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The use of c-abl-specific inhibitors such as Imatinib (IM) or Dasatinib has revolutionized the treatment of chronic myeloid leukemia (CML). However, a significant percentage of patients become resistant to IM. In this report, we have analyzed the possibility of using the proteasome as a molecular target in CML. Our results show that cells that express Bcr-Abl1 are more sensitive to the inhibition of the proteasome with Bortezomib (Btz) than control cells. This treatment reduces the proliferation of Bcr-Abl1-expressing cells, by inactivating NF-κB2 and decreasing the phosphorylation of Rb, eventually leading to an increase in caspase-dependent apoptosis. Furthermore, we show that Btz also induces cell-cycle arrest and apoptosis in cells expressing Bcr-Abl1 mutants that are resistant to IM. These results unravel a new molecular target of Btz, that is the Rb pathway, and open new possibilities in the treatment of CML especially for patients that become resistant to IM because of the presence of the T315I mutation. [ABSTRACT FROM AUTHOR] more...

Resistant (or refractory) hypertension (RH) is a clinical diagnosis based on blood pressure (BP) office measurements. About one third of subjects with suspected RH have indeed pseudo-resistant hypertension and 24-h ambulatory-blood pressure-monitoring aids to precisely identify them. Our aim was to determine those clinical, laboratory or echocardiographic variables that may be associated with subjects with sustained hypertension (namely true RH). We carried out a cross-sectional analysis of 143 patients consecutively enrolled with the clinical diagnosis of RH. All patients underwent clinical-demographic, laboratory evaluation, 2D-echocardiography and 24-h ambulatory-blood pressure-monitoring. Pseudo-resistant hypertension or white-coat RH was defined if office BP was 140 and/or 90 mm Hg and 24-h BP <130/80 mm Hg. One-hundred and three (72%) patients had true RH and 40 (28%) patients had white-coat RH. True RH patients had significantly higher diabetes prevalence and higher office-systolic blood pressure (SBP) levels. Regarding target organ damage, left ventricular mass index (LVMI) and 24-h urinary albumin excretion (UAE) were also higher in true RH after adjustment for possible confounders (P=0.031 and P=0.012, respectively). In a logistic regression analysis, only office-SBP (multivariate OR (95%CI): 1.030 (1.003–1.057), P=0.030) and UAE (multivariate OR (95% CI): 2.376 (1.225–4.608), P=0.010) were independently associated with true RH. We conclude that true resistant hypertension is associated with silent target organ damage, especially UAE. In patients with suspected RH, assessment of 24 h ambulatory BP is the most accurate way to detect a population with high risk for target-organ damage. [ABSTRACT FROM AUTHOR] more...

Nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy is a rare fibrotic condition that presents in patients with a history of renal disease. The aetiology is unknown, but it has recently been proposed that gadolinium, a paramagnetic contrast agent, may be a trigger of this disease. We report three patients with NSF with a history of use of gadolinium in magnetic resonance angiography a few weeks before the onset of symptoms. In the future, gadolinium should probably be avoided as much as possible in renal insufficiency patients until its role in the development of NSF is clarified. [ABSTRACT FROM AUTHOR] more...

To investigate the possible relationships between blood pressure, parathyroid hormone (PTH) and platelet cytosolic Ca concentration ([Ca]) in patients with essential hypertension, we studied 17 patients with this disease aged 48±2 years and 17 normotensive controls aged 44±3 years. Platelet [Ca] was measured by spectrofluorimetry using the dye Fura-2 acetoxymethylester. Patients with essential hypertension displayed lower levels of serum ionized Ca (0.99±0.03 versus 1.1±0.01 mmol/l, <0.05) and higher serum intact PTH levels (37±3 versus 26±2 pg/ml, <0.01) than the normotensive controls. Although serum levels of intact PTH were significantly correlated with mean arterial pressure (MAP) in the combined group of subjects (=0.42, <0.05), there was no correlation when each group was considered separately. Resting platelet [Ca] was also higher in patients than in controls (57±3 versus 48±2nmol/l, <0.005). When platelets were stimulated with thrombin, the increment in [ca] was also greater in patients than in controls in the presence of extracellular Ca (264±24 versus 194±19 nmol/l, <0.05) but not in its absence (123±12 versus 112±10 nmol/l). The thrombin-induced increment in [ca] was correlated with MAP in the hypertensive patients (=0.64, <0.01) and in the combined group of subjects (=0.42, <0.05). There was no relationship between resting or thrombin-induced [Ca] and serum PTH in either group of patients or in the combined group of subjects. Furthermore, preincubation of platelets with PTH had no effect neither on resting platelet [Ca] or on thrombin-induced increments in [ca], both in the presence and in the absence of extracellular Ca in either group of subjects. Therefore, despite platelet [Ca] and serum PTH seem to be related to blood pressure, it appears that PTH does not participate directly in the elevated platelet [Ca] found in patients with essential hypertension. [ABSTRACT FROM PUBLISHER] more...

The possible association between the insertion/deletion (I/D) polymorphism of the angiotensin I converting enzyme (ACE) gene and left ventricular hypertrophy (LVH) was investigated in a group of essential hypertensive patients. Seventy-one essential hypertensive patients (35 men and 36 women), aged 51 ± 1 years, were genotyped by PCR for the I/D polymorphism of the ACE gene. Cardiac morphology and function were assessed by means of M-mode echocardiography. The relative frequencies of the three genotypes, DD, DI, and II, were respectively: 24%, 55%, and 21%. Mean values of left ventricular mass index were 145, 144, and 150 g/m[SUP2] for DD, DI, and II genotypes, without significant differences among them (P = 0.82). Likewise, the prevalence of LVH (76%, 64%, and 87%) was not significantly different among the three genotypes (P = 0.23). We conclude that the ACE gene I/D polymorphism is not associated with LVH in essential hypertension. [ABSTRACT FROM AUTHOR] more...

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Direct stimulation of the antitumor activity of immune system through checkpoint inhibitors (ICIs) has demonstrated efficacy in the treatment of different cancer types. The activity of these antibodies takes place in the immunological synapse blocking the binding of the negative immunoregulatory proteins, thus leading to the finalization of the immune response. Despite having a favorable toxicity profile, its mechanism of action impedes the negative regulation of the immune activity which can potentially favor autoimmune attacks to normal tissues. Renal toxicity has been described in several ICI but not with atezolizumab, an IgG1 monoclonal antibody targeting PD-L1 (programmed death ligand 1), approved by FDA as a second-line therapy for advanced urothelial carcinoma. Here we present a patient with a single kidney and metastatic renal cell carcinoma treated with atezolizumab and bevacizumab combination, with biopsy-proven acute interstitial nephritis, who had a complete resolution of renal dysfunction after steroid therapy. [ABSTRACT FROM AUTHOR] more...