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International Journal of Molecular... Jun 2024Based on the lack of differences in progression-free and overall survival after a median follow-up of 93 months in our HOVON-65/GMMG-HD4 trial (German part; = 395)... (Randomized Controlled Trial)
Randomized Controlled Trial
Molecular Long-Term Analysis of the GMMG-HD4 Trial in Multiple Myeloma-Patterns of Association of Chromosomal Aberrations with Response and Proliferation Determining Survival in Selecting Treatments in View of Limited Resources in Low- and Middle-Income Countries.
Based on the lack of differences in progression-free and overall survival after a median follow-up of 93 months in our HOVON-65/GMMG-HD4 trial (German part; = 395) randomizing VAD induction (vincristin/adriamycin/dexamthasone)/tandem-transplantation/thalidomide-maintenance vs. PAD induction (bortezomib/adriamycin/dexamethasone)/tandem transplantation/bortezomib maintenance, we discern how chromosomal aberrations determine long-term prognosis by different patterns of association with proliferation and treatment-dependent response, whether responses achieved by different regimens are equal regarding prognosis, and whether subpopulations of patients could be defined as treatable without upfront "novel agents" in cases of limited resources, e.g., in low- or middle-income countries. Serum parameters and risk factors were assessed in 395 patients. CD138-purified plasma cells were subjected to fluorescence in situ hybridization ( = 354) and gene expression profiling ( = 204). We found chromosomal aberrations to be associated in four patterns with survival, proliferation, and response: deletion (del) del17p13, del8p21, del13q14, (gain) 1q21+, and translocation t(4;14) (all adverse) associate with higher proliferation. Of these, del17p is associated with an response (pattern 1), and 1q21+, t(4;14), and del13q14 with a treatment-dependent response (pattern 2). Hyperdiploidy associates with lower proliferation without impacting response or survival (pattern 3). Translocation t(11;14) has no association with survival but a treatment-dependent adverse response (pattern 4). Significantly fewer patients reach a near-complete response or better with "conventional" (VAD) vs. bortezomib-based treatment after induction or high-dose melphalan. These patients, however, show significantly median progression-free and overall survival. Molecularly, patients responding to the two regimens differ in gene expression, indicating distinct biological properties of the responding myeloma cells. Patients with normal renal function (89.4%), low cytogenetic risk (72.5%), or low proliferation rate (37.9%) neither benefit in progression-free nor overall survival from bortezomib-based upfront treatment. We conclude that response level, the treatment by which it is achieved, and molecular background determine long-term prognosis. Chromosomal aberrations are associated in four patterns with proliferation and treatment-dependent responses. Associations with faster and deeper responses can be deceptive in the case of prognostically adverse aberrations 1q21+ and t(4;14). Far from advocating a return to "outdated" treatments, if resources do not permit state-of-the-art-treatment, normal renal function and/or molecular profiling identifies patient subpopulations doing well without upfront "novel agents".
Topics: Humans; Multiple Myeloma; Chromosome Aberrations; Female; Male; Middle Aged; Aged; Antineoplastic Combined Chemotherapy Protocols; Cell Proliferation; Prognosis; Adult; Developing Countries; Dexamethasone; Bortezomib; Thalidomide
PubMed: 38928138
DOI: 10.3390/ijms25126431 -
Biomolecules Jun 2024Induced pluripotent stem cell (iPSC) based neuronal differentiation is valuable for studying neuropsychiatric disorders and pharmacological mechanisms at the cellular...
BACKGROUND
Induced pluripotent stem cell (iPSC) based neuronal differentiation is valuable for studying neuropsychiatric disorders and pharmacological mechanisms at the cellular level. We aimed to examine the effects of typical and atypical antipsychotics on human iPSC-derived neural progenitor cells (NPCs).
METHODS
Proliferation and neurite outgrowth were measured by live cell imaging, and gene expression levels related to neuronal identity were analyzed by RT-QPCR and immunocytochemistry during differentiation into hippocampal dentate gyrus granule cells following treatment of low- and high-dose antipsychotics (haloperidol, olanzapine, and risperidone).
RESULTS
Antipsychotics did not modify the growth properties of NPCs after 3 days of treatment. However, the characteristics of neurite outgrowth changed significantly in response to haloperidol and olanzapine. After three weeks of differentiation, mRNA expression levels of the selected neuronal markers increased (except for MAP2), while antipsychotics caused only subtle changes. Additionally, we found no changes in MAP2 or GFAP protein expression levels as a result of antipsychotic treatment.
CONCLUSIONS
Altogether, antipsychotic medications promoted neurogenesis in vitro by influencing neurite outgrowth rather than changing cell survival or gene expression. This study provides insights into the effects of antipsychotics on neuronal differentiation and highlights the importance of considering neurite outgrowth as a potential target of action.
Topics: Humans; Olanzapine; Risperidone; Neurogenesis; Hippocampus; Haloperidol; Antipsychotic Agents; Induced Pluripotent Stem Cells; Neural Stem Cells; Cell Differentiation; Cell Proliferation; Cells, Cultured; Neuronal Outgrowth
PubMed: 38927091
DOI: 10.3390/biom14060688 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the efficacy and safety of a treatment regimen based on daratumumab in patients with high-risk relapsed refractory multiple myeloma(MM) with mSMART 3.0...
OBJECTIVE
To investigate the efficacy and safety of a treatment regimen based on daratumumab in patients with high-risk relapsed refractory multiple myeloma(MM) with mSMART 3.0 score.
METHODS
Clinical data were collected from 16 patients with mSMART3.0 score high-risk relapsed refractory MM treated at the Affiliated Hospital of Shandong University of Traditional Chinese Medicine from May 2020 to May 2023, all of whom received daltezumab-based regimen (regimen drugs including dexamethasone, isazomib, bortezomib, lenalidomide). The efficacy and safety of the treatment were retrospectively analyzed.
RESULTS
The median age of 16 patients was 63.5 (47-70) years old, including 10 cases of IgG type, 2 cases of IgA type, and 4 cases of light chain type. The curative efficacy was judged in all 16 patients, with an overall response rate of 93.75% (15/16), including 4 cases of strict complete remission (sCR), 1 case of complete remission (CR), 2 case of very good partial remission (VGPR), partial remission (PR) in 5 cases, and minor remission (MR) in 3 cases. The median follow-up time was 11(2-30) months, and the median progression-free survival and median overall survival were not achieved in 16 patients at the median follow-up period. The hematologic adverse effects of the treatment regimen using daratumumab-based were mainly neutropenia, and the non-hematologic adverse effects were mainly infusion-related adverse reactions and infections.
CONCLUSION
Daratumumab-based regimen for the treatment of relapsed refractory MM patients with high risk of mSMART3.0 score has better efficacy and safety.
Topics: Humans; Multiple Myeloma; Middle Aged; Aged; Antineoplastic Combined Chemotherapy Protocols; Male; Retrospective Studies; Female; Antibodies, Monoclonal; Dexamethasone; Treatment Outcome; Antibodies, Monoclonal, Humanized; Lenalidomide; Bortezomib
PubMed: 38926966
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.018 -
Ceska a Slovenska Oftalmologie :... 2024The aim of this study was to evaluate the outcomes of Ozurdex® (DEX) implant in patients with diabetic macular edema (DME) in real-world clinical practice, and to...
OBJECTIVE
The aim of this study was to evaluate the outcomes of Ozurdex® (DEX) implant in patients with diabetic macular edema (DME) in real-world clinical practice, and to determine the correlation between known OCT biomarkers and the effect of treatment.
MATERIAL AND METHODS
This retrospective study included 42 eyes of 33 patients (16 women, 17 men) treated with DEX at the Department of Ophthalmology, Faculty of Medicine and Dentistry of Palacký University and University Hospital Olomouc for DME indication between 2020 and 2023. Follow-up examinations were conducted at 1, 3, and 6 months after the first DEX application. The main assessed parameters were: best-corrected visual acuity (BCVA), intraocular pressure (IOP), central retinal thickness (CRT), OCT biomarkers. The results were subsequently statistically evaluated.
RESULTS
At the first follow-up after DEX application, there was an average decrease in CRT of 186 ±146µm and a gain of 3 ±7 letters. Positive morphological and functional responses were observed in 39 eyes (92.9%) and 23 eyes (54.8%) respectively. The disorganization of retinal inner layers (DRIL) biomarker was initially present in 41 eyes (97.6%), with reduction or disappearance observed in 13 eyes (31%) post-application. Eyes with ellipsoid zone disruption (EZ disruption) had an average initial BCVA of 49.6 letters, compared to 57.8 letters in the group without this biomarker. The mean gain in BCVA was +8.7 letters in treatment-naive eyes and +2.1 letters in previously treated eyes. Chronic DME was less frequent in treatment-naive (n = 1, 14.3%) compared to previously treated eyes (n = 28, 84.8%). All these results were statistically significant (p < 0.05). An increase in IOP post-DEX application occurred in 9 patients (21.4%).
CONCLUSION
Our results confirm DEX as a safe and effective treatment option for DME. Treatment-naive patients achieved better functional outcomes. We confirmed ellipsoid zone disruption (EZ disruption) as a negative biomarker. Additionally, we demonstrated the capacity of DEX to reduce disorganization of the retinal inner layers (DRIL).
Topics: Humans; Macular Edema; Male; Female; Diabetic Retinopathy; Dexamethasone; Retrospective Studies; Middle Aged; Aged; Intravitreal Injections; Drug Implants; Visual Acuity; Glucocorticoids; Tomography, Optical Coherence
PubMed: 38925895
DOI: 10.31348/2024/29 -
Psychiatry Research Jun 2024Cannabidiol (CBD), as one of the phytocannabinoids, has a wide range of therapeutic properties for various neuropsychiatric disorders due to central nervous system... (Review)
Review
Cannabidiol (CBD), as one of the phytocannabinoids, has a wide range of therapeutic properties for various neuropsychiatric disorders due to central nervous system effects. These therapeutic properties demonstrated by preclinical and clinical studies encompass more than just anticonvulsant, anti-arthritic, analgesic, anti-inflammatory, antioxidant, antitumor, antiemetic, antipsychotic and neuroprotective effects. It has been hypothesized that CBD holds potential in the treatment of various neuropsychiatric and anxiety disorders. Thus, PRISMA was used as a guide for our systematic review. Eight of the 1550 articles screened in June 2023 were eligible for meta-analysis. Based on the 316 participants included in these eight articles, this meta-analysis revealed a substantial significant impact of CBD on anxiety with a considerable effect size (Hedges' g = -0.92, 95% CI -1.80 to -0.04). In addition, this meta-analysis focuses on the efficacy of CBD in treating anxiety disorders such as generalized anxiety disorder (GAD), social anxiety disorder (SAD), and post-traumatic stress disorder (PTSD). However, caution should be exercised in interpreting our findings due to the limited size of the clinical sample, and additional trials ought to be carried out if deemed necessary.
PubMed: 38924898
DOI: 10.1016/j.psychres.2024.116049 -
The New England Journal of Medicine Jun 2024
Topics: Humans; Brain Neoplasms; Glioblastoma; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; T-Lymphocytes; Clinical Trials, Phase I as Topic; Brain Diseases; Dexamethasone; Bevacizumab
PubMed: 38924746
DOI: 10.1056/NEJMc2405721 -
The New England Journal of Medicine Jun 2024
Topics: Humans; Male; Brain Neoplasms; Glioblastoma; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; T-Lymphocytes; Clinical Trials, Phase I as Topic; Bevacizumab; Dexamethasone
PubMed: 38924745
DOI: 10.1056/NEJMc2405721 -
American Journal of Reproductive... Jun 2024
Authors' reply: Commentary on "Intrauterine perfusion of dexamethasone improves pregnancy outcomes in recurrent reproductive failure patients with elevated uterine natural killer cells. A retrospective cohort study".
Topics: Humans; Female; Pregnancy; Dexamethasone; Killer Cells, Natural; Uterus; Pregnancy Outcome; Retrospective Studies; Perfusion; Abortion, Habitual
PubMed: 38923191
DOI: 10.1111/aji.13866 -
Annals of the Academy of Medicine,... Nov 2023AL amyloidosis is the most common form of systemic amyloidosis. However, the non-specific nature of presenting symptoms requires the need for a heightened clinical... (Review)
Review
AL amyloidosis is the most common form of systemic amyloidosis. However, the non-specific nature of presenting symptoms requires the need for a heightened clinical suspicion to detect unexplained manifestations in the appropriate clinical setting. Early detection and treatment are crucial as the degree of cardiac involvement emerges as a primary prognostic predictor of survival in a patient with AL amyloidosis. Following the diagnosis of AL amyloidosis with appropriate tissue biopsies, prompt treatment with a bortezomib, cyclophosphamide and dexamethasone-based first-line induction with or without daratumumab should be initiated. The goal of treatment is to achieve the best haematologic response possible, ideally with involved free light chain <20 mg/L, as it offers the best chance of organ function improvement. Treatment should be changed if patients do not achieve a partial response within 2 cycles of treatment or very good partial response after 4 cycles or after autologous stem cell transplant, as achievement of profound and prolonged clonal responses translates to better organ response and long-term outcomes. Early involvement of multidisciplinary subspecialists such as renal physicians, cardiologists, neurologists, and gastroenterologists for optimal maintenance and support of involved organs is recommended for optimal management of patients with AL amyloidosis.
Topics: Humans; Immunoglobulin Light-chain Amyloidosis; Dexamethasone; Singapore; Bortezomib; Cyclophosphamide; Antineoplastic Combined Chemotherapy Protocols; Consensus; Antibodies, Monoclonal; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation
PubMed: 38920149
DOI: 10.47102/annals-acadmedsg.2023101 -
Journal of Biosciences 2024Noradrenaline (NA) and serotonin (5-HT) induce nociception and antinociception. This antagonistic effect can be explained by the dose and type of activated receptors. We...
Noradrenaline (NA) and serotonin (5-HT) induce nociception and antinociception. This antagonistic effect can be explained by the dose and type of activated receptors. We investigated the existence of synergism between the noradrenergic and serotonergic systems during peripheral antinociception. The paw pressure test was performed in mice that had increased sensitivity by intraplantar injection of prostaglandin E (PGE). Noradrenaline (80 ng) administered intraplantarly induced an antinociceptive effect, that was reversed by the administration of selective antagonists of serotoninergic receptors 5-HT isamoltan, 5-HT BRL15572, 5-HT ketanserin, 5-HT ondansetron, but not by selective receptor antagonist 5-HT SB-269970. The administration of escitalopram, a serotonin reuptake inhibitor, potentiated the antinociceptive effect at a submaximal dose of NA. These results, indicate the existence of synergism between the noradrenergic and serotonergic systems in peripheral antinociception in mice.
Topics: Animals; Mice; Norepinephrine; Serotonin; Serotonin Antagonists; Male; Receptors, Serotonin; Dinoprostone; Citalopram; Nociception; Analgesics; Ondansetron; Ketanserin; Pain; Selective Serotonin Reuptake Inhibitors
PubMed: 38920106
DOI: No ID Found