Cistitis no complicada en mujeres: 5 estrategias para mejorar la prescripción

Antibiòtic; Resistències antimicrobianes; Infecció del tracte urinariAntibiótico; Resistencias antimicrobianas; Infección del tracto urinarioAntibiotic; Antimicrobial resistance; Urinary tract infectionLes resistències als antibiòtics afecten la capacitat de controlar les infeccions d’una manera efectiva. S’estima que l’any 2050 morirà més gent per infeccions de bacteris multiresistents que per càncer. En l’atenció primària es duen a terme el 90 % de les prescripcions d’antibiòtics, i es calcula que aproximadament entre el 30 i el 50 % de les prescripcions podrien ser inapropiades. Les infeccions del tracte urinari (ITU) es consideren una de les infeccions més freqüents en aquest àmbit, i amb creences errònies associades al seu maneig, com ara que cal tractar sistemàticament la bacteriúria en absència de símptomes, cosa que contribueix a una sobreprescripció d’antibiòtics. Hi ha evidència que ens indica que la fosfomicina trometamol en una dosi única de 3 grams és el tractament d’elecció, i la nitrofurantoïna és l’alternativa, sempre que el tractament no duri més de set dies. En general, no està indicat l’ús de cefalosporines de tercera generació i fluoroquinolones en el tractament empíric per tal d’evitar el desenvolupament de soques d’E. coli amb beta-lactamasa d’espectre estès (BLEE). En les cistitis recurrents, la profilaxi antibiòtica s’ha mostrat efectiva, però també hi ha altres estratègies, com ara augmentar la ingesta de líquids, utilitzar estrògens vaginals en dones postmenopàusiques o la micció postcoital, que en podrien reduir el risc. El paper dels nabius, els probiòtics, les autovacunes o la D-mannosa en la prevenció de les recurrències és limitat i controvertit.La resistencia a los antibióticos está afectando a nuestra capacidad de controlar las infecciones de forma efectiva. Se estima que en el año 2050 la mortalidad por infecciones de bacterias multiresistentes superará a la mortalidad asociada al cáncer. El 90% de las prescripciones de antibióticos se realizan en el contexto de la atención primaria y se estima que aproximadamente entre el 30 y el 50% de las prescripciones podrían ser inapropiadas. Las infecciones del tracto urinario se consideran una de las infecciones más frecuentes en este ámbito y algunas creencias erróneas, como que es necesario tratar sistemáticamente la bacteriuria en ausencia de síntomas, están contribuyendo a la sobreprescripción de antibióticos. La evidencia disponible indica que Fosfomicina trometamol 3g en dosis única es el tratamiento de elección y la nitrofurantoina su alternativa, siempre que la duración del tratamiento no supere los 7 días. En general no está indicado el uso de cefalosporinas de tercera generación y fluoroquinolonas como tratamiento empírico para evitar el desarrollo de cepas de E. coli BLEE. En las cistitis recurrentes la profilaxis antibiótica ha demostrado ser efectiva. Disponemos también de otras estrategias como aumentar la ingesta de líquidos, utilizar estrógenos vaginales en mujeres postmenopáusicas o la micción post coital que parece podrían reducir el riesgo de recurrencias. El papel de los arándanos, los probióticos, las autovacunas o la D-manosa en la prevención de las recurrencias es limitado y controvertido

Dual PI3K/mTOR inhibition is required to effectively impair microenvironment survival signals in mantle cell lymphoma

Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis and drug resistance. Antitumor activity has been observed with mTOR inhibitors. However, they have shown limited clinical efficacy in relation to drug activation of feedback loops. Selective PI3K inhibition or dual PI3K/mTOR catalytic inhibition are different therapeutic approaches developed to achieve effective pathway blockage. Here, we have performed a comparative analysis of the mTOR inhibitor everolimus, the pan-PI3K inhibitor NVP-BKM120 and the dual PI3K/mTOR inhibitor NVP-BEZ235 in primary MCL cells. We found NVP-BEZ235 to be more powerful than everolimus or NVP-BKM120 in PI3K/Akt/mTOR signaling inhibition, indicating that targeting the PI3K/Akt/mTOR pathway at multiple levels is likely to be a more effective strategy for the treatment of MCL than single inhibition of these kinases. Among the three drugs, NVP-BEZ235 induced the highest change in gene expression profile. Functional validation demonstrated that NVP-BEZ235 inhibited angiogenesis, migration and tumor invasiveness in MCL cells. NVP-BEZ235 was the only drug able to block IL4 and IL6/STAT3 signaling which compromise the therapeutic effect of chemotherapy in MCL. Our findings support the use of the dual PI3K/mTOR inhibitor NVP-BEZ235 as a promising approach to interfere with the microenvironment-related processes in MCL

Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells

Targeting Notch signaling has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL), particularly in NOTCH1-mutated patients. We provide first evidence that the Notch ligand DLL4 is a potent stimulator of Notch signaling in NOTCH1-mutated CLL cells while increases cell proliferation. Importantly, DLL4 is expressed in histiocytes from the lymph node, both in NOTCH1-mutated and -unmutated cases. We also show that the DLL4-induced activation of the Notch signaling pathway can be efficiently blocked with the specific anti-Notch1 antibody OMP-52M51. Accordingly, OMP-52M51 also reverses Notch-induced MYC, CCND1, and NPM1 gene expression as well as cell proliferation in NOTCH1-mutated CLL cells. In addition, DLL4 stimulation triggers the expression of protumor target genes, such as CXCR4, NRARP, and VEGFA, together with an increase in cell migration and angiogenesis. All these events can be antagonized by OMP-52M51. Collectively, our results emphasize the role of DLL4 stimulation in NOTCH1-mutated CLL and confirm the specific therapeutic targeting of Notch1 as a promising approach for this group of poor prognosis CLL patients

Synergistic anti-tumor activity of acadesine (AICAR) in combination with the anti-CD20monoclonal antibody rituximab in in vivo and in vitro models of mantle cell lymphoma

Mantle cell lymphoma (MCL) is considered one of the most challenging lymphoma, with limited responses to current therapies. Acadesine, a nucleoside analogue has shown antitumoral effects in different preclinical cancer models as well as in a recent phase I/II clinical trial conducted in patients with chronic lymphocytic leukemia. Here we observed that acadesine exerted a selective antitumoral activity in the majority of MCL cell lines and primary MCL samples, independently of adverse cytogenetic factors. Moreover, acadesine was highly synergistic, both in vitro and in vivo, with the anti-CD20 monoclonal antibody rituximab, commonly used in combination therapy for MCL. Gene expression profiling analysis in harvested tumors suggested that acadesine modulates immune response, actin cytoskeleton organization and metal binding, pointing out a substantial impact on metabolic processes by the nucleoside analog. Rituximab also induced changes on metal binding and immune responses.The combination of both drugs enhanced the gene signature corresponding to each single agent, showing an enrichment of genes involved in inflammation, metabolic stress, apoptosis and proliferation. These effects could be important as aberrant apoptotic and proinflammatory pathways play a significant role in the pathogenesis of MCL. In summary, our results suggest that acadesine exerts a cytotoxic effect in MCL in combination with rituximab, by decreasing the proliferative and survival signatures of the disease, thus supporting the clinical examination of this strategy in MCL patients

The splicing modulator sudemycin induces a specific antitumor response and cooperates with ibrutinib in chronic lymphocytic leukemia

Mutations or deregulated expression of the components of the spliceosome can influence the splicing pattern of several genes and contribute to the development of tumors. In this context, we report that the spliceosome modulator sudemycin induces selective cytotoxicity in primary chronic lymphocytic leukemia (CLL) cells when compared with healthy lymphocytes and tumor cells from other B-lymphoid malignancies, with a slight bias for CLL cases with mutations in spliceosome-RNA processing machinery. Consistently, sudemycin exhibits considerable antitumor activity in NOD/SCID/IL2Rγ-/- (NSG) mice engrafted with primary cells from CLL patients. The antileukemic effect of sudemycin involves the splicing modulation of several target genes important for tumor survival, both in SF3B1-mutated and -unmutated cases. Thus, the apoptosis induced by this compound is related to the alternative splicing switch of MCL1 toward its proapoptotic isoform. Sudemycin also functionally disturbs NF-κB pathway in parallel with the induction of a spliced RELA variant that loses its DNA binding domain. Importantly, we show an enhanced antitumor effect of sudemycin in combination with ibrutinib that might be related to the modulation of the alternative splicing of the inhibitor of Btk (IBTK). In conclusion, we provide first evidence that the spliceosome is a relevant therapeutic target in CLL, supporting the use of splicing modulators alone or in combination with ibrutinib as a promising approach for the treatment of CLL patients