A phase II dose-escalation trial was conducted to ascertain low-dose thalidomide safety and response in patients with advanced myelofibrosis with myeloid metaplasia (MMM).
Thalidomide was ...administered together with current therapy to 63 patients, starting at 50 mg daily and increasing to 400 mg as tolerated.
Half of the patients sustained daily doses more than 100 mg and the drop-out rate was 51% at 6 months: the drop-out rate was lower in patients with high baseline fatigue score. At efficacy analysis, anemia was ameliorated in 22% of the patients and transfusions were eliminated in 39% of transfusion-dependent patients. Platelet count increased by 50 x 10(9)/L or more in 22% of patients with an initial count lower than 100 x 10(9)/L. Splenomegaly decreased by more than 50% of the initial size in 19% of patients. Reduction of an overall disease severity score occurred in 31% of patients and was associated with a significant reduction of fatigue. Disease severity amelioration was independently predicted by a high baseline myeloproliferative index (ie, large splenomegaly, thrombocytosis, or leukocytosis).
Low-dose thalidomide displays an acceptable toxicity profile and provides an objective and subjective advantage to a relevant portion of MMM patients.
L’articolo si prefigge di ri-leggere il dispositivo pedagogico della progettazione attraverso la categoria interpretativa della cura, al fine di dare rilevanza alle molteplici relazioni che si creano ...nell’ambito dei processi formativi fungendo da collante per lo sviluppo di apprendimenti significativi e trasformativi. A sostegno di questa tesi, viene presentato il progetto “Scuola è dove scuola si fa” attuato nell’anno scolastico 2020-2021 presso l’Istituto Comprensivo “Salvo d’Acquisto” in provincia di La Spezia che, sulla base del Patto di Comunità siglato con l’Amministrazione comunale, ha permesso di realizzare esperienze didattiche outdoor interdisciplinari e trasversali progettate e verificate all’interno del curricolo scolastico e realizzate con la fattiva collaborazione di molte realtà associative del luogo che, in questo modo, hanno avuto l’opportunità di conoscere meglio e di contribuire a prendersi cura della comunità scolastica.
Imaging of joints in systemic lupus erythematosus Tani, Chiara; Carli, Linda; Stagnaro, Chiara ...
Clinical and experimental rheumatology,
2018 Sep-Oct, Letnik:
36 Suppl 114, Številka:
5
Journal Article
Recenzirano
Musculoskeletal symptoms are among the most common manifestations in patients with systemic lupus erythematosus (SLE), being reported in up to 95% of patients; joint and tendon involvement can range ...from arthralgia to severe deforming arthropathy; while myositis a rare manifestation, comorbid fibromyalgia is reported in up to 40% of SLE patients. All these manifestations have a significant impact on the patients' quality of life, possibly leading to disability and functional impairment in daily living activities. In recent years, thanks to the availability of new imaging techniques for the assessment of tendon and joint pathologies, the approach to the definition and characterisation of these manifestations in SLE is constantly evolving. In this review we will therefore illustrate the state of the art of imaging techniques in the assessment of joint involvement in SLE, focusing on ultrasounds (US) and magnetic resonance (MRI), discussing their advantages, drawbacks and possible future developments. The main findings that emerge from the recent literature is that imaging studies may allow a more accurate definition of disease subtypes revealing an unexpected higher prevalence of joint and tendon involvement with respect to what known by clinical evaluation and standard radiography. Indeed, US and MRI also made possible the identification of joints and tendons pathologies in patients with no or very mild clinical symptoms. On the other hand, the interpretation of some findings remains uncertain, as well as the validity and feasibility of this analysis in clinical practice. Thus, further studies should clarify the clinical meaning of subclinical abnormalities detected in US and MRI scans and their impact on the long-term outcomes.
Anemia is a common, but underestimated and undertreated, complication of patients with cancer receiving chemo- or radiotherapy, and negatively affects their quality of life (QoL). Erythropoietic ...proteins (EPS) offer an effective treatment of cancer anemia and ameliorate QoL, although their use requires the correct targeting of hemoglobin increase to avoid thromboembolic complications. Currently the effort is focused on offering patients this effective treatment with reduced frequency of administration. Higher weekly single doses of recombinant human Epo (rHuEpo) either alpha or beta, instead of three times per week, have been proposed for the treatment. The pharmacokinetic and pharmacodynamic characteristics of the hyperglycosylated protein darbepoetin alpha permit even longer inter vals between administrations. Every other week or every three weeks schedules have shown results (erythropoietic response, reduction of transfusion requirements, and improvement of QoL) comparable with those of weekly rHuEpo.
The development of refractory disease is often associated with the overexpression of multidrug resistance (MDR) proteins, especially in several hematological malignancies, such as acute myeloid ...leukemias (AML), multiple myeloma (MM) and non-Hodgkin's lymphomas (NHL). Since the recognition of these proteins, several attempts have been made to modulate their expression and activity (protein kinase C inhibitors, anti-MDR-1 oligonucleotides, pharmacological competitors and transcriptional inhibitors). Six new compounds (MM 36, CTS 4, CTS 9, CTS 12, CTS 27 and CTS 41), derived from verapamil (VRP), were designed and synthesized to improve their MDR-reverting activity and reduce cardiovascular effects. Cytotoxicity (WST-1 methods) and functional (calcein–acetoxymethyl (Calcein–AM)) assays were performed on a resistant cell line K-562/doxR and on the mononuclear cells (MNCs) of patients with AML. Furthermore, the six molecules were tested for their vasodilator, inotropic and chronotropic activity on guinea pig aortic strip and isolated atrium preparations, respectively. Comparison between survival plots and relative ID
50, obtained from the K-562/doxR cells treated with Idarubicin (IDA), in the presence or absence of inhibitors, showed that these compounds function well. All the resistance modifying agents potentiated IDA activity inducing a significant reduction (
P
<
0.01) in ID
50 values in comparison to VRP at each of the concentrations tested, but MM 36, CTS 27 and CTS 41 demonstrated the strongest activity. Results obtained from the MNCs were superimposible to K-562/doxR. Further studies on pump functional analysis confirmed the cytotoxic test results: MM 36, CTS 27 and CTS 41 showed a striking inhibition of P-glycoprotein (Pgp) efflux in K-562/doxR and MNCs. Cardiovascular activity of MM 36, CTS 27 and CTS 41, that are the most interesting compounds as MDR inhibitors, followed this course: MM 36
>
CTS 27
>
CTS 41, the last one presenting no cardiovascular activity. Chemosensivity to IDA in K-562/doxR cells and AML blasts could be enhanced in vitro by the adjuvant use of the six new VRP analogues. Compared to VRP, all the new compounds presented good MDR-reverting- and reduced cardiovascular activities along with no vasorelaxant effects. The particularly favourable results in some cases (MM 36, CTS 27 and CTS 41) suggests that anti-MDR activity should be further evaluated in clinical trials in patients with myeloid malignancies.
Twelve patients with myelodysplasia were treated with amifostine plus recombinant human erythropoietin (rHuEpo) for 6 weeks. A complete erythroid response was obtained in 2/12(16.6%) and a partial ...response in 4/12 (33.3%). Two of 8 patients with a platelet count
The rise of antimicrobial-resistant phenotypes and the spread of the global pandemic of COVID-19 are worsening the outcomes of hospitalized patients for invasive fungal infections. Among them, ...candidiases are seriously worrying, especially since the currently available drug armamentarium is extremely limited. We recently reported a new class of macrocyclic amidinoureas bearing a guanidino tail as promising antifungal agents. Herein, we present the design and synthesis of a focused library of seven derivatives of macrocyclic amidinoureas, bearing a second phenyl ring fused with the core. Biological activity evaluation shows an interesting antifungal profile for some compounds, resulting to be active on a large panel of
Candida
spp. and
C. neoformans
. PAMPA experiments for representative compounds of the series revealed a low passive diffusion, suggesting a membrane-based mechanism of action or the involvement of active transport systems. Also, compounds were found not toxic at high concentrations, as assessed through MTT assays.
Graphical abstract
Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and represents <2% of thyroid carcinomas. A therapeutic target for ATC is represented by anaplastic lymphoma kinase (ALK) ...rearrangements, involved in tumor growth. Crizotinib is an oral small-molecule tyrosine kinase inhibitor of the ALK, MET, and ROS1 kinases, approved in ALK-positive non-small cell lung cancer. Until now, the effect of crizotinib in “primary human ATC cells” (pATCs) with transforming striatin (STRN)–ALK fusion has not been reported in the literature. In this study, we aimed to obtain pATCs with STRN–ALK in vitro and evaluate the in vitro antineoplastic action of crizotinib. Thyroid surgical samples were obtained from 12 ATC patients and 6 controls (who had undergone parathyroidectomy). A total of 10/12 pATC cultures were obtained, 2 of which with transforming STRN–ALK fusion (17%). Crizotinib inhibited proliferation, migration, and invasion and increased apoptosis in 3/10 pATC cultures (2 of which with/1 without STRN–ALK), particularly in those with STRN–ALK. Moreover, crizotinib significantly inhibited the proliferation of AF cells (a continuous cell line obtained from primary ATC cells). In conclusion, the antineoplastic activity of crizotinib has been shown in human pATCs (with STRN–ALK) in preclinical studies in vitro, opening the way to future clinical evaluation in these patients.
Thyroid cancer is the most common (~90%) type of endocrine-system tumor, accounting for 70% of the deaths from endocrine cancers. In the last years, the high-throughput genomics has been able to ...identify pathways/molecular targets involved in survival and tumor progression. Targeted therapy and immunotherapy individually have many limitations. Regarding the first one, although it greatly reduces the size of the cancer, clinical responses are generally transient and often lead to cancer relapse after initial treatment. For the second one, although it induces longer-lasting responses in cancer patients than targeted therapy, its response rate is lower. The individual limitations of these two different types of therapies can be overcome by combining them. Here, we discuss MAPK pathway inhibitors, i.e., BRAF and MEK inhibitors, combined with checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4. Several mutations make tumors resistant to treatments. Therefore, more studies are needed to investigate the patient's individual tumor mutation burden in order to overcome the problem of resistance to therapy and to develop new combination therapies.
Plants play a fundamental role in maintaining coastal dunes but also accumulate littered microplastics (MPs). Migration tests suggest that naturally weathered MPs can leach out a broader range of ...potentially phytotoxic chemicals than virgin MPs. Thus, assessing MPs effects on plants using beached-collected particles rather than virgin ones is critically important. Here, the effects on plants of leachates from two pools of beach-collected and virgin MPs, high-density polyethylene (HDPE) and polypropylene (PP), and their mixture, were explored combining toxicity tests and chemical analyses. Phytotoxicity of MP leachates at different dilutions was evaluated under standard laboratory conditions using test species and under environmentally realistic conditions using the dune species Thinopyrum junceum. Leachates from beached PP and HDPE adversely affected all species, and the extent of these effects varied according to polymer type, concentration, and species. Virgin MPs had weaker effects than beached ones. Several potentially phytotoxic oxidized compounds were detected in water by GC/MS analysis, and their amount estimated. Results indicate that the molecular species leaching from beached MPs - at ppm concentration levels for the individual chemical species - can inhibit plant growth, and the effects of leachates from mixtures of degraded MPs can differ from those from individual polymers, highlighting the need for further investigation of MPs consequences for coastal ecosystems.
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•Leachates from beached PP and HDPE microplastics (MPs) were tested on plants.•MPs released many potentially phytotoxic oxidized degradation compounds.•Their amounts were determined by thermal desorption-GC-MS after SPE.•Leachates from beached MPs reduced seed germination and early plant growth.•Dune plants exposure to beached MPs is a potential threat to coastal ecosystems.
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