Shyu, Chi‐Ren

Background: Systolic blood pressure (SBP) fluctuation is linked to increased death or disability in intracerebral hemorrhage (ICH) patients. We analyzed data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH)-2 trial to explore whether the association between SBP fluctuation and 90-day outcomes varies with time from randomization. Methods: We calculated hourly SBP fluctuation based on the difference between maximum and minimum SBP during the first 24 hours post-randomization. Logistic regression models assessed the impact of SBP fluctuation on: 1) death or disability (modified Rankin scale [mRS] 4-6 at 90 days); 2) hematoma expansion (>33% increase in volume on 24-hour CT scan); 3) neurological deterioration within 24 hours (defined as ≥2-point decrease on Glasgow Coma Scale or ≥4-point increase on NIH Stroke Scale); and 4) acute kidney injury (AKI) within 72 hours. Adjustments were made for baseline Glasgow Coma Scale score, intraventricular hemorrhage, hematoma volume, and maximum SBP. Results: The hourly SBP fluctuations according to 90-day outcomes (dichotomized into good outcome, mRS 0-3, and poor outcome, mRS 4-6) in 961 patients with ICH are presented in Figure. The SBP fluctuation at 5 hours (p=0.014) and 6 hours (p=0.014) post randomization were significantly associated with death or disability at 90 days, with positive, but not statistically significant associations observed at all other points up to 13 hours after randomization. Risk of neurological deterioration within 24 hours was highly associated with SBP fluctuation, with the largest association observed between 1 (p<0.001) and 5 (p<0.001) hours following randomization, with significant associations observed up to 22 hours following randomization. Risk of hematoma expansion was associated with SBP fluctuation between 3 (p=0.015) and 8 (p=0.002) hours post randomization. Statistically significant associations between SPB fluctuations and risk of AKI were not observed. Conclusions: The first 8 hours following randomization are critical for reducing SBP fluctuations, as this period most strongly influences both short- and long-term outcomes in ICH patients. These findings suggest this time window is crucial for future interventions aimed at controlling SBP in ICH patients.

T cell lymphoblastic leukemia (T-ALL) is an aggressive cancer arising from transformed thymocytes. Most human T-ALL involves hyperactive NOTCH signaling that is often caused by activating NOTCH mutations. However, the identification of specific molecular signals that might induce or select for mutation and transformation are incompletely understood. We report that an understudied low-frequency, natural thymocyte subset expresses αβ T cell antigen receptor (TCR) earlier than most cells in mice and humans; engagement of the early αβTCR by major histocompatibility complexes (MHC) can cause outgrowth of NOTCH1 mutant clones and T-ALL leukemogenesis in a mouse model of T-ALL. Assessment of 5 recent human T-ALL cases found one to present this unique CD4-CD8- double- negative (DN) stage as the earliest identifiable developmental stage. These studies present a model of T-ALL leukemogenesis that identifies (i) a natural cell stage of origin susceptible to transformation, (ii) a matching mouse model showing that a signaling receptor (αβTCR) and its ligand (MHC) drive leukemogeneis and outgrowth of tumors bearing activating NOTCH1 mutations, and (iii) a human case that presents with a tumor consistent with this model and mechanism. In past work, the pre-TCR has been shown to impact T-ALL development in mice (Campese et al, Blood 2006), but an oncogenic role for the mature αβTCR is less well characterized and somewhat surprising. This is because, although T-ALL tumor cells may express variable levels of surface αβTCR/CD3, the earliest cell stages that are thought to transform are also thought to precede stages with αβTCR expression. Most conventional αβ thymocytes rearrange TCRβ and TCRα loci in separate, ordered developmental stages. However, some thymocytes in the conventional pathway rearrange both at DN stage thus exhibiting 'precocious' αβTCR (PAT) expression. Importantly, these PAT cells are indeed part of the conventional αβ lineage, being a 'subset' only due to early αβTCR expression but without known distinction in ultimate immune function (Aifantis et al, JEM 2006). We found that ~0.01% of mouse and human thymocytes are such PAT cells at steady state. To interrogate the PAT thymocyte surface phenotype, we performed multi-parametric flow cytometry with Spanning-tree Progression Analysis of Density-normalized Events (SPADE). This revealed that PAT thymocytes constitute a DN subset that is not associated with other well-described unconventional DN thymocytes known to express αβTCR, consistent with as the expectation that PATs are part of the conventional developmental pathway. We observed that the OT1 TCR transgene is expressed in mice with parallel timing and level to the natural PAT subset, allowing use of this model to study antigen-dependent signaling and oncogenesis. In a cohort study, no T-ALL was observed in wild-type C57BL/6 or OT-1.β2M-/- mice (deficient in endogenous antigen presentation), but MHC-sufficient OT-1 mice developed PAT-stage-specific T-ALL with activating NOTCH1 mutations. Transplant experiments corroborated a requirement for antigen presentation and TCR signaling for tumor maintenance as transplanted tumors grew in MHC+ but not MHC-deficient mice. This predicted that PAT thymocytes might have an unusual ability to signal through αβTCR even without coreceptor expression. When cultured in the presence of either exogenously added β2M or antigen presenting cells, both untransformed and neoplastic PAT cells upregulated CD69 in response to the OT-1 antigenic peptide, OVA. Furthermore, ex vivo analysis of PAT cells from polyclonal C57BL/6 versus MHC-deficient mice showed intrinsic upregulation of TCR-signaling-dependent Nur77 in an MHC-dependent manner. These data revealed a unique ability of PAT cells to engage in co-receptor independent but antigen-dependent signaling. Microarray analysis showed that the gene expression profile of neoplastic PAT cells from OT-1 T-ALL most closely resembled that of conventional post β-selection DN thymocytes, in agreement with the natural PAT stage during normal T cell development. These data support a model in which transformation occurred in the naturally occurring αβ PAT thymocyte subset as cell-of-origin. Collectively, our data suggest that precocious αβTCR expression and coreceptor-independent antigen engagement can cause activating NOTCH mutation and T-ALL development. Disclosures No relevant conflicts of interest to declare.