Valutazione dell'efficacia di un coadiuvante topico a base di argento micronizzato, zinco acetato e acido laurico nel trattamento dell'acne lieve-moderata

L'acne è una dermatosi ad eziopatogenesi multifattoriale in cui differenti fattori contribuiscono al mantenimento del processo infiammatorio. Il ruolo del P. acnes è stato, infatti, rideterminato in quanto trigger principale della risposta infiammatoria, essendo in grado di attivare la liberazione di numerose citochine proinfiammatorie. Non a caso, gli antibiotici sono tra i farmaci cardine della terapia topica dell'acne. Il loro uso è, tuttavia, limitato dallo sviluppo di resistenze batteriche. Ne deriva la necessità di utilizzare nuove molecole, le cui proprietà antibatteriche non siano suscettibili di fenomeni di resistenza. Tra le molecole che hanno destato maggiore interesse, per l'azione antibatterica non antibiotico-dipendente, e, pertanto, non soggetta allo sviluppo di resistenze, annoveriamo l'acido laurico, l'argento micronizzato e lo zinco acetato. Il nostro studio si propone di valutare l'efficacia nel trattamenti dell'acne lieve-moderata di una terapia topica a base di argento micronizzato, acido laurico e zinco acetato attraverso una valutazione sia oggettiva, mediante GAGS e Sebutape, che soggettiva, mediante l'ausilio di un nuovo strumento di valutazione della componente psicologica del paziente acneico: l'acne radar

Propranolol does not affect the oxidative burst of rat neutrophils or complement serum opsonizing capacity in in vivo and in vitro experiments

Propranolol is a ß-adrenergic antagonist used for the treatment of a variety of cardiac conditions and has a palliative value when used in situations in which adrenergic signals and symptoms are involved. It is used as a co-adjuvant in hyperthyroidism to decrease heart rate and output, as well as the tremor. The aim of this work was to study the effect of propranolol treatment on the oxidative burst of rat peripheral blood neutrophils and on the complement system.In the in vivo study, Wistar male rats were treated with propranolol by gavage for 16 days with 220 or 440 μg/animal/day. These doses are equivalent to 80 or 160 mg/adult human (~70 day/kg), respectively. Neutrophils were obtained and stimulated with opsonized immune complexes (opIC). The oxidative burst of control (from water treated rats) or propranolol-treated rat cells was measured by luminol- and lucigenin-dependent chemiluminescence (CL). The CL of treated rat neutrophils was not affected by any of the propranolol doses studied when compared to the control responses.In the in vitro study whole blood and serum from Wistar male rats were incubated for 1 h at 37C° with propranolol at three different concentrations (17.5, 35 and 70 μg/mL). After incubation, neutrophils were isolated from whole blood and stimulated with opIC while treated sera were used to opsonize IC. IC opsonized with treated sera were used to stimulate neutrophils from normal rats. In both cases oxidative burst was measured by luminol- and lucigenin-dependent CL. No differences in responses or activities were detected between in vitro treated neutrophils or sera and their respective controls.These results suggest that this drug, at the concentrations studied and with the experimental approach used, had no effect on the oxidative burst during phagocytosis of opIC or on the complement opsonization capacity of the sera

A dietary supplement to reduce side effects of oral isotretinoin therapy in acne patients.

AIM: The purpose of the study was to analyze the potential capacity of a dietary supplement, based on gamma linolenic acid, vitamin E, vitamin C, beta-carotene, coenzyme Q10 and Vitis Vitifera, to reduce side effects, in particular the dry skin, erythema and desquamation, due to treatment with oral isotretinoin, and evaluate the ability of the product to increase adherence to therapy in patients with acne. METHODS: Forty-eight patients with nodular acne (32 females and 16 males) were randomly divided into 2 groups: 24 receveid isotretinoin therapy (20-30 mg/day) for 6 months associated to dietary supplement (twice a day), while the other 24 patients received only isotretinoin (20-30 mg/day) for 6 months. For all patients the degree of acne severity, through GAGS (Global Acne Grading System), the sebum production by Sebutape, the hydration by Corneometer and the erythema by Mexameter, were measured. We have also evaluated the adherence to treatment, asking to patients how many days a week they follow the therapy. RERSULTS: Patients treated with dietary supplement had lower side effects, with a less degree of erythema and dryness, and greater degree of hydration; a greater adherence to therapy was also reported. CONCLUSION: Thanks to antioxidant and moisturizing properties, the dietary supplement containing gamma linolenic acid, vitamin E, vitamin C, betacarotene, coenzyme Q10 and Vitis Vitifera, can be considered a useful supplement in the treatment and prevention of dry skin associated with the use of oral isotretinoin

Role of Notch2 pathway in mature B cell malignancies

In recent decades, the Notch pathway has been characterized as a key regulatory signaling of cell-fate decisions evolutionarily conserved in many organisms and different tissues during lifespan. At the same time, many studies suggest a link between alterations of this signaling and tumor genesis or progression. In lymphopoiesis, the Notch pathway plays a fundamental role in the correct differentiation of T and B cells, but its deregulated activity leads to leukemic onset and evolution. Notch and its ligands Delta/Jagged exhibit a pivotal role in the crosstalk between leukemic cells and their environment. This review is focused in particular on Notch2 receptor activity. Members of Notch2 pathway have been reported to be mutated in Chronic Lymphocytic Leukemia (CLL), Splenic Marginal Zone Lymphoma (SMZL) and Nodal Marginal Zone Lymphoma (NMZL). CLL is a B cell malignancy in which leukemic clones establish supportive crosstalk with non-malignant cells of the tumor microenvironment to grow, survive, and resist even the new generation of drugs. SMZL and NMZL are indolent B cell neoplasms distinguished by a distinct pattern of dissemination. In SMZL leukemic cells affect mainly the spleen, bone marrow, and peripheral blood, while NMZL has a leading nodal distribution. Since Notch2 is involved in the commitment of leukemic cells to the marginal zone as a major regulator of B cell physiological differentiation, it is predominantly affected by the molecular lesions found in both SMZL and NMZL. In light of these findings, a better understanding of the Notch receptor family pathogenic role, in particular Notch2, is desirable because it is still incomplete, not only in the physiological development of B lymphocytes but also in leukemia progression and resistance. Several therapeutic strategies capable of interfering with Notch signaling, such as monoclonal antibodies, enzyme or complex inhibitors, are being analyzed. To avoid the unwanted multiple “on target” toxicity encountered during the systemic inhibition of Notch signaling, the study of an appropriate pharmaceutical formulation is a pressing need. This is why, to date, there are still no Notch-targeted therapies approved. An accurate analysis of the Notch pathway could be useful to drive the discovery of new therapeutic targets and the development of more effective therapies

Missense mutations in the PML/RAR alpha ligand binding domain in ATRA-resistant As2O3 sensitive relapsed acute promyelocytic leukemia

Background and Objectives. Acute promyelocytic leukemia is characterized by the chromosomal translocation t(15;17) which yields the fusion product PML/RAR alpha. Art-trans retinoic acid probably induces differentiation of atypical promyelocytes and clinical remission in APL patients by binding to the ligand binding domain (LBD) of the RAR alpha portion of the PML-RAR alpha chimeric protein. Structural alterations of the LED of the PML/RAR alpha have been revealed in ATRA-resistant APL cell lines and in a few APL patients with acquired clinical resistance to ATRA therapy. Two APL relapsed patients with clinical resistance to ATRA therapy were evaluated for the presence of nucleotide mutations in the LED of PML/RAR alpha gene and then treated with arsenic trioxide (As2O3). Design and Methods. DNA fragments from the LED of the PML/RAR alpha: chimeric transcript were obtained by reverse-transcribed polymerase chain reaction. Direct sequencing was performed by an unambiguous bidirectional automatic analysis. Samples representative of APL onset and relapse were analyzed from both patients. Results. In both patients, at the ATRA-resistant relapse, a missense point mutation in the LED of the PML/RAR alpha gene was found. The mutations, absent at APL onset, led to an Arg272Gln and to an Arg276Trp amino acid substitution, according to the sequence of the RAR alpha protein. Both patients had complete clinical and hematologic remission after treatment with As2O3. Interpretation and Conclusions. LED missense mutations appear to be a significant mechanism of acquired ATRA-resistance in vivo, closely related to clinical APL relapse. The two cases reported here provide the first in vivo evidence of Apt, relapsed patients, who have become ATRA-resistant for molecular reasons, being sensitive to arsenic trioxide

An 81-Year-Old Man with a 6-Year History of Chronic Lymphocytic Leukemia Presenting with Disease Flare Following Ibrutinib Discontinuation

Patient: Male, 81-year-old Final Diagnosis: Chronic lymphocytic leukemia Symptoms: Fever Medication: — Clinical Procedure: — Specialty: Hematology Objective: Background: Case Report: Conclusions: Unusual clinical course Chronic lymphocytic leukemia (CLL) is a mature B-cell neoplasm and the most common leukemia in adults in Western countries. Novel agents, including BTK inhibitors and the BCL2 inhibitor venetoclax, have dramati-cally changed the treatment landscape. Moreover, a disease flare, characterized by sudden worsening of clinical symptoms, radiographic findings of rapidly worsening splenomegaly or lymphadenopathy, and laboratory changes (increased absolute lymphocyte count or lactate dehydrogenase), is a phenomenon described in up to 25% of patients with CLL after ibrutinib discontinuation. We describe a patient with CLL with disease flare after ibrutinib discontinuation due to disease progression and describe the subsequent management of vene-toclax initial treatment in the course of the disease flare. We describe the case of an 81-year-old man with a 6-year history of CLL who was treated with multiple lines of therapy and developed worsening of disease-related signs and symptoms with fever, marked increase of lym-phocyte count, acute worsening of renal function, and increase in lymph nodes and spleen size following ces-sation of targeted therapy with ibrutinib at the time of disease progression. There was subsequent overlap-ping of ibrutinib during the venetoclax dose escalation period to prevent disease flare recurrence. Our report highlights the problem of disease flare after ibrutinib discontinuation in order to avoid associated patient morbidity, underscoring the importance of awareness of this phenomenon and focusing on the addition of venetoclax at time of progression in ibrutinib-treated patients, as a temporary overlap strategy, to prevent disease flare

Indoleamine 2, 3-Dioxygenase 1 Mediates Survival Signals in Chronic Lymphocytic Leukemia via Kynurenine/Aryl Hydrocarbon Receptor-Mediated MCL1 Modulation

The indoleamine 2,3-dioxygenase 1 (IDO1) metabolic circuitry, comprising the first tryptophan (Trp) catabolite L-kynurenine (Kyn) and the aryl hydrocarbon receptor (AHR), has emerged as a mechanism of cancer immune evasion. Here, we investigated the functional role of the IDO1/Kyn/AHR axis in chronic lymphocytic leukemia (CLL). Our data show that CLL cells expressed an active form of the IDO1 enzyme and microenvironmental stimuli can positively modulate its expression. Interferon (IFN)-γ induces IDO1 expression through the Jak/STAT1 pathway and mediates Kyn production concomitantly with Trp consumption in CLL-conditioned media, while INCB018424 (ruxolitinib), a JAK1/2 inhibitor, impaired both effects. To characterize the involvement of IDO1 in leukemic cell maintenance, we overexpressed IDO1 by vector transfection measuring enhanced resistance to spontaneous apoptosis. IDO1 pro-survival influence was confirmed by treating CLL cells with Kyn, which mediated the increase of induced myeloid leukemia cell differentiation protein (MCL1). Conversely, AHR silencing or its blockade via CH-223191 improved the apoptosis of leukemic clones and mitigated MCL1 expression. Moreover, Kyn-treated CLL cells are less affected by the pro-apoptotic effect of ABT-199 (venetoclax), while CH-223191 showed synergistic/additive cytotoxicity with this drug. Lastly, targeting directly MCL1 in CLL cells with AMG-176, we abrogate the pro-survival effect of Kyn. In conclusion, our data identify IDO1/Kyn/AHR signaling as a new therapeutic target for CLL, describing for the first time its role in CLL pathobiology

Desempenho de frangos de corte (22 a 42 dias) alimentados com dietas peletizadas contendo glicerina bruta.

A maior parte das rações produzidas para frangos de corte no Brasil são peletizadas. Como benefício deste processamento observa-se melhora na digestibilidade dos nutrientes, redução de contaminações por patógenos, bem como melhorias nas condições de transporte. Existem muitos aditivos umectantes que podem ser utilizados para melhorar o processo de peletização, contudo a glicerina além de ser um umectante eficiente (1) é um alimento energético que tem grande potencial de produção no país. Assim sendo, objetivou-se avaliar o desempenho de frangos de corte na fase final (22 a 42 dias) alimentados com rações peletizadas ou fareladas com a inclusão de níveis crescentes de glicerina bruta