Prospectus, October 28, 1981

SENIORS VISIT PARKLAND; News In Brief; Donate blood--help others: One that was helped; Gazette to go electronic; Get on P.C. blood donor team; Images: students at creative best; Homecoming idea conceived by 2 bored men; Western look phasing out; \u27Antigone\u27 opens Nov. 12; County moves to METCAD; Spend year abroad, see Scandinavia; Be safe on Halloween; Stories welcome; P.C. Happ\u27nin\u27s: Ski club plans finances, Prayers offered, EMT workshop set, Model ships presented, CHI sponsors program, Encouraging parents, Stugo discusses food; Chief Illiniwek -- Part of Illini tradition; Moody Blues: classic; Halloween hits early; Willie Nesbit wins Freddy contest; Sports Notes; Girls open at Sugar Grove; Illini football pleases fan; Fast Freddy Contest; Correction; \u27Gallipoli\u27 deals with war, friendship, death; Classifieds; Duvall stars in \u27Confessions\u27; \u27Marbles\u27: nice surprise; Library plans A-V Week; Laugh at \u27Merlin\u27https://spark.parkland.edu/prospectus_1981/1007/thumbnail.jp

Genomic complexity predicts resistance to endocrine therapy and CDK4/6 inhibition in hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer

PURPOSE: Clinical biomarkers to identify patients unlikely to benefit from CDK4/6 inhibition (CDK4/6i) in combination with endocrine therapy (ET) are lacking. We implemented a comprehensive circulating tumor DNA (ctDNA) analysis to identify genomic features for predicting and monitoring treatment resistance. EXPERIMENTAL DESIGN: ctDNA was isolated from 216 plasma samples collected from 51 patients with hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) on a phase II trial of palbociclib combined with letrozole or fulvestrant (NCT03007979). Boosted whole-exome sequencing (WES) was performed at baseline and clinical progression to evaluate genomic alterations, mutational signatures, and blood tumor mutational burden (bTMB). Low-pass whole-genome sequencing was performed at baseline and serial timepoints to assess blood copy-number burden (bCNB). RESULTS: High bTMB and bCNB were associated with lack of clinical benefit and significantly shorter progression-free survival (PFS) compared with patients with low bTMB or low bCNB (all P \u3c 0.05). Dominant APOBEC signatures were detected at baseline exclusively in cases with high bTMB (5/13, 38.5%) versus low bTMB (0/37, 0%; P = 0.0006). Alterations in ESR1 were enriched in samples with high bTMB (P = 0.0005). There was a high correlation between bTMB determined by WES and bTMB determined using a 600-gene panel (R = 0.98). During serial monitoring, an increase in bCNB score preceded radiographic progression in 12 of 18 (66.7%) patients. CONCLUSIONS: Genomic complexity detected by noninvasive profiling of bTMB and bCNB predicted poor outcomes in patients treated with ET and CDK4/6i and identified early disease progression before imaging. Novel treatment strategies including immunotherapy-based combinations should be investigated in this population

Microarray-Based Sketches of the HERV Transcriptome Landscape

Human endogenous retroviruses (HERVs) are spread throughout the genome and their long terminal repeats (LTRs) constitute a wide collection of putative regulatory sequences. Phylogenetic similarities and the profusion of integration sites, two inherent characteristics of transposable elements, make it difficult to study individual locus expression in a large-scale approach, and historically apart from some placental and testis-regulated elements, it was generally accepted that HERVs are silent due to epigenetic control. Herein, we have introduced a generic method aiming to optimally characterize individual loci associated with 25-mer probes by minimizing cross-hybridization risks. We therefore set up a microarray dedicated to a collection of 5,573 HERVs that can reasonably be assigned to a unique genomic position. We obtained a first view of the HERV transcriptome by using a composite panel of 40 normal and 39 tumor samples. The experiment showed that almost one third of the HERV repertoire is indeed transcribed. The HERV transcriptome follows tropism rules, is sensitive to the state of differentiation and, unexpectedly, seems not to correlate with the age of the HERV families. The probeset definition within the U3 and U5 regions was used to assign a function to some LTRs (i.e. promoter or polyA) and revealed that (i) autonomous active LTRs are broadly subjected to operational determinism (ii) the cellular gene density is substantially higher in the surrounding environment of active LTRs compared to silent LTRs and (iii) the configuration of neighboring cellular genes differs between active and silent LTRs, showing an approximately 8 kb zone upstream of promoter LTRs characterized by a drastic reduction in sense cellular genes. These gathered observations are discussed in terms of virus/host adaptive strategies, and together with the methods and tools developed for this purpose, this work paves the way for further HERV transcriptome projects

Repeated successful surgical rescues of early and delayed multiple ruptures of ventricular septum, right ventricle and aneurysmal left ventricle following massive biventricular infarction

A 58 year old man underwent 6 surgical interventions for various complications of massive biventricular myocardial infarction over a period of 2 years following acute occlusion of a possibly "hyperdominant" left anterior descending coronary artery. These included concomitant repair of apicoanterior post-infarction VSD and right ventricular free wall rupture, repeat repair of recurrent VSD following inferoposterior extension of VSD in the infarcted septum 5 weeks later, repair of delayed right ventricular free wall rupture 4 weeks subsequently, repair of a bleeding left ventricular aneurysm eroding through left chest wall 16 months thereafter, repair of right upper lobe lung tear causing massive anterior mediastinal haemorrhage, mimicking yet another cardiac rupture, 2 months later, followed, at the same admission, 2 weeks later, by sternal reconstruction for dehisced and infected sternum using pedicled myocutaneous latissimus dorsi flap. 5 years after the latissimus myoplasty, the patient remains in NYHA class 1 and is leading a normal life

A new method for isolation of human lymphocyte subsets reveals differential regulation of beta-adrenergic receptors by terbutaline treatment

We adapted a technique for isolation of mononuclear leukocyte (MNL) subsets with immunomagnetic beads to the study of beta-adrenergic receptors. Mixed MNL cells were sequentially incubated with monoclonal antibodies specific for certain MNL subsets. Sheep antimouse antibodies coupled to magnetic beads were then added, and the desired MNL subset was pulled out with a magnet. This method yielded subsets with high purity and did not alter beta-receptor density or function. Healthy volunteers were treated for 7 days with the beta 2-selective agonist terbutaline (5 mg t.i.d.). Terbutaline treatment decreased beta-receptor number and isoproterenol-stimulated cyclic adenosine monophosphate (cAMP) generation in natural killer cells, helper T cells, and suppressor/cytotoxic T cells but not in B cells. The decrease was greatest in suppressor/cytotoxic T cells and least in helper T cells. Thus beta-adrenergic receptor regulation by agonists appears to differ among MNL subset