Inorganically Connecting Colloidal Nanocrystals Significantly Improves Mechanical Properties.

Understanding and characterizing the mechanical behavior of colloidal nanocrystal (NC) assemblies are important for developing nanocrystalline materials with exceptional mechanical properties for robust electronic, thermoelectric, photovoltaic, and optoelectronic devices. However, the limited ranges of Young's modulus, hardness, and fracture toughness (≲1-10 GPa, ≲50-500 MPa, and ≲10-50 kPa m1/2, respectively) in as-synthesized NC assemblies present challenges for their mechanical stability and therefore their practical applications. In this work, we demonstrate using a combination of nanoindentation measurements and coarse-grained modeling that the mechanical response of assemblies of as-synthesized NCs is governed by the van der Waals interactions of the organic surface ligands. More importantly, we report tremendous ∼60× enhancements in Young's modulus and hardness and an ∼80× enhancement in fracture toughness of CdSe NC assemblies through a simple inorganic Sn2S64- ligand exchange process. Moreover, our observation of softening in nanocrystalline materials with decreasing CdSe NC diameter is consistent with atomistic simulations.

Complete-genome sequencing and comparative genomic characterization of blaNDM-5 carrying Citrobacter freundii isolates from a patient with multiple infections.

BACKGROUND: The emergence and wide spread of carbapenemase-producing Enterobacteriaceae (CPE) poses a growing threat to global public health. However, clinically derived carbapenemase-producing Citrobacter causing multiple infections has rarely been investigated. Here we first report the isolation and comparative genomics of two blaNDM-5 carrying Citrobacter freundii (C. freundii) isolates from a patient with bloodstream and urinary tract infections. RESULTS: Antimicrobial susceptibility testing showed that both blaNDM-5 carrying C. freundii isolates were multidrug-resistant. Positive modified carbapenem inactivation method (mCIM) and EDTA-carbapenem inactivation method (eCIM) results suggested metallo-carbapenemase production. PCR and sequencing confirmed that both metallo-carbapenemase producers were blaNDM-5 positive. Genotyping and comparative genomics analyses revealed that both isolates exhibited a high level of genetic similarity. Plasmid analysis confirmed that the blaNDM-5 resistance gene is located on IncX3 plasmid with a length of 46,161 bp, and could successfully be transferred to the recipient Escherichia coli EC600 strain. A conserved structure sequence (ISAba125-IS5-blaNDM-5-trpF-IS26-umuD-ISKox3) was found in the upstream and downstream of the blaNDM-5 gene. CONCLUSIONS: The data presented in this study showed that the conjugative blaNDM-5 plasmid possesses a certain ability to horizontal transfer. The dissemination of NDM-5-producing C. freundii isolates should be of close concern in future clinical surveillance. To our knowledge, this is the first study to characterize C. freundii strains carrying the blaNDM-5 gene from one single patient with multiple infections.

Acetylcysteine increases sensitivity of ceftazidime-avibactam-resistant enterobacterales with different enzymatic resistance to ceftazidime-avibactam in vitro and in vivo.

BACKGROUND: Ceftazidime-avibactam (CZA) improves treatment outcomes for infections caused by carbapenem-resistant organisms, but has led to serious bacterial resistance. Acetylcysteine (NAC) is an approved medication that protects the respiratory tract through antioxidant and anti-inflammatory effects. RESULTS: This study found that NAC combined with CZA effectively inhibits the growth of CZA-resistant clinical Enterobacterales strains. The CZA/NAC combination inhibits biofilm formation in vitro and decreases bacterial burden in a mouse thigh infection model. The combination is biocompatible and primarily increases cell membrane permeability to cause bacterial death. CONCLUSIONS: These findings prove that the CZA/NAC combination has potential as a treatment for CZA-resistant Enterobacterales infections.

A newly isolated bacteriophage vB8388 and its synergistic effect with aminoglycosides against multi-drug resistant Klebsiella oxytoca strain FK-8388.

The bacteriophage vB8388 can lyse multi-drug resistant Klebsiella oxytoca strain FK-8388 and maintain stability in a wide range of temperatures (from 4 °C to 80 °C) and pHs (3-11). Bioinformatics analysis showed that vB8388 is a linear double-stranded DNA virus that is 39,750 long with 50.65% G + C content and 44 putative open reading frames (ORFs). Phage vB8388 belongs to the family Autographviridae and possesses a non-contractile tail. The latency period of vB8388 was approximately 20 min. The combination of phage vB8388 and gentamicin, amikacin, or tobramycin could effectively inhibit the growth of K. oxytoca strain FK-8388, with a decrease of more than 4 log units within 12 h in vitro. Phage vB8388 showed a strong synergistic effect with gentamicin that could enhance the anti-biofilm effect of vB8388. The phage + gentamicin combination also showed synergy in vivo in the larval infection model of Galleria mellonella. In conclusion, the findings of this study suggest the potential of phage + antibiotic combination therapy to be used as an alternative therapeutic approach for treating infectious diseases caused by multidrug-resistant bacteria.

Surface Phonon Polariton-Mediated Near-Field Radiative Heat Transfer at Cryogenic Temperatures.

Recent experiments, at room temperature, have shown that near-field radiative heat transfer (NFRHT) via surface phonon polaritons (SPhPs) exceeds the blackbody limit by several orders of magnitude. Yet, SPhP-mediated NFRHT at cryogenic temperatures remains experimentally unexplored. Here, we probe thermal transport in nanoscale gaps between a silica sphere and a planar silica surface from 77-300 K. These experiments reveal that cryogenic NFRHT has strong contributions from SPhPs and does not follow the T^{3} temperature (T) dependence of far-field thermal radiation. Our modeling based on fluctuational electrodynamics shows that the temperature dependence of NFRHT can be related to the confinement of heat transfer to two narrow frequency ranges and is well accounted for by a simple analytical model. These advances enable detailed NFRHT studies at cryogenic temperatures that are relevant to thermal management and solid-state cooling applications.

Nanocrystal Ordering Enhances Thermal Transport and Mechanics in Single-Domain Colloidal Nanocrystal Superlattices.

Colloidal nanocrystal (NC) assemblies are promising for optoelectronic, photovoltaic, and thermoelectric applications. However, using these materials can be challenging in actual devices because they have a limited range of thermal conductivity and elastic modulus, which results in heat dissipation and mechanical robustness challenges. Here, we report thermal transport and mechanical measurements on single-domain colloidal PbS nanocrystal superlattices (NCSLs) that have long-range order as well as measurements on nanocrystal films (NCFs) that are comparatively disordered. Over an NC diameter range of 3.0-6.1 nm, we observe that NCSLs have thermal conductivities and Young's moduli that are up to ∼3 times higher than those of the corresponding NCFs. We also find that these properties are more sensitive to NC diameter in NCSLs relative to NCFs. Our measurements and computational modeling indicate that stronger ligand-ligand interactions due to enhanced ligand interdigitation and alignment in NCSLs account for the improved thermal transport and mechanical properties.

COVID-19 pneumonia: CD8+ T and NK cells are decreased in number but compensatory increased in cytotoxic potential.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is posing a huge threat to human health worldwide. We aim to investigate the immune status of CD8+ T and NK cells in COVID-19 patients. METHODS: The count and immune status of lymphocytes were detected by flow cytometry in 32 COVID-19 patients and 18 healthy individuals. RESULTS: As the disease progression in COVID-19 patients, CD8+ T and NK cells were significantly decreased in absolute number but highly activated. After patients' condition improved, the count and immune status of CD8+ T and NK cells restored to some extent. GrA+CD8+ T and perforin+ NK cells had good sensitivity and specificity for assisting diagnosis of COVID-19. CONCLUSIONS: As the disease progression, the declined lymphocytes in COVID-19 patients might lead to compensatory activation of CD8+ T and NK cells. GrA+CD8+ T and perforin+ NK cells might be used as meaningful indicators for assisting diagnosis of COVID-19.

A Joint Symbol-Detection, Channel-Estimation and Decoding Scheme under Few-Bit ADCs in mmWave Communications.

Few-bit analog-to-digital converter (ADC) is regarded as a promising technique to greatly reduce power consumption of Internet of Things (IoT) devices in millimeter-wave (mmWave) communications. In this work, based on the recently proposed parametric bilinear generalized approximate message passing (PBiGAMP), we propose a new scheme to perform joint symbol detection, channel estimation and decoding. The proposed scheme is flexible to deal with discrete prior on symbols, Gaussian mixture prior on channels and quantized likelihood on observations. Furthermore, we introduce doping factor to control the portion of "extrinsic" and "posterior" information with negligible complexity increase. Since this joint scheme can be implemented via fast Fourier transformation (FFT), the complexity grows only logarithmically. Compared to the benchmark algorithms, numerical results show that the proposed joint scheme can achieve significant performance gain, and demonstrate the effectiveness in dealing with the nonlinear distortion from few-bit ADC.

Ligand Crosslinking Boosts Thermal Transport in Colloidal Nanocrystal Solids.

The ongoing interest in colloidal nanocrystal solids for electronic and photonic devices necessitates that their thermal-transport properties be well understood because heat dissipation frequently limits performance in these devices. Unfortunately, colloidal nanocrystal solids generally possess very low thermal conductivities. This very low thermal conductivity primarily results from the weak van der Waals interaction between the ligands of adjacent nanocrystals. We overcome this thermal-transport bottleneck by crosslinking the ligands to exchange a weak van der Waals interaction with a strong covalent bond. We obtain thermal conductivities of up to 1.7 Wm-1 K-1 that exceed prior reported values by a factor of 4. This improvement is significant because the entire range of prior reported values themselves only span a factor of 4 (i.e., 0.1-0.4 Wm-1 K-1 ). We complement our thermal-conductivity measurements with mechanical nanoindentation measurements that demonstrate ligand crosslinking increases Young's modulus and sound velocity. This increase in sound velocity is a key bridge between mechanical and thermal properties because sound velocity and thermal conductivity are linearly proportional according to kinetic theory. Control experiments with non-crosslinkable ligands, as well as transport modeling, further confirm that ligand crosslinking boosts thermal transport.

Distributed Joint Cooperative Self-Localization and Target Tracking Algorithm for Mobile Networks.

: Location information is a key issue for applications of the Internet of Things. In this paper, we focus on mobile wireless networks with moving agents and targets. The positioning process is divided into two phases based on the factor graph, i.e., a prediction phase and a joint self-location and tracking phase. In the prediction phase, we develop an adaptive prediction model by exploiting the correlation of trajectories within a short period to formulate the prediction message. In the joint positioning phase, agents calculate the cooperative messages according to variational message passing and locate themselves. Simultaneously, the average consensus algorithm is employed to realize distributed target tracking. The simulation results show that the proposed prediction model is adaptive to the random movement of nodes. The performance of the proposed joint self-location and tracking algorithm is better than the separate cooperative self-localization and tracking algorithms.

Clinical Characteristics and Correlation Analysis of Subjects with Chronic Hepatitis B Virus (HBV) Infection and Sustained Low Levels of Hepatitis B Surface Antigen (HBsAg).

BACKGROUND The aim of this study was to investigate the clinical characteristics of individuals with chronic hepatitis B virus (HBV) infection with persistent low levels of hepatitis B surface antigen (HBsAg) and to undertake a correlation analysis of the clinical characteristics. MATERIAL AND METHODS The study included 1,204 subjects with chronic HBV infection. Serum HBsAg, HBV envelope antigen (HBeAg), and HBV core antigen (HBcAg) levels were measured using the chemiluminescent microparticle immunoassay (CMIA) and the neutralization test. HBV DNA was measured using real-time fluorescence quantitative polymerase chain reaction (RT-FQ-PCR). RESULTS There were 1,023 subjects in the high-level HBsAg group (HBsAg level ≥10 IU/mL) and 181 subjects in the low-level HBsAg group (HBsAg level <10 IU/mL). In the low-level HBsAg group, the main serological pattern (93.37%) was HBsAg and HBeAg and HBcAg-positive (HBV-M2), and the asymptomatic carrier (ASC) status was 98.34%. The low-level HBsAg group had a lower HBV DNA-positive rate compared with the high-level HBsAg group (40.33% vs. 75.07%), with a normal distribution across all age groups (P>0.05). The low-level HBsAg group included an older age group. A low-level of HBsAg was positively correlated with a low level of replication of HBV DNA (r=0.452). CONCLUSIONS The findings of this study showed that individuals with chronic HBV infection and sustained low-levels of HBsAg were an older population and had a lower level of replicating HBV DNA when compared with individuals with high levels of HBsAg, and the majority (93.7%) were also HBsAg and HBeAg and HBcAg-positive.

MiR-30a-5p is induced by Wnt/ß-catenin pathway and promotes glioma cell invasion by repressing NCAM.

Wnt/ß-catenin signaling pathway is frequently dysregulated in human tumors and plays a critical role in tumorigenesis; however, the roles of microRNAs in mediating Wnt/ß-catenin pathway are not well understood. Herein, we show that miR-30a-5p is activated by Wnt/ß-catenin pathway through direct binding of ß-catenin/TCF4 to two sites in the promoter region of miR-30a-5p. We also found that miR-30a-5p represses neural cell adhesion molecule (NCAM) expression by directly targeting two sites in the 3' untranslated region (3'-UTR) of NCAM mRNA. Moreover, Wnt/ß-catenin pathway represses NCAM expression in glioma cells, which depends on miR-30a-5p. Finally, we found that miR-30a-5p promotes glioma cell growth invasion by repressing NCAM. Our findings demonstrate a novel Wnt/ß-catenin-miR-30a-5p-NCAM regulatory axis which plays important roles in controlling glioma cell invasion and tumorigenesis.

[Association of polymorphism in the promoter region of PCA3 gene with risk of prosate cancer].

OBJECTIVE: To investigate the polymorphism in the promoter region of PCA3 gene and its relationship with risk of prostate cancer (PCa). METHODS: The promoter region of PCA3 gene of the DNA of peripheral blood mononuclear cells was detected by sequence analysis in the 186 PCa and 141 BPH patients and 135 healthy control individuals. If the samples were detected with polymorphism of insection/deletion, clone sequence analysis was used with pBS-T carrier to verify it. RESULTS: There were 5 polymorphisms. TAAA repeat times: 4, 5, 6, 7, 8, and 8 genotypes (TAAA 4/5, TAAA 4/6, TAAA 5/5, TAAA 5/6, TAAA 5/7, TAAA 5/8, TAAA 6/6, and TAAA 6/7) were detected in the promoter region of PCA3 gene. The eight genotypes were divided into three groups: ≤10TAAA, 11TAAA, ≥12TAAA. Unconditional logistic regression analysis models were used to analyze the relationship between different genotypes and cancer risks adjusted by sex and age. The type 11TAAA and ≥12TAAA was associated with higher relative risk for prostate cancer than the group ≤10TAAA [OR=1.74, 95% CI=1.06-2.87 (for type 11TAAA); OR=5.63, 95% CI=1.85-17.19 (for type ≥12TAAA)]. In the 186 PCa patients, there was 62.4% allele of PCA3 gene with AG/CA mutation found in the promoter 18-19 bp region of PCA3 gene and it had a close relation with the development of prostate cancer. CONCLUSIONS: Short tandem repeats are found in the promoter region of the PCA3 gene in PCa patients, and the increase of TAAA repeat sequences highly enhance the relative risk of prostate cancer development. The occurrence of such STR might be related to the mutations in their upstream loci.

[Tumor angiogenesis promoted by fusion of glioma stem/progenitor cells with bone marrow mesenchymal stem cells].

OBJECTIVE: The aim of this study was to clarify whether the fusion of bone marrow mesenchymal stem cells (MSCs) with tumor cells can promote tumor angiogensis. METHODS: Human glioma stem/progenitor cells (GSPCs) (SU3 cells) were transfected with red fluorescent protein (RFP) gene. Bone marrow mesenchymal stem cells (MSCs) were harvested from nude mice with whole-body green fluorescent protein (GFP) gene expression. Then the two kinds of cells were co-cultured in vitro. At the same time SU3-RFP was transplanted into the brain of GFP-expressing nude mice to establish xenograft tumors. The co-cultured cells, GFP/RFP double positive (yellow) cells and blood vessels obtained from the xenograft tumors were observed under fluorescent microscope and laser scanning confocal microscope. RESULTS: After five passages in vitro, MSCs maintained the proliferative activity and highly expressed CD105. CD105 was also expressed in the femurs of GFP-expressing nude mice, tumor cells, blood vessels of SU3 xenograft tumors, and clinical malignant gliomas. When MSCs were co-cultured with SU3-RFP, the ratio of yellow cells co-expressing RFP and GFP was significantly increased after extended time and continuous passages. According to the flow cytometry, yellow cells co-expressing RFP and GFP were 83.7% of the cultured cells. In tissue slices of the xenograft tumors, bundles of yellow vessel-like structure and cross-sectioned yellow vascular wall structures including vascular wall stroma cells were observed with RFP and GFP expression, and were identified as de novo formed vessels derived from fusion of MSCs with SU3-RFP cells. CONCLUSION: Cell fusion occurs between tumor cells and host MSCs and it promotes tumor angiogenesis.

Long noncoding RNA PCA3 gene promoter region is related to the risk of prostate cancer on Chinese males.

INTRODUCTION: Long noncoding RNA prostate cancer gene antigen 3 (PCA3) is one of the most prostate cancer-specific genes at present. Consequently, the prostate-specific expression and the sharp up-regulation of PCA3 RNA in prostate cancer suggest a unique transcriptional regulation, which possibly can be attributed to promoter polymorphism. In this study, we investigated a short tandem repeat (STR) polymorphism of TAAA in the promoter region of PCA3 gene found in our previous study in prostate cancer (PCa) patients and benign prostatic hypertrophy (BPH) patients, aiming to evaluate the association between the STR and increased risk for PCa. MATERIAL AND METHODS: 120 PCa cases and 120 benign prostatic hypertrophy (BPH) cases were identified among participants. The region encompassing the TAAA repeat was amplified with a specific primer set we designed and screened by PCR-based cloning and sequencing in paired peripheral blood leukocytes and prostate tissues. Genotype-specific risks were estimated as odds ratios (ORs) associated with 95% confidence intervals (CIs) and adjusted for age by means of unconditional logistic regression. RESULTS: 5 PCA3 TAAA STR polymorphisms and 8 genotypes were found in both peripheral blood leukocytes and prostate tissues, the carriers with more TAAA repeats were associated with increased risk for PCa than individuals having less TAAA repeats. Interestingly, 18 (15.0%) of 120 PCa patients had more (TAAA)n repeats in prostate tissues than that in peripheral blood leukocytes, and 3 (2.5%) of 120 had less (TAAA)n repeats in prostate tissues. CONCLUSIONS: The results of this study suggest that short tandem repeat polymorphism of TAAA in the promoter region of PCA3 gene is a risk-increasing factor for prostate cancer in the Chinese population. In addition to the hereditary factor, the insertion mutation of (TAAA)n in a local tissue maybe another mechanism of the onset of PCa.

[Malignant transformation of glioma stromal cells induced by glioma stem cells heterotopically inoculated in host liver].

OBJECTIVE: Tumor stromal cells have the potential of undergoing malignant transformation induced by glioma stem cells (GSCs) in orthotopic glioma model. The purpose of this study was to explore whether malignant transformation of tumor stromal cells induced by GSCs is dependent on specific local microenvironment. METHODS: Human glioma stem/progenitor cell line SU3 transfected with red fluorescent protein (SU3-RFP) gene were implanted into the liver of nude mice with whole-body expressing green fluorescence protein (GFP). Then hepatic tumors were harvested to prepare single cell suspension and analyzed with routine pathological examinations. GFP cells with high proliferative abilities were obtained from the cultivation of single cell suspension. Immortalized glioma stromal cells only expressing GFP and double expressing GFP/RFP were further monocloned with micro-pipetting techniques and under continuous passages. Cell phenotypic analysis and tumorigenicity tests were also performed. RESULTS: SU3-RFP was transplanted into liver with a tumor formation rate of 83%. Immortalized glioma stromal cells were obtained from re-cultured xenograft tumor tissue. Three monoclonal cell lines B4, B9, B10 were established and proved to be host-derived cells. B4 was found to be a fusion cell co-expressing GFP/RFP and dendritic cell markers CD1 a, CD83 and CD86. Both B9 and B10 were GFP⁺ cells. B9 expressed macrophage markers CD68 and F4/80 while B10 produced fibroblast marker proteins FAP-α, α-SMA and S100. Three cells were all aneuploid with a tumorigenicity rate of 100% in nude mice. CONCLUSION: Tumor stromal cells have the potential of malignant transformation in a heterotopic xenograft glioma model. Malignant transformation may also occur outside the central nervous system and contribute to tumor heterogeneity. Further studies are warranted for elucidating the relationship between tumorigenesis, evolution and tumor microenvironment.

Antiparasitic nitazoxanide potentiates colistin against colistin-resistant Acinetobacter baumannii and Escherichia coli in vitro and in vivo.

IMPORTANCE: Colistin is used as a last resort in many infections caused by multidrug-resistant Gram-negative bacteria; however, colistin-resistant (COL-R) is on the rise. Hence, it is critical to develop new antimicrobial strategies to overcome COL-R. We found that nitazoxanide (NTZ) combined with colistin showed notable synergetic antibacterial activity. These findings suggest that the NTZ/colistin combination may provide an effective alternative route to combat COL-R A. baumannii and COL-R Escherichia coli infections.

Plumbagin enhances antimicrobial and anti-biofilm capacities of chlorhexidine against clinical Klebsiella pneumoniae while reducing resistance mutations.

With the widespread misuse of disinfectants, the clinical susceptibility of Klebsiella pneumoniae (K. pneumoniae) to chlorhexidine (CHX) has gradually diminished, posing significant challenges to clinical disinfection and infection control. K. pneumoniae employs overexpression of efflux pumps and the formation of thick biofilms to evade the lethal effects of CHX. Plumbagin (PLU) is a natural plant extract that enhances membrane permeability and reduces proton motive force. In this study, we elucidated the synergistic antimicrobial activity of PLU in combination with CHX, effectively reducing the MIC of CHX against K. pneumoniae to 1 µg/mL and below. Crucially, through crystal violet staining and confocal laser scanning microscopy live/dead staining, we discovered that PLU significantly enhances the anti-biofilm capability of CHX. Mechanistically, experiments involving membrane permeability, alkaline phosphatase leakage, reactive oxygen species, and RT-qPCR suggest that the combination of PLU and CHX improves the permeability of bacterial inner and outer membranes, promotes bacterial oxidative stress, and inhibits oqxA/B efflux pump expression. Furthermore, we conducted surface disinfection experiments on medical instruments to simulate clinical environments, demonstrating that the combination effectively reduces bacterial loads by more than 3 log10 CFU/mL. Additionally, results from resistance mutation frequency experiments indicate that combined treatment reduces the generation of resistant mutants within the bacterial population. In summary, PLU can serve as an adjuvant, enhancing the anti-biofilm capability of CHX and reducing the occurrence of resistance mutations, thereby extending the lifespan of CHX.IMPORTANCEAs disinfectants are extensively and excessively utilized worldwide, clinical pathogens are progressively acquiring resistance against these substances. However, high concentrations of disinfectants can lead to cross-resistance to antibiotics, and concurrent use of different disinfectants can promote bacterial resistance mutations and facilitate the horizontal transfer of resistance genes, which poses significant challenges for clinical treatment. Compared with the lengthy process of developing new disinfectants, enhancing the effectiveness of existing disinfectants with natural plant extracts is important and meaningful. CHX is particularly common and widely used compared with other disinfectants. Meanwhile, Klebsiella pneumoniae, as a clinically significant pathogen, exhibits high rates of resistance and pathogenicity. Previous studies and our data indicate a significant decrease in the sensitivity of clinical K. pneumoniae to CHX, highlighting the urgent need for novel strategies to address this issue. In light of this, our research is meaningful.

A novel transposon Tn7540 carrying blaNDM-9 and fosA3 in chromosome of a pathogenic multidrug-resistant Salmonella enterica serovar Indiana isolated from human faeces.

OBJECTIVES: Emergence of multidrug-resistant (MDR) Salmonella enterica serovar Indiana has raised global concern. Mobile genetic elements (MGEs) play vital roles in accelerating the dissemination of resistance genes in bacteria communities. The study aims to improve our understanding of the underlying resistance mechanisms and characterize the MGEs in a MDR S. Indiana isolate. METHODS: Here, we report the characteristics of a MDR pathogenic S. Indiana isolate. The antimicrobial susceptibility pattern of S. Indiana QT6365 was determined. The genomic structure of the chromosome and the plasmid, serotype, and multi-locus sequence type were analysed by whole genome sequencing. The circular form derived from IS26-flanked transposon was confirmed by reverse polymerase chain reaction and sequencing. RESULTS: S. Indiana QT6365 exhibited resistance to all tested antimicrobials except for aztreonam, amikacin, polymyxin, and tigecycline, was defined as MDR, and belonged to ST17. S. Indiana QT6365 was closely related with food resource S. Indiana C629 with similar resistance gene profiles. Multiple resistance genes are mainly carried by a novel transposon Tn7540 located on the chromosome and an IncHI2/HI2A/N plasmid. Sequence analysis and the formed circular intermediate suggested Tn7540 might be generated through homologous recombination by IS26-bounded translocatable units (IS26-fosA-IS26-intI1-dfrA12-aadA2-sul1-ISCR1-blaNDM-9-IS26). CONCLUSIONS: To the best of our knowledge, this is the first report of the novel chromosomal transposon possessing blaNDM-9 and fosA3 in S. Indiana isolated from human specimen, which might facilitate the dissemination of resistance genes and should arouse serious awareness.

Heterogenous profiles between primary lung cancers and paired brain metastases reveal tumor evolution.

Background: Brain metastases (BMs) are the most common central nervous system (CNS) malignant tumors, with rapid disease progression and extremely poor prognosis. The heterogeneity between primary lung cancers and BMs leads to the divergent efficacy of the adjuvant therapy response to primary tumors and BMs. However, the extent of heterogeneity between primary lung cancers and BMs, and the evolutionary process remains little known. Methods: To deeply insight into the extent of inter-tumor heterogeneity at a single-patient level and the process of these evolutions, we retrospectively analyzed a total of 26 tumor samples from 10 patients with matched primary lung cancers and BMs. One patient underwent four times brain metastatic lesion surgery with diverse locations and one operation for the primary lesion. The genomic and immune heterogeneity between primary lung cancers and BMs were evaluated by utilizing whole-exome sequencing (WESeq) and immunohistochemical analysis. Results: In addition to inheriting genomic phenotype and molecular phenotype from the primary lung cancers, massive unique genomic phenotype and molecular phenotype were also observed in BMs, which revealed unimaginable complexity of tumor evolution and extensive heterogeneity among lesions at a single-patient level. By analysis of a multi-metastases case (Case 3) of cancer cells' subclonal composition, we found similar multiple subclonal clusters in the four spatial and temporal isolated brain metastatic focus, with the characteristics of polyclonal dissemination. Our study also verified that the expression level of immune checkpoints-related molecule Programmed Death-Ligand 1 (PD-L1) (P = 0.0002) and the density of tumor-infiltrating lymphocytes (TILs) (P = 0.0248) in BMs were significantly lower than that in paired primary lung cancers. Additionally, tumor microvascular density (MVD) also differed between primary tumors and paired BMs, indicating that temporal and spatial diversity profoundly contributes to the evolution of BMs heterogeneity. Conclusion: Our study revealed the significance of temporal and spatial factors to the evolution of tumor heterogeneity by multi-dimensional analysis of matched primary lung cancers and BMs, which also provided novel insight for formulating individualized treatment strategies for BMs.