RESUMEN
Viral infections, including those caused by COVID-19, can produce striking morphologic changes in peripheral blood. Distinguishing between reactive changes and abnormal morphology of monocytes remains particularly difficult, with low consensus rates reported amongst hematopathologists. Here, we report a patient who developed transient monocytosis of 11.06 × 109/L with 32% promonocytes and 1% blasts during hospitalization that was secondary to severe COVID-19 infection. Three days later, the clinical status of the patient improved and the WBC had decreased to 8.47 × 109/L with 2.2 × 109/L monocytes. Flow cytometry studies did not reveal immunophenotypic findings specific for an overt malignant population. At no time during admission did the patient develop cytopenia(s), and she was discharged upon clinical improvement. However, the peripheral blood sample containing promonocytes was sent for molecular testing with an extended next-generation sequencing myeloid panel and was positive for pathogenic NPM1 Type A and DNMT3A R882H mutations. Subsequently, despite an essentially normal complete blood count, the patient underwent a bone marrow assessment that showed acute myeloid leukemia with 77% promonocytes. This case emphasizes the critical importance of a full work up to exclude acute leukemia when classical promonocyte morphology is encountered in the peripheral blood. Promonocytes are not a part of the reactive changes associated with COVID-19 and remain specific to myeloid neoplasia.
RESUMEN
Giant condyloma acuminatum (GCA) is a benign anogenital lesion caused by human papilloma virus. It is rarely found on the cervix and is difficult to differentiate from malignancy. It is associated with a propensity for invasion, recurrence, and malignant transformation. A 35-year-old woman presented with abnormal uterine bleeding and a suspicious cervical mass. After a Pap test revealed high-grade squamous intraepithelial lesion, cervical biopsies revealed cervical dysplasia. A diagnostic loop electrical excision procedure identified a giant condyloma. A total hysterectomy was performed, confirming the diagnosis. This condition should be in the differential diagnosis for a cervical mass suspicious for malignancy. Prompt biopsy of mass is crucial.
Asunto(s)
Tumor de Buschke-Lowenstein , Condiloma Acuminado , Neoplasias del Cuello Uterino , Adulto , Tumor de Buschke-Lowenstein/diagnóstico , Tumor de Buschke-Lowenstein/patología , Cuello del Útero/patología , Condiloma Acuminado/diagnóstico , Condiloma Acuminado/patología , Condiloma Acuminado/cirugía , Femenino , Humanos , Neoplasias del Cuello Uterino/patología , Frotis VaginalRESUMEN
ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.
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Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Quinasa de Linfoma Anaplásico/análisis , Trastornos Histiocíticos Malignos/tratamiento farmacológico , Trastornos Histiocíticos Malignos/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Adolescente , Adulto , Quinasa de Linfoma Anaplásico/genética , Niño , Preescolar , Femenino , Trastornos Histiocíticos Malignos/complicaciones , Trastornos Histiocíticos Malignos/genética , Humanos , Lactante , Masculino , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/patología , Proteínas de Fusión Oncogénica/análisis , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Proteínas de Fusión Oncogénica/genética , Estudios Retrospectivos , Adulto JovenRESUMEN
Given the increasing prevalence of obesity and the metabolic syndrome, identification of intrinsic molecular programs responsible for ensuring fuel homeostasis and preventing metabolic disease is needed. We investigated whether the orphan nuclear receptor estrogen-related receptor α (ERRα), a major regulator of energy metabolism, plays a role in lipid homeostasis and the development of nonalcoholic fatty liver disease (NAFLD) in response to chronic high-fat diet (HFD) consumption and long-term fasting. Systemic ablation of ERRα in mice demonstrated clear beneficial effects for loss of ERRα function in protection from HFD-provoked body weight gain manifested not only from a reduction in white adipose tissue stores but also from an impediment in intrahepatic lipid accumulation. The prevention of HFD-induced NAFLD in ERRα-null mice was underscored by transcriptional repression of de novo lipogenesis, which was upregulated in wild-type mice, a known contributing factor to lipid-stimulated hepatic steatosis. Surprisingly, given these findings, ERRα deficiency had no significant impact on the degree of fasting-induced NAFLD, involving the mobilization of adipocyte triglyceride (TG) stores into the liver. However, the presence of ERRα was essential for acute refeeding-mediated reversal of fasting-induced hepatic TG accretion, underpinned by impaired downregulation of adipose TG lipolysis and reduced hepatic mitochondrial oxidative activity. Taken together, the regulation of lipid handling by ERRα depended on the nutritional state, suggesting that negative modulation of ERRα activity could be envisaged to prevent lipid-induced NAFLD, whereas inducing its activity would be useful to treat and reverse the instilled disease.
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Dieta Alta en Grasa , Ayuno/metabolismo , Lipogénesis/genética , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Obesidad/genética , Receptores de Estrógenos/genética , Tejido Adiposo Blanco/metabolismo , Animales , Metabolismo Energético/genética , Metabolismo de los Lípidos/genética , Lipólisis/genética , Ratones , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Triglicéridos/metabolismo , Aumento de Peso , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
5α-Reductase types 1 and 2, encoded by SRD5A1 and SRD5A2, are the two enzymes that can catalyze the conversion of testosterone to dihydrotestosterone, the most potent androgen receptor (AR) agonist in prostate cells. 5α-Reductase type 2 is the predominant isoform expressed in the normal prostate. However, its expression decreases during prostate cancer (PCa) progression, whereas SRD5A1 increases, and the mechanism underlying this transcriptional regulatory switch is still unknown. Interrogation of SRD5A messenger RNA expression in three publicly available data sets confirmed that SRD5A1 is increased in primary and metastatic PCa compared with nontumoral prostate tissues, whereas SRD5A2 is decreased. Activation of AR, a major oncogenic driver of PCa, induced the expression of SRD5A1 from twofold to fourfold in three androgen-responsive PCa cell lines. In contrast, AR repressed SRD5A2 expression in this context. Chromatin-immunoprecipitation studies established that AR is recruited to both SRD5A1 and SRD5A2 genes following androgen stimulation but initiates transcriptional activation only at SRD5A1 as monitored by recruitment of RNA polymerase II and the presence of the H3K27Ac histone mark. Furthermore, we showed that the antiandrogens bicalutamide and enzalutamide block the AR-mediated regulation of both SRD5A1 and SRD5A2, highlighting an additional mechanism explaining their beneficial effects in patients. In summary, we identified an AR-dependent transcriptional regulation that explains the differential expression of 5α-reductase types 1 and 2 during PCa progression. Our work thus defines a mechanism by which androgens control their own synthesis via differential regulatory control of the expression of SRD5A1 and SRD5A2.
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3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/metabolismo , Proteínas de la Membrana/metabolismo , Próstata/metabolismo , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Andrógenos/farmacología , Línea Celular Tumoral , Progresión de la Enfermedad , Humanos , Calicreínas/metabolismo , Masculino , Metribolona/farmacología , Próstata/efectos de los fármacos , Próstata/patología , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata/patologíaRESUMEN
Translational control of gene expression plays a key role during the early phases of embryonic development. Here we describe a transcriptional regulator of mouse embryonic stem cells (mESCs), Yin-yang 2 (YY2), that is controlled by the translation inhibitors, Eukaryotic initiation factor 4E-binding proteins (4E-BPs). YY2 plays a critical role in regulating mESC functions through control of key pluripotency factors, including Octamer-binding protein 4 (Oct4) and Estrogen-related receptor-ß (Esrrb). Importantly, overexpression of YY2 directs the differentiation of mESCs into cardiovascular lineages. We show that the splicing regulator Polypyrimidine tract-binding protein 1 (PTBP1) promotes the retention of an intron in the 5'-UTR of Yy2 mRNA that confers sensitivity to 4E-BP-mediated translational suppression. Thus, we conclude that YY2 is a major regulator of mESC self-renewal and lineage commitment and document a multilayer regulatory mechanism that controls its expression.
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Empalme Alternativo/fisiología , Diferenciación Celular , Autorrenovación de las Células/fisiología , Células Madre Embrionarias/metabolismo , Regulación del Desarrollo de la Expresión Génica , Factores de Transcripción/metabolismo , Animales , Blastocisto/metabolismo , Proteínas Portadoras/metabolismo , Linaje de la Célula , Autorrenovación de las Células/genética , Ribonucleoproteínas Nucleares Heterogéneas/genética , Intrones , Ratones , Ratones Noqueados , Modelos Biológicos , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Fosfoproteínas , Proteína de Unión al Tracto de Polipirimidina/genética , Biosíntesis de Proteínas/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Receptores de Estrógenos/metabolismo , Factores de Transcripción/genética , Transcripción Genética/fisiología , Factor de Transcripción YY1/metabolismoRESUMEN
Despite the initial benefits of treating HER2-amplified breast cancer patients with the tyrosine kinase inhibitor lapatinib, resistance inevitably develops. Here we report that lapatinib induces the degradation of the nuclear receptor ERRα, a master regulator of cellular metabolism, and that the expression of ERRα is restored in lapatinib-resistant breast cancer cells through reactivation of mTOR signalling. Re-expression of ERRα in resistant cells triggers metabolic adaptations favouring mitochondrial energy metabolism through increased glutamine metabolism, as well as ROS detoxification required for cell survival under therapeutic stress conditions. An ERRα inverse agonist counteracts these metabolic adaptations and overcomes lapatinib resistance in a HER2-induced mammary tumour mouse model. This work reveals a molecular mechanism by which ERRα-induced metabolic reprogramming promotes survival of lapatinib-resistant cancer cells and demonstrates the potential of ERRα inhibition as an effective adjuvant therapy in poor outcome HER2-positive breast cancer.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Quinazolinas/uso terapéutico , Receptores de Estrógenos/genética , Animales , Neoplasias de la Mama/metabolismo , Supervivencia Celular , Humanos , Lapatinib , Células MCF-7 , Neoplasias Mamarias Experimentales/metabolismo , Virus del Tumor Mamario del Ratón , Ratones , Receptor ErbB-2/metabolismo , Infecciones por Retroviridae , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Infecciones Tumorales por Virus , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
The identification of two genes encoding polypeptides with structural features common with the estrogen receptor more than a quarter century ago, referred to as the estrogen-related receptors (ERRs), subsequently led to the discovery of several previously unrecognized hormone responsive systems through the application of reverse endocrinology. Paradoxically, the natural ligand(s) associated with members of the ERR subfamily remains to be identified. While initial studies on the mode of action and physiological functions of the ERRs focused on interaction with estrogen signalling in breast cancer, subsequent work showed that the ERRs are ubiquitous master regulators of cellular energy metabolism. This review aims to demonstrate that the ERRs occupy a central node at the interface of cancer and metabolism, and that modulation of their activity may represent a worthwhile strategy to induce metabolic vulnerability in tumors of various origins and thus achieve a more comprehensive response to current therapies.
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Biomarcadores de Tumor/metabolismo , Metabolismo Energético/fisiología , Neoplasias/metabolismo , Receptores de Estrógenos/metabolismo , Neoplasias de la Mama/metabolismo , Estrógenos/metabolismo , Femenino , Humanos , Neoplasias/patología , Elementos de Respuesta , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
Muscle fitness is an important determinant of health and disease. However, the molecular mechanisms involved in the coordinate regulation of the metabolic and structural determinants of muscle endurance are still poorly characterized. Herein, we demonstrate that estrogen-related receptor α (ERRα, NR3B1) is essential for skeletal muscle fitness. Notably, we show that ERRα-null animals are hypoactive and that genetic or therapeutic disruption of ERRα in mice results in reduced exercise tolerance. Mice lacking ERRα also exhibited lactatemia at exhaustion. Gene expression profiling demonstrates that ERRα plays a key role in various metabolic processes important for muscle function including energy substrate transport and use (Ldhd, Slc16a1, Hk2, and Glul), the tricarboxylic acid cycle (Cycs, and Idh3g), and oxidative metabolism (Pdha1, and Uqcrq). Metabolomics studies revealed impairment in replenishment of several amino acids (eg, glutamine) during recovery to exercise. Moreover, loss of ERRα was found to alter the expression of genes involved in oxidative stress response (Hmox1), maintenance of muscle fiber integrity (Trim63, and Hspa1b), and muscle plasticity and neovascularization (Vegfa). Taken together, our study shows that ERRα plays a key role in directing transcriptional programs required for optimal mitochondrial oxidative potential and muscle fitness, suggesting that modulation of ERRα activity could be used to manage metabolic myopathies and/or promote the adaptive response to physical exercise.
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Tolerancia al Ejercicio/fisiología , Músculo Esquelético/metabolismo , Receptores de Estrógenos/metabolismo , Animales , Tolerancia al Ejercicio/genética , Femenino , Masculino , Ratones Noqueados , Receptores de Estrógenos/genética , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
The most common mechanism of resistance to aminoglycoside antibiotics entails bacterial expression of drug-metabolizing enzymes, such as the clinically widespread aminoglycoside N-6'-acetyltransferase (AAC(6')). Aminoglycoside-CoA bisubstrates are highly potent AAC(6') inhibitors; however, their inability to penetrate cells precludes in vivo studies. Some truncated bisubstrates are known to cross cell membranes, yet their activities against AAC(6') are in the micromolar range at best. We report here the synthesis and biological activity of aminoglycoside-pantetheine derivatives that, although devoid of AAC(6') inhibitory activity, can potentiate the antibacterial activity of kanamycin A against an aminoglycoside-resistant strain of Enterococcus faecium. Biological studies demonstrate that these molecules are potentially extended to their corresponding full-length bisubstrates by enzymes of the coenzyme A biosynthetic pathway. This work provides a proof-of-concept for the utility of prodrug compounds activated by enzymes of the coenzyme A biosynthetic pathway, to resensitize resistant strains of bacteria to aminoglycoside antibiotics.