Bromodomain inhibition overcomes treatment resistance in distinct molecular subtypes of melanoma.

Therapy of BRAF-mutant melanoma with selective inhibitors of BRAF (BRAFi) and MEK (MEKi) represents a major clinical advance but acquired resistance to therapy has emerged as a key obstacle. To date, no clinical approaches successfully resensitize to BRAF/MEK inhibition. Here, we develop a therapeutic strategy for melanoma using bromosporine, a bromodomain inhibitor. Bromosporine (bromo) monotherapy produced significant anti-tumor effects against established melanoma cell lines and patient-derived xenografts (PDXs). Combinatorial therapy involving bromosporine and cobimetinib (bromo/cobi) showed synergistic anti-tumor effects in multiple BRAFi-resistant PDX models. The bromo/cobi combination was superior in vivo to standard BRAFi/MEKi therapy in the treatment-naive BRAF-mutant setting and to MEKi alone in the setting of immunotherapy-resistant NRAS- and NF1-mutant melanoma. RNA sequencing of xenografts treated with bromo/cobi revealed profound down-regulation of genes critical to cell division and mitotic progression. Bromo/cobi treatment resulted in marked DNA damage and cell-cycle arrest, resulting in induction of apoptosis. These studies introduce bromodomain inhibition, alone or combined with agents targeting the mitogen activated protein kinase pathway, as a rational therapeutic approach for melanoma refractory to standard targeted or immunotherapeutic approaches.

Niraparib Suppresses Cholangiocarcinoma Tumor Growth by Inducing Oxidative and Replication Stress.

Cholangiocarcinoma (CCA) is the second most common hepatobiliary cancer, an aggressive malignancy with limited therapeutic options. PARP (poly (ADP-ribose) polymerase) 1 and 2 are important for deoxyribonucleotide acid (DNA) repair and maintenance of genomic stability. PARP inhibitors (PARPi) such as niraparib have been approved for different malignancies with genomic alteration in germline BRCA and DNA damage response (DDR) pathway genes. Genomic alterations were analyzed in DDR genes in CCA samples employing The Cancer Genome Atlas (TCGA) database. Mutations were observed in various DDR genes, and 35.8% cases had alterations in at least one of three genes (ARID1A, BAP1 and ATM), suggesting their susceptibility to PARPi. Niraparib treatment suppressed cancer cell viability and survival, and also caused G2/M cell cycle arrest in patient-derived xenograft cells lines (PDXC) and established CCA cells harboring DDR gene mutations. PARPi treatment also induced apoptosis and caspase3/7 activity in PDXC and CCA cell lines, and substantially reduced expression of BCL2, BCL-XL and MCL1 proteins. Niraparib caused a significant increase in oxidative stress, and induced activation of DNA damage markers, phosphorylation of CHK2 and replication fork stalling. Importantly, niraparib, in combination with gemcitabine, produced sustained and robust inhibition of tumor growth in vivo in a patient-derived xenograft (PDX) model more effectively than either treatment alone. Furthermore, tissue samples from mice treated with niraparib and gemcitabine display significantly lower expression levels of pHH3 and Ki-67, which are a mitotic and proliferative marker, respectively. Taken together, our results indicate niraparib as a novel therapeutic agent alone or in combination with gemcitabine for CCA.

A Novel Large Scale Integrated Telemonitoring Program for COVID-19.

Introduction: Coronavirus disease 2019 (COVID-19) has forced health care systems to rethink the optimal delivery of health care services and has dramatically increased demand for general medicine providers (internal medicine, family medicine, emergency medicine), while simultaneously reducing demand for many subspecialty services. At Kaiser Permanente, we implemented a program wherein health care providers drawn from multiple disciplines perform daily telemedicine check-ins on COVID-19 patients, allowing us to both maintain social distancing and make use of providers in specialties who otherwise may have had lower in-clinic volumes. Methods: Kaiser Permanente patients testing positive for COVID-19 between March and October 2020 were referred to our program. Physicians and nurses (RNs) were invited to participate in our program and were trained using Microsoft Teams™ meetings. Patients receive daily phone calls by a physician or RN. Select patients receive portable pulse oximeter devices based on standardized criteria incorporating age and comorbidities. When patients are determined to be clinically stable, they are discharged back to their primary care physician for ongoing management. Results: Descriptive results for the virtual home care program (VHCP) are reported through October 2020, though these results do not represent a planned statistical analysis. Forty-two percent of the patients were male, 43% were black, and 30% were Hispanic. The most common comorbidities of patients in our program were obesity (body mass index >30 kg/m2; 35%), followed by hypertension (32%) and diabetes mellitus (19%). Then, 8.2% of patients ultimately required hospital admission. Mortality rate for patients in our program was 1.33%. Discussion: Our program was able to provide virtual care for thousands of COVID-19 positive Kaiser members in the Washington, DC, and Baltimore Metro regions. We did so by utilizing physicians and RNs from specialties experiencing a decrease in clinic volume attributable to the COVID-19 pandemic. The experiences of our program may be valuable to clinicians wishing to establish similar programs of their own.

Dual Targeting of G9a and DNA Methyltransferase-1 for the Treatment of Experimental Cholangiocarcinoma.

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is a devastating disease often detected at advanced stages when surgery cannot be performed. Conventional and targeted systemic therapies perform poorly, and therefore effective drugs are urgently needed. Different epigenetic modifications occur in CCA and contribute to malignancy. Targeting epigenetic mechanisms may thus open therapeutic opportunities. However, modifications such as DNA and histone methylation often coexist and cooperate in carcinogenesis. We tested the therapeutic efficacy and mechanism of action of a class of dual G9a histone-methyltransferase and DNA-methyltransferase 1 (DNMT1) inhibitors. APPROACH AND RESULTS: Expression of G9a, DNMT1, and their molecular adaptor, ubiquitin-like with PHD and RING finger domains-1 (UHRF1), was determined in human CCA. We evaluated the effect of individual and combined pharmacological inhibition of G9a and DNMT1 on CCA cell growth. Our lead G9a/DNMT1 inhibitor, CM272, was tested in human CCA cells, patient-derived tumoroids and xenograft, and a mouse model of cholangiocarcinogenesis with hepatocellular deletion of c-Jun-N-terminal-kinase (Jnk)-1/2 and diethyl-nitrosamine (DEN) plus CCl4 treatment (JnkΔhepa + DEN + CCl4 mice). We found an increased and correlative expression of G9a, DNMT1, and UHRF1 in CCAs. Cotreatment with independent pharmacological inhibitors G9a and DNMT1 synergistically inhibited CCA cell growth. CM272 markedly reduced CCA cell proliferation and synergized with Cisplatin and the ERBB-targeted inhibitor, Lapatinib. CM272 inhibited CCA tumoroids and xenograft growth and significantly antagonized CCA progression in JnkΔhepa + DEN + CCl4 mice without apparent toxicity. Mechanistically, CM272 reprogrammed the tumoral metabolic transcriptome and phenotype toward a differentiated and quiescent status. CONCLUSIONS: Dual targeting of G9a and DNMT1 with epigenetic small molecule inhibitors such as CM272 is a potential strategy to treat CCA and/or enhance the efficacy of other systemic therapies.

Gastro-allergic anisakiasis: The first case reported in Colombia and a literature review / Anisakiasis gastro-alérgica, primera descripción de un caso en Colombia y revisión bibliográfica

Anisakiasis is a zoonotic parasitic disease caused by consumption of raw or undercooked fish or seafood infected with nematodes of the Anisakis, Pseudoterranova or Contracaecum genera. Here, we describe the first case of anisakiasis in Colombia and summarize the available literature. A 52-year-old female with a history of abrupt-onset sharp epigastric pain, nausea, vomit, diarrhea, and urticaria following fish consumption consulted the health service. The physical examination revealed moderate tenderness of the epigastric region; the laboratory evaluation showed leukocytosis and a simple X-ray and ECG showed no abnormalities. The diagnosis was made by endoscopic examination, which revealed a thickened gastric wall and a moving larval worm. An Anisakis larva was found and extracted endoscopically, which relieved the pain of the patient. Clinically, anisakiasis may present as a gastric, intestinal, extragastrointestinal or allergic disease. Diagnosis and treatment of anisakiasis are made by a dietary history, direct visualization and endoscopic extraction of possible larvae, which is the only effective therapy.

La anisakiasis es una enfermedad parasitaria zoonótica causada por el consumo de pescados o mariscos crudos o poco cocidos infectados con nematodos de los géneros Anisakis, Pseudoterranova y Contracaecum. Se describe el primer caso de anisakiasis en Colombia y se resume la literatura médica disponible. Una mujer de 52 años de edad consultó por dolor epigástrico agudo de inicio abrupto, náuseas, vómitos, diarrea y urticaria después de consumir pescado. El examen físico reveló sensibilidad moderada en el epigastrio. El examen de laboratorio evidenció leucocitosis, en tanto que la radiografía simple y el electrocardiograma no reflejaron ninguna anormalidad. El diagnóstico se hizo mediante una endoscopia de vías digestivas altas, la cual reveló engrosamiento de la pared gástrica y un parásito en movimiento. Se encontró una larva de Anisakis y se la extrajo por endoscopia, lo que alivió el dolor de la paciente. Clínicamente, la anisakiasis puede presentarse como una enfermedad gástrica, intestinal, en otros sistemas o alérgica. El diagnóstico se hace con base en la elaboración del historial alimentario del paciente y la visualización directa de las larvas; el único tratamiento efectivo consiste en su extracción endoscópica.

Anisakiasis gastro-alérgica, primera descripción de un caso en Colombia y revisión bibliográfica / Gastro-allergic anisakiasis: The first case reported in Colombia and a literature review

Resumen La anisakiasis es una enfermedad parasitaria zoonótica causada por el consumo de pescados o mariscos crudos o poco cocidos infectados con nematodos de los géneros Anisakis, Pseudoterranova y Contracaecum. Se describe el primer caso de anisakiasis en Colombia y se resume la literatura médica disponible. Una mujer de 52 años de edad consultó por dolor epigástrico agudo de inicio abrupto, náuseas, vómitos, diarrea y urticaria después de consumir pescado. El examen físico reveló sensibilidad moderada en el epigastrio. El examen de laboratorio evidenció leucocitosis, en tanto que la radiografía simple y el electrocardiograma no reflejaron ninguna anormalidad. El diagnóstico se hizo mediante una endoscopia de vías digestivas altas, la cual reveló engrosamiento de la pared gástrica y un parásito en movimiento. Se encontró una larva de Anisakis y se la extrajo por endoscopia, lo que alivió el dolor de la paciente. Clínicamente, la anisakiasis puede presentarse como una enfermedad gástrica, intestinal, en otros sistemas o alérgica. El diagnóstico se hace con base en la elaboración del historial alimentario del paciente y la visualización directa de las larvas; el único tratamiento efectivo consiste en su extracción endoscópica.

Abstract Anisakiasis is a zoonotic parasitic disease caused by consumption of raw or undercooked fish or seafood infected with nematodes of the Anisakis, Pseudoterranova or Contracaecum genera. Here, we describe the first case of anisakiasis in Colombia and summarize the available literature. A 52-year-old female with a history of abrupt-onset sharp epigastric pain, nausea, vomit, diarrhea, and urticaria following fish consumption consulted the health service. The physical examination revealed moderate tenderness of the epigastric region; the laboratory evaluation showed leukocytosis and a simple X-ray and ECG showed no abnormalities. The diagnosis was made by endoscopic examination, which revealed a thickened gastric wall and a moving larval worm. An Anisakis larva was found and extracted endoscopically, which relieved the pain of the patient. Clinically, anisakiasis may present as a gastric, intestinal, extragastrointestinal or allergic disease. Diagnosis and treatment of anisakiasis are made by a dietary history, direct visualization and endoscopic extraction of possible larvae, which is the only effective therapy.

Pulmonary alveolar microlithiasis / Microlitiasis alveolar pulmonar

Pulmonary alveolar microlithiasis is an uncommon disease of unknown etiology, and is characterized by the presence of multiple sub-pleural and intra-alveolar microcalcifications. We present the case of a patient with rheumatoid arthritis and chronic renal disease, but with no respiratory symptoms.

La microlitiasis pulmonar alveolar es una enfermedad infrecuente, de etiología desconocida, caracterizada por la presencia de múltiples microcalcificaciones intraalveolares y subpleurales. Presentamos el caso de un paciente asintomático respiratorio, con historia clínica de artritis reumatoide y enfermedad renal crónica.

Entesis, entesopatía y espondiloartritis / Entheses, enthesopathy and spondyloarthritis

Las espondiloartritis (SpA) comprenden un grupo heterogéneo de enfermedades inflamatorias articulares que comparten varias características clínicas y de laboratorio, una fuerte tendencia a la asociación familiar dada por una susceptibilidad genética relacionada con la presencia del antígeno de histocompatibilidad HLA-B27, compromiso de las entesis, afectación predominante del esqueleto axial, artritis asimétrica de grandes articulaciones en los miembros inferiores y relación con la infección como factor desencadenante de las mismas. Las SpA incluyen varios subtipos: la artropatía psoriásica (PsA), las espondiloartritis no definidas (uSpA), la artritis asociada a enfermedades inflamatorias intestinales (EII), la artritis reactiva (ReA) y la espondilitis anquilosante (EA). La característica histopatológica fundamental de las SpA es la entesitis, la cual está dada por la inflamación patológica de las entesis comprometidas, que son los sitios de inserción de los tendones, ligamentos, fascias y cápsulas articulares al hueso; así como también el sitio de unión del cartílago al hueso subcondral.

Spondyloarthritis are a heterogeneous group of inflammatory joint diseases, which share clinic and laboratory characteristics, a strong relation to hereditary factors (mainly antigen HLA-B27), enthesesitis (most commonly affecting axial skeleton), large joints asymmetric arthritis mostly in lower limbs, and its relationship with infections as a triggering factor. Spondyloarthitis include various subtypes: Psoriatic Arthropathy (PsA), Undifferentiated Spondiloarthritis (uSpA), Arthritis related to inflammatory bowel disease (IBD), Ankylosing Spondylitis (AS) and Reactive Arthritis (ReA). Fundamental histopathologic characteristic of the Spondyloarthritis is enthesitis on the sites of attachment of tendons, ligaments, joint capsules and fascias to the bone, but also over the cartilage at the subchondral bone.

Diagnóstico de Artritis Psoriática / Diagnosis of Psoriatic Arthritis

La artritis psoriática es una enfermedad de relativamente reciente descripción en el campo de la reumatología, pues previamente se consideraba que este tipo de pacientes cursaban con dos entidades nosológicas distintas que convergían en el tiempo: psoriasis y artritis reumatoide. Han sido múltiples los intentos por clasificar adecuadamente a estos pacientes y esto ha llevado a la aparición de 7 criterios de clasificación en los últimos 36 años. En el presente artículo haremos un recuento de las principales características clínicas, de laboratorio e imagenológicas de la artritis psoriática. Además, cada uno de los criterios de clasificación se describirá en orden cronológico de aparición.

Psoriatic arthritis is a relatively recent description disease in the rheumatology field. Previously physicians considered that the patient with psoriasis and any type of arthropathy had two diseases that coincided at the time: psoriasis and rheumatoid arthritis. There have been many attempts to classify these patients adequately. In the last 36 years seven criteria for the classification of this entity have appeared. In this article we made a summary of the clinical characteristics, laboratories and imaging in psoriatic arthritis. Furthermore, we intend to describe the classification criteria in chronological order.