climate on the relationships between empathy and burnout among clinical nurses.

AIMS AND OBJECTIVES: To investigate how nurses who worked in Guangdong province in China perceived empathy, nursing organization climate and burnout. DESIGN: A cross-sectional quantitative research design was used. We carried out the research in accordance with the Strengthening the Reporting of Observational studies in Epidemiology checklist. METHODS: The study was carried out from August-October of 2018 using a structured electronic questionnaire. A total of 965 participants were selected with convenience sampling in Guangdong province. RESULTS: A total of 786 valid questionnaires were collected in this study. The average burnout score of participants was 38.19 (SD 13.32) and 67.4% of them rated their burnout as more than 30 points, while 5.7% were higher than 60 points. The multi-variable linear regression model explained 9.4% of the variance in burnout related to sociodemographic variables (p < 0.001). Empathy was significantly and positively associated with nursing organizational climate and emotional exhaustion while negatively associated with reduced personal accomplishment. In addition, nursing organizational climate mediated the relationship between empathy and reduced personal accomplishment. CONCLUSION: Our findings suggest that both empathy and nursing organizational climate are protective factors that prevent burnout in this population. Managers can alleviate nurses' burnout through developing empathy and improving the organizational climate. IMPACT: This study demonstrates that empathy is not the cause of burnout; rather, it can prevent nurses from experiencing burnout. Nursing organizational climate is another protective factor that has a mediating effect on empathy and burnout. Improving empathy and nursing organizational climate could help reduce nurse burnout.

Immune gene expression in kidney biopsies of lupus nephritis patients at diagnosis and at renal flare.

BACKGROUND: Up to 50% of lupus nephritis (LN) patients experience renal flares after their initial episode of LN. These flares contribute to poor renal outcomes. We postulated that intrarenal immune gene expression is different in flares compared with de novo LN, and conducted these studies to test this hypothesis. METHODS: Glomerular and tubulointerstitial immune gene expression was evaluated in 14 patients who had a kidney biopsy to diagnose LN and another biopsy at their first LN flare. Ten healthy living kidney donors were included as controls. RNA was extracted from laser microdissected formalin-fixed paraffin-embedded kidney biopsies. Gene expression was analyzed using the Nanostring nCounter® platform and validated by quantitative real-time polymerase chain reaction. Differentially expressed genes were analyzed by the Ingenuity Pathway Analysis and Panther Gene Ontology tools. RESULTS: Over 110 genes were differentially expressed between LN and healthy control kidney biopsies. Although there was considerable molecular heterogeneity between LN biopsies at diagnosis and flare, for about half the LN patients gene expression from the first LN biopsy clustered with the repeated LN biopsy. However, in all patients, a set of eight interferon alpha-controlled genes had a significantly higher expression in the diagnostic biopsy compared with the flare biopsy. In contrast, nine tumor necrosis factor alpha-controlled genes had higher expression in flare biopsies. CONCLUSIONS: There is significant heterogeneity in immune-gene expression of kidney tissue from LN patients. There are limited but important differences in gene expression between LN flares, which may influence treatment decisions.

Infected bone resection plus adjuvant antibiotic-impregnated calcium sulfate versus infected bone resection alone in the treatment of diabetic forefoot osteomyelitis.

BACKGROUND: Managing with diabetic foot osteomyelitis (DFO) is challenging. Even after infective bone resection and thorough debridement, DFO is still difficult to cure and has a high recurrence rate. This retrospective study aims to compare the outcomes of two treatment methods, infected bone resection combined with adjuvant antibiotic-impregnated calcium sulfate and infected bone resection alone, for the treatment of diabetic foot osteomyelitis. METHODS: Between 2015 to 2017, 48 limbs (46 patients) with DFO met the criteria were included for assessment. 20 limbs (18 patients) were included in the calcium sulfate group (the CS group) in which vancomycin and/or gentamicin-impregnated calcium sulfate was used as an adjuvant after infected bone resection while 28 limbs (28 patients) as the control group were undergone infected bone resection only. Systemic antibiotics, postoperative wound care and offloading were continued to be applied following surgery in both groups. The time to healing, healing rate, recurrence rate and amputation rate were compared between the two groups. RESULTS: In total, 90% (18/20) limbs in the CS group as compared to 78.6% (22/28) infected limbs in the control group went to heal (P = 0.513). The Mean time to healing was 13.3 weeks in the CS group and 11.2 weeks in control group (P = 0.132). Osteomyelitis recurrence rate was 0% (0/18) in the CS group and 36.4% (8/22) in the control group (P = 0.014). Postoperative leakage in calcium sulfate group was 30.0% (6/20) with a mean duration of 8.5 weeks. Amputation rate in the control group was 7.1% (2/28) compared to 0% (0/20) in the CS group (P = 0.153). CONCLUSIONS: Antibiotic-impregnated calcium sulfate as an adjuvant prevents the recurrence of DFO but cannot improve the healing rate, reduce the postoperative amputation rate or shorten the time to healing. Prolonged postoperative leakage as the most common complication can be managed with regular dressing. LEVEL OF EVIDENCE: III, Retrospective Comparative Study.

Metal distribution and biological diversity of crusts in paddy fields polluted with different levels of cadmium.

The paddy-crusts (PCs) play an important pole in the transformation and transfer of heavy metal in paddy. Different PCs were collected from paddy fields whose soils contained cadmium (Cd) at four concentration levels (0.61, 0.71, 1.53, and 7.08 mg/kg) in Hunan Province, China P.R. at Sep 2017. This metal's distribution among and biological community structures of PCs were both measured. Our results indicated that PCs were able to accumulate Cd from irrigation water and soil. With greater Cd levels in paddy fields, the weak EPS-binding Cd fraction decreased whereas the non-EDTA-exchangeable Cd fraction increased. The sorbed Cd fraction was initially enhanced at low-to mid-level Cd concentrations, but then gradually declined. Biomineralization was shown to function as the dominant Cd accumulation mechanism in non-EDTA-exchangeable fractions. The biological diversity of soil microbes decreased with more Cd in soil, and the Proteobacteria, Bacteroidetes, and Cyanobacteria were the dominant phyla in all the sampled PCs. Canonical correspondence analysis (CCA) between the composition of microbial communities and soil chemical variables in the PCs clustered all samples based on the Cd-contaminated level, and demonstrated that Cd, Mn, and Fe all significantly influenced the microbial communities. In particular, the Alphaproteobacteria and Chloroplast classes of bacteria may play a significant role in Cd accumulation via the bio-mineralization process. Taken together, our results provide basic empirical information to better understand the heavy metal speciation transformation mechanisms of PCs upon Cd-contaminated paddy fields.

Manganese enhances the immobilization of trace cadmium from irrigation water in biological soil crust.

The effect of biological soil crust (BSC) in paddy field on the immobilization and removal of heavy metal from irrigation water is an important issue. BSC was cultured in solutions with different concentrations of manganese (Mn) salt and cadmium (Cd) sulfate for 15 days. We analyzed the Mn, Cd and Fe contents in the BSC and investigated the effects of Mn salt on the Cd distribution in different binding-forms in BSC as well. The results show that Mn salt was effective at enabling BSC to immobilize the Cd, and its removal efficiency from irrigation water improved with an increase in the Mn concentration used. The removal of 50.00 µg/L of Cd from irrigation water by BSC reached as high as 95.70% in present of 20.00 mg/L Mn. The highest obtained biological concentrated factor of BSC for Cd is ~2.7 × 104. The mainly Cd species (75%) in BSC is the non-EDTA extracted minerals. Based on the SEM-EDS and XPS analyses, it was reasonably inferred that the Mn ion was oxidized by Mn oxidizing bacteria (MOB), to yield the porous spongy-like birnessite with d-spacing of 2.31 Ǻ, while Cd was scavenged and immobilized in the crystal lattice. The MOB was identified as Bacillus. This study provides a potentially novel method to decontaminate irrigation water polluted with Cd by using BSC in presence of Mn.