Temperature Trajectory Subphenotypes in Oncology Patients with Neutropenia and Suspected Infection.

Rationale: Despite etiologic and severity heterogeneity in neutropenic sepsis, management is often uniform. Understanding host response clinical subphenotypes might inform treatment strategies for neutropenic sepsis. Objectives: In this retrospective two-hospital study, we analyzed whether temperature trajectory modeling could identify distinct, clinically relevant subphenotypes among oncology patients with neutropenia and suspected infection. Methods: Among adult oncologic admissions with neutropenia and blood cultures within 24 hours, a previously validated model classified patients' initial 72-hour temperature trajectories into one of four subphenotypes. We analyzed subphenotypes' independent relationships with hospital mortality and bloodstream infection using multivariable models. Measurements and Main Results: Patients (primary cohort n = 1,145, validation cohort n = 6,564) fit into one of four temperature subphenotypes. "Hyperthermic slow resolvers" (pooled n = 1,140 [14.8%], mortality n = 104 [9.1%]) and "hypothermic" encounters (n = 1,612 [20.9%], mortality n = 138 [8.6%]) had higher mortality than "hyperthermic fast resolvers" (n = 1,314 [17.0%], mortality n = 47 [3.6%]) and "normothermic" (n = 3,643 [47.3%], mortality n = 196 [5.4%]) encounters (P < 0.001). Bloodstream infections were more common among hyperthermic slow resolvers (n = 248 [21.8%]) and hyperthermic fast resolvers (n = 240 [18.3%]) than among hypothermic (n = 188 [11.7%]) or normothermic (n = 418 [11.5%]) encounters (P < 0.001). Adjusted for confounders, hyperthermic slow resolvers had increased adjusted odds for mortality (primary cohort odds ratio, 1.91 [P = 0.03]; validation cohort odds ratio, 2.19 [P < 0.001]) and bloodstream infection (primary odds ratio, 1.54 [P = 0.04]; validation cohort odds ratio, 2.15 [P < 0.001]). Conclusions: Temperature trajectory subphenotypes were independently associated with important outcomes among hospitalized patients with neutropenia in two independent cohorts.

4,300 steps per day prior to surgery are associated with improved outcomes after pancreatectomy.

BACKGROUND: Decreased preoperative physical fitness and low physical activity have been associated with preoperative functional reserve and surgical complications. We sought to evaluate daily step count as a measure of physical activity and its relationship with post-pancreatectomy outcomes. METHODS: Patients undergoing pancreatectomy were given a remote telemonitoring device to measure their preoperative levels of physical activity. Patient activity, demographics, and perioperative outcomes were collected and compared in univariate and multivariate logistic regression analysis. RESULTS: 73 patients were included. 45 (61.6%) patients developed complications, with 17 (23.3%) of those patients developing severe complications. These patients walked 3437.8 (SD 1976.7) average daily steps, compared to 5918.8 (SD 2851.1) in patients without severe complications (p < 0.001). In logistic regression analysis, patients who walked less than 4274.5 steps had significantly higher odds of severe complications (OR = 7.5 (CI 2.1, 26.8), p = 0.002). CONCLUSION: Average daily steps below 4274.5 before surgery are associated with severe complications after pancreatectomy. Preoperative physical activity levels may represent a modifiable target for prehabilitation protocols.

Mutational Analyses of the Cysteine-Rich Domain of Yvh1, a Protein Required for Translational Competency in Yeast.

Ribosome assembly is a complex biological process facilitated by >200 trans-acting factors (TAFs) that function as scaffolds, place-holders or complex remodelers to promote efficient and directional ribosomal subunit assembly but are not themselves part of functional ribosomes. One such yeast TAF is encoded by Mrt4 which assembles onto pre-60S complexes in the nuclear compartment and remains bound to pre-60S complexes as they are exported into the cytoplasm. There, Mrt4 is displaced from pre-60S complexes facilitating the subsequent addition of the ribosomal stalk complex (P0/P1/P2). Ribosomal stalk proteins interact with translational GTPases (trGTPase) which facilitate and control protein synthesis on the ribosome. The rRNA-binding domain of Mrt4 is structurally similar to P0, with both proteins binding to the same interface of pre-60S subunits in a mutually exclusive manner; the addition of the ribosomal stalk therefore requires the displacement of Mrt4 from pre-60S subunits. Mrt4 removal requires the C-terminal cysteine-rich domain (CRD) of the dual-specificity phosphatase Yvh1. Unlike many other TAFs, yeast lacking Yvh1 are viable but retain Mrt4 on cytoplasmic pre-60S complexes precluding ribosomal stalk addition. Although Yvh1's role in Mrt4 removal is well established, how Yvh1 accomplishes this is largely unknown. Here, we report an unbiased genetic screen to isolate Yvh1 variants that fail to displace Mrt4 from pre-60S ribosomes. Bioorthogonal non-canonical amino acid tagging (BONCAT) approaches demonstrate that these YVH1 loss-of-function variants also display defects in nascent protein production. The further characterization of one LOF variant, Yvh1F283L, establishes it as an expression-dependent, dominant-negative variant capable of interfering with endogenous Yvh1 function, and we describe how this Yvh1 variant can be used as a novel probe to better understand ribosome maturation and potentially ribosome heterogeneity in eukaryotes.

Neurofibromatosis-1 Gene Mutational Profiles Differ Between Syndromic Disease and Sporadic Cancers.

Objectives: Variants in the neurofibromatosis type 1 (NF1) gene are not only responsible for the NF1 cancer predisposition syndrome, but also frequently identified in cancers arising in the general population. While germline variants are pathogenic, it is not known whether those that arise in cancer (somatic variants) are passenger or driver variants. To address this question, we sought to define the landscape of NF1 variants in sporadic cancers. Methods: NF1 variants in sporadic cancers were compiled using data curated on the c-Bio database and compared with published germline variants and Genome Aggregation Database data. Pathogenicity was determined using Polyphen and Sorting Intolerant From Tolerant prediction tools. Results: The spectrum of NF1 variants in sporadic tumors differ from those most commonly seen in individuals with NF1. In addition, the type and location of the variants in sporadic cancer differ from germline variants, where a high proportion of missense variants were found. Finally, many of the sporadic cancer NF1 variants were not predicted to be pathogenic. Discussion: Taken together, these findings suggest that a significant proportion of NF1 variants in sporadic cancer may be passenger variants or hypomorphic alleles. Further mechanistic studies are warranted to define their unique roles in nonsyndromic cancer pathobiology.

Asthma reduces glioma formation by T cell decorin-mediated inhibition of microglia.

To elucidate the mechanisms underlying the reduced incidence of brain tumors in children with Neurofibromatosis type 1 (NF1) and asthma, we leverage Nf1 optic pathway glioma (Nf1OPG) mice, human and mouse RNAseq data, and two different experimental asthma models. Following ovalbumin or house dust mite asthma induction at 4-6 weeks of age (WOA), Nf1OPG mouse optic nerve volumes and proliferation are decreased at 12 and 24 WOA, indicating no tumor development. This inhibition is accompanied by reduced expression of the microglia-produced optic glioma mitogen, Ccl5. Human and murine T cell transcriptome analyses reveal that inhibition of microglia Ccl5 production results from increased T cell expression of decorin, which blocks Ccl4-mediated microglia Ccl5 expression through reduced microglia NFκB signaling. Decorin or NFκB inhibitor treatment of Nf1OPG mice at 4-6 WOA inhibits tumor formation at 12 WOA, thus establishing a potential mechanistic etiology for the attenuated glioma incidence observed in children with asthma.