Nuclear factor kB as a target for new drug development in myeloid malignancies.

The transcription nuclear factor k B (NF-kB) can intervene in oncogenesis through to its capacity to regulate the expression of a large number of genes that regulate apoptosis, cell proliferation and differentiation as well as inflammation, angiogenesis and tumor migration. Impaired NF-kB activity has been demonstrated not only in solid cancers but also in various types of hematologic malignancies including acute myeloid leukemia, chronic myelogenous leukemia and in a subset of myelodysplastic syndromes. The underlying mechanisms, illustrated in the text and although quite diverse in different diseases, provide the rationale for new therapeutic strategies combining different NF-kB or proteasome inhibitors. It has, therefore, been proposed that inhibition of NF-kB could be an adjuvant therapy for cancer and many phase I/II clinical studies are ongoing with different inhibitors. This review highlights the in vitro and in vivo results of NF-kB inhibition in myeloid malignancies

patients with hypertensive nephropathy and chronic kidney disease might not benefit from strict blood pressure control

Background/Aims: In patients with chronic kidney disease (CKD) strict blood pressure (BP) control is reno-protective. However, renal benefits from BP control might depend also on the etiology of CKD. We investigated if maintenance of BP at target is equally effective in subjects with hypertensive nephropathy (HN+) and in those with other nephropathies (HN-). Methods: We evaluated 148 patients with CKD (stages 3-5) in two visits at least 12 months apart. BP was measured both as office BP and 24h ambulatory blood pressure (ABP). Glomerular filtration rate (eGFR) was estimated with CKD-EPI formula. The slope of eGFR variation (ΔeGFR) was calculated as: (eGFR1-eGFR0)/months of follow up. Results: Cohort characteristics were: HN-(n=82) and HN+ (n=66), age (71±9 vs 74±9 years; p=0.09); prevalence of diabetes (57 vs 43%; p=0.19); average follow up (19±7 vs 21±9 months; p=0.3). HN- and HN+ did not differ regarding both baseline eGFR (34±18 vs 35±14 ml/min; p=0.97) and ΔeGFR (0.00±0.53 vs -0.06±0.35 ml/min/month, p=0.52). The proportion of patients with BP at target at both visits was similar in HN- and HN+ (office BP: HN- 18% and HN+ 27%; p=0.21; ABP: HN- 42% and HN+ 43; p=0.96). In patients with office BP at target at both visits HN- showed a significant improvement of ΔeGFR respect to HN+ (HN-: 0.240 ± 0.395 and HN+: -0.140±0.313 ml/min/ month; p=0.026). In patients with office BP not at target HN- and HN+ did not show any difference in ΔeGFR (HN- 0.00±0.47; HN+ -0.030±0.420 ml/min/month; p=0.66). ABP was not associated with differences in ΔeGFR either if it was at target (HN- 0.104±0.383 and HN+ 0.00±0.476 ml/min/month; p=0.42) or not (HN- -0.057±0.503 and HN+ -0.092±0.325 ml/ min/month; p=0.87). Conclusion: In patients with CKD and HN+ maintenance of BP targets recommended by current guidelines is less reno-protective than it is in HN-

Early prediction of treatment outcome in acute myeloid leukemia by measurement of WT1 transcript levels in peripheral blood samples collected after chemotherapy

The Wilms' tumor gene WT1 is a reliable marker for minimal residual disease assessment in acute leukemia patients. The study was designed to demonstrate the potential use of WT1 to establish quality of remission in acute leukemia patients for early identification of patients at high risk of relapse. A prospective study based on a quantitative Real-Time PCR (TaqMan) assay in 562 peripheral blood samples collected from 82 acute leukemia patients at diagnosis and during follow-up was established. The evaluation of WT1 in peripheral blood samples after induction chemotherapy can distinguish the continuous complete remission patients from those who obtain only an "apparent" complete remission and who could relapse within a few months. WT1 helps identify patients at high risk of relapse soon after induction chemotherapy allowing post-induction therapy in high risk patients to be intensified

Validazione della Diagnosi Molecolare di Rene Policistico Autosomico Dominante Mediante la Tecnologia Next Generation Sequencing

Abstract non disponibil

Acute kidney injury and chronic kidney disease after liver transplant: A retrospective observational study.

BACKGROUND AND RATIONALE Chronic kidney disease remains an important risk factor for morbidity and mortality among LT recipients, but its exact incidence and risk factors are still unclear. MATERIAL AND METHODS We carried out a retrospective cohort study of consecutive adults who underwent liver transplant (January 2009-December 2018) and were followed (at least 6 months) at our institution. CKD was defined following the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guidelines. Long-term kidney function was classified into 4 groups: no CKD (eGFR, ≥60mL/min/1.73m2), mild CKD (eGFR, 30-59mL/min/1.73m2), severe CKD (eGFR, 15-29mL/min/1.73m2), and end-stage renal disease (ESRD). RESULTS We enrolled 410 patients followed for 53.2±32.6 months. 39 had CKD at baseline, and 95 developed de novo CKD over the observation period. There were 184 (44.9%) anti-HCV positive, 47 (11.5%) HBsAg positive, and 33 (8.1%) HBV/HDV positive recipients. Recipient risk factors for baseline CKD were advanced age (P=0.044), raised levels of serum uric acid (P<0.0001), and insulin dependent DM (P=0.0034). Early post-transplant AKI was common (n=95); logistic regression analysis found that baseline serum creatinine was an independent predictor of early post-LT AKI (P=0.0154). According to our Cox proportional hazards model, recipient risk factors for de novo CKD included aging (P<0.0001), early post-transplant AKI (P=0.007), and baseline serum creatinine (P=0.0002). At the end of follow-up, there were 116 LT recipients with CKD - 109 (93.9%) and 7 (6.1%) had stage 3 and advanced CKD, respectively. Only two of them are undergoing long-term dialysis. CONCLUSION The incidence of CKD was high in our cohort of LT recipients, but only a slight decline in kidney function over time was recorded. Prevention of post-transplant AKI will improve kidney function in the long run. We need more studies to analyze the function of kidneys among LT recipients over extended follow-ups and their impact on mortality

Subtelomeric FISH analysis in 76 patients with syndromic developmental delay/intellectual disability

<p>Abstract</p> <p>Background</p> <p>Intellectual disability affects approximately 1 to 3% of the general population. The etiology is still poorly understood and it is estimated that one-half of the cases are due to genetic factors. Cryptic subtelomeric aberrations have been found in roughly 5 to 7% of all cases.</p> <p>Methods</p> <p>We performed a subtelomeric FISH analysis on 76 unrelated children with normal standard karyotype ascertained by developmental delay or intellectual disability, associated with congenital malformations, and/or facial dysmorphisms.</p> <p>Results</p> <p>Ten cryptic chromosomal anomalies have been identified in the whole cohort (13,16%), 8 in the group of patients characterized by developmental delay or intellectual disability associated with congenital malformations and facial dysmorphisms, 2 in patients with developmental delay or intellectual disability and facial dysmorphisms only.</p> <p>Conclusion</p> <p>We demonstrate that a careful clinical examination is a very useful tool for pre-selection of patients for genomic analysis, clearly enhancing the chromosomal anomaly detection rate. Clinical features of most of these patients are consistent with the corresponding emerging chromosome phenotypes, pointing out these new clinical syndromes associated with specific genomic imbalances.</p

Deciphering Variability of PKD1 and PKD2 in an Italian Cohort of 643 Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary kidney disease. We analysed PKD1 and PKD2, in a large cohort of 440 unrelated Italian patients with ADPKD and 203 relatives by direct sequencing and MLPA. Molecular and detailed phenotypic data have been collected and submitted to the PKD1/PKD2 LOVD database. This is the first large retrospective study in Italian patients, describing 701 variants, 249 (35.5%) already associated with ADPKD and 452 (64.5%) novel. According to the criteria adopted, the overall detection rate was 80% (352/440). Novel variants with uncertain significance were found in 14% of patients. Among patients with pathogenic variants, in 301 (85.5%) the disease is associated with PKD1, 196 (55.7%) truncating, 81 (23%) non truncating, 24 (6.8%) IF indels, and in 51 (14.5%) with PKD2. Our results outline the high allelic heterogeneity of variants, complicated by the presence of variants of uncertain significance as well as of multiple variants in the same subject. Classification of novel variants may be particularly cumbersome having an important impact on the genetic counselling. Our study confirms the importance to improve the assessment of variant pathogenicity for ADPKD; to this point databasing of both clinical and molecular data is crucial