Human Immunodeficiency Virus-Associated Myocardial Diastolic Dysfunction and Soluble ST2 Concentration in Tanzanian Adults: A Cross-Sectional Study.

BACKGROUND: The aims of this study were (1) to compare the prevalence of myocardial diastolic dysfunction (DD) in antiretroviral therapy (ART)-naive people living with human immunodeficiency virus (PLWH) to human immunodeficiency virus (HIV)-uninfected adults in East Africa and (2) to determine the association between serum concentration of the cardiac biomarkers ST2 and DD. METHODS: In this cross-sectional study, we enrolled PLWH and uninfected adults at a referral HIV clinic in Mwanza, Tanzania. Standardized history, echocardiography, and serum were obtained. Regression models were used to quantify associations. RESULTS: We enrolled 388 ART-naive PLWH and 461 HIV-uninfected adults with an average age of 36.0 ± 10.2 years. Of PLWH in the third, fourth, and fifth decades of life, 5.0%, 12.5%, and 32.7%, respectively, had DD. PLWH had a higher prevalence of DD (adjusted odds ratio, 2.71 [95% confidence interval, 1.62-4.55]; P < .0001). PLWH also had a higher probability of dysfunction with one or fewer traditional risk factors present. Serum ST2 concentration was associated with dysfunction in PLWH but not uninfected participants (P = .04 and P = .90, respectively). CONCLUSIONS: In a large population of young adults in sub-Saharan Africa, DD prevalence increased starting in the third decade of life. HIV was independently associated with dysfunction. Serum ST2 concentration was associated with DD in PLWH but not HIV-uninfected participants. This pathway may provide insight into the mechanisms of HIV-associated dysfunction.

Select Bcl-2 antagonism restores chemotherapy sensitivity in high-risk neuroblastoma.

BACKGROUND: Pediatric patients with high-risk neuroblastoma (HR NB) often fail to respond to upfront intensive multimodal therapy. Tumor-acquired suppression of apoptosis contributes to therapy resistance. Many HR NB tumors depend on the anti-apoptotic protein Bcl-2 for survival, through Bcl-2 sequestration and inhibition of the pro-apoptotic protein, Bim. Bcl-2 dependent xenografts derived from aggressive human NB tumors are cured with a combination of cyclophosphamide and ABT-737, a Bcl-2/Bcl-XL/Bcl-w small molecule antagonist. The oral analogue to ABT-737, Navitoclax (ABT-263), clinically causes an immediate drop in peripheral platelet counts as mature platelets depend on Bcl-xL for survival. This led to the creation of a Bcl-2 selective inhibitor, ABT-199 (Venetoclax). A Phase I trial of ABT-199 in CLL showed remarkable antitumor activity and stable patient platelet counts. Given Bcl-XL does not play a role in HR NB survival, we hypothesized that ABT-199 would be equally potent against HR NB. METHODS: Cytotoxicity and apoptosis were measured in human derived NB cell lines exposed to ABT-199 combinations. Co-Immunoprecipitation evaluated Bim displacement from Bcl-2, following ABT-199. Murine xenografts of NB cell lines were grown and then exposed to a 14-day course of ABT-199 alone and with cyclophosphamide. RESULTS: Bcl-2 dependent NB cell lines are exquisitely sensitive to ABT-199 (IC50 1.5-5 nM) in vitro, where Mcl-1 dependent NBs are completely resistant. Treatment with ABT-199 displaces Bim from Bcl-2 in NB to activate caspase 3, confirming the restoration of mitochondrial apoptosis. Murine xenografts of Mcl-1 and Bcl-2 dependent NBs were treated with a two-week course of ABT-199, cyclophosphamide, or ABT-199/cyclophosphamide combination. Mcl-1 dependent tumors did not respond to ABT-199 alone and showed no significant difference in time to tumor progression between chemotherapy alone or ABT-199/cyclophosphamide combination. In contrast, Bcl-2 dependent xenografts responded to ABT-199 alone and had sustained complete remission (CR) to the ABT-199/cyclophosphamide combination, with one recurrent tumor maintaining Bcl-2 dependence and obtaining a second CR after a second course of therapy. CONCLUSION: HR NB patients are often thrombocytopenic at relapse, raising concerns for therapies like ABT-263 despite its HR NB tumor targeting potential. Our data confirms that Bcl-2 selective inhibitors like ABT-199 are equally potent in HR NB in vitro and in vivo and given their lack of platelet toxicity, should be translated into the clinic for HR NB.

A Longitudinal Study of Multimodal Bronchoscopy Training in Uganda.

Background: Flexible bronchoscopy is an essential tool in diagnosing and managing pulmonary diseases. However, there is limited capacity for bronchoscopy in low and middle income countries (LMICs). In 2019, a pilot program for flexible bronchoscopy training was launched for local physicians in Kampala, Uganda. We then conducted a follow up multimodal bronchoscopy course after 2 years. Objective: The aim of this study is to assess a longitudinal multimodal bronchoscopy training in an LMIC setting. Methods: A multimodal follow up curriculum was developed with pulmonologists from Uganda and the United States. The training was delivered to Ugandan providers who attended previous bronchoscopy training and new participants. The training included a prepared curriculum consisting of lectures, simulations, and deliberate practice-based proctoring. A 12-question multiple-choice exam was administered at the beginning and end of the course, assessing knowledge. Procedural competency was measured using a validated assessment tool called the BSTAT (Bronchoscopic Skills and Tasks Assessment Tool). Results were analyzed to evaluate the retention of knowledge among those who took part in previous training and the efficacy of the follow-up curriculum for participants without previous training. Results: Among the participants who attended didactic training in 2022 (11), mean exam scores were improved after training, from 43.9 (standard deviation [SD], 11.3) to 59.8 (SD, 16.1) (mean difference [MD], +15.9; SD, 13.9; P = 0.008), but were lower compared with post didactic scores in 2019: 90.8 (SD, 6.1; MD, -31; P < 0.0001). Participants who completed BSTAT assessments (8) had mean scores similar in 2019 and 2022, at 72.1 and 75.2, respectively (MD, 3.1; P = 0.38). Conclusion: This study provides an example of how a longitudinal multimodal bronchoscopy curriculum can improve competency and proficiency for local physicians in an LMIC.

Functional imaging for assessing regional lung ventilation in preclinical and clinical research.

Dynamic heterogeneity in lung ventilation is an important measure of pulmonary function and may be characteristic of early pulmonary disease. While standard indices like spirometry, body plethysmography, and blood gases have been utilized to assess lung function, they do not provide adequate information on regional ventilatory distribution nor function assessments of ventilation during the respiratory cycle. Emerging technologies such as xenon CT, volumetric CT, functional MRI and X-ray velocimetry can assess regional ventilation using non-invasive radiographic methods that may complement current methods of assessing lung function. As a supplement to current modalities of pulmonary function assessment, functional lung imaging has the potential to identify respiratory disease phenotypes with distinct natural histories. Moreover, these novel technologies may offer an optimal strategy to evaluate the effectiveness of novel therapies and therapies targeting localized small airways disease in preclinical and clinical research. In this review, we aim to discuss the features of functional lung imaging, as well as its potential application and limitations to adoption in research.

Stroke and spinal infarct caused by percutaneous coronary intervention.

Acute ischaemic stroke is a known risk of percutaneous coronary intervention (PCI). The incidence of such complications has increased in frequency over the last decade due to higher comorbidity burden and increased complexity of PCI procedures. The overall incidence of post-PCI ischaemic stroke remains low at 0.56%, but some groups of patients have significantly higher risk. Risk factors include atherosclerotic plaques, atrial fibrillation, cardiogenic shock, older age and arterial disease. Although the overall incidence of acute ischaemic stroke following PCI is low, it can result in lifelong disability and is associated with high morbidity, mortality and significant costs. Spinal infarctions due to PCI are exceedingly rare. Here, we discuss a 71-year-old woman who presented with a non ST-elevation myocardial infarction and developed both stroke and spinal infarction post PCI due to a thromboembolic event resulting in long-term debility.

EGFR signaling defines Mcl⁻1 survival dependency in neuroblastoma.

The pediatric solid tumor neuroblastoma (NB) often depends on the anti-apoptotic protein, Mcl(-)1, for survival through Mcl(-)1 sequestration of pro-apoptotic Bim. High affinity Mcl(-)1 inhibitors currently do not exist such that novel methods to inhibit Mcl(-)1 clinically are in high demand. Receptor tyrosine kinases (RTK) regulate Mcl(-)1 in many cancers and play a role in NB survival, yet how they regulate Bcl(-)2 family interactions in NB is unknown. We found that NB cell lines derived to resist the Bcl(-)2/-xl/-w antagonist, ABT-737, acquire a dependence on Mcl(-)1 and show increased expression and activation of the RTK, EGFR. Mcl(-)1 dependent NB cell lines derived at diagnosis and from the same tumor following relapse also have increased EGFR expression compared to those dependent on Bcl(-)2. Inhibition of EGFR by shRNA or erlotinib in Mcl(-)1 dependent NBs disrupts Bim binding to Mcl(-)1 and enhances its affinity for Bcl(-)2, restoring sensitivity to ABT-737 as well as cytotoxics in vitro. Mechanistically treatment of NBs with small molecule inhibitors of EGFR (erlotinib, cetuximab) and ERK (U0126) increases Noxa expression and dephosphorylates Bim to promote Bim binding to Bcl(-)2. Thus, EGFR regulates Mcl(-)1 dependence in high-risk NB via ERK-mediated phosphorylation of Bim such that EGFR/ERK inhibition renders Mcl(-)1 dependent tumors now reliant on Bcl(-)2. Clinically, EGFR inhibitors are ineffective as single agent compounds in patients with recurrent NB, likely due to this transferred survival dependence to Bcl(-)2. Likewise, EGFR or ERK inhibitors warrant further testing in combination with Bcl(-)2 antagonists in vivo as a novel future combination to overcome therapy resistance in the clinic.

NF-κB activity is inversely correlated to RNF11 expression in Parkinson's disease.

RING finger protein 11 (RNF11), a negative regulator of NF-κB signaling pathway, colocalizes with α-synuclein and is sequestered in Lewy bodies in Parkinson's disease (PD). Since persistent NF-κB activation is reported in PD, in this report we investigated if RNF11 expression level is correlated to activated NF-κB in PD. We examined RNF11 expression levels in correlation to phospho-p65, a marker for activated NF-κB, in control and PD brain tissue from cerebral cortex. In addition we performed double immunofluorescence labeling experiments to confirm this correlation. Our investigations demonstrated that the neuronal RNF11 expression was down-regulated in PD and was usually associated with increased expression of phospho-p65. Double labeling confirmed that loss of neuronal RNF11 was linked to increased phospho-p65 expression, suggesting that persistent presence of NF-κB activation could be due to decreased levels of its negative regulator. Our data exemplifies the relevance of RNF11 and persistent NF-κB activation in PD.

Comparative distribution of protein components of the A20 ubiquitin-editing complex in normal human brain.

Activation of innate and adaptive immune responses is tightly regulated, as insufficient activation could result in defective clearance of pathogens, while excessive activation might lead to lethal systemic inflammation or autoimmunity. A20 functions as a negative regulator of innate and adaptive immunity by inhibiting NF-κB activation. A20 mediates its inhibitory function in a complex with other proteins including RNF11 and Itch, both E3 ubiquitin ligases and TAX1BP1, an adaptor protein. Since NF-κB has been strongly implicated in various neuronal functions, we predict that its inhibitor, the A20 complex, is also present in the nervous system. In efforts to better understand the role of A20 complex and NF-κB signaling pathway, we determined regional distribution of A20 mRNA as well as protein expression levels and distribution of RNF11, TAX1BP1 and Itch, in different brain regions. The distribution of TRAF6 was also investigated since TRAF6, also an E3 ligase, has an important role in NF-κB signaling pathway. Our investigations, for the first time, describe and demonstrate that the essential components of the A20 ubiquitin-editing complex are present and mainly expressed in neurons. The A20 complex components are also differentially expressed throughout the human brain. This study provides useful information about region specific expression of the A20 complex components that will be invaluable while determining the role of NF-κB signaling pathway in neuronal development and degeneration.