Alteration of Gut Microbiota Composition in the Progression of Liver Damage in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex disorder whose prevalence is rapidly growing in South America. The disturbances in the microbiota-gut-liver axis impact the liver damaging processes toward fibrosis. Gut microbiota status is shaped by dietary and lifestyle factors, depending on geographic location. We aimed to identify microbial signatures in a group of Chilean MASLD patients. Forty subjects were recruited, including healthy controls (HCs), overweight/obese subjects (Ow/Ob), patients with MASLD without fibrosis (MASLD/F-), and MASLD with fibrosis (MASLD/F+). Both MASLD and fibrosis were detected through elastography and/or biopsy, and fecal microbiota were analyzed through deep sequencing. Despite no differences in α- and ß-diversity among all groups, a higher abundance of Bilophila and a lower presence of Defluviitaleaceae, Lachnospiraceae ND3007, and Coprobacter was found in MASLD/F- and MASLD/F+, compared to HC. Ruminococcaceae UCG-013 and Sellimonas were more abundant in MASLD/F+ than in Ow/Ob; both significantly differed between MASLD/F- and MASLD/F+, compared to HC. Significant positive correlations were observed between liver stiffness and Bifidobacterium, Prevotella, Sarcina, and Acidaminococcus abundance. Our results show that MASLD is associated with changes in bacterial taxa that are known to be involved in bile acid metabolism and SCFA production, with some of them being more specifically linked to fibrosis.

Relación entre la compresión maxilar y potencial impactación del canino superior: Scoping review

El canino maxilar permanente corresponde al segundo diente más frecuentemente impactado en el arco dental. La etiología de esta patología aún no está totalmente definida, sin embargo, investigadores plantean la deficiencia del ancho del hueso maxilar como una posible causa. Objetivo: Investigar la evidencia que asocia menores dimensiones transversales del maxilar a la ocurrencia de la impactación de caninos superiores y esclarecer la posible relación. Materiales y métodos: Se realizó una revisión sistemática exploratoria a partir de una búsqueda amplia de la literatura en bases de datos PubMed, Cochrane, EBSCO y Multibuscador UNAB. Los artículos fueron recopilados, identificados y filtrados según el diagrama de flujo de declaración PRISMA. Resultados: La búsqueda identificó 755 estudios, de los cuales 14 fueron incluidos. Los estudios varían en diseño, edad de estudio y métodos de diagnóstico. La mitad de los estudios reporta una asociación positiva entre compresión maxilar e impactación canina superior, mientras que la otra mitad una asociación negativa. Conclusiones: No hay evidencia suficiente para poder asociar compresión maxilar con impactación de caninos superiores. Estudios con métodos de diagnóstico rigurosos son necesarios para una mejor comprensión. No obstante, se enfatiza la importancia de un diagnóstico precoz, para garantizar mejores resultados y pronóstico más favorable.

The permanent maxillary canine is the second most frequently impacted tooth in the dental arch. The etiology of this disease is not completely defined, yet some researchers propose the deficiency of the width from the maxilla as a possible cause. Objective: To investigate available evidence correlating smaller transverse maxilla dimensions with the occurrence of potential impaction of upper canines and clarify the possible relation. Materials and methods: A systematic exploratory review was carried out based on comprehensive search of the literature in databases such as PubMed, Cochrane, EBSCO and UNAB multi search engine. The articles were compiled, identified and filtered systematically according to the PRISMA flow diagram. Results: Our search identified 755 studies, 14 of which were included. These studies vary in design, patients age, and methods for detection. Half of the studies show a positive correlation between maxillary compression and potential upper canine impaction, whereas the other half show a negative correlation. Conclusions: There is not enough evidence to link maxillary compression to upper canine impaction. Studies with rigorous diagnostic methods for detection are necessary for a better understanding of this relation. Nonetheless, the importance of early diagnosis must be emphasized to guarantee better results and a more favorable prognosis.

A synaptic molecular dependency network in knockdown of autism- and schizophrenia-associated genes revealed by multiplexed imaging.

The complex functions of neuronal synapses depend on their tightly interconnected protein network, and their dysregulation is implicated in the pathogenesis of autism spectrum disorders and schizophrenia. However, it remains unclear how synaptic molecular networks are altered biochemically in these disorders. Here, we apply multiplexed imaging to probe the effects of RNAi knockdown of 16 autism- and schizophrenia-associated genes on the simultaneous joint distribution of 10 synaptic proteins, observing several protein composition phenotypes associated with these risk genes. We apply Bayesian network analysis to infer hierarchical dependencies among eight excitatory synaptic proteins, yielding predictive relationships that can only be accessed with single-synapse, multiprotein measurements performed simultaneously in situ. Finally, we find that central features of the network are affected similarly across several distinct gene knockdowns. These results offer insight into the convergent molecular etiology of these widespread disorders and provide a general framework to probe subcellular molecular networks.

Síndrome de intestino irritable en la enfermedad inflamatoria intestinal. ¿Sinergia en las alteraciones del eje cerebro-intestino? / Irritable bowel syndrome in inflammatory bowel disease. Synergy in alterations of the gut-brain axis?

La presencia de síntomas digestivos asociados al síndrome de intestino irritable (SII) en pacientes con enfermedad inflamatoria intestinal (EII) en remisión es un tema de interés creciente. Si bien existe una heterogeneidad de los estudios clínicos en relación con el uso de criterios de remisión de la EII y del diagnóstico de SII, los datos disponibles indican que la superposición EII-SII afectaría hasta un tercio de los pacientes en remisión, y coinciden en el hallazgo de un impacto negativo en la salud mental y calidad de vida de los individuos que la padecen. Las bases fisiopatológicas que explicarían esta potencial superposición no están completamente dilucidadas, sin embargo, la alteración en el eje cerebro-intestino asociada al aumento en la permeabilidad intestinal, la activación neuroinmune y la disbiosis serían fenómenos comunes a ambas condiciones. La hipótesis de una nueva entidad clínica o síndrome de «enfermedad inflamatoria intestinal irritable» o «SII postinflamatorio» con un perfil de microinflamación distintivo del SII, es motivo de intensa investigación. El reto clínico supone certificar la remisión de la actividad de la EII y descartar otras causas no inflamatorias de síntomas digestivos funcionales persistentes potencialmente tratables. En el caso de síntomas asociados a SII, a falta de evidencia suficiente, se debe realizar un control integral y personalizado del cuadro clínico (medidas dietéticas, farmacológicas y psicoterapéuticas), similar a un SII genuino.

The presence of digestive symptoms associated with irritable bowel syndrome (IBS) in patients with inflammatory bowel disease (IBD) in remission is a topic of growing interest. Although there is heterogeneity in clinical studies regarding the use of IBD remission criteria and the diagnosis of IBS, the available data indicate that the IBD-IBS overlap would affect up to one third of patients in remission, and they agree on the finding of a negative impact on the mental health and quality of life of the individuals who suffer from it. The pathophysiological bases that would explain this potential overlap are not completely elucidated; however, an alteration in the gut-brain axis associated with an increase in intestinal permeability, neuroimmune activation and dysbiosis would be common to both conditions. The hypothesis of a new clinical entity or syndrome of “Irritable Inflammatory Bowel Disease” or “Post-inflammatory IBS” is the subject of intense investigation. The clinical approach is based on certifying the remission of IBD activity and ruling out other non-inflammatory causes of potentially treatable persistent functional digestive symptoms. In the case of symptoms associated with IBS and in the absence of sufficient evidence, comprehensive and personalized management of the clinical picture (dietary, pharmacological and psychotherapeutic measures) should be carried out, similar to a genuine IBS.

Irritable bowel syndrome in inflammatory bowel disease. Synergy in alterations of the gut-brain axis? / Síndrome de intestino irritable en la enfermedad inflamatoria intestinal. ¿Sinergia en las alteraciones del eje cerebro-intestino?

The presence of digestive symptoms associated with irritable bowel syndrome (IBS) in patients with inflammatory bowel disease (IBD) in remission is a topic of growing interest. Although there is heterogeneity in clinical studies regarding the use of IBD remission criteria and the diagnosis of IBS, the available data indicate that the IBD-IBS overlap would affect up to one third of patients in remission, and they agree on the finding of a negative impact on the mental health and quality of life of the individuals who suffer from it. The pathophysiological bases that would explain this potential overlap are not completely elucidated; however, an alteration in the gut-brain axis associated with an increase in intestinal permeability, neuroimmune activation and dysbiosis would be common to both conditions. The hypothesis of a new clinical entity or syndrome of "Irritable Inflammatory Bowel Disease" or "Post-inflammatory IBS" is the subject of intense investigation. The clinical approach is based on certifying the remission of IBD activity and ruling out other non-inflammatory causes of potentially treatable persistent functional digestive symptoms. In the case of symptoms associated with IBS and in the absence of sufficient evidence, comprehensive and personalized management of the clinical picture (dietary, pharmacological and psychotherapeutic measures) should be carried out, similar to a genuine IBS.

The Dilemma of Persistent Irritable Bowel Syndrome Symptoms in Patients with Quiescent Inflammatory Bowel Disease.

Irritable bowel syndrome and inflammatory bowel disease differ in their natural evolution, etiopathogenesis, diagnostic criteria, and therapeutic approach. However, recent evidence has suggested some similarities in mechanisms underlying symptom development and progression. There is a relevant role for alterations in the microbiome-brain-gut axis in both diseases. The presence of irritable bowel syndrome symptoms in patients with quiescent inflammatory bowel disease is common in clinical practice. To determine the cause of irritable bowel syndrome symptoms in patients with quiescent inflammatory bowel disease is a clinical challenge. This review aims to illustrate possible causes and solutions for these patients.

The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a gut-brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation-predominant IBS (IBS-C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta-analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS-C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow-up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS-C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis.

Sexual Dysfunction in Inflammatory Bowel Disease: What the Specialist Should Know and Ask.

Inflammatory bowel disease (IBD) is a chronic condition that globally affects the health of people who suffer from it, deteriorating their quality of life (QoL). An aspect rarely explored by healthcare providers is the influence of the disease on the sexual functioning of individuals. This discretion is mainly due to an unconscious resistance when asking our patients about their sexual functioning because of a lack of knowledge and skills to tackle this topic or disinterest on the part of professionals, and fear or shame on the part of patients. Sexual function is a constant concern in IBD patients that has been reflected in several studies, especially if we consider that the prevalence of sexual dysfunction (SD) in IBD is higher than that reported in the general population. The etiology of SD in patients with IBD remains unclear but is likely to be multifactorial, where biological, psychosocial, and disease-specific factors are involved. Currently, there are no formal recommendations in the IBD clinical guidelines on how to manage SD in these patients. The use of validated clinical scales could improve the detection of SD and allow the treatment of the underlying causes in order to improve the QoL of patients with IBD. This review aims to illustrate the different aspects involved in SD in IBD patients and the importance of the participation of a multidisciplinary team in the early detection and treatment of SD at different stages of the disease.

Molecular Diversity of Glutamatergic and GABAergic Synapses from Multiplexed Fluorescence Imaging.

Neuronal synapses contain hundreds of different protein species important for regulating signal transmission. Characterizing differential expression profiles of proteins within synapses in distinct regions of the brain has revealed a high degree of synaptic diversity defined by unique molecular organization. Multiplexed imaging of in vitro rat primary hippocampal culture models at single synapse resolution offers new opportunities for exploring synaptic reorganization in response to chemical and genetic perturbations. Here, we combine 12-color multiplexed fluorescence imaging with quantitative image analysis and machine learning to identify novel synaptic subtypes within excitatory and inhibitory synapses based on the expression profiles of major synaptic components. We characterize differences in the correlated expression of proteins within these subtypes and we examine how the distribution of these synapses is modified following induction of synaptic plasticity. Under chronic suppression of neuronal activity, phenotypic characterization revealed coordinated increases in both excitatory and inhibitory protein levels without changes in the distribution of synaptic subtypes, suggesting concerted events targeting glutamatergic and GABAergic synapses. Our results offer molecular insight into the mechanisms of synaptic plasticity.

[Biomarkers in inflammatory bowel disease]. / Biomarcadores en enfermedad inflamatoria intestinal: ¿sabe cómo utilizarlos?

Biomarkers in inflammatory bowel disease are an essential tool in clinical practice. They allow a non-invasive evaluation of patients and thus guide decision-making at different stages of the disease, including diagnostic suspicion, severity assessment, relapse prediction, and treatment response. Although biomarkers in blood such as erythrocyte sedimentation rate and C-reactive protein, are the most commonly used biomarkers, because their low cost and accessibility, they lack specificity. Currently, fecal biomarkers offer greater reliability, applicability, and specificity. Fecal calprotectin is the most commonly used marker. This review discusses the advantages and disadvantages of biomarkers in inflammatory bowel disease, as well as their clinical applications and new biomarkers currently under research.

Biomarcadores en enfermedad inflamatoria intestinal: ¿sabe cómo utilizarlos? / Biomarkers in inflammatory bowel disease

Biomarkers in inflammatory bowel disease are an essential tool in clinical practice. They allow a non-invasive evaluation of patients and thus guide decision-making at different stages of the disease, including diagnostic suspicion, severity assessment, relapse prediction, and treatment response. Although biomarkers in blood such as erythrocyte sedimentation rate and C-reactive protein, are the most commonly used biomarkers, because their low cost and accessibility, they lack specificity. Currently, fecal biomarkers offer greater reliability, applicability, and specificity. Fecal calprotectin is the most commonly used marker. This review discusses the advantages and disadvantages of biomarkers in inflammatory bowel disease, as well as their clinical applications and new biomarkers currently under research.

Multiplexed and high-throughput neuronal fluorescence imaging with diffusible probes.

Synapses contain hundreds of distinct proteins whose heterogeneous expression levels are determinants of synaptic plasticity and signal transmission relevant to a range of diseases. Here, we use diffusible nucleic acid imaging probes to profile neuronal synapses using multiplexed confocal and super-resolution microscopy. Confocal imaging is performed using high-affinity locked nucleic acid imaging probes that stably yet reversibly bind to oligonucleotides conjugated to antibodies and peptides. Super-resolution PAINT imaging of the same targets is performed using low-affinity DNA imaging probes to resolve nanometer-scale synaptic protein organization across nine distinct protein targets. Our approach enables the quantitative analysis of thousands of synapses in neuronal culture to identify putative synaptic sub-types and co-localization patterns from one dozen proteins. Application to characterize synaptic reorganization following neuronal activity blockade reveals coordinated upregulation of the post-synaptic proteins PSD-95, SHANK3 and Homer-1b/c, as well as increased correlation between synaptic markers in the active and synaptic vesicle zones.

Efecto del envejecimiento en el estudio y manejo de la enfermedad por reflujo gastroesofágico / Effect of aging on the study and management of Gastroesophageal Reflux Disease

The prevalence of Gastroesophageal Reflux Disease (GERD) seems to increase in the elderly population, being more severe and associating more complications than younger subjects. A high frequency of atypical symptoms (chest pain, dysphagia, vomiting, and respiratory symptoms) and less frequently heartburn and / or regurgitation that are of mild intensity are described, due to the decrease of the visceral sensitivity of the esophagus with age, which delays the diagnosis. Factors associated with aging predispose to the development of GERD in the geriatric population: the reduction of salivary flow and bicarbonate secretion, alterations in esophageal motility and the greater frequency of hiatal hernias are some of them. Given the high frequency of complications of reflux (erosive esophagitis, Barrett's esophagus, stenosis and ulcers, and esophageal cancer), elderly patients benefit from an early endoscopic study. Its management must be aggressive and start with changes in lifestyle and dietary modifications. Proton pump inhibitors (PPIs) continue to be the first line of pharmacological treatment as well as in the youngest population. Surgical treatment is reserved in selected patients considering risks/benefits.

La prevalencia de la enfermedad por reflujo gastroesofágico (ERGE) parece aumentar en la población adulto mayor, siendo más severa y asociando más complicaciones que en los sujetos más jóvenes. Clínicamente se caracteriza una alta frecuencia de síntomas atípicos (dolor torácico, disfagia, vómitos, síntomas respiratorios) y menos frecuentemente por pirosis y/o regurgitación que son de leve intensidad, debido a la disminución de la sensibilidad visceral del esófago con la edad, lo que hace retardar el diagnóstico. Factores asociados al envejecimiento predisponen al desarrollo de ERGE en la población geriátrica: la disminución de la secreción salival y de bicarbonato, las alteraciones de la motilidad esofágica y la mayor frecuencia de hernias hiatales, son algunos de ellos. Dada la alta frecuencia de complicaciones del reflujo (esofagitis erosiva, esófago de Barrett, estenosis y úlceras y cáncer de esófago), los pacientes adultos mayores se benefician de un estudio endoscópico precoz. Su manejo debe ser agresivo e iniciar con cambios de estilo de vida y modificaciones dietarias. Los inhibidores de bomba de protones (IBP) siguen siendo la primera línea de tratamiento farmacológico al igual que en la población más joven. El tratamiento quirúrgico queda reservado en pacientes seleccionados considerando riesgos/beneficios.

Las alteraciones de la microbiota intestinal en la patogenia del hígado graso no alcohólico / Alterations of the intestinal microbiota in the pathogenesis of nonalcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is currently considered in Chile and worldwide, as the main cause of cirrhosis and liver transplantation. It is therefore one of the main public health objectives for reducing its prevalence. In last years, it was suggested that the intestinal microbiota (IM) might contribute to the pathophysiology of NAFLD, as well as in the progression toward nonalcoholic steatohepatitis (NASH) and cirrhosis. It is known that changes in the composition of IM are associated with alterations in intestinal permeability and the production of inflammatory metabolites. These alterations are part of the pathophysiological mechanisms leading to the development of NASH. However studies on MI in patients with NAFLD and NASH in Chile are scarce. Through a research grant, recently awarded at the Hospital Clínico Universidad de Chile, we aim to confirm and characterize the intestinal dysbiosis associated with NAFLD in Chilean patients and to establish the relationship between the changes in microbial composition with the progression of liver damage. The description of these alterations represents an opportunity to explore new therapeutic approaches for future interventions. In effect, through the restoration of an intestinal microbial environment towards homeostasis in these patients, we expect to reverse or improve the progression of damage provoked by this disease. (AU)

Retención de cápsula endoscópica en enfermedad de Crohn ¿cómo manejarla? / Retained capsule endoscopy in Crohn´s disease: how to manage it?

Capsule endoscopy is a technique that allows the study of the small intestine, through a device that is swallowed by the patient, capturing images as it travels through the digestive tract. Capsule retention is the most serious complication. We report the case of a 69 year-old male presenting with iron deficiency anemia, with normal upper endoscopy and colonoscopy; but obscure gastrointestinal bleeding was diagnosed and therefore a study with capsule endoscopy was requested. The patient evolves with retained capsule in the small intestine with ulcerated stenosis as shown by imaging. This finding was confirmed by enteroscopy with biopsy, without being able to extract the capsule. Medical management with corticosteroids was indicated for intestinal obstruction secondary to inflammatory stenosis in the context of Crohn's disease: The capsule was expelled after 21 days of ingestion, with a positive outcome

La cápsula endoscópica es una técnica que permite el estudio del intestino delgado, mediante un dispositivo que es deglutido por el paciente y captura imágenes en su recorrido por el tubo digestivo. La complicación más grave es la retención de la cápsula. Se reporta el caso de un paciente de sexo masculino, de 69 años con anemia ferropénica, con endoscopia alta y colonoscopia normal; planteándose sangrado gastrointestinal de origen oscuro por lo que se solicita estudio con cápsula endoscópica. El paciente evoluciona con retención de la cápsula en intestino delgado, visualizándose en las imágenes la presencia de estenosis ulcerada, hallazgo que se confirma mediante enteroscopia con toma de biopsias, sin lograr extraer la cápsula. Se indica manejo médico con corticoides por obstrucción intestinal secundario a estenosis inflamatoria en contexto de enfermedad de Crohn, expulsando espontáneamente la cápsula al día 21 de su ingestión, sin complicaciones.

[Delusional parasitosis intestinal and dermatological: clinical cases]. / Parasitosis ilusoria intestinal y dermatológica: casos clínicos.

Illusory parasitosis, better known as delusional parasitosis, is a neuropsychiatric syndrome in which patients have the belief of suffering a parasitic disease, that can not be demonstrated after an exhaustive medical study. These patients are characterized by being polyconsultants in different medical specialties and, many of them, have antecedents of psychiatric disorders, some of them undiagnosed. Knowing the existence of the clinical picture, diagnosing early and empathizing with the patient, could give to clinician some clues for a timely and assertive psychiatric referral, and improve patient adherence to the proposed treatment.

Parasitosis ilusoria intestinal y dermatológica: casos clínicos / Delusional parasitosis intestinal and dermatological: clinical cases

Illusory parasitosis, better known as delusional parasitosis, is a neuropsychiatric syndrome in which patients have the belief of suffering a parasitic disease, that can not be demonstrated after an exhaustive medical study. These patients are characterized by being polyconsultants in different medical specialties and, many of them, have antecedents of psychiatric disorders, some of them undiagnosed. Knowing the existence of the clinical picture, diagnosing early and empathizing with the patient, could give to clinician some clues for a timely and assertive psychiatric referral, and improve patient adherence to the proposed treatment.

La parasitosis ilusoria, más conocida como delusión parasitaria, es un síndrome neuropsiquiátrico donde los pacientes tienen el convencimiento de padecer una infestación parasitaria, que no puede ser demostrada tras un exhaustivo estudio médico. Estos pacientes se caracterizan por ser policonsultantes en distintas especialidades médicas y, muchos de ellos, poseen antecedentes de trastornos psiquiátricos, algunos de ellos no diagnosticados. Conocer la existencia del cuadro, diagnosticar precozmente y empatizar con el paciente, pueden dar al médico clínico algunas claves para una derivación psiquiátrica oportuna y asertiva, y mejorar la adherencia del paciente al tratamiento propuesto. Se presentan cuatro casos clínicos que consultaron por esta extraña condición.

Dual Inhibition of Bruton's Tyrosine Kinase and Phosphoinositide-3-Kinase p110δ as a Therapeutic Approach to Treat Non-Hodgkin's B Cell Malignancies.

Although new targeted therapies, such as ibrutinib and idelalisib, have made a large impact on non-Hodgkin's lymphoma (NHL) patients, the disease is often fatal because patients are initially resistant to these targeted therapies, or because they eventually develop resistance. New drugs and treatments are necessary for these patients. One attractive approach is to inhibit multiple parallel pathways that drive the growth of these hematologic tumors, possibly prolonging the duration of the response and reducing resistance. Early clinical trials have tested this approach by dosing two drugs in combination in NHL patients. We discovered a single molecule, MDVN1003 (1-(5-amino-2,3-dihydro-1H-inden-2-yl)-3-(8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), that inhibits Bruton's tyrosine kinase and phosphatidylinositol-3-kinase δ, two proteins regulated by the B cell receptor that drive the growth of many NHLs. In this report, we show that this dual inhibitor prevents the activation of B cells and inhibits the phosphorylation of protein kinase B and extracellular signal-regulated kinase 1/2, two downstream mediators that are important for this process. Additionally, MDVN1003 induces cell death in a B cell lymphoma cell line but not in an irrelevant erythroblast cell line. Importantly, we found that this orally bioavailable dual inhibitor reduced tumor growth in a B cell lymphoma xenograft model more effectively than either ibrutinib or idelalisib. Taken together, these results suggest that dual inhibition of these two key pathways by a single molecule could be a viable approach for treatment of NHL patients.