Ultrasonic Cavitation-Enabled Treatment for Therapy of Hypertrophic Cardiomyopathy: Proof of Principle

Ultrasound myocardial cavitation-enabled treatment was applied to the SS-16^BN rat model of hypertrophic cardiomyopathy for proof of the principle underlying myocardial reduction therapy. A focused ultrasound transducer was targeted using 10-MHz imaging (10 S, GE Vivid 7) to the left ventricular wall of anesthetized rats in a warmed water bath. Pulse bursts of 4-MPa peak rarefactional pressure amplitude were intermittently triggered 1:8 heartbeats during a 10-min infusion of a microbubble suspension. Methylprednisolone was given to reduce initial inflammation, and Losartan was given to reduce fibrosis in the healing tissue. At 28 d post therapy, myocardial cavitation-enabled treatment significantly reduced the targeted wall thickness by 16.2% (p?<0.01) relative to shams, with myocardial strain rate and endocardial displacement reduced by 34% and 29%, respectively, which are sufficient for therapeutic treatment. Premature electrocardiogram complexes and plasma troponin measurements were found to identify optimal and suboptimal treatment cohorts and would aid in achieving the desired impact. With clinical translation, myocardial cavitation-enabled treatment should fill the need for a new non-invasive hypertrophic cardiomyopathy therapy option.     

TDP-43 is associated with a reduced likelihood of rendering a clinical diagnosis of dementia with Lewy bodies in autopsy-confirmed cases of transitional/diffuse Lewy body disease

Journal of Neurology - Trans-active response DNA-binding protein of 43&nbsp;kDa (TDP-43) can be detected in up to 63% of autopsy-confirmed Lewy body disease (LBD) cases. It is unclear whether...     

Allogeneic hematopoietic cell transplantation for metastatic breast cancer

We reviewed 66 women with poor-risk metastatic breast cancer from 15 centers to describe the efficacy of allogeneic hematopoietic cell transplantation (HCT). Median follow-up for survivors was 40 months (range, 3-64). A total of 39 patients (59%) received myeloablative and 27 (41%) reduced-intensity conditioning (RIC) regimens. More patients in the RIC group had poor pretransplant performance status (63 vs 26%, P=0.002). RIC group developed less chronic GVHD (8 vs 36% at 1 year, P=0.003). Treatment-related mortality rates were lower with RIC (7 vs 29% at 100 days, P=0.03). A total of 9 of 33 patients (27%) who underwent immune manipulation for persistent or progressive disease had disease control, suggesting a graft-vs-tumor (GVT) effect. Progression-free survival (PFS) at 1 year was 23% with myeloablative conditioning and 8% with RIC (P=0.09). Women who developed acute GVHD after an RIC regimen had lower risks of relapse or progression than those who did not (relative risk, 3.05: P=0.03), consistent with a GVT effect, but this did not affect PFS. These findings support the need for preclinical and clinical studies that facilitate targeted adoptive immunotherapy for breast cancer to explore the benefit of a GVT effect in breast cancer.     

Four categories of gamma-globin gene triplications: DNA sequence comparison of low G gamma and high G gamma triplications

The human fetal gamma chains are produced by closely linked G gamma and A gamma genes, and unequal crossing over between them leads to gamma gene deletions and triplications. Nine gamma gene triplications from seven ethnic groups were analyzed for G gamma and hemoglobin F (Hb F) values of heterozygotes and for the presence of polymorphic XmnI restriction sites 5' to the gamma genes. Four categories of triplication were found: I had low G gamma and low Hb F values and lacked XmnI sites 5' to the three gamma genes [---]. II had high G gamma and slightly elevated Hb F values but was also [---]. III was similar to II, except that XmnI was [+--]. IV had very high G gamma and slightly elevated Hb F values, and XmnI was [++-]. One case each of triplications I and IV were cloned into Charon 35. For both, the two 5' gamma gene code for G gamma chain, while the 3' gamma gene codes for A gamma chain. DNA sequencing showed that the unequal crossover occurred between 472 and 398 base pairs (bp) 5' to the gamma gene Cap sites (- 472 and -398) for the type IV triplication and between -271 and codon 136 for the type I triplication. In addition, type I had a 4-bp deletion of AGCA from -225 to -222. The high G gamma values of the type IV triplication are explained by its -G gamma-G gamma-A gamma-gene arrangement and the XmnI sites 5' to the G gamma genes. We hypothesize that the low G gamma value of the type I triplication, which is also -G gamma-G gamma-A gamma-, is due to inactivation of the middle G gamma gene by the AGCA deletion at -225 to -222.