Antimyeloma Effects of the Heat Shock Protein 70 Molecular Chaperone Inhibitor MAL3-101

Multiple myeloma (MM) is the second most common hematologic malignancy and remains incurable, primarily due to the treatment-refractory/resistant nature of the disease. A rational approach to this compelling challenge is to develop new drugs that act synergistically with existing effective agents. This approach will reduce drug concentrations, avoid treatment resistance, and also improve treatment effectiveness by targeting new and nonredundant pathways in MM. Toward this goal, we examined the antimyeloma effects of MAL3-101, a member of a new class of non-ATP-site inhibitors of the heat shock protein (Hsp) 70 molecular chaperone. We discovered that MAL3-101 exhibited antimyeloma effects on MM cell lines in vitro and in vivo in a xenograft plasmacytoma model, as well as on primary tumor cells and bone marrow endothelial cells from myeloma patients. In combination with a proteasome inhibitor, MAL3-101 significantly potentiated the in vitro and in vivo antimyeloma effects. These data support a preclinical rationale for small molecule inhibition of Hsp70 function, either alone or in combination with other agents, as an effective therapeutic strategy for MM

Parents' perception of self-advocacy of children with myositis: an anonymous online survey

<p>Abstract</p> <p>Background</p> <p>Children with complex medical issues experience barriers to the transition of care from pediatric to adult providers. We sought to identify these barriers by elucidating the experiences of patients with idiopathic inflammatory muscle disorders.</p> <p>Methods</p> <p>We collected anonymous survey data using an online website. Patients and their families were solicited from the US and Canada through established clinics for children with idiopathic inflammatory muscle diseases as well as with the aid of a nonprofit organization for the benefit of such individuals. The parents of 45 older children/young adults suffering from idiopathic inflammatory muscle diseases were surveyed. As a basis of comparison, we similarly collected data from the parents of 207 younger children with inflammatory muscle diseases. The survey assessed transition of care issues confronting families of children and young adults with chronic juvenile myositis.</p> <p>Results</p> <p>Regardless of age of the patient, respondents were unlikely to have a designated health care provider assigned to aid in transition of care and were unlikely to be aware of a posted policy concerning transition of care at their pediatrician's office. Additionally, regardless of age, patients and their families were unlikely to have a written plan for moving to adult care.</p> <p>Conclusions</p> <p>We identified deficiencies in the health care experiences of families as pertain to knowledge, self-advocacy, policy, and vocational readiness. Moreover, as children with complex medical issues grow up, parents attribute less self-advocacy to their children's level of independence.</p

The 2021 EULAR/American College of Rheumatology points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and deficiency of the interleukin-1 receptor antagonist

BACKGROUND: The interleukin-1 (IL-1) mediated systemic autoinflammatory diseases, including the cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD) and deficiency of the IL-1 receptor antagonist (DIRA), belong to a group of rare immunodysregulatory diseases that primarily present in early childhood with variable multiorgan involvement. When untreated, patients with severe clinical phenotypes have a poor prognosis, and diagnosis and management of these patients can be challenging. However, approved treatments targeting the proinflammatory cytokine IL-1 have been life changing and have significantly improved patient outcomes. OBJECTIVE: To establish evidence-based recommendations for diagnosis, treatment and monitoring of patients with IL-1 mediated autoinflammatory diseases to standardise their management. METHODS: A multinational, multidisciplinary task force consisting of physician experts, including rheumatologists, patients or caregivers and allied healthcare professionals, was established. Evidence synthesis, including systematic literature review and expert consensus (Delphi) via surveys, was conducted. Consensus methodology was used to formulate and vote on statements to guide optimal patient care. RESULTS: The task force devised five overarching principles, 14 statements related to diagnosis, 10 on therapy, and nine focused on long-term monitoring that were evidence and/or consensus-based for patients with IL-1 mediated diseases. An outline was developed for disease-specific monitoring of inflammation-induced organ damage progression and reported treatments of CAPS, TRAPS, MKD and DIRA. CONCLUSION: The 2021 EULAR/American College of Rheumatology points to consider represent state-of-the-art knowledge based on published data and expert opinion to guide diagnostic evaluation, treatment and monitoring of patients with CAPS, TRAPS, MKD and DIRA, and to standardise and improve care, quality of life and disease outcomes

Defining the optimal dose of radiation in leukemic patients with extramedullary lesions

<p>Abstract</p> <p>Background</p> <p>Analysis of the clinical response of extramedullary lesions in leukemic patients treated with radiation therapy (RT) and defining the optimal dose of radiation.</p> <p>Methods</p> <p>Forty-two extramedullary lesions found in 24 leukemic patients treated with RT were reviewed. The radiation was delivered usually 2 Gy/day, up to a median of 20 Gy (range: 18.0-40.8). The clinical response and symptom palliation effect were analyzed. The factors affecting the response were also included in the analysis.</p> <p>Results</p> <p>After a median time of 7.9 weeks, the overall response rate was 76.2%. A complete response (CR) was achieved in 35.7%, a partial response in 40.5%. The symptom was relieved in 85.7% sites. The overall response rate was better in patients whose initial tumor size was smaller than 10 cm²(<it>p = 0.010</it>) or who were treated with more than 25 Gy (<it>p = 0.031</it>). The overall CR rate was also higher in those who had smaller tumors (smaller than 6 cm or 30 cm²) (<it>p = 0.015)</it>, or when the tumor was located in soft tissue (<it>p = 0.029</it>).</p> <p>Conclusions</p> <p>Extramedullary lesions in leukemic patients can be successfully treated with RT. The tumor response rate was excellent and symptom relief was achieved in almost all patients. There was a better response to treatment when the tumor was small or it was located in soft tissue. Although, there was no definite correlation between volume reduction and total dose, it seems that higher total dose more of than 25 Gy is needed for better response.</p

The Sariçiçek Howardite Fall in Turkey: Source Crater of HED Meteorites on Vesta and İmpact Risk of Vestoids

The Sariçiçek howardite meteorite shower consisting of 343 documented stones occurred on 2 September 2015 in Turkey and is the first documented howardite fall. Cosmogenic isotopes show that Sariçiçek experienced a complex cosmic ray exposure history, exposed during ~12–14 Ma in a regolith near the surface of a parent asteroid, and that an ~1 m sized meteoroid was launched by an impact 22 ± 2 Ma ago to Earth (as did one third of all HED meteorites). SIMS dating of zircon and baddeleyite yielded 4550.4 ± 2.5 Ma and 4553 ± 8.8 Ma crystallization ages for the basaltic magma clasts. The apatite U-Pb age of 4525 ± 17 Ma, K-Ar age of ~3.9 Ga, and the U,Th-He ages of 1.8 ± 0.7 and 2.6 ± 0.3 Ga are interpreted to represent thermal metamorphic and impact-related resetting ages, respectively. Petrographic, geochemical and O-, Cr- and Tiisotopic studies confirm that Sariçiçek belongs to the normal clan of HED meteorites. Petrographic observations and analysis of organic material indicate a small portion of carbonaceous chondrite material in the Sariçiçek regolith and organic contamination of the meteorite after a few days on soil. Video observations of the fall show an atmospheric entry at 17.3 ± 0.8 kms-1 from NW, fragmentations at 37, 33, 31 and 27 km altitude, and provide a pre-atmospheric orbit that is the first dynamical link between the normal HED meteorite clan and the inner Main Belt. Spectral data indicate the similarity of Sariçiçek with the Vesta asteroid family (V-class) spectra, a group of asteroids stretching to delivery resonances, which includes (4) Vesta. Dynamical modeling of meteoroid delivery to Earth shows that the complete disruption of a ~1 km sized Vesta family asteroid or a ~10 km sized impact crater on Vesta is required to provide sufficient meteoroids ≤4 m in size to account for the influx of meteorites from this HED clan. The 16.7 km diameter Antonia impact crater on Vesta was formed on terrain of the same age as given by the 4He retention age of Sariçiçek. Lunar scaling for crater production to crater counts of its ejecta blanket show it was formed ~22 Ma ago