Expression of MALT1 oncogene in hematopoietic stem/progenitor cells recapitulates the pathogenesis of human lymphoma in mice.

Chromosomal translocations involving the MALT1 gene are hallmarks of mucosa-associated lymphoid tissue (MALT) lymphoma. To date, targeting these translocations to mouse B cells has failed to reproduce human disease. Here, we induced MALT1 expression in mouse Sca1(+)Lin(-) hematopoietic stem/progenitor cells, which showed NF-κB activation and early lymphoid priming, being selectively skewed toward B-cell differentiation. These cells accumulated in extranodal tissues and gave rise to clonal tumors recapitulating the principal clinical, biological, and molecular genetic features of MALT lymphoma. Deletion of p53 gene accelerated tumor onset and induced transformation of MALT lymphoma to activated B-cell diffuse large-cell lymphoma (ABC-DLBCL). Treatment of MALT1-induced lymphomas with a specific inhibitor of MALT1 proteolytic activity decreased cell viability, indicating that endogenous Malt1 signaling was required for tumor cell survival. Our study shows that human-like lymphomas can be modeled in mice by targeting MALT1 expression to hematopoietic stem/progenitor cells, demonstrating the oncogenic role of MALT1 in lymphomagenesis. Furthermore, this work establishes a molecular link between MALT lymphoma and ABC-DLBCL, and provides mouse models to test MALT1 inhibitors. Finally, our results suggest that hematopoietic stem/progenitor cells may be involved in the pathogenesis of human mature B-cell lymphomas.

Loss of Pax5 Exploits Sca1-BCR-ABLp190 Susceptibility to Confer the Metabolic Shift Essential for pB-ALL.

Preleukemic clones carrying BCR-ABLp190 oncogenic lesions are found in neonatal cord blood, where the majority of preleukemic carriers do not convert into precursor B-cell acute lymphoblastic leukemia (pB-ALL). However, the critical question of how these preleukemic cells transform into pB-ALL remains undefined. Here, we model a BCR-ABLp190 preleukemic state and show that limiting BCR-ABLp190 expression to hematopoietic stem/progenitor cells (HS/PC) in mice (Sca1-BCR-ABLp190) causes pB-ALL at low penetrance, which resembles the human disease. pB-ALL blast cells were BCR-ABL-negative and transcriptionally similar to pro-B/pre-B cells, suggesting disease onset upon reduced Pax5 functionality. Consistent with this, double Sca1-BCR-ABLp190+Pax5+/- mice developed pB-ALL with shorter latencies, 90% incidence, and accumulation of genomic alterations in the remaining wild-type Pax5 allele. Mechanistically, the Pax5-deficient leukemic pro-B cells exhibited a metabolic switch toward increased glucose utilization and energy metabolism. Transcriptome analysis revealed that metabolic genes (IDH1, G6PC3, GAPDH, PGK1, MYC, ENO1, ACO1) were upregulated in Pax5-deficient leukemic cells, and a similar metabolic signature could be observed in human leukemia. Our studies unveil the first in vivo evidence that the combination between Sca1-BCR-ABLp190 and metabolic reprogramming imposed by reduced Pax5 expression is sufficient for pB-ALL development. These findings might help to prevent conversion of BCR-ABLp190 preleukemic cells.Significance: Loss of Pax5 drives metabolic reprogramming, which together with Sca1-restricted BCR-ABL expression enables leukemic transformation. Cancer Res; 78(10); 2669-79. ©2018 AACR.

Comparison of sublingual therapeutic vaccine with antibiotics for the prophylaxis of recurrent urinary tract infections.

OBJECTIVE: To compare the clinical impact of a prophylactic treatment with sublingual immunostimulation in the prevention of recurrent urinary tract infections (rUTIs) with the use of antibiotics. MATERIAL AND METHODS: Retrospective cohort study evaluating the medical records of 669 women with rUTIs; 339 had a 6-month prophylaxis with antibiotics and 360 a 3-month prophylaxis with a sublingual bacterial preparation (MV 140-Uromune®). The time frame after the prophylaxis-period until the appearance of a new infection (assessed by uroculture) was scored and followed during 1 year. The absolute risk reduction (ARR) and number needed to treat (NNT) were also calculated. RESULTS: All patients treated with antibiotics experienced a new UTI during the scoring period of 12 months, being 19 days the median number of days free of UTIs (range 5-300). In the group treated with the bacterial preparation, 35 (9.7%) patients experienced an UTI in the same period. Kaplan-Meier curves comparing the accumulated survival (disease-free time) between both groups were significant different (P < 0.0001). The absolute risk reduction (ARR) was 90.28% (87.18-93.38) and the number needed to treat (NNT) 1.1 (1.1-1.1). CONCLUSIONS: These results suggest that the treatment with this bacterial preparation significantly reduces the incidence of rUTIs, arising as an effective strategy to reduce the frequency of rUTIs. It reduces antibiotic consumption, matching the current recommendations due to the raise of antimicrobial resistance. Randomized, double-blind and placebo-controlled, clinical trials are needed to establish, more accurately, the clinical impact of this bacterial preparation in patients with rUTIs.

Urinary tract infections in women with stress urinary incontinence treated with transobturator suburethral tape and benefit gained from the sublingual polibacterial vaccine.

INTRODUCTION AND OBJECTIVES: Stress urinary incontinence (SUI) and recurrent urinary tract infections (RUTIs) are highly prevalent diseases. Our purpose was to investigate the relationship between RUTIs and surgical correction of SUI with transobturator suburethral tape (TOT) and to describe the benefit gained from a sublingual polibacterial preparation on RUTIs developed after TOT. MATERIALS AND METHODS: A retrospective study was performed on 420 women who underwent TOT surgery due to SUI between April 2003 and October 2011. Group A: patients without urinary tract infections (UTIs) before TOT (n = 294). Group B: patients with UTIs before TOT (n = 126). VARIABLES: age, personal history, number of UTIs/month prior to and after surgery, appearance of urgent urinary incontinence (UUI) with or without UTIs, response to International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF) and Short Form 36 (SF-36) questionnaires. RESULTS: Group A: 85% dry; 5% UUI; 4% de novo UTIs with good response to antibiotics over 6 days. No RUTIs during the follow-up period, 2% with sporadic UTIs. Group B: 47.61% RUTIs; 52.39% sporadic UTIs; greater incidence of diabetes mellitus (p < 0.0025) and smoking (p < 0.0031) than group A. After TOT: 79.36% dry; 10% RUTIs. After treatment with antibiotics for 6 days and bacterial preparation for 3 months, 82% of patients did not have a UTI anymore. Postoperative cystourethrogram revealed 38% of nondiagnosed cystoceles before TOT. No patient had a postvoiding volume greater than 100 cm(3) after TOT. Improvement of ICIQ-SF (p < 0.001) and SF-36 (p < 0.0004) in both groups. CONCLUSION: After eliminating bias associated with the tape, the technique and the surgeon's skills, SUI correction may decrease the number of UTIs and improve the quality of life. UTIs disappeared in 82% of patients with RUTIs after TOT.

Cardiotrophin-1 administration protects from ischemia-reperfusion renal injury and inflammation.

BACKGROUND: Ischemia-reperfusion injury (IRI) remains a major problem in renal transplantation, and the inflammatory response to IRI exacerbates the resultant renal injury. We have investigated whether the systemic administration of cardiotrophin-1 (CT-1) is able to improve renal function and to decrease inflammatory responses in a rat model of renal IRI. METHODS: IRI was induced by renal pedicle clamping (60 min) followed by reperfusion and contralateral nephrectomy. CT-1 was injected through the penile vein 30 min before clamping release and its effects were compared with a saline-treated group at five different time points of reperfusion. RESULTS: Survival in the CT-1-treated group was higher than in the untreated group and prevented IRI-induced reduction in the glomerular filtration rate, as shown by blunted increases in creatinine and urea plasma levels and less severe decrease in creatinine clearance. These effects of CT-1 seem to be mediated by reduction in oxygen-radical production, increased superoxide dismutase expression, attenuation of neutrophil and macrophage infiltration, lower adhesion molecule expression, lower inflammation demonstrated by a decrease of plasma levels of proinflammatory cytokine secretion such as tumor necrosis factor-α, interleukin-1ß and interferon-γ, lower inducible nitric oxide synthase expression and lower nuclear factor-κB activation, and reduced apoptosis. CONCLUSIONS: Therefore, these results suggest that CT-1 administration prevents IRI and it might be used as a therapeutic strategy to protect the kidney against IRI.