Sweet dreams could be made of this: carbohydrate-responsive element-binding protein (ChREBP) as a target for hepatocellular carcinoma therapy.

Rewiring of cellular metabolism is now fully recognized as a hallmark of cancer. Tumor cells reprogram metabolic pathways to meet the energetic and macromolecular demands to support unrestricted growth and survival under unfavorable conditions. It is becoming apparent that these adaptations underpin most of the traits that define a cancer cell's identity, including the ability to avoid immune surveillance, endure nutrient and oxygen restrictions, detach and migrate from their natural histological niche, and avert human-made aggressions (i.e., therapy). In a recent study, Benichou and collaborators identify carbohydrate-responsive element-binding protein (ChREBP), a master regulator of physiological glucose metabolism, as an oncogene in hepatocellular carcinoma (HCC) development. Upregulation of ChREBP expression results in a self-stimulatory loop interconnecting PI3K/AKT signaling and glucose metabolism to feed fatty acid and nucleotide synthesis supporting tumorigenesis. Importantly, pharmacological inhibition of ChREBP activity quells in vivo HCC tumor growth without causing systemic toxicity. This study identifies novel oncometabolic pathways and open up new avenues to improve the treatment of a deadly tumor.

Application of Graph Models to the Identification of Transcriptomic Oncometabolic Pathways in Human Hepatocellular Carcinoma.

Whole-tissue transcriptomic analyses have been helpful to characterize molecular subtypes of hepatocellular carcinoma (HCC). Metabolic subtypes of human HCC have been defined, yet whether these different metabolic classes are clinically relevant or derive in actionable cancer vulnerabilities is still an unanswered question. Publicly available gene sets or gene signatures have been used to infer functional changes through gene set enrichment methods. However, metabolism-related gene signatures are poorly co-expressed when applied to a biological context. Here, we apply a simple method to infer highly consistent signatures using graph-based statistics. Using the Cancer Genome Atlas Liver Hepatocellular cohort (LIHC), we describe the main metabolic clusters and their relationship with commonly used molecular classes, and with the presence of TP53 or CTNNB1 driver mutations. We find similar results in our validation cohort, the LIRI-JP cohort. We describe how previously described metabolic subtypes could not have therapeutic relevance due to their overall downregulation when compared to non-tumoral liver, and identify N-glycan, mevalonate and sphingolipid biosynthetic pathways as the hallmark of the oncogenic shift of the use of acetyl-coenzyme A in HCC metabolism. Finally, using DepMap data, we demonstrate metabolic vulnerabilities in HCC cell lines.

Strategies to enhance the response of liver cancer to pharmacological treatments.

In contrast to other types of cancers, there is no available efficient pharmacological treatment to improve the outcomes of patients suffering from major primary liver cancers, i.e., hepatocellular carcinoma and cholangiocarcinoma. This dismal situation is partly due to the existence in these tumors of many different and synergistic mechanisms of resistance, accounting for the lack of response of these patients, not only to classical chemotherapy but also to more modern pharmacological agents based on the inhibition of tyrosine kinase receptors (TKIs) and the stimulation of the immune response against the tumor using immune checkpoint inhibitors (ICIs). This review summarizes the efforts to develop strategies to overcome this severe limitation, including searching for novel drugs derived from synthetic, semisynthetic, or natural products with vectorial properties against therapeutic targets to increase drug uptake or reduce drug export from cancer cells. Besides, immunotherapy is a promising line of research that is already starting to be implemented in clinical practice. Although less successful than in other cancers, the foreseen future for this strategy in treating liver cancers is considerable. Similarly, the pharmacological inhibition of epigenetic targets is highly promising. Many novel "epidrugs," able to act on "writer," "reader," and "eraser" epigenetic players, are currently being evaluated in preclinical and clinical studies. Finally, gene therapy is a broad field of research in the fight against liver cancer chemoresistance, based on the impressive advances recently achieved in gene manipulation. In sum, although the present is still dismal, there is reason for hope in the non-too-distant future.

SUMOylation controls Hu antigen R posttranscriptional activity in liver cancer.

The posttranslational modification of proteins critically influences many biological processes and is a key mechanism that regulates the function of the RNA-binding protein Hu antigen R (HuR), a hub in liver cancer. Here, we show that HuR is SUMOylated in the tumor sections of patients with hepatocellular carcinoma in contrast to the surrounding tissue, as well as in human cell line and mouse models of the disease. SUMOylation of HuR promotes major cancer hallmarks, namely proliferation and invasion, whereas the absence of HuR SUMOylation results in a senescent phenotype with dysfunctional mitochondria and endoplasmic reticulum. Mechanistically, SUMOylation induces a structural rearrangement of the RNA recognition motifs that modulates HuR binding affinity to its target RNAs, further modifying the transcriptomic profile toward hepatic tumor progression. Overall, SUMOylation constitutes a mechanism of HuR regulation that could be potentially exploited as a therapeutic strategy for liver cancer.

Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis.

Progressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS-/-) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS-/- mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS-/- livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.

Comprehensive analysis of epigenetic and epitranscriptomic genes' expression in human NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition with a complex etiology. Its incidence is increasing globally in parallel with the obesity epidemic, and it is now considered the most common liver disease in Western countries. The precise mechanisms underlying the development and progression of NAFLD are complex and still poorly understood. The dysregulation of epigenetic and epitranscriptomic mechanisms is increasingly recognized to play pathogenic roles in multiple conditions, including chronic liver diseases. Here, we have performed a comprehensive analysis of the expression of epigenetic and epitranscriptomic genes in a total of 903 liver tissue samples corresponding to patients with normal liver, obese patients, and patients with non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), advancing stages in NAFLD progression. We integrated ten transcriptomic datasets in an unbiased manner, enabling their robust analysis and comparison. We describe the complete landscape of epigenetic and epitranscriptomic genes' expression along the course of the disease. We identify signatures of genes significantly dysregulated in association with disease progression, particularly with liver fibrosis development. Most of these epigenetic and epitranscriptomic effectors have not been previously described in human NAFLD, and their altered expression may have pathogenic implications. We also performed a comprehensive analysis of the expression of enzymes involved in the metabolism of the substrates and cofactors of epigenetic and epitranscriptomic effectors. This study provides novel information on NAFLD pathogenesis and may also guide the identification of drug targets to treat this condition and its progression towards hepatocellular carcinoma.

Identification and experimental validation of druggable epigenetic targets in hepatoblastoma.

BACKGROUND & AIMS: Hepatoblastoma (HB) is the most frequent childhood liver cancer. Patients with aggressive tumors have limited therapeutic options; therefore, a better understanding of HB pathogenesis is needed to improve treatment. HBs have a very low mutational burden; however, epigenetic alterations are increasingly recognized. We aimed to identify epigenetic regulators consistently dysregulated in HB and to evaluate the therapeutic efficacy of their targeting in clinically relevant models. METHODS: We performed a comprehensive transcriptomic analysis of 180 epigenetic genes. Data from fetal, pediatric, adult, peritumoral (n = 72) and tumoral (n = 91) tissues were integrated. Selected epigenetic drugs were tested in HB cells. The most relevant epigenetic target identified was validated in primary HB cells, HB organoids, a patient-derived xenograft model, and a genetic mouse model. Transcriptomic, proteomic and metabolomic mechanistic analyses were performed. RESULTS: Altered expression of genes regulating DNA methylation and histone modifications was consistently observed in association with molecular and clinical features of poor prognosis. The histone methyltransferase G9a was markedly upregulated in tumors with epigenetic and transcriptomic traits of increased malignancy. Pharmacological targeting of G9a significantly inhibited growth of HB cells, organoids and patient-derived xenografts. Development of HB induced by oncogenic forms of ß-catenin and YAP1 was ablated in mice with hepatocyte-specific deletion of G9a. We observed that HBs undergo significant transcriptional rewiring in genes involved in amino acid metabolism and ribosomal biogenesis. G9a inhibition counteracted these pro-tumorigenic adaptations. Mechanistically, G9a targeting potently repressed the expression of c-MYC and ATF4, master regulators of HB metabolic reprogramming. CONCLUSIONS: HBs display a profound dysregulation of the epigenetic machinery. Pharmacological targeting of key epigenetic effectors exposes metabolic vulnerabilities that can be leveraged to improve the treatment of these patients. IMPACT AND IMPLICATIONS: In spite of recent advances in the management of hepatoblastoma (HB), treatment resistance and drug toxicity are still major concerns. This systematic study reveals the remarkable dysregulation in the expression of epigenetic genes in HB tissues. Through pharmacological and genetic experimental approaches, we demonstrate that the histone-lysine-methyltransferase G9a is an excellent drug target in HB, which can also be harnessed to enhance the efficacy of chemotherapy. Furthermore, our study highlights the profound pro-tumorigenic metabolic rewiring of HB cells orchestrated by G9a in coordination with the c-MYC oncogene. From a broader perspective, our findings suggest that anti-G9a therapies may also be effective in other c-MYC-dependent tumors.

Mapping early serum proteome signatures of liver regeneration in living donor liver transplant cases.

The liver is the only solid organ capable of regenerating itself to regain 100% of its mass and function after liver injury and/or partial hepatectomy (PH). This exceptional property represents a therapeutic opportunity for severe liver disease patients. However, liver regeneration (LR) might fail due to poorly understood causes. Here, we have investigated the regulation of liver proteome and phosphoproteome at a short time after PH (9 h), to depict a detailed mechanistic background of the early LR phase. Furthermore, we analyzed the dynamic changes of the serum proteome and metabolome of healthy living donor liver transplant (LDLT) donors at different time points after surgery. The molecular profiles from both analyses were then correlated. Insulin and FXR-FGF15/19 signaling were stimulated in mouse liver after PH, leading to the activation of the main intermediary kinases (AKT and ERK). Besides, inhibition of the hippo pathway led to an increased expression of its target genes and of one of its intermediary proteins (14-3-3 protein), contributing to cell proliferation. In association with these processes, metabolic reprogramming coupled to enhanced mitochondrial activity cope for the energy and biosynthetic requirements of LR. In human serum of LDLT donors, we identified 56 proteins and 13 metabolites statistically differential which recapitulate some of the main cellular processes orchestrating LR in its early phase. These results provide mechanisms and protein mediators of LR that might prove useful for the follow-up of the regenerative process in the liver after PH as well as preventing the occurrence of complications associated with liver resection.

Hepatocyte Dedifferentiation Profiling In Alcohol-Related Liver Disease Identifies CXCR4 As A Driver Of Cell Reprogramming.

Background and Aims: Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to cells with a hepatobiliary (HB) phenotype expressing biliary and hepatocytes markers and showing immature features. However, the mechanisms and the impact of hepatocyte dedifferentiation in liver disease are poorly understood. Methods: HB cells and ductular reaction (DR) cells were quantified and microdissected from liver biopsies from patients with alcohol-related liver disease (ALD). Hepatocyte- specific overexpression or deletion of CXCR4, and CXCR4 pharmacological inhibition were assessed in mouse liver injury. Patient-derived and mouse organoids were generated to assess plasticity. Results: Here we show that HB and DR cells are increased in patients with decompensated cirrhosis and AH, but only HB cells correlate with poor liver function and patients' outcome. Transcriptomic profiling of HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming, inflammation, stemness and cancer gene programs. CXCR4 pathway was highly enriched in HB cells, and correlated with disease severity and hepatocyte dedifferentiation. In vitro , CXCR4 was associated with biliary phenotype and loss of hepatocyte features. Liver overexpression of CXCR4 in chronic liver injury decreased hepatocyte specific gene expression profile and promoted liver injury. CXCR4 deletion or its pharmacological inhibition ameliorated hepatocyte dedifferentiation and reduced DR and fibrosis progression. Conclusions: This study shows the association of hepatocyte dedifferentiation with disease progression and poor outcome in AH. Moreover, the transcriptomic profiling of HB cells revealed CXCR4 as a new driver of hepatocyte-to-biliary reprogramming and as a potential therapeutic target to halt hepatocyte dedifferentiation in AH. Lay summary: Here we describe that hepatocyte dedifferentiation is associated with disease severity and a reduced synthetic capacity of the liver. Moreover, we identify the CXCR4 pathway as a driver of hepatocyte dedifferentiation and as a therapeutic target in alcohol-related hepatitis.

Hepatocyte dedifferentiation profiling in alcohol-related liver disease identifies CXCR4 as a driver of cell reprogramming.

BACKGROUND & AIMS: Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to cells with a hepatobiliary (HB) phenotype expressing biliary and hepatocyte markers and showing immature features. However, the mechanisms and impact of hepatocyte dedifferentiation in liver disease are poorly understood. METHODS: HB cells and ductular reaction (DR) cells were quantified and microdissected from liver biopsies from patients with alcohol-related liver disease (ArLD). Hepatocyte-specific overexpression or deletion of C-X-C motif chemokine receptor 4 (CXCR4), and CXCR4 pharmacological inhibition were assessed in mouse liver injury. Patient-derived and mouse organoids were generated to assess plasticity. RESULTS: Here, we show that HB and DR cells are increased in patients with decompensated cirrhosis and AH, but only HB cells correlate with poor liver function and patients' outcome. Transcriptomic profiling of HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming, inflammation, stemness, and cancer gene programs. The CXCR4 pathway was highly enriched in HB cells and correlated with disease severity and hepatocyte dedifferentiation. In vitro, CXCR4 was associated with a biliary phenotype and loss of hepatocyte features. Liver overexpression of CXCR4 in chronic liver injury decreased the hepatocyte-specific gene expression profile and promoted liver injury. CXCR4 deletion or its pharmacological inhibition ameliorated hepatocyte dedifferentiation and reduced DR and fibrosis progression. CONCLUSIONS: This study shows the association of hepatocyte dedifferentiation with disease progression and poor outcome in AH. Moreover, the transcriptomic profiling of HB cells revealed CXCR4 as a new driver of hepatocyte-to-biliary reprogramming and as a potential therapeutic target to halt hepatocyte dedifferentiation in AH. IMPACT AND IMPLICATIONS: Here, we show that hepatocyte dedifferentiation is associated with disease severity and a reduced synthetic capacity of the liver. Moreover, we identify the CXCR4 pathway as a driver of hepatocyte dedifferentiation and as a therapeutic target in alcohol-related hepatitis. Therefore, this study reveals the importance of preserving strict control over hepatocyte plasticity in order to preserve liver function and promote tissue repair.

SLU7: A New Hub of Gene Expression Regulation-From Epigenetics to Protein Stability in Health and Disease.

SLU7 (Splicing factor synergistic lethal with U5 snRNA 7) was first identified as a splicing factor necessary for the correct selection of 3' splice sites, strongly impacting on the diversity of gene transcripts in a cell. More recent studies have uncovered new and non-redundant roles of SLU7 as an integrative hub of different levels of gene expression regulation, including epigenetic DNA remodeling, modulation of transcription and protein stability. Here we review those findings, the multiple factors and mechanisms implicated as well as the cellular functions affected. For instance, SLU7 is essential to secure liver differentiation, genome integrity acting at different levels and a correct cell cycle progression. Accordingly, the aberrant expression of SLU7 could be associated with human diseases including cancer, although strikingly, it is an essential survival factor for cancer cells. Finally, we discuss the implications of SLU7 in pathophysiology, with particular emphasis on the progression of liver disease and its possible role as a therapeutic target in human cancer.

New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming.

BACKGROUND: Cholangiocarcinoma (CCA) is still a deadly tumour. Histological and molecular aspects of thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats mimic those of human iCCA. Carcinogenic changes and therapeutic vulnerabilities in CCA may be captured by molecular investigations in bile, where we performed bile proteomic and metabolomic analyses that help discovery yet unknown pathways relevant to human iCCA. METHODS: Cholangiocarcinogenesis was induced in rats (TAA) and mice (JnkΔhepa + CCl4 + DEN model). We performed proteomic and metabolomic analyses in bile from control and CCA-bearing rats. Differential expression was validated in rat and human CCAs. Mechanisms were addressed in human CCA cells, including Huh28-KRASG12D cells. Cell signaling, growth, gene regulation and [U-13C]-D-glucose-serine fluxomics analyses were performed. In vivo studies were performed in the clinically-relevant iCCA mouse model. RESULTS: Pathways related to inflammation, oxidative stress and glucose metabolism were identified by proteomic analysis. Oxidative stress and high amounts of the oncogenesis-supporting amino acids serine and glycine were discovered by metabolomic studies. Most relevant hits were confirmed in rat and human CCAs (TCGA). Activation of interleukin-6 (IL6) and epidermal growth factor receptor (EGFR) pathways, and key genes in cancer-related glucose metabolic reprogramming, were validated in TAA-CCAs. In TAA-CCAs, G9a, an epigenetic pro-tumorigenic writer, was also increased. We show that EGFR signaling and mutant KRASG12D can both activate IL6 production in CCA cells. Furthermore, phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine-glycine pathway, was upregulated in human iCCA correlating with G9a expression. In a G9a activity-dependent manner, KRASG12D promoted PHGDH expression, glucose flow towards serine synthesis, and increased CCA cell viability. KRASG12D CAA cells were more sensitive to PHGDH and G9a inhibition than controls. In mouse iCCA, G9a pharmacological targeting reduced PHGDH expression. CONCLUSIONS: In CCA, we identified new pro-tumorigenic mechanisms: Activation of EGFR signaling or KRAS mutation drives IL6 expression in tumour cells; Glucose metabolism reprogramming in iCCA includes activation of the serine-glycine pathway; Mutant KRAS drives PHGDH expression in a G9a-dependent manner; PHGDH and G9a emerge as therapeutic targets in iCCA.

DNA Methylation Regulates a Set of Long Non-Coding RNAs Compromising Hepatic Identity during Hepatocarcinogenesis.

BACKGROUND: Long noncoding RNAs (lncRNAs) are emerging as key players in cancer, including hepatocellular carcinoma (HCC). Here we identify the mechanism implicated in the HCC inhibition of a set of lncRNAs, and their contribution to the process of hepatocarcinogenesis. METHODS AND RESULTS: The top-ranked 35 lncRNAs downregulated in HCC (Top35 LNDH) were validated in several human HCC cohorts. We demonstrate that their inhibition is associated with promoter hypermethylation in HCC compared to control tissue, and in HCC human cell lines compared to primary hepatocytes. Moreover, demethylating treatment of HCC human cell lines induced the expression of these lncRNAs. The Top35 LNDH were preferentially expressed in the adult healthy liver compared to other tissues and fetal liver and were induced in well-differentiated HepaRG cells. Remarkably, their knockdown compromised the expression of other hepato-specific genes. Finally, the expression of the Top35 LNDH positively correlates with the grade of tumor differentiation and, more importantly, with a better patient prognosis. CONCLUSIONS: Our results demonstrate that the selected Top35 LNDH are not only part of the genes that compose the hepatic differentiated signature but participate in its establishment. Moreover, their downregulation through DNA methylation occurs during the process of hepatocarcinogenesis compromising hepatocellular differentiation and HCC patients' prognosis.

Clinical relevance of biomarkers in cholangiocarcinoma: critical revision and future directions.

Cholangiocarcinoma (CCA) is a malignant tumour arising from the biliary system. In Europe, this tumour frequently presents as a sporadic cancer in patients without defined risk factors and is usually diagnosed at advanced stages with a consequent poor prognosis. Therefore, the identification of biomarkers represents an utmost need for patients with CCA. Numerous studies proposed a wide spectrum of biomarkers at tissue and molecular levels. With the present paper, a multidisciplinary group of experts within the European Network for the Study of Cholangiocarcinoma discusses the clinical role of tissue biomarkers and provides a selection based on their current relevance and potential applications in the framework of CCA. Recent advances are proposed by dividing biomarkers based on their potential role in diagnosis, prognosis and therapy response. Limitations of current biomarkers are also identified, together with specific promising areas (ie, artificial intelligence, patient-derived organoids, targeted therapy) where research should be focused to develop future biomarkers.

The Amphiregulin/EGFR axis protects from lupus nephritis via downregulation of pathogenic CD4+ T helper cell responses.

Systemic lupus erythematosus (SLE) is a common autoimmune disorder with a complex and poorly understood immuno-pathogenesis. Lupus nephritis (LN) is a frequent and difficult to treat complication, which causes high morbidity and mortality. The multifunctional cytokine amphiregulin (AREG) has been implicated in SLE pathogenesis, but its function in LN currently remains unknown. We thus studied the model of pristane-induced LN and found increasing renal and systemic AREG expression during the course of disease. Importantly, renal injury was significantly aggravated in the absence of AREG, revealing a net anti-inflammatory role. Analyses of immune responses showed dual effects. On the one hand, AREG enhanced activation of pro-inflammatory myeloid cells, which however did not play a major role for the course of LN. More importantly, on the other hand, AREG strongly suppressed pathogenic cytokine production by T helper effector cells. This effect was more general in nature and could be reproduced in response to antigen immunization. Since AREG has been postulated to downregulate T cell responses via enhancing Treg suppressive capacity, we followed up on this aspect. Interestingly, however, in vitro studies revealed potential direct and Treg independent effects of AREG on T helper effector cells. In favor of this notion, we found significantly enhanced T cell responses and consecutive aggravation of LN, only if epidermal growth factor receptor (EGFR) signaling was abrogated in total T cells, but not if the EGFR was absent on Tregs alone. Finally, we also found enhanced AREG expression in plasma and renal biopsies of patients with LN, supporting the relevance of our findings for human disease. In summary, our data identify AREG as an anti-inflammatory mediator of LN via broad downregulation of pathogenic T cell immunity. These findings further highlight the AREG/EGFR axis as a potential therapeutic target.

Descripción de una cepa de Klebsiella pneumoniae con gen blaOXA-48 en Lima-Perú / Description of a Klebsiella pneumoniae strain with blaOXA-48 gene in Lima-Peru

Señor editor: La propagación de enterobacterales productoras de carbapenemasas se ha convertido en una importante amenaza para la salud mundial. El gen blaOXA-48 produce una carbapenemasa de clase "D" (según la clasificación de Ambler) que expresa un fenotipo resistente a penicilinas, penicilinas con inhibidores de beta-lactamasas, cefalosporinas de primera generación y sensibilidad reducida a los carbapenemes, sensibilidad reducida o casi nula a las cefalosporinas de amplio espectro.

Dear Editor: The spread of carbapenemase-producing Enterobacteriaceae has become a major threat to global health. The blaOXA- gene blaOXA-48 produces a class "D" carbapenemase (according to Ambler's classification) that expresses a phenotype resistant to penicillins, penicillins with beta-lactamase inhibitors, first-generation cephalosporins and reduced sensitivity to carbapenems, reduced or near-zero sensitivity to broad-spectrum cephalosporins.48 produces a class "D" carbapenemase (according to Ambler's classification) that expresses a phenotype resistant to penicillins, penicillins with beta-lactamase inhibitors, first-generation cephalosporins and reduced sensitivity to carbapenems, reduced or near-zero sensitivity to broad-spectrum cephalosporins.