Emergence of carbapenem-resistant Klebsiella pneumoniae species complex from agrifood systems: detection of ST6326 co-producing KPC-2 and NDM-1.

BACKGROUND: Klebsiella pneumoniae species complex (KpSC) is an important disseminator of carbapenemase-encoding genes, mainly blaKPC-2 and blaNDM-1, from hospitals to the environment. Consequently, carbapenem-resistant strains can be spread through the agrifood system, raising concerns about food safety. This study therefore aimed to isolate carbapenem-resistant KpSC strains from the agricultural and environmental sectors and characterize them using phenotypic, molecular, and genomic analyses. RESULTS: Klebsiella pneumoniae and Klebsiella quasipneumoniae strains isolated from soils used for lemon, guava, and fig cultivation, and from surface waters, displayed an extensive drug-resistance profile and carried blaKPC-2, blaNDM-1, or both. In addition to carbapenemase-encoding genes, KpSC strains harbor a broad resistome (antimicrobial resistance and metal tolerance) and present putative hypervirulence. Soil-derived K. pneumoniae strains were assigned as high-risk clones (ST11 and ST307) and harbored the blaKPC-2 gene associated with Tn4401b and Tn3-like elements on IncN-pST15 and IncX5 plasmids. In surface waters, the coexistence of blaKPC-2 and blaNDM-1 genes was identified in K. pneumoniae ST6326, a new carbapenem-resistant regional Brazilian clone. In this case, blaKPC-2 with Tn4401a isoform and blaNDM-1 associated with a Tn125-like transposon were located on different plasmids. Klebsiella quasipneumoniae ST526 also presented the blaNDM-1 gene associated with a Tn3000 transposon on an IncX3 plasmid. CONCLUSION: These findings provide a warning regarding the transmission of carbapenemase-positive KpSC across the agricultural and environmental sectors, raising critical food safety and environmental issues. © 2024 Society of Chemical Industry.

Genetic diversity of KPC-2-producing Klebsiella pneumoniae complex from aquatic ecosystems.

During the COVID-19 pandemic, the occurrence of carbapenem-resistant Klebsiella pneumoniae increased in human clinical settings worldwide. Impacted by this increase, international high-risk clones harboring carbapenemase-encoding genes have been circulating in different sources, including the environment. The blaKPC gene is the most commonly disseminated carbapenemase-encoding gene worldwide, whose transmission is carried out by different mobile genetic elements. In this study, blaKPC-2-positive Klebsiella pneumoniae complex strains were isolated from different anthropogenically affected aquatic ecosystems and characterized using phenotypic, molecular, and genomic methods. K. pneumoniae complex strains exhibited multidrug-resistant and extensively drug-resistant profiles, spotlighting the resistance to carbapenems, ceftazidime-avibactam, colistin, and tigecycline, which are recognized as last-line antimicrobial treatment options. Molecular analysis showed the presence of several antimicrobial resistance, virulence, and metal tolerance genes. In-depth analysis showed that the blaKPC-2 gene was associated with three different Tn4401 isoforms (i.e., Tn4401a, Tn4401b, and Tn4401i) and NTEKPC elements. Different plasmid replicons were detected and a conjugative IncN-pST15 plasmid harboring the blaKPC-2 gene associated with Tn4401i was highlighted. K. pneumoniae complex strains belonging to international high-risk (e.g., ST11 and ST340) and unusual clones (e.g., ST323, ST526, and ST4216) previously linked to clinical settings. In this context, some clones were reported for the first time in the environmental sector. Therefore, these findings evidence the occurrence of carbapenemase-producing K. pneumoniae complex strains in aquatic ecosystems and contribute to the monitoring of carbapenem resistance worldwide.

Phase 2 study of ibrutinib in classic and variant hairy cell leukemia.

Hairy cell leukemia (HCL) is a rare B-cell malignancy, and there is a need for novel treatments for patients who do not benefit from purine analogs. Ibrutinib, an oral agent targeting Bruton tyrosine kinase in the B-cell receptor signaling pathway, is highly effective in several malignancies. Its activity in HCL was unknown, so we conducted a multisite phase 2 study of oral ibrutinib in patients with either relapsed classic or variant hairy cell leukemia. The primary outcome measure was the overall response rate (ORR) at 32 weeks, and we also assessed response at 48 weeks and best response during treatment. Key secondary objectives were characterization of toxicity and determination of progression-free survival (PFS) and overall survival (OS). Thirty-seven patients were enrolled at 2 different doses (24 at 420 mg, 13 at 840 mg). The median duration of follow-up was 3.5 years (range, 0-5.9 years). The ORR at 32 weeks was 24%, which increased to 36% at 48 weeks. The best ORR was 54%. The estimated 36-month PFS was 73% and OS was 85%. The most frequent adverse events were diarrhea (59%), fatigue (54%), myalgia (54%), and nausea (51%). Hematologic adverse events were common: anemia (43%), thrombocytopenia (41%), and neutropenia (35%). Ibrutinib can be safely administered to patients with HCL with objective responses and results in prolonged disease control. Although the initial primary outcome objective of the study was not met, the observation of objective responses in heavily pretreated patients coupled with a favorable PFS suggests that ibrutinib may be beneficial in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01841723.

Occupational allergic diseases among harvesting fishermen on the open sea: A systematic review.

BACKGROUND: Nearly 60 million people work in the fishing and aquaculture sectors worldwide and are exposed to specific allergens. Some reviews have been published in occupational allergic diseases in seafood workers but none in fishermen. OBJECTIVE: To describe the morbidity and main causal agents of allergic diseases among harvesting fishermen. METHODS: A protocol with predefined objectives and inclusion criteria was used in accord with the Preferred Items for Reporting Systematic Reviews and Meta-analyses-Protocols statement. Population was defined as harvesting fishermen, and the conditions of interest were allergic pulmonary diseases, occupational allergic rhinitis, and allergic dermatologic disease. A literature search was carried out in EMBASE, MEDLINE, Web of Science, and PASCAL databases. After the title-abstract and full-text selection of eligible studies, data were extracted and synthesized qualitatively. RESULTS: A total of 25 studies were selected, 15 articles on occupational asthma (OA) and 10 on dermatologic diseases. Most studies were case reports and case series from European countries. Most OAs were sensitizer induced, with common crab, Anisakis simplex, red soft coral, and cuttlefish as causal agents. Irritant-induced OA because of metabisulfites was also described. Occupational eczema caused by bryozoans was the most common of the cases among fishermen working in the North Sea and the Channel. CONCLUSION: Occupational allergic diseases in harvesting fishermen are described in well-resourced countries, but there are few studies from countries with a high number of fishermen, such as in Asia, and these mostly include immunoglobulin E-mediated diseases. The presence of the healthy worker effect is probable. Atmospheric allergen concentration is a major risk factor for OA. Specific conditions, including cold air, fish-juice contact, and salt-water contact, are other risk factors. There is a need to investigate occupational allergic disease in all countries and develop specific studies in fishermen.

Integrative clinical genomics of metastatic cancer.

Metastasis is the primary cause of cancer-related deaths. Although The Cancer Genome Atlas has sequenced primary tumour types obtained from surgical resections, much less comprehensive molecular analysis is available from clinically acquired metastatic cancers. Here we perform whole-exome and -transcriptome sequencing of 500 adult patients with metastatic solid tumours of diverse lineage and biopsy site. The most prevalent genes somatically altered in metastatic cancer included TP53, CDKN2A, PTEN, PIK3CA, and RB1. Putative pathogenic germline variants were present in 12.2% of cases of which 75% were related to defects in DNA repair. RNA sequencing complemented DNA sequencing to identify gene fusions, pathway activation, and immune profiling. Our results show that integrative sequence analysis provides a clinically relevant, multi-dimensional view of the complex molecular landscape and microenvironment of metastatic cancers.

Patterns of antimicrobial resistance and metal tolerance in environmental Pseudomonas aeruginosa isolates and the genomic characterization of the rare O6/ST900 clone.

Pseudomonas aeruginosa can harbor several virulence and antimicrobial resistance genes (ARGs). In this regard, virulent and multidrug-resistant (MDR) P. aeruginosa strains are closely related to severe infections. In addition, this species can also carry metal tolerance genes, selecting mainly antimicrobial-resistant strains. The action of several pollutants on the environment may favor the occurrence of antimicrobial-resistant and metal-tolerant strains. Therefore, the aim of this study was to characterize potentially pathogenic, antimicrobial-resistant, and/or metal-tolerant P. aeruginosa isolates from different environmental samples (waters, soils, sediments, or sands) and to perform a whole-genome sequence-based analysis of a rare clone from residual water. Environmental isolates carried virulence genes related to adherence, invasion, and toxin production, and 79% of the isolates harbored at least five virulence genes. In addition, the isolates were resistant to different antimicrobials, including important antipseudomonal agents, and 51% of them were classified as MDR, but only ARGs associated with aminoglycoside resistance were found. Furthermore, some isolates were tolerant mainly to copper, cadmium, and zinc, and presented metal tolerance genes related to these compounds. Whole-genome characterization of an isolate with unique phenotype with simultaneous resistance to antimicrobials and metals showed nonsynonymous mutations in different antimicrobial resistance determinants and revealed a classification of O6/ST900 clone as rare, potentially pathogenic, and predisposed to acquire multidrug resistance genes. Therefore, these results draw attention to the dissemination of potentially pathogenic, antimicrobial-resistant, and metal-tolerant P. aeruginosa isolates in environmental niches, alerting to a potential risk mainly to human health.

Ultrasonography of Superficial Soft-Tissue Masses: Society of Radiologists in Ultrasound Consensus Conference Statement.

The Society of Radiologists in Ultrasound convened a panel of specialists from radiology, orthopedic surgery, and pathology to arrive at a consensus regarding the management of superficial soft-tissue masses imaged with US. The recommendations in this statement are based on analysis of current literature and common practice strategies. This statement reviews and illustrates the US features of common superficial soft-tissue lesions that may manifest as a soft-tissue mass and suggests guidelines for subsequent management.

PRAME expression in spindle cell melanoma, malignant peripheral nerve sheath tumour, and other cutaneous sarcomatoid neoplasms: a comparative analysis.

Diagnosis of spindle cell/sarcomatoid melanoma may be challenging due to frequent loss of expression of melanocytic marker(s) and histomorphologic resemblance to various mesenchymal tumours, particularly malignant peripheral nerve sheath tumour (MPNST). Overexpression of PReferentially expressed Antigen in MElanoma (PRAME) supports a diagnosis of melanoma when evaluating challenging melanocytic tumours. PRAME expression in MPNST and other cutaneous sarcomatoid neoplasms, however, has not been well characterised. We aimed to determine the utility of PRAME immunostain in distinguishing spindle cell melanoma from MPNST and other sarcomatoid mimics. PRAME expression was scored by extent (0 to 4+) and intensity (0 to 3) of staining. A strong positive correlation was observed between the extent and intensity scores (r = 0.84). An extent score of 4+, defined by staining in 76-100% of tumour cells, was seen in 56% (23/41) of spindle cell melanomas, 18% (7/38) of MPNSTs, 15% (4/27) of cutaneous sarcomatoid squamous cell carcinomas (SCCs), 33% (5/15) of poorly differentiated cutaneous angiosarcomas, 12% (4/33) of atypical fibroxanthomas (AFXs), 4% (1/25) of pleomorphic dermal sarcomas (PDSs), and none (0/16) of the high-grade cutaneous leiomyosarcomas. A significant difference was found between spindle cell melanoma and all other examined sarcomatoid neoplasms except angiosarcoma. While diffuse (and often strong) PRAME expression is more frequently observed in spindle cell melanoma than MPNST, sarcomatoid SCC, AFX, PDS, and high-grade leiomyosarcoma, its limited sensitivity and specificity caution against its use as a standalone diagnostic marker. PRAME may complement other epigenetic or lineage-specific markers and should only be used as part of an immunohistochemical panel when evaluating these sarcomatoid neoplasms.

Imaging Characteristics of the Proximal Lateral Collateral Ligament of the Knee: Findings on Ultrasound and MRI With Histologic Correlation.

OBJECTIVES: Determine prevalence of increased signal intensity of the lateral collateral ligament (LCL) of the knee on MRI and decreased echogenicity on ultrasound, and compare with cadaveric histologic evaluation. METHODS: After IRB approval of this prospective study with informed consent, patients having knee MRI were additionally evaluated with ultrasound. Signal intensities of LCL on MRI (low, intermediate, high), echogenicity at ultrasound (hyperechoic, hypoechoic, anechoic), and extent of findings were assessed. Descriptive statistics, Wilcoxon signed ranked test, and intraclass correlation coefficient (ICC) were calculated. Two cadaveric knees were imaged with MRI and ultrasound, including histologic LCL evaluation. RESULTS: Seventy-three subjects were included (39 males, 34 females; mean age 48 ± 14 years) with 77 knee examinations. On MRI, low, intermediate, and high signals were present in 21% (16/77), 75% (58/77), and 4% (3/77), respectively. On ultrasound, echogenicity was assessed as hyperechoic, hypoechoic, and anechoic in 62% (48/77), 38% (29/77), and 0% (0/77), respectively. Mean length of increased signal was 8.6 mm (±4.9) on MRI, and 6.5 mm (±4.8) on ultrasound. The ICC showed a good to excellent intermodality reliability (0.735-0.899) without statistically significant difference for interreader measurements (P = .163-.795). Histology evaluation showed transition of ligament fibers to fibrocartilage at its insertion with increased connective tissue mucin corresponding to MRI and ultrasound findings. CONCLUSIONS: Increased signal intensity of the proximal LCL on ultrasound and MRI is common and corresponds to normal connective tissue mucin.

Ultrasound of myxofibrosarcoma.

The ultrasound appearance of myxofibrosarcoma is highly variable corresponding to its variable and at times heterogeneous histopathologic appearance. Myxofibrosarcomas may mimic a benign process and the infiltrative tumor margins may be difficult to precisely delineate on ultrasound imaging. These tumor characteristics pose a diagnostic challenge on ultrasound evaluation. The radiologist should be aware of the variable morphologic presentation and infiltrative nature of myxofibrosarcoma and the limitations of ultrasound in the initial diagnosis, biopsy guidance, and post-surgical follow-up of this tumor.

Occurrence of clinically relevant antimicrobial resistance genes, including mcr-3 and mcr-7.1, in soil and water from a recreation club.

We researched clinically relevant antimicrobial resistance genes (ARGs) and mobile genetic elements (MGEs) in environmental samples from a recreation club in Brazil. A total of 172 amplicons (105 from soil and 67 from water) of 26 ARGs (20 among the soil and water samples; four only in soil samples; two only in water samples) were detected. Nine MGEs were detected, including plasmids and class 1 integron. The absolute abundance of the mcr-3 gene ranged from 1.12 × 102 to 1.81 × 103 copies/mL-1 in water samples. The rapid spread of mcr-like genes in several sources has generated a huge concern to public health. Accordingly, understanding of antimicrobial resistance, carry out surveillance studies may contribute to tackle antimicrobial resistance. As the environmental samples were collected from a popular recreation club in Brazil, this study points out to the risk and exposure to clinically relevant ARGs, especially to mcr-3 and mcr-7.1 genes.

YAP1-TFE3-fused hemangioendothelioma: a multi-institutional clinicopathologic study of 24 genetically-confirmed cases.

YAP1-TFE3-fused hemangioendothelioma is an extremely rare malignant vascular tumor. We present the largest multi-institutional clinicopathologic study of YAP1-TFE3-fused hemangioendothelioma to date. The 24 cases of YAP1-TFE3-fused hemangioendothelioma showed a female predominance (17 female, 7 male) across a wide age range (20-78 years old, median 44). Tumors were most commonly located in soft tissue (50%), followed by bone (29%), lung (13%), and liver (8%), ranging from 3 to 115 mm in size (median 40 mm). About two-thirds presented with multifocal disease, including 7 cases with distant organ metastasis. Histopathologically, we describe three dominant architectural patterns: solid sheets of coalescing nests, pseudoalveolar and (pseudo)vasoformative pattern, and discohesive strands and clusters of cells set in a myxoid to myxohyaline stroma. These patterns were present in variable proportions across different tumors and often coexisted within the same tumor. The dominant cytomorphology (88%) was large epithelioid cells with abundant, glassy eosinophilic to vacuolated cytoplasm, prominent nucleoli and well-demarcated cell borders. Multinucleated or binucleated cells, prominent admixed erythrocytic and lymphocytic infiltrates, and intratumoral fat were frequently present. Immunohistochemically, ERG, CD31, and TFE3 were consistently expressed, while expression of CD34 (83%) and cytokeratin AE1/AE3 (20%) was variable. CAMTA1 was negative in all but one case. All cases were confirmed by molecular testing to harbor YAP1-TFE3 gene fusions: majority with YAP1 exon 1 fused to TFE3 exon 4 (88%), or less commonly, TFE3 exon 6 (12%). Most patients (88%) were treated with primary surgical resection. Over a follow-up period of 4-360 months (median 36 months) in 17 cases, 35% of patients remained alive without disease, and 47% survived many years with stable, albeit multifocal and/or metastatic disease. Five-year progression-free survival probability was 88%. We propose categorizing YAP1-TFE3-fused hemangioendothelioma as a distinct disease entity given its unique clinical and histopathologic characteristics in comparison to conventional epithelioid hemangioendothelioma.

Olfactory subsystems in the peripheral olfactory organ of anuran amphibians.

Anuran amphibians (frogs and toads) typically have a complex life cycle, involving aquatic larvae that metamorphose to semi-terrestrial juveniles and adults. However, the anuran olfactory system is best known in Xenopus laevis, an animal with secondarily aquatic adults. The larval olfactory organ contains two distinct sensory epithelia: the olfactory epithelium (OE) and vomeronasal organ (VNO). The adult organ contains three: the OE, the VNO, and a "middle cavity" epithelium (MCE), each in its own chamber. The sensory epithelia of Xenopus larvae have overlapping sensory neuron morphology (ciliated or microvillus) and olfactory receptor gene expression. The MCE of adults closely resembles the OE of larvae, and senses waterborne odorants; the adult OE is distinct and senses airborne odorants. Olfactory subsystems in other (non-pipid) anurans are diverse. Many anuran larvae show a patch of olfactory epithelium exposed in the buccal cavity (bOE), associated with a grazing feeding mode. And other anuran adults do not have a sensory MCE, but many have a distinct patch of epithelium adjacent to the OE, the recessus olfactorius (RO), which senses waterborne odorants. Olfaction plays a wide variety of roles in the life of larval and adult anurans, and some progress has been made in identifying relevant odorants, including pheromones and feeding cues. Increased knowledge of the diversity of olfactory structure, of odorant receptor expression patterns, and of factors that affect the access of odorants to sensory epithelia will enable us to better understand the adaptation of the anuran olfactory system to aquatic and terrestrial environments.

Transducin ß-like protein 1 controls multiple oncogenic networks in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common Non-Hodgkin's lymphoma and is characterized by a remarkable heterogeneity with diverse variants that can be identified histologically and molecularly. Large-scale gene expression profiling studies have identified the germinal center B-cell (GCB-) and activated B-cell (ABC-) subtypes. Standard chemo-immunotherapy remains standard front line therapy, curing approximately two thirds of patients. Patients with refractory disease or those who relapse after salvage treatment have an overall poor prognosis highlighting the need for novel therapeutic strategies. Transducin ß-like protein 1 (TBL1) is an exchange adaptor protein encoded by the TBL1X gene and known to function as a master regulator of the Wnt signalling pathway by binding to ß-CATENIN and promoting its downstream transcriptional program. Here, we show that, unlike normal B-cells, DLBCL cells express abundant levels of TBL1 and its overexpression correlates with poor clinical outcome regardless of DLBCL molecular subtype. Genetic deletion of TBL1 and pharmacological approach using tegavivint, a first-in-class small molecule targeting TBL1 (Iterion Therapeutics), promotes DLBCL cell death in vitro and in vivo. Through an integrated genomic, biochemical, and pharmacologic analyses, we characterized a novel, ß-CATENIN independent, post-transcriptional oncogenic function of TBL1 in DLBCL where TBL1 modulates the stability of key oncogenic proteins such as PLK1, MYC, and the autophagy regulatory protein BECLIN-1 through its interaction with a SKP1-CUL1-F-box (SCF) protein supercomplex. Collectively, our data provide the rationale for targeting TBL1 as a novel therapeutic strategy in DLBCL.

Too afraid to vote? The effects of COVID-19 on voting behaviour.

This paper studies the causal effect of local exposure to COVID-19 on voting behaviour and electoral outcomes using evidence from the regional elections held in Spain on 12 July 2020. Exploiting the variation in exposure to COVID-19 and using a difference-in-differences identification strategy, we show that turnout was between 2.6 and 5.1 percentage points lower in municipalities that experienced positive cases of COVID-19. In addition, the results show a substantial increase in the probability of voting for nationalist parties. We discuss the idea of perceived fear being the potential mechanism driving our results.

[Smell and care: from professionalism to emotions]. / Odeurs et soins, du professionnalisme aux émotions.

The sense of smell presents itself to us as a means of forging an opinion of a situation, sending us back to our memories and giving us a form of knowledge of the patient. In addition, besides the obvious repulsion that certain wounds can engender, the sense of smell can also, conversely, lead us into an eroticization of care.

[Impact of the Covid-19 pandemic on the health of nurses in a university hospital]. / Impact de la pandémie de Covid-19 sur la santé des infirmiers d'un CHU.

In a university hospital in Brittany, health monitoring of the staff was set up at the beginning of the Covid-19 pandemic. The first results of the studies carried out in this context showed that nurses showed a greater deterioration of their physical health than other professionals. However, thanks to psychological balancing measures, nurses did not appear to be more affected in terms of psychological health and well-being at work than the other hospital workers.

Co-occurrence of mcr-1, mcr-3, mcr-7 and clinically relevant antimicrobial resistance genes in environmental and fecal samples.

Multidrug-resistant bacteria harboring different antimicrobial resistance genes (ARGs) have been detected worldwide. The association of plasmid-mediated colistin resistance genes (mcr-like) and other ARGs in bacteria isolated from animals is a huge concern worldwide. Therefore, this study aimed to investigate the presence of mcr-like genes and clinically relevant ARGs as well as plasmids in samples from a zoo. Fecal and environmental (soil and water) samples were collected from a zoo and the DNA of cultivable aerobic bacteria was extracted. ARGs were screened by PCR and the plasmids were detected using the PCR-based replicon typing method. A total of 74 amplicons from 27 ARGs [mcr-1, mcr-3, mcr-7.1, blaCTX-M-Gp1, blaCTX-M-Gp2, blaCTX-M-Gp9, blaVEB, blaPER, blaCMY, tetA, tetB, tetC, aadA, aac(6')-Ib, aph(3')-Ia, ant(2'')-Ia, qnrA, qnrB, qnrS, oqxA, oqxB, sul1, sul2, sul3, cmlA, mefAE, ermB] and 21 amplicons from eight plasmid families (IncY, ColE-like, IncFrepB, IncFIA, IncFIB, IncHI1, IncFIC, IncP) were detected. These findings reinforce that the zoo acts as a reservoir of clinically relevant ARGs, including mcr-like, and call attention to the monitoring studies in the zoo. Therefore, to the best of our knowledge, this is the first report of the world of mcr-1, mcr-3 and mcr-7.1 in environmental samples from the zoo.

High Level of Resistance to Antimicrobials and Heavy Metals in Multidrug-Resistant Pseudomonas sp. Isolated from Water Sources.

Antimicrobial-resistant bacteria (ARB) carrying antimicrobial resistance genes (ARGs) have been increasingly detected in water sources. Pseudomonas sp. are opportunistic pathogens commonly reported in water samples and different antimicrobial resistance mechanisms have been described in Pseudomonas sp., producing multidrug-resistant (MDR) phenotype. Besides, the presence of heavy metal resistance genes (HMRGs) may select ARB, which is worrying. Therefore, this study aimed to characterize the genotypes of Pseudomonas sp. isolated from different water sources. Water samples (i.e., rivers, streams, lakes and sewage treatment plants) were collected from different cities in Brazil. The bacterial identification was performed by sequencing the 16S rDNA and the resistance profile to antimicrobials and heavy metals were determined by minimum inhibitory concentration (MIC). Several ARGs, HMRGs, and plasmids were researched by PCR and the amplicons were sequenced for confirmation. A total of 23 Pseudomonas sp. isolates were obtained and identified as Pseudomonas saponiphila, Pseudomonas hunanensis, Pseudomonas aeruginosa, and Pseudomonas asiatica. These isolates presented high MICs to antimicrobials and heavy metals, being the great majority (n = 21; 91%) classified as MDR. Different clinically important ARGs were detected, such as blaGES, qnrS, qepA, tetB, aac(3')-IIa, and ant(2″)-Ia. The czcA gene was the only HMRG detected and no plasmids were found. To the best of our knowledge, this is the first report of the world of P. saponiphila carrying ARGs (i.e., blaGES, qnrS, aac(3')-IIa, tetB) and QepA-producing P. hunanensis and the first time of P. saponiphila, P. asiatica, and P. hunanensis in Brazil.

p53-/- synergizes with enhanced NrasG12D signaling to transform megakaryocyte-erythroid progenitors in acute myeloid leukemia.

Somatic mutations in TP53 and NRAS are associated with transformation of human chronic myeloid diseases to acute myeloid leukemia (AML). Here, we report that concurrent RAS pathway and TP53 mutations are identified in a subset of AML patients and confer an inferior overall survival. To further investigate the genetic interaction between p53 loss and endogenous NrasG12D/+ in AML, we generated conditional NrasG12D/+p53-/- mice. Consistent with the clinical data, recipient mice transplanted with NrasG12D/+p53-/- bone marrow cells rapidly develop a highly penetrant AML. We find that p53-/- cooperates with NrasG12D/+ to promote increased quiescence in megakaryocyte-erythroid progenitors (MEPs). NrasG12D/+p53-/- MEPs are transformed to self-renewing AML-initiating cells and are capable of inducing AML in serially transplanted recipients. RNA sequencing analysis revealed that transformed MEPs gain a partial hematopoietic stem cell signature and largely retain an MEP signature. Their distinct transcriptomes suggests a potential regulation by p53 loss. In addition, we show that during AML development, transformed MEPs acquire overexpression of oncogenic Nras, leading to hyperactivation of ERK1/2 signaling. Our results demonstrate that p53-/- synergizes with enhanced oncogenic Nras signaling to transform MEPs and drive AML development. This model may serve as a platform to test candidate therapeutics in this aggressive subset of AML.