scholarly journals Non-Hematologic Toxicity of Bortezomib in Multiple Myeloma: The Neuromuscular and Cardiovascular Adverse Effects

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2540 ◽  
Author(s):  
Elia Pancheri ◽  
Valeria Guglielmi ◽  
Grzegorz M. Wilczynski ◽  
Manuela Malatesta ◽  
Paola Tonin ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Multiple Myeloma ◽  
Adverse Effects ◽  
Molecular Mechanisms ◽  
Proteasome Inhibitors ◽  
Hematologic Toxicity ◽  
Negative Effects ◽  
Early Discontinuation ◽  
Cardiovascular Side Effects

The overall approach to the treatment of multiple myeloma (MM) has undergone several changes during the past decade. and proteasome inhibitors (PIs) including bortezomib, carfilzomib, and ixazomib have considerably improved the outcomes in affected patients. The first-in-class selective PI bortezomib has been initially approved for the refractory forms of the disease but has now become, in combination with other drugs, the backbone of the frontline therapy for newly diagnosed MM patients, as well as in the maintenance therapy and relapsed/refractory setting. Despite being among the most widely used and highly effective agents for MM, bortezomib can induce adverse events that potentially lead to early discontinuation of the therapy with negative effects on the quality of life and outcome of the patients. Although peripheral neuropathy and myelosuppression have been recognized as the most relevant bortezomib-related adverse effects, cardiac and skeletal muscle toxicities are relatively common in MM treated patients, but they have received much less attention. Here we review the neuromuscular and cardiovascular side effects of bortezomib. focusing on the molecular mechanisms underlying its toxicity. We also discuss our preliminary data on the effects of bortezomib on skeletal muscle tissue in mice receiving the drug.

scholarly journals Molecular mechanisms of cardiovascular benefits of exercise: Running for cover from heart disease

2016 ◽  
Vol 2016 (1) ◽  
Author(s):  
Mohamed Hassan ◽  
Yasmine Aguib ◽  
Magdi Yacoub
Keyword(s):  
Skeletal Muscle ◽  
Molecular Mechanisms ◽  
Potential Role ◽  
Peak Exercise ◽  
Physically Active ◽  
Risk Of Death ◽  
Heart Study ◽  
Patients With Heart Failure ◽  
Ancient Times

The benefits of exercise have been recognized since ancient times. Physically active men and women have an approximately 30% lower risk of death compared with inactive people. Several trials have recently shown the favorable impact of exercise on survival and quality of life. In the PARIS study, four months of endurance exercise training in elderly patients with heart failure and preserved ejection fraction caused a significant improvement in peak exercise capacity. Moreover in the Copenhagen City Heart Study, jogging up to 2.5 h per week at a slow or average pace and a frequency of 3 times per week was associated with a significant increase in survival (6.2 years in men and 5.6 years in women). These findings imply that exercise improves peripheral vascular, microvascular, and/or skeletal muscle functions and causes an increase in oxygen transport and utilization by the active skeletal muscle.1 However, the exact molecular mechanisms of the cardiovascular benefits of exercise remained largely unknown until very recently. Two recent reports serve to shed some light on the potential role for irisin and miRNA-222 in this subject. 

scholarly journals A Network Analysis of Multiple Myeloma Related Gene Signatures

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1452 ◽  
Author(s):  
Yu Liu ◽  
Haocheng Yu ◽  
Seungyeul Yoo ◽  
Eunjee Lee ◽  
Alessandro Laganà ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Response ◽  
Molecular Mechanisms ◽  
Proteasome Inhibitors ◽  
Risk Groups ◽  
Rank Test ◽  
P Value ◽  
Causal Network ◽  
Gene Signatures ◽  
Network Analyses

Multiple myeloma (MM) is the second most prevalent hematological cancer. MM is a complex and heterogeneous disease, and thus, it is essential to leverage omics data from large MM cohorts to understand the molecular mechanisms underlying MM tumorigenesis, progression, and drug responses, which may aid in the development of better treatments. In this study, we analyzed gene expression, copy number variation, and clinical data from the Multiple Myeloma Research Consortium (MMRC) dataset and constructed a multiple myeloma molecular causal network (M3CN). The M3CN was used to unify eight prognostic gene signatures in the literature that shared very few genes between them, resulting in a prognostic subnetwork of the M3CN, consisting of 178 genes that were enriched for genes involved in cell cycle (fold enrichment = 8.4, p value = 6.1 × 10−26). The M3CN was further used to characterize immunomodulators and proteasome inhibitors for MM, demonstrating the pleiotropic effects of these drugs, with drug-response signature genes enriched across multiple M3CN subnetworks. Network analyses indicated potential links between these drug-response subnetworks and the prognostic subnetwork. To elucidate the structure of these important MM subnetworks, we identified putative key regulators predicted to modulate the state of these subnetworks. Finally, to assess the predictive power of our network-based models, we stratified MM patients in an independent cohort, the MMRF-CoMMpass study, based on the prognostic subnetwork, and compared the performance of this subnetwork against other signatures in the literature. We show that the M3CN-derived prognostic subnetwork achieved the best separation between different risk groups in terms of log-rank test p-values and hazard ratios. In summary, this work demonstrates the power of a probabilistic causal network approach to understanding molecular mechanisms underlying the different MM signatures.

scholarly journals The Prognostic Value of Whole-Blood PSMB5, CXCR4, POMP and RPL5 mRNA Expression in Patients with Multiple Myeloma Treated with Bortezomib

2021 ◽  
Author(s):  
Paweł Robak ◽  
Dariusz Jarych ◽  
Damian Mikulski ◽  
Izabela Dróżdż ◽  
Edyta Węgłowska ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Mrna Expression ◽  
Molecular Mechanisms ◽  
Multiple Drug Resistance ◽  
Mrna Level ◽  
Proteasome Inhibitors ◽  
Progression Free Survival ◽  
High Expression ◽  
Multiple Drug ◽  
Healthy Controls

Proteasome inhibitors, like bortezomib, play a key role in the treatment of multiple myeloma (MM); however, most patients eventually relapse and eventually show multiple drug resistance, and the molecular mechanisms of this resistance remain unclear. The present study examines the expression of previously-described genes that may influence resistance to bortezomib treatment at the mRNA level (ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN and XBP1). mRNA expression was determined in 73 MM patients treated with bortezomib-based regimens (30 bortzomib-sensitive and 43 bortezomib-refractory patients) and 11 healthy controls. RPL5 was significantly down-regulated in multiple myeloma patients as compared with healthy controls. Moreover, POMP was significantly up-regulated in MM patients refractory to bortezomib-based treatment. In multivariate analysis, high expression of PSMB5 and CXCR and autologous stem cell transplantation were independent predictors of progression-free survival, and high expression of POMP and RPL5 was associated with shorter overall survival.

scholarly journals Positive and Negative Effects of Antipsychotic Medication: An International Online Survey of 832 Recipients

2019 ◽  
Vol 14 (3) ◽  
pp. 173-181 ◽  
Author(s):  
John Read ◽  
James Williams
Keyword(s):  
Side Effects ◽  
Adverse Effects ◽  
Antipsychotic Medication ◽  
Online Survey ◽  
Negative Effects ◽  
Duration Of Treatment ◽  
Direct To Consumer ◽  
Poor Outcomes

Background: Antipsychotic medication is currently the treatment of choice for psychosis, but few studies directly survey the first-hand experience of recipients. Objective: To ascertain the experiences and opinions of an international sample of users of antipsychotic drugs, regarding positive and negative effects. Methods: An online direct-to-consumer questionnaire was completed by 832 users of antipsychotics, from 30 countries – predominantly USA, UK and Australia. This is the largest such sample to date. Results: Over half (56%) thought, the drugs reduced the problems they were prescribed for, but 27% thought they made them worse. Slightly less people found the drugs generally ‘helpful’ (41%) than found them ‘unhelpful’ (43%). While 35% reported that their ‘quality of life’ was ‘improved’, 54% reported that it was made ‘worse’. The average number of adverse effects reported was 11, with an average of five at the ‘severe’ level. Fourteen effects were reported by 57% or more participants, most commonly: ‘Drowsiness, feeling tired, sedation’ (92%), ‘Loss of motivation’ (86%), ‘Slowed thoughts’ (86%), and ‘Emotional numbing’ (85%). Suicidality was reported to be a side effect by 58%. Older people reported particularly poor outcomes and high levels of adverse effects. Duration of treatment was unrelated to positive outcomes but significantly related to negative outcomes. Most respondents (70%) had tried to stop taking the drugs. The most common reasons people wanted to stop were the side effects (64%) and worries about long-term physical health (52%). Most (70%) did not recall being told anything at all about side effects. Conclusion: Clinical implications are discussed, with a particular focus on the principles of informed consent, and involving patients in decision making about their own lives.

The Physician Self-Referral Dilemma: Enforcing Antitrust Law as a Solution

1993 ◽  
Vol 19 (4) ◽  
pp. 523-546
Author(s):  
Julie E. Mathews
Keyword(s):  
United States ◽  
Health Care ◽  
Quality Of Care ◽  
Adverse Effects ◽  
The United States ◽  
The Self ◽  
Health Care Market ◽  
Negative Effects ◽  
Antitrust Laws

As health care reform pervades the United States, lawmakers have subjected physician self-referrals to heightened scrutiny. Recent evidence indicates that sending patients to facilities in which a physician has an ownership interest often causes overutilization, overpricing, and lower quality of care. This Note analyzes how physician self-referral arrangements can have negative effects on competition. To combat the adverse effects, the Note examines how enforcing antitrust laws can ameliorate the self-referral dilemma and aid in restoring competition to the health care market. This solution will maintain the doctor's right to invest while protecting the patient's vulnerability.

Induction Therapy With Continuous Alternate-Day Low Dose Lenalidomide Combined With Low-Dose Prednisone In Octogenarian Multiple Myeloma Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5394-5394
Author(s):  
Luca Pezzullo ◽  
Bianca Serio ◽  
Raffaele Fontana ◽  
Idalucia Ferrara ◽  
Mariarosaria Sessa ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nk Cells ◽  
Low Dose ◽  
Nk Cell ◽  
Conflicts Of Interest ◽  
Performance Status ◽  
Progressive Increase ◽  
Hematologic Toxicity ◽  
Dose Prednisone

Abstract About 30% of patients with newly diagnosed multiple myeloma (NDMM) are older than 75 years. Immunomodulatory drugs (IMIDs) have improved response rates and outcomes of NDMM, except for patients older than 75 years more vulnerable to side effects of IMIDs because of their frailty and comorbidities. We evaluated efficacy, toxicity and health-related quality of life (HRQOL) associated with continuous alternate-day low dose lenalidomide (LD-R, 10 mg on alternate days) and low dose prednisone (15 mg/day) (LD-RP) in 7 octogenarian NDMM patients (5 males and 2 females) with a median age of 82 years (range 80-87). All octogenarian patients had IgG MM, except 1 oligosecretory lambda chain MM; all were in Durie-Salmon stage III, except 1 in stage II, and had poor WHO performance status (median: 2, range 1-3). Patients were evaluated at baseline and every 6 months for HRQOL according to MM-specific questionnaire QLQ-MY20 of European Organisation for Research and Treatment of Cancer (EORTC). All patients received aspirin thromboprophylaxis, 57% of them requiring from diagnosis erythropoietin and zoledronic acid treatment. In these 7 octogenarian NDMM patients completing at least three months of therapy, the overall response rate (ORR) was 86%, including 1 complete remission (CR), 2 very good partial remission (VgPR) and 3 PR. After a median follow-up of 12 months (range 3-24), the quality of response improved with continuous LD-RP treatment with a cumulative median reduction in monoclonal protein levels of 85% (range 20-100%); none of the patients required discontinuation of treatment secondary to specific hematologic and/or extra-hematologic toxicity. In addition, QLQ MY-20 questionnaires revealed that 70% of patients treated with continuous LD-RP reported improvements of QOL scores. Two out of 7 octogenarian patients died (1 for progression after 12 months and 1 for sepsis no treatment-related), and 2-year overall survival and progression-free survival estimates were 41% and 75%, respectively. Noteworthy, all patients treated with continuous alternate-day LD-RP showed a progressive increase in the percentage of CD3+ CD56+ NK cells during the first 6 months of LD-RP therapy reaching a plateau maintained until +12 months after initiation of therapy: the median percentage of NK cells was 4% before LD-RP treatment versus 10%, 13%, 30%, 31%, and 27% at +1, +3, +6, +9 and +12 months, respectively. Mean fold increase of NK cells during LD-RP therapy was 1.5, 2.5, and 6.5 at +1, +3 and +6 months, respectively. Progressive increase of NK cells was concomitantly associated with reduction in tumor-linked monoclonal immunoglobulin in all patients and increased circulating NK cells further support that this drug may mediate its anti-MM effect, at least in part by modulating NK-cell number and function. Our data provide evidence that continuous alternate-day low dose lenalidomide is a manageable and effective frontline treatment for octogenarian NDMM patients and increases circulating NK cells. These preliminary results require further validation in prospective larger studies. Disclosures: No relevant conflicts of interest to declare.

Identifying and Mitigating the Negative Effects of Power in Organizations

2021 ◽  
pp. 193672442110147
Author(s):  
Pawel Ziemianski
Keyword(s):  
Adverse Effects ◽  
Detrimental Effect ◽  
Organizational Level ◽  
Negative Effects ◽  
Building Relationships ◽  
Holding Power ◽  
And Performance ◽  
Structural Aspects ◽  
Negative Phenomena

This article investigates the possible negative effects of power in organizations. It demonstrates how holding power may affect an individual’s perception of others, actions, and cognition. Ways in which power may have a detrimental effect on different aspects of a manager’s functioning within an organization, including building relationships, communication, and performance are analyzed. It is argued that individuals are unaware of these effects, and thus it is necessary to introduce methods of their diagnosis and countermeasures on the organizational level. In addition, negative phenomena associated with the power’s distribution among organizations’ units and its structural aspects are analyzed. A set of questions is proposed, which can be used by individuals and organizations to reveal the extent to which adverse effects of power are present in an organization. These inquiries can be used to design and introduce specific countermeasures and improve communications and the quality of interactions within organizations. Selected countermeasures are also proposed in the article.

scholarly journals How Should We Treat Elderly Newly Diagnosed Multiple Myeloma Patients?

2015 ◽  
Vol 11 (1) ◽  
pp. 50
Author(s):  
María-Victoria Mateos ◽  
Keyword(s):  
Quality Of Life ◽  
Multiple Myeloma ◽  
Elderly Patients ◽  
Proteasome Inhibitors ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Prolonged Treatment ◽  
Term Therapy ◽  
Close Monitoring

Multiple myeloma is the second most frequent hematologic disease, which usually affects patients over 65 years of age. Treatment goals for these non-transplant-eligible patients should be to prolong survival by achieving the best response, while ensuring quality of life. Melphalan plus prednisone has been the classic backbone to which proteasome inhibitors and immunomodulatory drugs were added and, recently, lenalidomide plus low-dose dexamethasone emerged as a new standard of care, free of alkylator, and also as a backbone to which second-generation proteasome inhibitors are being added. Monoclonal antibodies will take part of these treatments regimens in the future. Prolonged treatment in elderly patients also improves the quality and duration of clinical responses, extending time to progression and progression-free survival; however, the optimal scheme, appropriate doses, and duration of long-term therapy have not yet been fully determined. Finally, elderly patients under treatment require close monitoring and individualized, dose-modified regimens to improve tolerability and treatment efficacy, while maintaining their quality of life.

scholarly journals Inflammation Based Regulation of Cancer Cachexia

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Jill K. Onesti ◽  
Denis C. Guttridge
Keyword(s):  
Quality Of Life ◽  
Skeletal Muscle ◽  
Cancer Cachexia ◽  
Molecular Mechanisms ◽  
Muscle Wasting ◽  
Nutritional Intake ◽  
Clinical Implications ◽  
Life Outcomes ◽  
Skeletal Muscle Wasting

Cancer cachexia, consisting of significant skeletal muscle wasting independent of nutritional intake, is a major concern for patients with solid tumors that affects surgical, therapeutic, and quality of life outcomes. This review summarizes the clinical implications, background of inflammatory cytokines, and the origin and sources of procachectic factors including TNF-α, IL-6, IL-1, INF-γ, and PIF. Molecular mechanisms and pathways are described to elucidate the link between the immune response caused by the presence of the tumor and the final result of skeletal muscle wasting.

scholarly journals Molecular Mechanisms of the Teratogenic Effects of Thalidomide

2020 ◽  
Vol 13 (5) ◽  
pp. 95 ◽  
Author(s):  
Tomoko Asatsuma-Okumura ◽  
Takumi Ito ◽  
Hiroshi Handa
Keyword(s):  
Multiple Myeloma ◽  
Transcription Factor ◽  
Adverse Effects ◽  
Molecular Mechanisms ◽  
Therapeutic Effects ◽  
Teratogenic Effects ◽  
Ring E3 Ligase ◽  
Direct Target ◽  
Transcription Factor 4 ◽  
Ring E3

Thalidomide was sold worldwide as a sedative over 60 years ago, but it was quickly withdrawn from the market due to its teratogenic effects. Thalidomide was later found to have therapeutic effects in several diseases, although the molecular mechanisms remained unclear. The discovery of cereblon (CRBN), the direct target of thalidomide, a decade ago greatly improved our understanding of its mechanism of action. Accumulating evidence has shown that CRBN functions as a substrate of Cullin RING E3 ligase (CRL4CRBN), whose specificity is controlled by ligands such as thalidomide. For example, lenalidomide and pomalidomide, well-known thalidomide derivatives, degrade the neosubstrates Ikaros and Aiolos, resulting in anti-proliferative effects in multiple myeloma. Recently, novel CRBN-binding drugs have been developed. However, for the safe handling of thalidomide and its derivatives, a greater understanding of the mechanisms of its adverse effects is required. The teratogenic effects of thalidomide occur in multiple tissues in the developing fetus and vary in phenotype, making it difficult to clarify this issue. Recently, several CRBN neosubstrates (e.g., SALL4 (Spalt Like Transcription Factor 4) and p63 (Tumor Protein P63)) have been identified as candidate mediators of thalidomide teratogenicity. In this review, we describe the current understanding of molecular mechanisms of thalidomide, particularly in the context of its teratogenicity.

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