73 research outputs found
Novel Approaches Outside the Setting of Immunotherapy for the Treatment of Multiple Myeloma: The Case of Melflufen, Venetoclax, and Selinexor
Although the survival rate of patients with multiple myeloma has significantly improved in the
last years thanks to the introduction of various classes of new drugs, such as proteasome
inhibitors, immunomodulatory agents, and monoclonal antibodies, the vast majority of these
subjects relapse with a more aggressive disease due to the acquisition of further genetic
alterations that may cause resistance to current salvage therapies. The treatment of these
often âtripleâ (or even more) refractory patients remains challenging, and alternative
approaches are required to overcome the onset of that resistance. Immunotherapies with
novel monoclonal, drug-conjugated, or bi-specific antibodies, as well as the use of chimeric
antigen receptor T cells, have been recently developed and are currently investigated.
However, other non-immunologic therapeutic regimens based on melfluflen, venetoclax, or
selinexor, three molecules with new mechanisms of action, have also shown promising
results in the setting of relapsed/refractory myeloma. Here we report themost recent literature
data regarding these three drugs, focusing on their efficacy and safety in multiple myelom
SARS-CoV-2 infection in fully vaccinated patients with multiple myeloma
No abstract availabl
Identification and monitoring of Copy Number Variants (CNV) in monoclonal gammopathy
Monoclonal gammopathy of undetermined significance (MGUS) represents the pre-clinical stage of Multiple Myeloma (MM) with the 5% of MGUS progresses to MM. Although the progression from MGUS to MM has not been completely characterized, it is possible to monitor the DNA modifications of patients diagnosed with MGUS to detect early specific genomic abnormalities, including copy number variations (CNV). The CNVs of chromosome 1q and chromosome 13q are associated with a worse prognosis in MM.In the present study, we showed that it is possible to monitor the 1q21 gain and 13q deletion frequencies in gDNA using digital PCR. The CNV analysis of three cell lines with a well-characterized cytogenetic profile were compared with measures performed by a real-time PCR approach and with a digital PCR approach. Then, we analyzed CNVs in CD138+ plasma cells isolated from bone marrow of MGUS and MM patients.Our results show that digital PCR and targeted DNA monitoring represent a specific and accurate technique for the early detection of specific genomic abnormalities both in MM and in MGUS patients.Our results could represent a remarkable advancement in MM and MGUS diagnosis and in CNV analysis for the evaluation of the risk of progression from MGUS to MM
What Is New in the Treatment of Smoldering Multiple Myeloma?
Smoldering multiple myeloma (SMM), an asymptomatic plasma cell neoplasm, is currently
diagnosed according to the updated IMWG criteria, which reflect an intermediate tumor mass
between monoclonal gammopathy of undetermined significance (MGUS) and active MM. However,
SMM is a heterogeneous entity and individual case may go from an âMGUS-likeâ behavior to âearly
MMâ with rapid transformation into symptomatic disease. This wide range of clinical outcomes
poses challenges for prognostication and management of individual patients. However, initial studies
showed a benefit in terms of progression or even survival for early treatment of high-risk SMM
patients. While outside of clinical trials the conventional approach to SMM generally remains that of
close observation, these studies raised the question of whether early treatment should be offered in
high-risk patients, prompting evaluation of several different therapeutic approaches with different
goals. While delay of progression to MM with a non-toxic treatment is clearly achievable by early
treatment, a convincing survival benefit still needs to be proven by independent studies. Furthermore,
if SMM is to be considered less biologically complex than MM, early treatment may offer the chance
of cure that is currently not within reach of any active MM treatment. In this paper, we present
updated results of completed or ongoing clinical trials in SMM treatment, highlighting areas of
uncertainty and critical issues that will need to be addressed in the near future before the âwatch and
waitâ paradigm in SMM is abandoned in favor of early treatmen
Outcome of Very Late Relapse in Patients with Hodgkin's Lymphomas
Recurrences of Hodgkin's Lymphoma (HL) 5 years after the initial therapy are rare. The aim of this study is to report a single centre experience of the clinical characteristics, outcome, and toxicity of pts who experienced very late relapses, defined as relapses that occurred 5 or more years after the achievement of first complete remission. Of 532 consecutive pts with classical HL treated at our Institute from 1985 to 1999, 452 pts (85%) achieved a complete remission. Relapse occurred in 151âpts: 135 (29.8%) within 5âyears and 16 over 5âyears (3.5%, very late relapses). Very late relapses occurred after a median disease-free interval of 7âyears (range: 5â18). Salvage treatment induced complete remission in 14âpts (87.5%). At a median of 4âyears after therapy for very late relapse, 10âpts (63%) are still alive and free of disease and 6 (37%) died (1 from progressive HL, 1 from cardiac disease, 1 from thromboembolic disease, 1 from HCV reactivation, and 2 from bacterial infection). The probability of failure-free survival at 5âyears was 75%. The majority of deaths are due to treatment-related complications. Therapy regimens for very late relapse HL are warranted to minimize complications
ATP Sensitive Potassium Channels in the Skeletal Muscle Function: Involvement of the KCNJ11(Kir6.2) Gene in the Determination of Mechanical Warner Bratzer Shear Force
The ATP-sensitive K-channels (KATP) are distributed in the tissues coupling metabolism with K ions efflux. KATP subunits are encoded by KCNJ8 (Kir6.1), KCNJ11 (Kir6.2), ABCC8 (SUR1), and ABCC9 (SUR2) genes, alternative RNA splicing give rise to SUR variants that confer distinct physiological properties on the channel. An high expression/activity of the sarco-KATP channel is observed in various rat fast-twitch muscles, characterized by elevated muscle strength, while a low expression/activity is observed in the slow twitch muscles characterized by reduced strength and frailty. Down-regulation of the KATP subunits of fast-twitch fibers is found in conditions characterized by weakness and frailty. KCNJ11 gene knockout mice have reduced glycogen, lean phenotype, lower body fat, and weakness. KATP channel is also a sensor of muscle atrophy. The KCNJ11 gene is located on BTA15, close to a QTL for meat tenderness, it has also a role in glycogen storage, a key mechanism of the postmortem transformation of muscle into meat. The role of KCNJ11 gene in muscle function may underlie an effect of KCNJ11 genotypes on meat tenderness, as recently reported. The fiber phenotype and genotype are important in livestock production science. Quantitative traits including meat production and quality are influenced both by environment and genes. Molecular markers can play an important role in the genetic improvement of animals through breeding strategies. Many factors influence the muscle Warner-Bratzler shear force including breed, age, feeding, the biochemical, and functional parameters. The role of KCNJ11gene and related genes on muscle tenderness will be discussed in the present review
Transcript Regulation of the Recoded Archaeal α-L-Fucosidase In Vivo
Genetic decoding is flexible, due to programmed deviation of the ribosomes from standard translational rules, globally termed ârecodingâ. In Archaea, recoding has been unequivocally determined only for termination codon readthrough events that regulate the incorporation of the unusual amino acids selenocysteine and pyrrolysine, and for â1 programmed frameshifting that allow the expression of a fully functional α-l-fucosidase in the crenarchaeon Saccharolobus solfataricus, in which several functional interrupted genes have been identified. Increasing evidence suggests that the flexibility of the genetic code decoding could provide an evolutionary advantage in extreme conditions, therefore, the identification and study of interrupted genes in extremophilic Archaea could be important from an astrobiological point of view, providing new information on the origin and evolution of the genetic code and on the limits of life on Earth. In order to shed some light on the mechanism of programmed â1 frameshifting in Archaea, here we report, for the first time, on the analysis of the transcription of this recoded archaeal α-l-fucosidase and of its full-length mutant in different growth conditions in vivo. We found that only the wild type mRNA significantly increased in S. solfataricus after cold shock and in cells grown in minimal medium containing hydrolyzed xyloglucan as carbon source. Our results indicated that the increased level of fucA mRNA cannot be explained by transcript up-regulation alone. A different mechanism related to translation efficiency is discusse
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