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International Journal of Biological... Jun 2024Anti-osteoporotic agents are clinically employed to improve bone health and prevent osteoporotic fractures. In the current study, we investigated the potential of...
Anti-osteoporotic agents are clinically employed to improve bone health and prevent osteoporotic fractures. In the current study, we investigated the potential of chitosan-quercetin bio-conjugate as an anti-osteoporotic agent. The conjugate was prepared and characterized by FTIR and found notable interactions between chitosan and quercetin. Treating mouse MSCs with the bioconjugate in osteogenic conditions for a week led to elevated expression of differentiation markers Runx2, ALP, and Col-I, as determined by real-time PCR analysis. Evaluation at the cellular level using alizarin red staining demonstrated enhanced calcium deposition in MSCs following treatment with the bioconjugate. Likewise, ELISA analysis showed significantly elevated levels of secretory osteocalcin and osteonectin in groups treated with the conjugate. To broaden our comprehension, we utilized a zebrafish-based in vivo model of dexamethasone-induced osteoporosis to investigate bone regeneration. Toxicity profiling with zebrafish larvae confirmed the bio-conjugate's compatibility at a concentration of 25 μg/ml, underscoring the significance of finding the right dosage. Furthermore, in zebrafish models of osteoporosis, the bio-conjugate demonstrated significant potential for bone regeneration, as indicated by improved bone calcification, callus formation, and overall bone healing in a tail fin fracture model. Additionally, the study revealed that the bio-conjugate inhibited osteoclastic activity, leading to reduced TRAP activity and hydroxyproline release, suggesting its effectiveness in mitigating bone resorption. In conclusion, our research provides compelling evidence for the osteogenic capabilities of the chitosan-quercetin bio-conjugate, highlighting its promising applications in regenerative medicine and the treatment of conditions like osteoporosis.
PubMed: 38944072
DOI: 10.1016/j.ijbiomac.2024.133492 -
The International Journal of Risk &... Jun 2024The ubiquity of social media has ushered in an era where uncontrolled content sharing extends to all subjects, including sensitive topics such as medication consumption.
BACKGROUND
The ubiquity of social media has ushered in an era where uncontrolled content sharing extends to all subjects, including sensitive topics such as medication consumption.
OBJECTIVE
To quantify the prevalence of YouTube videos providing information on glucocorticoids and to underscore the risks associated with inaccurate information, which might inadvertently promote inappropriate use of these medications.
METHODS
The YouTube videos were selected using predefined keywords from February 20 to March 4, 2023. The videos were categorized into two groups. Category 1 promotes the misuse of corticosteroids, while Category 2 raises awareness about the risks associated with these drugs.
RESULTS
In total, 843 YouTube videos were included. Approximately 76% of the creators were women. Of these, category 1 videos (69.63%) predominated over Category 2 videos (30.37%). Regarding Category 1, dexamethasone was mentioned in 41.53% of cases, followed by hydrocortisone (17.30%). According to these YouTubers, these products/medications are mainly obtained from community pharmacies (58.09%), online shops (20.01%), and through illicit markets and the black market (13.46%). Weight gain was the most common objective, according to 32.62% of the YouTubers.
CONCLUSION
This study highlights the prevalence of YouTube videos regarding the misuse of corticosteroids. The common focus on weight gain as an objective underscores the importance of educating content creators and viewers about responsible corticosteroid use. Targeted interventions are needed to promote safe and informed medication practices within this online environment.
PubMed: 38943400
DOI: 10.3233/JRS-230061 -
American Journal of Hematology Jun 2024Multiple myeloma accounts for approximately 10% of hematologic malignancies.
DISEASE OVERVIEW
Multiple myeloma accounts for approximately 10% of hematologic malignancies.
DIAGNOSIS
The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE): CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) attributable to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L and urine monoclonal protein is ≥200 mg/24 h), or >1 focal lesion on magnetic resonance imaging.
RISK STRATIFICATION
The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation is considered high-risk multiple myeloma. Presence of any two high risk factors is considered double-hit myeloma; three or more high risk factors is triple-hit myeloma.
RISK-ADAPTED INITIAL THERAPY
In patients who are candidates for autologous stem cell transplantation, induction therapy consists of anti-CD38 monoclonal antibody plus bortezomib, lenalidomide, dexamethasone (VRd) followed by autologous stem cell transplantation (ASCT). Selected standard risk patients can delay transplant until first relapse. Frail patients who not candidates for transplant are treated with VRd for approximately 8-12 cycles followed by maintenance or alternatively with daratumumab, lenalidomide, dexamethasone (DRd) until progression.
MAINTENANCE THERAPY
Standard risk patients need lenalidomide maintenance, while bortezomib plus lenalidomide maintenance is needed for high-risk myeloma.
MANAGEMENT OF RELAPSED DISEASE
A triplet regimen is usually needed at relapse, with the choice of regimen varying with each successive relapse. Chimeric antigen receptor T (CAR-T) cell therapy and bispecific antibodies are additional options.
PubMed: 38943315
DOI: 10.1002/ajh.27422 -
Nature Communications Jun 2024Dexamethasone is the standard of care for critically ill patients with COVID-19, but the mechanisms by which it decreases mortality and its immunological effects in this...
Dexamethasone is the standard of care for critically ill patients with COVID-19, but the mechanisms by which it decreases mortality and its immunological effects in this setting are not understood. Here we perform bulk and single-cell RNA sequencing of samples from the lower respiratory tract and blood, and assess plasma cytokine profiling to study the effects of dexamethasone on both systemic and pulmonary immune cell compartments. In blood samples, dexamethasone is associated with decreased expression of genes associated with T cell activation, including TNFSFR4 and IL21R. We also identify decreased expression of several immune pathways, including major histocompatibility complex-II signaling, selectin P ligand signaling, and T cell recruitment by intercellular adhesion molecule and integrin activation, suggesting these are potential mechanisms of the therapeutic benefit of steroids in COVID-19. We identify additional compartment- and cell- specific differences in the effect of dexamethasone that are reproducible in publicly available datasets, including steroid-resistant interferon pathway expression in the respiratory tract, which may be additional therapeutic targets. In summary, we demonstrate compartment-specific effects of dexamethasone in critically ill COVID-19 patients, providing mechanistic insights with potential therapeutic relevance. Our results highlight the importance of studying compartmentalized inflammation in critically ill patients.
Topics: Dexamethasone; Humans; COVID-19 Drug Treatment; COVID-19; SARS-CoV-2; Lung; Cytokines; Critical Illness; Male; Single-Cell Analysis; Female; Middle Aged; T-Lymphocytes; Aged; Lymphocyte Activation
PubMed: 38942804
DOI: 10.1038/s41467-024-49756-2 -
EBioMedicine Jun 2024Drug development for atrial fibrillation (AF) has failed to yield new approved compounds. We sought to identify and prioritise potential druggable targets with support...
BACKGROUND
Drug development for atrial fibrillation (AF) has failed to yield new approved compounds. We sought to identify and prioritise potential druggable targets with support from human genetics, by integrating the available evidence with bioinformatics sources relevant for AF drug development.
METHODS
Genetic hits for AF and related traits were identified through structured search of MEDLINE. Genes derived from each paper were cross-referenced with the OpenTargets platform for drug interactions. Confirmation/validation was demonstrated through structured searches and review of evidence on MEDLINE and ClinialTrials.gov for each drug and its association with AF.
FINDINGS
613 unique drugs were identified, with 21 already included in AF Guidelines. Cardiovascular drugs from classes not currently used for AF (e.g. ranolazine and carperitide) and anti-inflammatory drugs (e.g. dexamethasone and mehylprednisolone) had evidence of potential benefit. Further targets were considered druggable but remain open for drug development.
INTERPRETATION
Our systematic approach, combining evidence from different bioinformatics platforms, identified drug repurposing opportunities and druggable targets for AF.
FUNDING
KK is supported by Barts Charity grant G-002089 and is mentored on the AFGen 2023-24 Fellowship funded by the AFGen NIH/NHLBI grant R01HL092577. RP is supported by the UCL BHF Research Accelerator AA/18/6/34223 and NIHR grant NIHR129463. AFS is supported by the BHF grants PG/18/5033837, PG/22/10989 and UCL BHF Accelerator AA/18/6/34223 as well as the UK Research and Innovation (UKRI) under the UK government's Horizon Europe funding guarantee EP/Z000211/1 and by the UKRI-NIHR grant MR/V033867/1 for the Multimorbidity Mechanism and Therapeutics Research Collaboration. AF is supported by UCL BHF Accelerator AA/18/6/34223. CF is supported by UCL BHF Accelerator AA/18/6/34223.
PubMed: 38941956
DOI: 10.1016/j.ebiom.2024.105194 -
Medicine Jun 2024Evidence on real-world clinical and economic outcomes in patients with multiple myeloma (MM) and renal impairment (RI) is limited in the United States. This... (Observational Study)
Observational Study
Evidence on real-world clinical and economic outcomes in patients with multiple myeloma (MM) and renal impairment (RI) is limited in the United States. This retrospective study aimed to generate an updated comprehensive assessment of the clinical and economic outcomes of MM patients with RI using the Medicare research identifiable files data with Part D linkage, which might assist in assessing the total clinical and socioeconomic burden of these high-risk and challenging-to-treat patients. Treatment patterns and clinical and economic outcomes in first line (1L) to fourth line (4L) therapy were described in Medicare beneficiaries (2012 to 2018) for MM patients with RI (RI MM cohort). For reference purposes, information on a general cohort of MM patients was generated and reported to highlight the clinical and economic burden of RI. Since the goal was to describe the burden of these patients, this study was not designed as a comparison between the 2 cohorts. Compared with the general MM cohort (n = 13,573), RI MM patients (24.9%) presented high MM-associated comorbidities. In the RI MM cohort, bortezomib-dexamethasone (45.7%), bortezomib-lenalidomide (18.6%), lenalidomide (12.3%), and bortezomib-cyclophosphamide (12.1%) were the most prevalent regimens in 1L; carfilzomib and pomalidomide were mostly received in 3L to 4L; and daratumumab in 4L. Across 1L to 4L, the RI MM cohort presented shorter median real-world progression-free survival (1L: 12.9 and 16.4 months) and overall survival (1L: 31.1 and 46.8 months) and higher all-cause healthcare resource utilization (1L incidence rate of inpatient days: 12.1 and 7.8 per person per year) than the general MM cohort. In the RI MM cohort, the mean all-cause total cost increased from 1L to 4L ($14,549-$18,667 per person per month) and was higher than that of the general MM cohort. RI MM patients presented higher clinical and economic burdens across 1L to 4L than the general MM patients in real-world clinical practice.
Topics: Humans; Multiple Myeloma; United States; Male; Female; Aged; Retrospective Studies; Medicare; Aged, 80 and over; Renal Insufficiency; Cost of Illness; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38941411
DOI: 10.1097/MD.0000000000038609 -
European Journal of Endocrinology Jun 2024To assess whether clinical and imaging characteristics predict hormonal subtype, growth, and adrenalectomy for incidental adrenal cortical adenomas (ACA).
OBJECTIVE
To assess whether clinical and imaging characteristics predict hormonal subtype, growth, and adrenalectomy for incidental adrenal cortical adenomas (ACA).
DESIGN
Single center cohort study.
METHODS
Consecutive adult patients with incidental ACA diagnosed between 2000 and 2016.
RESULTS
Of 1516 patients with incidental ACA (median age 59 years, 62% women), 699 (46%) had nonfunctioning adenomas (NFA), 482 (31%) had mild autonomous cortisol secretion (MACS), 62 (4%) had primary aldosteronism (PA), 39 (3%) had Cushing syndrome (CS), 18 (1%) had PA and MACS (PA-MACS), and 226 (15%) had incomplete workup. Age, sex, tumor size, and tumor laterality, but not unenhanced computed tomography Hounsfield units (HU), were associated with hormonal subtypes. In a multivariable analysis, ≥1cm growth was associated with younger age (odds ratio per 5-year increase, OR=0.8, P=0.0047) and longer imaging follow-up (OR=1.2 per year, P<.0001). Adrenalectomy was performed in 355 (23%) patients, including 38% of MACS and 15% of NFA. Adrenalectomy for NFA and MACS was more common in younger patients (OR=0.79 per 5-year increase, P=0.002), larger initial tumor size (OR=2.3 per 1-cm increase, P<.0001), ≥1cm growth (OR=15.3, P<.0001), and higher post-dexamethasone cortisol (OR=6.6 for >5 vs <1.8 mcg/dL, P=0.002).
CONCLUSIONS
Age, sex, tumor size, and laterality were associated with ACA hormonal subtype and can guide diagnosis and management. Tumor growth was more common with younger age and longer follow-up. Unenhanced HU did not predict hormonal subtype or growth. Adrenalectomy for MACS and NFA was mainly performed in younger patients with larger tumor size, growth, and elevated post-dexamethasone cortisol.
PubMed: 38941271
DOI: 10.1093/ejendo/lvae078 -
BdRCN4, a Brachypodium distachyon TFL1 homologue, is involved in regulation of apical meristem fate.Plant Molecular Biology Jun 2024In higher plants, the shift from vegetative to reproductive development is governed by complex interplay of internal and external signals. TERMINALFLOWER1 (TFL1) plays a...
In higher plants, the shift from vegetative to reproductive development is governed by complex interplay of internal and external signals. TERMINALFLOWER1 (TFL1) plays a crucial role in the regulation of flowering time and inflorescence architecture in Arabidopsis thaliana. This study aimed to explore the function of BdRCN4, a homolog of TFL1 in Brachypodium distachyon, through functional analyses in mutant and transgenic plants. The results revealed that overexpression of BdRCN4 in B. distachyon leads to an extended vegetative phase and reduced production of spikelets. Similar results were found in A. thaliana, where constitutive expression of BdRCN4 promoted a delay in flowering time, followed by the development of hypervegetative shoots, with no flowers or siliques produced. Our results suggest that BdRCN4 acts as a flowering repressor analogous to TFL1, negatively regulating AP1, but no LFY expression. To further validate this hypothesis, a 35S::LFY-GR co-transformation approach on 35::BdRCN4 lines was performed. Remarkably, AP1 expression levels and flower formation were restored to normal in co-transformed plants when treated with dexamethasone. Although further molecular studies will be necessary, the evidence in B. distachyon support the idea that a balance between LFY and BdRCN4/TFL1 seems to be essential for activating AP1 expression and initiating floral organ identity gene expression. This study also demonstrates interesting conservation through the molecular pathways that regulate flowering meristem transition and identity across the evolution of monocot and dicot plants.
Topics: Brachypodium; Meristem; Gene Expression Regulation, Plant; Plant Proteins; Flowers; Plants, Genetically Modified; Arabidopsis; Arabidopsis Proteins
PubMed: 38940986
DOI: 10.1007/s11103-024-01467-4 -
Annals of Intensive Care Jun 2024A notable increase in severe cases of COVID-19, with significant hospitalizations due to the emergence and spread of JN.1 was observed worldwide in late 2023 and early...
Clinical phenotypes and outcomes associated with SARS-CoV-2 Omicron sublineage JN.1 in critically ill COVID-19 patients: a prospective, multicenter cohort study in France, November 2022 to January 2024.
BACKGROUND
A notable increase in severe cases of COVID-19, with significant hospitalizations due to the emergence and spread of JN.1 was observed worldwide in late 2023 and early 2024. However, no clinical data are available regarding critically-ill JN.1 COVID-19 infected patients.
METHODS
The current study is a substudy of the SEVARVIR prospective multicenter observational cohort study. Patients admitted to any of the 40 participating ICUs between November 17, 2022, and January 22, 2024, were eligible for inclusion in the SEVARVIR cohort study (NCT05162508) if they met the following inclusion criteria: age ≥ 18 years, SARS-CoV-2 infection confirmed by a positive reverse transcriptase-polymerase chain reaction (RT-PCR) in nasopharyngeal swab samples, ICU admission for acute respiratory failure. The primary clinical endpoint of the study was day-28 mortality. Evaluation of the association between day-28 mortality and sublineage group was conducted by performing an exploratory multivariable logistic regression model, after systematically adjusting for predefined prognostic factors previously shown to be important confounders (i.e. obesity, immunosuppression, age and SOFA score) computing odds ratios (OR) along with their corresponding 95% confidence intervals (95% CI).
RESULTS
During the study period (November 2022-January 2024) 56 JN.1- and 126 XBB-infected patients were prospectively enrolled in 40 French intensive care units. JN.1-infected patients were more likely to be obese (35.7% vs 20.8%; p = 0.033) and less frequently immunosuppressed than others (20.4% vs 41.4%; p = 0.010). JN.1-infected patients required invasive mechanical ventilation support in 29.1%, 87.5% of them received dexamethasone, 14.5% tocilizumab and none received monoclonal antibodies. Only one JN-1 infected patient (1.8%) required extracorporeal membrane oxygenation support during ICU stay (vs 0/126 in the XBB group; p = 0.30). Day-28 mortality of JN.1-infected patients was 14.6%, not significantly different from that of XBB-infected patients (22.0%; p = 0.28). In univariable logistic regression analysis and in multivariable analysis adjusting for confounders defined a priori, we found no statistically significant association between JN.1 infection and day-28 mortality (adjusted OR 1.06 95% CI (0.17;1.42); p = 0.19). There was no significant between group difference regarding duration of stay in the ICU (6.0 [3.5;11.0] vs 7.0 [4.0;14.0] days; p = 0.21).
CONCLUSIONS
Critically-ill patients with Omicron JN.1 infection showed a different clinical phenotype than patients infected with the earlier XBB sublineage, including more frequent obesity and less immunosuppression. Compared with XBB, JN.1 infection was not associated with higher day-28 mortality.
PubMed: 38940865
DOI: 10.1186/s13613-024-01319-w -
British Journal of Haematology Jun 2024Mantle cell lymphoma (MCL) is a rare lymphoproliferative neoplasm considered incurable, with a median survival of 3-5 years. In recent years, Bruton's tyrosine kinase...
Mantle cell lymphoma (MCL) is a rare lymphoproliferative neoplasm considered incurable, with a median survival of 3-5 years. In recent years, Bruton's tyrosine kinase inhibitors (BTKi) have been introduced, demonstrating high therapeutic activity. However, the prognosis for MCL patients failing ibrutinib therapy is particularly poor, with a survival expectation of a few months. In this phase II trial, we assessed the efficacy and safety of the carfilzomib-lenalidomide-dexamethasone (KRD) combination in MCL patients who were relapsed/refractory (R/R) or intolerant to BTKi and in need of treatment. The primary objective of the study was to evaluate the antitumor efficacy of the KRD combination in terms of 12-month overall survival (12-month OS). From September 2019 to December 2020, 16 patients were enrolled from 11 Italian centers. After a median follow-up of 2.37 months (95% CI 0.92-6.47), the 12-month OS was 13%. The rate of grade 3-4 adverse events (AEs) was 35%, and the overall response rate (ORR) was 19%. These results led to the premature termination of enrollment, as defined in the protocol stopping rules. The efficacy of the KRD combination in advanced-stage MCL patients who are R/R to BTKi is unsatisfactory and too toxic.
PubMed: 38938122
DOI: 10.1111/bjh.19617