Potassium/sodium cation carriers robustly up-regulate CD20 antigen by targeting MYC, and synergize with anti-CD20 immunotherapies to eliminate malignant B cells.

Our investigation uncovers that nanomolar concentrations of salinomycin, monensin, nigericin, and narasin (a group of potassium/sodium cation carriers) robustly enhance surface expression of CD20 antigen in B-cell-derived tumor cells, including primary malignant cells of chronic lymphocytic leukemia and diffuse large B-cell lymphoma. Experiments in vitro, ex vivo, and animal model reveal a novel approach of combining salinomycin or monensin with therapeutic anti-CD20 monoclonal antibodies or anti-CD20 CAR-T cells, significantly improving non- Hodgkin lymphoma (NHL) therapy. The results of RNA-seq, genetic editing, and chemical inhibition delineate the molecular mechanism of CD20 upregulation, at least partially, to the downregulation of MYC, the transcriptional repressor of the MS4A1 gene encoding CD20.

IDIOPATHIC RETINAL VASCULITIS, ANEURYSMS, AND NEURORETINITIS COMPLICATED BY CILIORETINAL ARTERY OCCLUSION: MULTIMODAL IMAGING AND 5-YEAR FOLLOW-UP.

Purpose: To describe a multimodal imaging and a 5-year follow-up of a case of cilioretinal artery occlusion (CLRAO) in a 40-year-old woman with idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome.

Methods: Fundus photography, indocyanine green and fluorescein angiography, optical coherence tomography (OCT), OCT angiography (OCTA), and a literature review of retinal artery occlusions associated with IRVAN syndrome were performed.

Results: Fundus examination revealed bilateral blurred margins of the discs and peri-vascular hard exudates.

NFKBIE mutations are selected by the tumor microenvironment and contribute to immune escape in chronic lymphocytic leukemia.

Loss-of-function mutations in NFKBIE, which encodes for the NF-κB inhibitor IκBε, are frequent in chronic lymphocytic leukemia (CLL) and certain other B-cell malignancies and have been associated with accelerated disease progression and inferior responses to chemotherapy. Using in vitro and in vivo murine models and primary patient samples, we now show that NFKBIE-mutated CLL cells are selected by microenvironmental signals that activate the NF-κB pathway and induce alterations within the tumor microenvironment that can allow for immune escape, including expansion of CD8+ T-cells with an exhausted phenotype and increased PD-L1 expression on the malignant B-cells. Consistent with the latter observations, we find increased expression of exhaustion markers on T-cells from patients with NFKBIE-mutated CLL.

A molecular circuit linking the BCR to the NAD biosynthetic enzyme NAMPT is an actionable target in Richter syndrome.

This works defines, to the best of our knowledge, for the first time a molecular circuit connecting nicotinamide mononucleoside phosphoribosyl transferase (NAMPT) activity to the B-cell receptor (BCR) pathway. Using 4 distinct xenograft models derived from patients with Richter syndrome (RS-PDX), we show that BCR cross-linking results in transcriptional activation of the nicotinamide adenine dinucleotide (NAD) biosynthetic enzyme NAMPT, with increased protein expression, in turn, positively affecting global cellular NAD levels and sirtuins activity. NAMPT blockade, by using the novel OT-82 inhibitor in combination with either BTK or PI3K inhibitors (BTKi or PI3Ki), induces rapid and potent apoptotic responses in all 4 models, independently of their mutational profile and the expression of the other NAD biosynthetic enzymes, including nicotinate phosphoribosyltransferase.

Macrophage- and BCR-derived but not TLR-derived signals support the growth of CLL and Richter syndrome murine models in vivo.

A large amount of circumstantial evidence has accumulated suggesting that Toll-like receptor (TLR) signals are involved in driving chronic lymphocytic leukemia (CLL) cell proliferation, but direct in vivo evidence for this is still lacking. We have now further addressed this possibility by pharmacologically inhibiting or genetically inactivating the TLR pathway in murine CLL and human Richter syndrome (RS) patient-derived xenograft (PDX) cells. Surprisingly, we show that pharmacologic inhibition of TLR signaling by treatment with an IRAK1/4 inhibitor delays the growth of the transplanted malignant cells in recipient mice, but genetic inactivation of the same pathway by CRISPR/Cas9-mediated disruption of IRAK4 or its proximal adaptor MyD88 has no effect.

B-cell receptor signaling and genetic lesions in TP53 and CDKN2A/CDKN2B cooperate in Richter transformation.

B-cell receptor (BCR) signals play a critical role in the pathogenesis of chronic lymphocytic leukemia (CLL), but their role in regulating CLL cell proliferation has still not been firmly established. Unlike normal B cells, CLL cells do not proliferate in vitro upon engagement of the BCR, suggesting that CLL cell proliferation is regulated by other signals from the microenvironment, such as those provided by Toll-like receptors or T cells. Here, we report that BCR engagement of human and murine CLL cells induces several positive regulators of the cell cycle, but simultaneously induces the negative regulators CDKN1A, CDKN2A, and CDKN2B, which block cell-cycle progression.

Preserving Airway Smooth Muscle Contraction in Precision-Cut Lung Slices.

Precision-cut lung slices (PCLS) are ideal for measuring small airway contraction. However, these measurements are currently limited to acute exposure scenarios that typically last a few minutes to a few hours. Using an insulin-supplemented culture medium, we prolong the small airway contractility in mouse PCLS for up to two weeks.

Inhibition of SYK or BTK augments venetoclax sensitivity in SHP1-negative/BCL-2-positive diffuse large B-cell lymphoma.

The BCL-2 inhibitor venetoclax has only limited activity in DLBCL despite frequent BCL-2 overexpression. Since constitutive activation of the B cell receptor (BCR) pathway has been reported in both ABC and GCB DLBCL, we investigated whether targeting SYK or BTK will increase sensitivity of DLBCL cells to venetoclax. We report that pharmacological inhibition of SYK or BTK synergistically enhances venetoclax sensitivity in BCL-2-positive DLBCL cell lines with an activated BCR pathway in vitro and in a xenograft model in vivo, despite the only modest direct cytotoxic effect.

ABT-199 (Venetoclax), a BH3-mimetic Bcl-2 inhibitor, does not cause Ca -signalling dysregulation or toxicity in pancreatic acinar cells.

Background And Purpose: Many cancer cells depend on anti-apoptotic B-cell lymphoma 2 (Bcl-2) proteins for their survival. Bcl-2 antagonism through Bcl-2 homology 3 (BH3) mimetics has emerged as a novel anti-cancer therapy. ABT-199 (Venetoclax), a recently developed BH3 mimetic that selectively inhibits Bcl-2, was introduced into the clinic for treatment of relapsed chronic lymphocytic leukaemia.

Constitutive IP signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP receptor disruptor BIRD-2.

Anti-apoptotic Bcl-2 proteins are upregulated in different cancers, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), enabling survival by inhibiting pro-apoptotic Bcl-2-family members and inositol 1,4,5-trisphosphate (IP) receptor (IPR)-mediated Ca-signaling. A peptide tool (Bcl-2/IPR Disruptor-2; BIRD-2) was developed to abrogate the interaction of Bcl-2 with IPRs by targeting Bcl-2's BH4 domain. BIRD-2 triggers cell death in primary CLL cells and in DLBCL cell lines.

Capecitabine with/without mitomycin C: results of a randomized phase II trial of second-line therapy in advanced biliary tract adenocarcinoma.

Purpose: Advanced biliary tract adenocarcinoma (BTA) is a rare tumor with a poor prognosis. Since no standard salvage chemotherapy regimen exists, we explored the activity of capecitabine alone or combined with mitomycin C.

Methods: Patients aged 18-75 years and with KPS >50, with pathological diagnosis of BTA stratified based on site and stage of disease, were randomized to receive capecitabine 2000 mg/m(2) day 1-14 alone (ARM A) or in combination with mitomycin C 6 mg/m(2) day 1 (ARM B) as second-line therapy.

[Sequential inhibition of angiogenesis in metastatic colorectal cancer: activity and efficacy of aflibercept].

We report a case of a young adult affected by an adenocarcinoma of the ascending colon with synchronous, unresectable liver metastases, diagnosed on April, 2011. The patient received a first-line of bio-chemotherapy with standard folfox regimen in association with bevacizumab. Deriving from which a good partial remission of the disease with its conversion to operability; so he underwent a right hemicolectomy with liver metastasectomy.

Translational challenges from the 2014 Gastrointestinal Cancers Symposium: toward a true tailored therapy through effective research.

Gastrointestinal Cancers Symposium 2014, San Francisco, CA, USA, 16-18 January 2014. The Gastrointestinal Cancers Symposium represents an indisputable occasion for sharing results and research opportunities for investigators around the globe. Across the years along with clinical trials presentations the meeting increasingly acquired a distinct role as a scientific arena for translational research.

Target organ damage and ambulatory blood pressure in stage I hypertension. The Hypertension and Ambulatory Recording Venetia Study.

According to recent international guidelines the decision on whether to treat young subjects during the early phase of hypertension should be based not only on their office blood pressure but also on their ambulatory blood pressure and whether target organ damage has occurred. Few data on the prevalence of hypertensive complications in young subjects with mild hypertension are available. In the Hypertension and Ambulatory Recording Venetia Study (HARVEST), a multicenter trial conducted in northeast Italy, the percentage of young borderline-to-mild hypertensive subjects with echocardiographic left ventricular hypertrophy was 4.

[Alcohol consumption and coronary disease in men].

It has been recently suggested by many epidemiological studies, and emphasized by a nonspecialistic press, that a moderate alcohol intake may exert a protective role in coronary heart diseases. In our study, by means of a questionnaire, the consumption of alcohol in 100 male patients, less than 70 years old, affected by myocardial infarction and/ or angina pectoris, has been evaluated during a period before and after the admission to our Coronary Care Unit. On the basis of their alcohol intake, patients were divided into five categories: abstainers (8%), daily intake lower than one drink (7%), between one and two drinks (8%) between three and four drinks (46%) and equal or higher than five drinks (31%).

[Colchicine in the treatment of idiopathic recurrent pericarditis. Report of a case].

Treatment of recurrence, which is one of the major complications of pericarditis, is often difficult. After three recurrences of idiopathic acute pericarditis, over a period of four months, despite therapy with acetylsalicylic acid, indomethacin and methilprednisolone, a patient, 37 years old, responded favorably to colchine treatment. No recurrences, no side effects were observed, after a prolonged low dose treatment.

Effect of phenobarbital on the pharmacokinetics of carbamazepine-10,11-epoxide, an active metabolite of carbamazepine.

The single oral dose kinetics of carbamazepine-10,11-epoxide (CBZ-E), the active metabolite of carbamazepine, were studied in six epileptic patients, stabilized on phenobarbital (PB) monotherapy, and in six drug-free health volunteers. The epoxide metabolite was administered as an enteric-coated tablet at the dose of 200 mg to the patients and at the dose of 100 mg to the volunteers. Patients had a significantly higher plasma clearance of CBZ-E than the control group (mean values +/- SD = 220.

Debrisoquine oxidation phenotype during neuroleptic monotherapy.

The debrisoquine oxidation phenotype was determined in 91 schizophrenic patients on monotherapy with different neuroleptics and in 67 untreated healthy volunteers. The prevalence of poor metabolizers of debrisoquine was significantly higher in the patients (46.2%) than in the healthy subjects (7.

The disposition of primidone in elderly patients.

1. The pharmacokinetics and metabolism of primidone at steady-state were studied in 10 elderly patients aged 70-81 years and eight control subjects aged 18-26 years. 2.

[Pharmacodynamics and pharmacokinetics of flecainide in cardiac pre-excitation of the bundle of Kent].

In order to identify the flecainide plasma concentrations capable to inhibit the abnormal Kent's pathways, 9 patients affected by a Wolff-Parkinson-White syndrome were studied. One of them (a female 21 years old) previously received 200 mg oral flecainide "una tantum", 8 received 100 mg bid for at least 2 weeks. They had a short PR interval and an evident delta wave on the surface ECG, diagnostic for pre-excitation syndrome.