[Biological characteristics of triple negative breast cancer with low expression of HER2].

Objective: To investigate the biological characteristics of triple negative breast cancer (TNBC) with low expression of HER2 (HER2-low). Methods: A total of 93 TNBC cases in Shanxi Cancer Hospital from 2017 to 2019 were collected and divided into HER2-negative and HER2-low groups according to HER2 expression status. The clinicopathological features and prognostic differences between the two groups were retrospectively analyzed and compared, and genetic detection of tumor tissues was performed to clarify somatic mutation status and differences between the two groups. Results: Ninety-three patients aged 26 to 86 years were enrolled, including 60 patients in the HER2-negative group and 33 patients in the HER2-low group. The distribution of HER2-low in luminal androgen receptor (LAR) subtype (14/23, 60.87%) and non-LAR subtype (19/70, 27.14%) was significantly different (P=0.005). There were no significant differences in age, pT stage, histological grade, infiltration mode, lymph node metastasis and survival analysis. The expression of HER2-low in the tumor was heterogeneous, including different proportions of weak, weak to moderate intensity, and incomplete to intact membrane staining. With the change of the proportion of HER2-positive cells, the different distribution of those cells in the total tumor cells was noted, including cluster, mosaic and scattered patterns. The concentration and quality of DNA extracted from 71 of the 93 samples met the requirements for making libraries, including 43 in the HER2-negative group and 28 in the HER2-low group. Genetic mutations were mainly missense mutations, single nucleotide mutations, and point mutations in which base C was replaced by base T. There was no significant difference in genes with mutation frequency>3 times between the two groups. CTNNB1 and FGFR3 genes were only mutated in HER2-low group; while ALK, CYP2D6 and FAT1 genes were only mutated in HER2-negative group. HER2-low group included 18 HER2 1+ cases and 10 HER2 2+ cases. Genes with mutation frequency>3 times between the two groups included PIK3CA, TP53, SLX4, ATM and BRCA1. The mutation frequency of PIK3CA in HER2 2+ was significantly higher than that in HER2 1+ group (P<0.05), and SLX4 gene was only mutated in HER2 1+ group. Conclusions: There are some differences of histological morphology and genetic variation between HER2-negative group and HER2-low group, and also differences in genetic variation between HER2 1+ and HER2 2+ in HER2-low group, which are helpful for more accurate stratification of TNBC and useful for finding the therapeutic target and precise treatment of HER2-low TNBC.

The impact of BCG dose and revaccination on trained immunity.

The innate immune system can display heterologous memory-like responses termed trained immunity after stimulation by certain vaccinations or infections. In this randomized, placebo-controlled trial, we investigated the modulation of Bacille Calmette-Guérin (BCG)-induced trained immunity by BCG revaccination or high-dose BCG administration, in comparison to a standard dose. We show that monocytes from all groups of BCG-vaccinated individuals exerted increased TNFα production after ex-vivo stimulation with various unrelated pathogens. Similarly, we observed increased amounts of T-cell-derived IFNγ after M. tuberculosis exposure, regardless of the BCG intervention. NK cell cytokine production, especially after heterologous stimulation with the fungal pathogen Candida albicans, was predominantly boosted after high dose BCG administration. Cytokine production capacity before vaccination was inversely correlated with trained immunity. While the induction of a trained immunity profile is largely dose- or frequency independent, baseline cytokine production capacity is associated with the magnitude of the innate immune memory response after BCG vaccination.

Perception of indexical cues in speech by children and adults with and without dyslexia: Regional dialect and gender identification.

Auditory research in developmental dyslexia proposes that deficient auditory processing of speech underlies difficulties with reading and spelling. Focusing predominantly on phonological processing, studies have not yet addressed the role of the speaker-related (indexical) properties of speech that enable the formation of phonological representations. Here, we assess auditory processing of indexical characteristics cueing a speaker's regional dialect and gender to determine whether dyslexia constraints recognition of dialect features and voice gender. Adults and children aged 11-14 years with dyslexia and their age-matched controls responded to 360 unique sentences extracted from spontaneous conversations of 40 speakers. In addition to the original unprocessed speech, there were two focused filtered conditions (using lowpass filtering at 400 Hz and 8-channel noise vocoding) probing listeners' responses to segmental and prosodic cues. Compared with controls, both groups with dyslexia were significantly limited in their abilities to recognize dialect features from either set of cues. The results for gender suggest that their comparatively worse gender recognition in the noise-vocoded condition was possibly related to poor temporal resolution. We propose that the deficient processing of indexical cues by individuals with dyslexia originates in peripheral auditory processes, of which impaired processing of relevant temporal cues in amplitude envelope is a likely candidate.

Enhanced sequestration of molybdenum(VI) using composite constructed wetlands and responses of microbial communities.

The molybdenum (Mo) non-point source pollution in the mining area has an irreversible impact on the surrounding water and soil ecosystems. Herein, three integrated vertical subsurface flow constructed wetlands (CWs) were constructed to assess the effects of combination substrates and plant on the removal of Mo(VI). Results showed that CW1 with combination substrates and cattail exhibited a favorable removal performance for Mo(VI) at 80.90%. Moreover, most Mo(VI) retained in the CWs was retained in the substrate (58.13-88.04%), and the largest fraction of Mo(VI) retained was the water-soluble fraction on the surface of the combination substrates. Mo(VI) removal was also influenced by the microbial community composition in substrate, especially their co-occurrence networks. The species that showed significant positive correlation with Mo(VI) removal were Planctomycetes, Latescibacteria, Armatimonadetes, and Gemmatimonadetes. Moreover, CWs added plants showed that more co-occurrences interaction between taxa occurs, which means that the wetlands efficiently select recruitment of potential microbial consortia and change the co-occurrences to remove pollution in the substrate. These results could be useful in providing an ecology-based solution for the treatment of Mo(VI) in wastewater, especially in adjusting the microbial communities for Mo(VI) removal at the genetic level.

[Prognostic factors of autologous hematopoietic stem cell transplantation in intermediate-risk acute myeloid leukemia patients with minimal residual disease negativity].

To explore prognostic factors in intermediate-risk acute myeloid leukemia (AML) patients with minimal residual disease (MRD) negativity (MRD<0.1%,MRD-)receiving autologous hematopoietic stem cell transplantation (auto-HSCT).A total of 59 intermediate-risk AML patients with MRD-were treated with auto-HSCT from January 2015 to September 2021 at Affiliated People's Hospital of Ningbo University. The clinical data and laboratory results were collected retrospectively. Efficacy, clinical outcome and prognostic factors were analyzed. Univariate analysis was conducted by using log-rank test, the multivariate analysis by Cox proportional risk model.Among 59 patients, there were 27 males and 32 females with median age of 55 (31-69) years old.The median follow-up was 761(317-1 861)days. The 2-year overall survival (OS) rate and event-free survival (EFS) rate were 76.1%±11.4% and 73.4%±11.6% respectively.The univariate analysis showed that age older than 50 years, TET2 gene mutation (TET2+), achieving MRD negativity over 30 days (MRD30+) were unfavorable factors of OS (χ2=6.20, 33.20, 7.18;P=0.013,<0.001, 0.007). TET2+, WT1 gene mutation (WT1+), CD34+cells<2×106/kg, MRD30+were negative factors of EFS (χ2=17.29, 4.47, 3.94, 9.393;P<0.001, 0.035, 0.047, 0.002).Multivariate analysis showed that MRD30+, TET2+ were independent prognostic factors of OS and EFS (OS:HR=9.251, 25.839, P=0.036, 0.001;EFS:HR=5.851, 9.199, P=0.043, 0.002). Intermediate-risk AML patients with MRD30+or TET2+ have very poor prognosis after auto-HSCT. Alternative regimens should be investigated.

[Analysis of differences and influencing factors of liver injury associated with different strains of 2019-nCoV infection].

Objective: To analyze whether there are differences and related influencing factors in liver injury associated with different strains of 2019-nCoV/SARS-CoV-2 infection. Methods: Data of epidemiology, clinical symptoms, laboratory tests, and treatment outcomes of patients with COVID-19 infection confirmed with Alpha and Delta virus strain in Zhejiang Province were retrospectively collected. Statistical analysis was performed using independent samples t-test or Mann-Whitney U test, χ2 test or Fisher's exact test, and logistic regression analysis. Results: A total of 788 and 381 cases with Alpha and Delta virus strain were included. Vaccination ratio was 0% in Alpha and 85.30% in Delta group (P<0.001), The proportion of patients with fever (80.71% vs. 40.94%, P<0.001) was significantly higher in Alpha than Delta strain group. The proportion of critical ill patients was significantly higher in Delta group (9.90% vs. 1.57%, respectively, P<0.001). The virus negative conversion time was significantly longer in Delta than Alpha group (22 d vs. 11 d, P<0.001), but the incidence of liver injury was significantly higher in Alpha than Delta group (20.05% vs. 13.91%, P=0.011). Univariate analysis showed that Alpha virus strain infection, male sex, body mass index, chronic liver disease, fever, diarrhea, shortness of breath, severe/critical illness, elevated creatine kinase (CK), elevated international normalized ratio (INR) and an elevated neutrophil/lymphocyte ratio was significantly associated with an increased risk of liver injury occurrence, and in patients with pharyngeal pain the risk of liver injury occurrence was significantly reduced. Multivariate analysis showed that shortness of breath [OR, 2.667 (CI: 1.389-5.122); P=0.003], increased CK [OR, 2.544 (CI: 1.414-4.576); P=0.002] and increased INR [OR, 1.721] (CI: 1.074-2.758); P=0.024] was significantly associated with an increased risk of liver injury occurrence, and in patients with pharyngeal pain the risk of liver injury occurrence was significantly reduced [OR, 0.424 (CI: 0.254-0.709); P=0.001]. Conclusion: Although the virulence of the Delta is stronger than Alpha strain, most patients infected with Delta strain vaccinated against COVID-19 in Zhejiang province had milder clinical symptoms and a lower incidence and degree of liver injury. Notably, the infection risk even remains after vaccination; however, symptoms and the incidence of severe and critical illness can be significantly reduced.

[The relevance of electrocardiographic abnormalities and prognosis in patients with paraquat poisoning].

Objective: To investigate the relationship between electrocardiographic (ECG) changes and prognosis of paraquat poisoning patients, so as to provide evidence for the condition assessment in paraquat poisoning patients. Methods: In January 2022, The clinical data of paraquat poisoning patients were retrospectively analyzed in the First Affiliated Hospital of Wenzhou Medical University from January 1, 2016 to December 31, 2021. The patients' basic information (age, sex, underlying disease, and occupation) and the ECG within 24 hours were collected, and the data were statistically analyzed by SPSS 22.0. One variable analysis and multivariable logistic regression analysis were used to analyze the risk factors related to prognosis determine in their ECG. The receiver operating characteristic (ROC) curve were used to evaluate the diagnostic value of ECG indexes in patients with paraquat poisoning. Results: A total of 145 patients with paraquat poisoning were finally enrolled in this study, there were 84 patients survived and 60 patients died. One variable analysis revealed that heart rate (P=0.000) , QTc changes (P=0.000) , and ST-T changes (P=0.007) of ECG had statistically significant differences in the prognosis of paraquat poisoning patients between the survival group and the death group. Multifactorial logistic results showed that heart rate (OR=1.059, 95%CI: 1.033~1.086) and QTc (OR=1.015, 95%CI: 1.000~1.029) were independent risk factors for death diagnosis of patients with paraquat poisoning (P<0.05) . ROC curve analysis revealed that the area under the cure (AUC) of the prediction model constructed based on heart rate and QTc was 0.832 (95%CI: 0.765~0.899) , with the best diagnostic efficacy. Conclusion: Heart rate, QTc and the prediction model constructed based on both can be used as prognostic indicators for the diagnosis of patients with paraquat poisoning, and which have reference value for clinical prognosis diagnosis.

The Benzimidazole SPR719 Shows Promising Concentration-Dependent Activity and Synergy against Nontuberculous Mycobacteria.

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is emerging worldwide. Currently recommended multidrug treatment regimens yield poor outcomes, and new drugs and regimens are direly needed. SPR719, the active moiety of SPR720, is a new benzimidazole antibiotic with limited data on antimycobacterial activity. We determined MICs and MBCs against 138 clinical and reference strains of M. avium complex (MAC), M. kansasii, M. abscessus, M. xenopi, M. malmoense, and M. simiae and determined synergy with antimycobacterial drugs by checkerboard titrations. To study pharmacodynamics, we performed time-kill kinetics assays of SPR719 alone and in combinations against M. avium, M. kansasii, and M. abscessus and assessed synergy by response surface analysis according to Bliss independence. SPR719 showed potent activity against MAC (MIC90, 2 mg/liter) and M. kansasii (MIC90, 0.125 mg/liter) and modest activity against M. abscessus (MIC90, 8 mg/liter); its activity is bacteriostatic and concentration-dependent. We recorded a potential for combination therapy with ethambutol against M. kansasii and M. avium and synergy with clarithromycin against M. abscessus Ethambutol increased the SPR719 kill rate against M. kansasii but only prevented SPR719 resistance in M. avium SPR719 is active in vitro against NTM; its activity is strongest against M. kansasii, followed by MAC and M. abscessus SPR719 shows promise for combination therapy with ethambutol against MAC and M. kansasii and synergy with clarithromycin against M. abscessus The parent drug SPR720 could have a role especially in MAC pulmonary disease treatment. Further studies in dynamic models and trials are ongoing to advance clinical development.

An In Vitro Perspective on What Individual Antimicrobials Add to Mycobacterium avium Complex Therapies.

For Mycobacterium avium complex pulmonary disease (MAC-PD), current treatment regimens yield low cure rates. To obtain an evidence-based combination therapy, we assessed the in vitro activity of six drugs, namely, clarithromycin (CLR), rifampin (RIF), ethambutol (EMB), amikacin (AMK), clofazimine (CLO), and minocycline (MIN), alone and in combination, against Mycobacterium avium and studied the contributions of individual antibiotics to efficacy. The MICs of all antibiotics against M. avium ATCC 700898 were determined by broth microdilution. We performed kinetic time-kill assays of all single drugs and clinically relevant two-, three-, four-, and five-drug combinations against M. avium. Pharmacodynamic interactions of these combinations were assessed using area under the time-kill curve-derived effect size and Bliss independence. Adding a second drug yielded an average increase of the effect size (E) of 18.7% ± 32.9%, although antagonism was seen in some combinations. Adding a third drug showed a smaller increase in effect size (+12.2% ± 11.5%). The RIF-CLO-CLR (E of 102 log10 CFU/ml · day), RIF-AMK-CLR (E of 101 log10 CFU/ml · day), and AMK-MIN-EMB (E of 97.8 log10 CFU/ml · day) regimens proved more active than the recommended RIF-EMB-CLR regimen (E of 89.1 log10 CFU/ml · day). The addition of a fourth drug had little impact on effect size (+4.54% ± 3.08%). In vitro, several two- and three-drug regimens are as effective as the currently recommended regimen for MAC-PD. Adding a fourth drug to any regimen had little additional effect. In vitro, the most promising regimen would be RIF-AMK-macrolide or RIF-CLO-macrolide.

Variability in within-category implementation of stop consonant voicing in American English-speaking children.

The development of stop consonant voicing in English-speaking children has been documented as a progressive mastery of phonological contrast, but implementation of voicing within one voicing category has not been systematically examined. This study provides a comprehensive account of structured variability in phonetic realization of /b/ in running speech by 8-12-year-old American children (n = 48) when compared to adults (n = 36). The stop always occurred word-initially, was followed by either a voiced or voiceless coda, and its position varied in a sentence, which created systematic conditions to examine acoustic variability in closure duration (CD) and voicing during the closure (VDC) stemming from phonetic context and prosodic prominence. Children demonstrated command of long-distance anticipatory coarticulation, providing evidence that information about coda voicing is distributed over an entire monosyllabic word and is available in the onset stop. They also manifested covariation of cues to stop voicing and command of prosodic variation, despite greater random variability, greater CD, reduced VDC, and exaggerated execution of sentential focus when compared to adults. Controlling for regional variation, dialect was a significant predictor for adults but not for children, who no longer adhered to the marked local variants in their implementation of stop voicing.

How pronunciation distance impacts word recognition in children and adults.

Although unfamiliar accents can pose word identification challenges for children and adults, few studies have directly compared perception of multiple nonnative and regional accents or quantified how the extent of deviation from the ambient accent impacts word identification accuracy across development. To address these gaps, 5- to 7-year-old children's and adults' word identification accuracy with native (Midland American, British, Scottish), nonnative (German-, Mandarin-, Japanese-accented English) and bilingual (Hindi-English) varieties (one talker per accent) was tested in quiet and noise. Talkers' pronunciation distance from the ambient dialect was quantified at the phoneme level using a Levenshtein algorithm adaptation. Whereas performance was worse on all non-ambient dialects than the ambient one, there were only interactions between talker and age (child vs adult or across age for the children) for a subset of talkers, which did not fall along the native/nonnative divide. Levenshtein distances significantly predicted word recognition accuracy for adults and children in both listening environments with similar impacts in quiet. In noise, children had more difficulty overcoming pronunciations that substantially deviated from ambient dialect norms than adults. Future work should continue investigating how pronunciation distance impacts word recognition accuracy by incorporating distance metrics at other levels of analysis (e.g., phonetic, suprasegmental).

Enhanced molybdenum(VI) removal using sulfide-modified nanoscale zerovalent iron: kinetics and influencing factors.

The overall goal of this study is to investigate the effect of sulfidated nanoscale zerovalent iron (S-nZVI) on the removal of hexavalent molybdate (MoO42-) under different aquatic chemistry conditions. Surface analysis suggests that Mo(VI) is removed mainly by adsorption and co-precipitation onto the surface of S-nZVI and a small amount of Mo(VI) can be reduced to Mo(V) species. The results of batch tests show that Mo(VI) removal by S-nZVI are well described with the pseudo-second-order adsorption model. The removal rate increases with a decrease in solution pH (4.0-9.0) and is significantly affected by the S/Fe ratio of S-nZVI, with the optimal S/Fe ratio being 0.5. The presence of anions WO42- or CrO42- can reduce the Mo(VI) removal, which is likely because they compete for adsorption sites on the solid surfaces. The divalent cations Ni2+, Cu2+ and Co2+ also inhibit the removal of Mo(VI) whereas Zn2+, Ca2+ and Mg2+ enhance it. After being aged for 35 d in water, S-nZVI still exhibits high reactivity towards Mo(VI) removal (57.39%). The study demonstrates that S-nZVI can be used as an environmentally friendly material for effectively removing Mo(VI) from contaminated water.

[Role of Orai 1-mediated store-operated calcium entry in the immune function of CD4+ T cells in septic mice].

Objective: To investigate the role of Orai1-mediated store-operated calcium entry in the immune damage of CD4+ T cells in septic mice. Methods: Sepsis mouse model was established by cecal ligation and puncture(CLP). Balb/c mice of clean grade were sacrificed 1, 3, and 5 days after operation. Spleen samples were harvested at given intervals. Splenic CD4+ T cells were selected by immunomagnetic beads and the expression of Orai1 protein was detected by western blotting, the storage operated calcium entry (SOCE) was detected by flow cytometry, the apoptosis of CD4+ T cells was detected by flow cytometry, the proliferation of CD4+ T cells was detected by CCK-8, and the IFN-γ and IL-4 were detected by enzyme-linked immunosorbent assay (ELISA). Then the expression of Orai1 protein was regulated to further detect the SOCE and immune function of splenic CD4+ T cells in mice. The experiment was divided into 4 groups, sham group, CLP3 group, Orai1 down group (Orai1-down group) and Orai1 up regulation group (Orai1-up group). Results: The relative expression of Orai1 protein in splenic CD4+ T cells in sham group was 1.03±0.16. Compared with sham group, Orai1 protein levels in CLP Group were all significantly lower (F=19.64, P=0.000 5). The increased value of splenic CD4+ T cells fluorescence intensity in sham group was 494±41. Compared with sham group, the levels of SOCE in CLP Group were all lower (F=30.01, P=0.001). The ratio of early and late apoptosis of CD4+ T cells in sham group was 8.7%±1.5%. Compared with sham group, the early and late apoptosis rates of CLP Group were significantly higher (F=32.29, P=0.000 1). The OD of sham group was 0.81±0.10 at 450 nm. Compared with sham group, the proliferation ability of splenic CD4+ T cells in CLP Group were significantly decreased (F=7.26, P=0.001 8). Compared with sham group, the secretion of IFN-γ and IL-4 by CD4+ T cells and the ratio of IFN-γ/IL-4 in CLP Group were all significantly decreased (F=19.690, 6.183, 11.230, all P<0.05). Compared with CLP3 group, the increased value of fluorescence intensity of CD4+ T cells was significantly decreased, the early and late apoptosis ratio of CD4+ T cells was significantly increased, the OD450 nm value of CD4+ T cells was decreased, the multiplication capacity of splenic CD4+ T cells were decreased, the level of IFN-γ and IL-4 secreted by T cells were decreased, and the value of IFN-γ/IL-4 in orai1-down group was decreased (t=4.819, 7.952, 2.988, 28.760, 3.140, 7.670, all P<0.05). However, Orail-up group showed the opposite trend. Conclusion: Orai1-mediated store-operated calcium entry can alleviate the immune dysfunction of CD4+ T cells in septic mice.

[Analysis of the effect of preventive intervention on occupational exposure of nurses after tumor particle implantation in thoracic surgery].

Objective: To study the effect of preventive intervention on occupational exposure of nurses after tumor particle implantation in thoracic surgery. Methods: In March 2020, 99 nurses who were engaged in postoperative nursing of tumor particle implantation in thoracic surgery department of our hospital from February 2019 to February 2020 were selected as the research objects. According to different preventive interventions, they were divided into observation group (51 cases) and control group (48 cases) . The observation group received preventive intervention, while the control group received routine intervention. The differences of radiation dose, psychological state and abnormal rate of important organ function between the two groups were analyzed. Results: Compared with the control group, the radiation dose of the observation group was significantly less, and the scores of anxiety and depression were lower after the intervention, the difference were statistically significant (P<0.05) . There was no significant difference of the abnormal rate of important organ function between the two groups (P>0.05) . Conclusion: Preventive intervention can reduce the risk of occupational exposure and improve the psychological status of nurses after tumor particle implantation in thoracic surgery.

Thioridazine Is an Efflux Pump Inhibitor in Mycobacterium avium Complex but of Limited Clinical Relevance.

Treatment of Mycobacterium avium complex pulmonary disease (MAC-PD) is challenging partly due to high efflux pump expression. Thioridazine might block these efflux pumps. We explore the efficacy of thioridazine against M. avium isolates using MICs, time-kill combination assays, ex vivo macrophage infection assays, and efflux assays. Thioridazine is bactericidal against M. avium, inhibits intracellular growth at 2× MIC, and blocks ethidium bromide efflux. However, its toxicity and low plasma concentrations make it unlikely to add efficacy to MAC-PD therapy.

Inhaled tigecycline is effective against Mycobacterium abscessus in vitro and in vivo.

BACKGROUND: Mycobacterium abscessus causes chronic pulmonary infections. Owing to its resistance to most classes of antibiotics, treatment is complex and cure rates are only 45%. Tigecycline is active against M. abscessus, but severe toxicity and the need for IV administration limit its use. OBJECTIVES: To assess the potential of inhaled tigecycline as a treatment for M. abscessus pulmonary disease, by measuring its efficacy in a mouse model of chronic M. abscessus pulmonary disease, establishing the intracellular activity of tigecycline against M. abscessus in human macrophages and measuring the activity of tigecycline in the sputum of cystic fibrosis patients. METHODS: We infected GM-CSF knockout mice with M. abscessus by intrapulmonary aerosol. Infected mice were treated with tigecycline in 0.25, 1.25 and 2.5 mg doses, by inhalation, or untreated, for 28 days. Tigecycline was added to human peripheral blood-derived macrophages infected with M. abscessus to assess its intracellular activity. We performed a time-kill kinetics experiment of tigecycline against M. abscessus with and without sputum of cystic fibrosis patients. RESULTS: Inhaled tigecycline proved highly effective against M. abscessus in GM-CSF knockout mice. The effect was dose dependent. Tigecycline showed potent activity against M. abscessus in macrophages and retained most of its activity in the presence of sputum of cystic fibrosis patients. CONCLUSIONS: Inhaled tigecycline may represent a viable treatment option for M. abscessus pulmonary disease, where treatment outcomes are currently very poor. A stable and safe formulation is required to proceed to further pharmacodynamic studies and ultimately clinical trials.

Is there a role for tedizolid in the treatment of non-tuberculous mycobacterial disease?

BACKGROUND: Pulmonary infections caused by non-tuberculous mycobacteria (NTM) are hard to treat and have low cure rates despite intensive multidrug therapy. OBJECTIVES: To assess the feasibility of tedizolid, a new oxazolidinone, for the treatment of Mycobacterium avium and Mycobacterium abscessus. METHODS: We determined MICs of tedizolid for 113 isolates of NTM. Synergy with key antimycobacterial drugs was assessed using the chequerboard method and calculation of the FIC index (FICI). We performed time-kill kinetics assays of tedizolid alone and combined with amikacin for M. abscessus and with ethambutol for M. avium. Human macrophages were infected with M. abscessus and M. avium and subsequently treated with tedizolid; intracellular and extracellular cfu were quantified over time. RESULTS: NTM isolates generally had a lower MIC of tedizolid than of linezolid. FICIs were lowest between tedizolid and amikacin for M. abscessus (FICI = 0.75) and between tedizolid and ethambutol for M. avium (FICI = 0.72). Clarithromycin and tedizolid showed initial synergy, which was abrogated by erm(41)-induced macrolide resistance (FICI = 0.53). Tedizolid had a weak bacteriostatic effect on M. abscessus and combination with amikacin slightly prolonged its effect. Tedizolid had concentration-dependent activity against M. avium and its efficacy was enhanced by ethambutol. Both combinations had a concentration-dependent synergistic effect. Tedizolid could inhibit the intracellular bacterial population of both M. avium and M. abscessus. CONCLUSIONS: Tedizolid should be further investigated in pharmacodynamic studies and clinical trials for M. avium complex pulmonary disease. It is less active against M. abscessus, but still promising.

Higher order genomic organization and epigenetic control maintain cellular identity and prevent breast cancer.

Cells establish and sustain structural and functional integrity of the genome to support cellular identity and prevent malignant transformation. In this review, we present a strategic overview of epigenetic regulatory mechanisms including histone modifications and higher order chromatin organization (HCO) that are perturbed in breast cancer onset and progression. Implications for dysfunctions that occur in hormone regulation, cell cycle control, and mitotic bookmarking in breast cancer are considered, with an emphasis on epithelial-to-mesenchymal transition and cancer stem cell activities. The architectural organization of regulatory machinery is addressed within the contexts of translating cancer-compromised genomic organization to advances in breast cancer risk assessment, diagnosis, prognosis, and identification of novel therapeutic targets with high specificity and minimal off target effects.

[Clinical characteristics and influencing factors of patients with novel coronavirus pneumonia combined with liver injury in Shaanxi region].

Objective: To understand the clinical characteristics, change of liver function, influencing factors and prognosis in hospitalized patients with coronavirus disease-19 (COVID-19) combined with liver injury. Methods: The general conditions, biochemical indicators of liver, blood clotting mechanism, routine blood test, UGT1A1 * 28 gene polymorphism and other data of 40 cases with COVID-19 admitted to the isolation ward of Tangdu Hospital were retrospectively analyzed. The clinical characteristics, influencing factors and prognosis of liver injury in patients with liver injury group and those with normal liver function group were compared. The mean of two samples in univariate analysis was compared by t-test and analysis of variance. The counting data was measured by χ(2) tests. The non-normal distribution measurement data were described by the median, and the non-parametric test was used. Statistically significant influencing factors were used as the independent variables in univariate analysis. Multiple logistic regression analysis was used to analyze the main influencing factors of liver injury. Results: Of the 40 cases, 25 were male (62.5%) and 15 were female (37.5%), aged 22 to 83 (53.87 ± 15.84) years. Liver injury was occurred in 22 cases (55%) during the course of the disease. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level was initially increased (4.4 to 3.5 times of the normal value) along with decrease of albumin in the second week, and the difference was statistically significant (P < 0.001). Ten cases (43.5%) had highest abnormal total blood bilirubin (54.1 µmol/ L). There was no correlation between the increase in transaminase and the increase in total blood bilirubin (R = -0.006, P = 0.972). Three cases had prothrombin activity (PTA) of ≤50%, 10 cases had elevated FDP, and 13 cases had elevated D-dimer, all of whom were severe or critically ill. Liver function injury was more likely to occur in patients who used many types of drugs and large amounts of hormones (P = 0.002, P = 0.031), and there was no correlation with the TA6TA7 mutation in the UGT1A1 * 28 gene locus. Multiple regression analysis showed that the occurrence of liver injury was only related to critical illness. The liver function of all patients had recovered within one week after conventional liver protection treatment. Conclusion: COVID-19 combined with liver function injury may be due to the slight elevation of transaminase, mostly around the second week of the disease course. Severe patients have a higher proportion of liver injury, and critical type is an independent risk factor for liver injury.

Auranofin Activity Exposes Thioredoxin Reductase as a Viable Drug Target in Mycobacterium abscessus.

Nontuberculous mycobacteria (NTM) are highly drug-resistant, opportunistic pathogens that can cause pulmonary disease. The outcomes of the currently recommended treatment regimens are poor, especially for Mycobacterium abscessus New or repurposed drugs are direly needed. Auranofin, a gold-based antirheumatic agent, was investigated for Mycobacterium tuberculosis Here, we test auranofin against NTM in vitro and ex vivo We tested the susceptibility of 63 NTM isolates to auranofin using broth microdilution. Next, we assessed synergy between auranofin and antimycobacterial drugs using the checkerboard method and calculated the fractional inhibition concentration index (FICI). Using time-kill kinetics assays (TK), we assessed pharmacodynamics of auranofin alone and in combination with drug combinations showing the lowest FICIs for M. abscessus CIP 104536. A response surface analysis was used to assess synergistic interactions over time in TKs. Primary isolated macrophages were infected with M. abscessus and treated with auranofin. Finally, using KEGG Orthology, we looked for orthologues to auranofins drug target in M. tuberculosisM. abscessus had the lowest auranofin MIC50 (2 µg/ml) among the tested NTM. The lowest average FICIs were observed between auranofin and amikacin (0.45) and linezolid (0.50). Auranofin exhibited concentration-dependent killing of M. abscessus, with >1-log killing at concentrations of >2× MIC. Only amikacin was synergistic with auranofin according to Bliss independence. Auranofin could not lower the intracellular bacterial load in macrophages. Auranofin itself may not be feasible for M. abscessus treatment, but these data point toward a promising, unutilized drug target.