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Advances in treatment have reduced mortality from Hodgkin lymphoma; therefore, greater attention should be focused on minimizing the late effects. A variety of risk-adapted treatment regimens exist that prioritize disease presentation but not patient-specific comorbidities. Herein, we describe a patient with sickle cell disease diagnosed with Hodgkin lymphoma and the considerations made in treatment planning to minimize therapy-related acute toxicity and late effects that overlap with the patient’s preexisting sickle cell disease complications.

Background: Cross-linking of lysine residues in elastic and collagen fibers is a vital process in aortic development. Inhibition of lysyl oxidase by BAPN (β-aminopropionitrile) leads to thoracic aortopathies in mice. Although the renin-angiotensin system contributes to several types of thoracic aortopathies, it remains unclear whether inhibition of the renin-angiotensin system protects against aortopathy caused by the impairment of elastic fiber/collagen crosslinking. Methods: BAPN (0.5% wt/vol) was started in drinking water to induce aortopathies in male C57BL/6J mice at 4 weeks of age for 4 weeks. Five approaches were used to investigate the impact of the renin-angiotensin system. Bulk RNA sequencing was performed to explore potential molecular mechanisms of BAPN-induced thoracic aortopathies. Results: Losartan increased plasma renin concentrations significantly, compared with vehicle-infused mice, indicating effective angiotensin II type 1 receptor inhibition. However, losartan did not suppress BAPN-induced aortic rupture and dilatation. Since losartan is a surmountable inhibitor of the renin-angiotensin system, irbesartan, an insurmountable inhibitor, was also tested. Although increased plasma renin concentrations indicated effective inhibition, irbesartan did not ameliorate aortic rupture and dilatation in BAPN-administered mice. Thus, BAPN-induced thoracic aortopathies were refractory to angiotensin II type 1 receptor blockade. Next, we inhibited angiotensin II production by pharmacological or genetic depletion of AGT (angiotensinogen), the unique precursor of angiotensin II. However, neither suppressed BAPN-induced thoracic aortic rupture and dilatation. Aortic RNA sequencing revealed molecular changes during BAPN administration that were distinct from other types of aortopathies in which angiotensin II type 1 receptor inhibition protects against aneurysm formation. Conclusions: Inhibition of either angiotensin II action or production of the renin-angiotensin system does not attenuate BAPN-induced thoracic aortopathies in mice.

Outcomes for children and adolescents with relapsed and refractory Hodgkin lymphoma (HL) are poor, with approximately 50% of patients experiencing a subsequent relapse. The anti-CD30 antibody-drug conjugate brentuximab vedotin improved progression-free survival (PFS) when used as consolidation after autologous stem cell transplant (ASCT) in adults with high-risk relapsed/refractory HL. Data on brentuximab vedotin as consolidative therapy after ASCT in pediatric patients with HL are extremely limited, with only 11 patients reported in the literature. We performed a retrospective analysis of 67 pediatric patients who received brentuximab vedotin as consolidation therapy following ASCT for the treatment of relapsed/refractory HL to describe the experience of this regimen in the pediatric population. This is the largest cohort reported to date. We found that brentuximab vedotin was well tolerated with a safety profile similar to adult patients. With a median follow up of 37 months, the 3-year PFS was 85%. These data suggest a potential role for the use of brentuximab vedotin as consolidation therapy after ASCT for children with relapsed/refractory Hodgkin lymphoma.

BackgroundThe regional heterogeneity of vascular components is an important determinant of aortic biology. This notion has been explored in multiple mouse studies, but not in human aortas due to the difficulty of acquiring normal tissues. In the present study, we examined the regional heterogeneity of aortas in healthy non-human primates that have similarities to humans.MethodsAortic samples were harvested from the ascending, descending, suprarenal, and infrarenal regions of young cynomolgus monkeys. The regional heterogeneity of aortic structure and transcriptomes were examined by histological and bulk RNA sequencing analyses.ResultsImmunostaining of CD31 and αSMA revealed that endothelial and smooth muscle cells were distributed homogeneously across the aortic regions. In contrast, elastic fibers were less abundant and disorganized in the infrarenal aorta compared to other regions. Bulk RNA sequencing identified differences in collagen mRNA abundance among the regions.COL1A1, a major collagen gene, was highly abundant in the infrarenal aorta. Movat’s staining revealed consistently that collagen fibers were more abundant in the media and adventitia of the infrarenal aorta than in other regions. Proteoglycan accumulated in the intima of the infrarenal region. Polarized imaging of picrosirius red staining demonstrated that type 1 collagen was distributed predominantly in the adventitia and media of the infrarenal aorta adjacent to disarrayed elastic fibers. Immunostaining of COL1A1 verified type 1 collagen in the intima and adventitia close to the elastic fiber disruption.ConclusionsAortas of young cynomolgus monkeys display regional heterogeneity of its transcriptome and the structure of elastin and collagens. Elastic fibers in the infrarenal aorta are disarrayed along with the deposition of collagen fibers and proteoglycan.HIGHLIGHTS-The present study determined the regional heterogeneity of aortic biology in aortas of young cynomolgus monkeys.-Aortas of young cynomolgus monkeys displayed region-specific aortic structure and transcriptomes.-Elastic fibers are disarrayed in the infrarenal aorta along with the deposition of collagen fibers and proteoglycan.GRAPHIC ABSTRACT

Objective: A cardinal feature of Marfan syndrome is thoracic aortic aneurysm. The contribution of the renin-angiotensin system via AT1aR (Ang II [angiotensin II] receptor type 1a) to thoracic aortic aneurysm progression remains controversial because the beneficial effects of angiotensin receptor blockers have been ascribed to off-target effects. This study used genetic and pharmacological modes of attenuating angiotensin receptor and ligand, respectively, to determine their roles on thoracic aortic aneurysm in mice with fibrillin-1 haploinsufficiency ( Fbn1 C1041G/+ ). Approach and Results: Thoracic aortic aneurysm in Fbn1 C1041G/+ mice was found to be strikingly sexual dimorphic. Males displayed aortic dilation over 12 months while aortic dilation in Fbn1 C1041G/+ females did not differ significantly from wild-type mice. To determine the role of AT1aR, Fbn1 C1041G/+ mice that were either +/+ or −/− for AT1aR were generated. AT1aR deletion reduced expansion of ascending aorta and aortic root diameter from 1 to 12 months of age in males. Medial thickening and elastin fragmentation were attenuated. An antisense oligonucleotide against angiotensinogen was administered to male Fbn1 C1041G/+ mice to determine the effects of Ang II depletion. Antisense oligonucleotide against angiotensinogen administration attenuated dilation of the ascending aorta and aortic root and reduced extracellular remodeling. Aortic transcriptome analyses identified potential targets by which inhibition of the renin-angiotensin system reduced aortic dilation in Fbn1 C1041G/+ mice. Conclusions: Deletion of AT1aR or inhibition of Ang II production exerted similar effects in attenuating pathologies in the proximal thoracic aorta of male Fbn1 C1041G/+ mice. Inhibition of the renin-angiotensin system attenuated dysregulation of genes within the aorta related to pathology of Fbn1 C1041G/+ mice.

Vascular smooth muscle cells (vSMC) exert a critical role in sensing and maintaining vascular integrity. These cells abundantly express the low-density lipoprotein receptor-related protein 1 (LRP1), a large endocytic and signaling receptor that recognizes numerous ligands including ApoE-rich lipoproteins, proteases, and protease-inhibitor complexes. We observed the spontaneous formation of aneurysms in the superior mesenteric artery (SMA) of both male and female mice in which LRP1 was genetically deleted in v SMC (smLRP1-/- mice). Quantitative proteomics revealed elevated abundance of several proteins in smLRP1-/- mice that are known to be induced by angiotensin II (AngII)-mediated signaling, suggesting that this pathway is dysregulated. Administration of losartan, an AngII type I receptor antagonist, or an angiotensinogen antisense oligonucleotide to reduce plasma angiotensinogen concentrations restored the normal SMA phenotype in smLRP1-/- mice and prevented aneurysm formation. Additionally, employing a vascular injury model, we noted excessive vascular remodeling and neointima formation in smLRP1-/- mice that was restored by losartan administration. Together, these findings reveal that LRP1 regulates vascular integrity and remodeling of the SMA by attenuating excessive AngII-mediated signaling.

Advances in treatment have reduced mortality from Hodgkin Lymphoma (HL) and made it so greater attention can be focused on minimizing late effects. A variety of risk-adapted treatment regimens exist that prioritize disease presentation, but not patient-specific comorbidities. Herein we describe a patient with sickle cell disease diagnosed with HL and the considerations made in treatment planning to minimize therapy-related acute toxicity and late effects that overlap with the patient's preexisting sickle cell disease complications.

Atherosclerosis is a leading cause of morbidity and mortality in many countries. Mice are the most frequently used animal model to study the pathogenesis and molecular mechanisms of atherosclerosis. En face analyses of the aorta and cross-sections of the aortic root are the two common modes for quantifying the severity of atherosclerosis in mice. This mini-review introduces these two methods, discusses their pros and cons, and provides suggestions to optimize the quantification of atherosclerosis, thereby enhancing rigor and reproducibility in preclinical research.

A novel Bayesian Monte Carlo integration (BMCI) technique was developed to retrieve geophysical variables from satellite microwave radiometer data in the presence of tropical cyclones. The BMCI technique includes three steps: generating a stochastic database, simulating satellite brightness temperatures using a radiative transfer model, and retrieving geophysical variables such as profiles of temperature, relative humidity, and cloud liquid and ice water content from real observations. The technique also provides uncertainty estimates for each retrieval and can output the error covariance matrix of selected parameters. The measurements from the Advanced Technology Microwave Sounder (ATMS) on board Suomi National Polar-Orbiting Partnership (Suomi NPP) and the Global Precipitation Measurement (GPM) Microwave Imager (GMI) were used as input. A new technique was developed to correct the ATMS and GMI observations for the beam-filling effect, which is due to small-scale variability of precipitation and clouds when compared with the instrument footprint and also the nonlinear relation between the brightness temperature and precipitation. In addition, the assimilation of the BMCI retrievals into the NASA GEOS model is discussed for Hurricane Maria. The results show that assimilating the BMCI retrievals can influence the dynamical features of the cyclone, including a stronger warm core, a symmetric eye, and vertically aligned wind columns. Two possible factors that may limit the impact of the BMCI retrievals include 1) the resolution of the model (about 25 km), which was too coarse to show the potential of the BMCI data in improving the representation of tropical storms in the model forecast, and 2) the data assimilation system not being able to consider vertically correlated observation errors.

Background: The ascending aorta is a common location for aneurysm and dissection. This aortic region is populated by a mosaic of medial and adventitial cells that are embryonically derived from either the second heart field (SHF) or the cardiac neural crest. SHF-derived cells populate areas that coincide with the spatial specificity of thoracic aortopathies. The purpose of this study was to determine whether and how SHF-derived cells contribute to ascending aortopathies. Methods: Ascending aortic pathologies were examined in patients with sporadic thoracic aortopathies and angiotensin II (AngII)–infused mice. Ascending aortas without overt pathology from AngII-infused mice were subjected to mass spectrometry–assisted proteomics and molecular features of SHF-derived cells were determined by single-cell transcriptomic analyses. Genetic deletion of either Lrp1 (low-density lipoprotein receptor–related protein 1) or Tgfbr2 (transforming growth factor–β receptor type 2) in SHF-derived cells was conducted to examine the effect of SHF-derived cells on vascular integrity. Results: Pathologies in human ascending aortic aneurysmal tissues were predominant in outer medial layers and adventitia. This gradient was mimicked in mouse aortas after AngII infusion that was coincident with the distribution of SHF-derived cells. Proteomics indicated that brief AngII infusion before overt pathology occurred evoked downregulation of smooth muscle cell proteins and differential expression of extracellular matrix proteins, including several LRP1 ligands. LRP1 deletion in SHF-derived cells augmented AngII-induced ascending aortic aneurysm and rupture. Single-cell transcriptomic analysis revealed that brief AngII infusion decreased Lrp1 and Tgfbr2 mRNA abundance in SHF-derived cells and induced a unique fibroblast population with low abundance of Tgfbr2 mRNA. SHF-specific Tgfbr2 deletion led to embryonic lethality at E12.5 with dilatation of the outflow tract and retroperitoneal hemorrhage. Integration of proteomic and single-cell transcriptomics results identified PAI1 (plasminogen activator inhibitor 1) as the most increased protein in SHF-derived smooth muscle cells and fibroblasts during AngII infusion. Immunostaining revealed a transmural gradient of PAI1 in both ascending aortas of AngII-infused mice and human ascending aneurysmal aortas that mimicked the gradient of medial and adventitial pathologies. Conclusions: SHF-derived cells exert a critical role in maintaining vascular integrity through LRP1 and transforming growth factor–β signaling associated with increases of aortic PAI1.