Objectives Acute pancreatitis (AP) is a complex disease representing a significant portion of gastrointestinal-related hospitalizations in the U.S. Understanding risk factors of AP might provide attractive therapeutic targets. We evaluated hypophosphatemia a prognostic marker in AP. Methods We performed a retrospective review of electronic health records of patients with AP from 01/ 01/2012–12/31/2021 at Cedars-Sinai Medical Center with serum phosphate measured within 48 hours of admission. Multivariable logistic regression modeling was used to evaluate associations with ICU admission and AP severity. Multivariable log-linear modeling was employed to examine associations with length of stay (LOS). Results Of 1526 patients admitted for AP, 33% (499) had a serum phosphate level measured within 48 hours. Patients with hypophosphatemia were more likely to have ICU admission (adjusted odds ratio (AOR) = 4.57; 95% confidence interval (CI): 2.75–7.62; P < 0.001), have a longer hospital stay (log-LOS = 0.34; SE; 0.09; 95% CI: 0.17–0.52; P < 0.001), and have moderate or severe AP (AOR = 1.80; 95% CI: 1.16–2.80; P < 0.001) compared with those without hypophosphatemia. Conclusion Serum phosphate is infrequently measured in patients with AP and shows promise as an early prognostic marker for outcomes of AP.
Altered expression of XPO1, the main nuclear export receptor in eukaryotic cells, has been observed in cancer, and XPO1 has been a focus of anticancer drug development. However, mechanistic evidence for cancer-specific alterations in XPO1 function is lacking. Here, genomic analysis of 42,793 cancers identified recurrent and previously unrecognized mutational hotspots in XPO1. XPO1 mutations exhibited striking lineage specificity, with enrichment in a variety of B-cell malignancies, and introduction of single amino acid substitutions in XPO1 initiated clonal, B-cell malignancy in vivo. Proteomic characterization identified that mutant XPO1 altered the nucleocytoplasmic distribution of hundreds of proteins in a sequence-specific manner that promoted oncogenesis. XPO1 mutations preferentially sensitized cells to inhibitors of nuclear export, providing a biomarker of response to this family of drugs. These data reveal a new class of oncogenic alteration based on change-of-function mutations in nuclear export signal recognition and identify therapeutic targets based on altered nucleocytoplasmic trafficking. SIGNIFICANCE: Here, we identify that heterozygous mutations in the main nuclear exporter in eukaryotic cells, XPO1, are positively selected in cancer and promote the initiation of clonal B-cell malignancies. XPO1 mutations alter nuclear export signal recognition in a sequence-specific manner and sensitize cells to compounds in clinical development inhibiting XPO1 function.This article is highlighted in the In This Issue feature, p. 1325.
Pain is the most common symptom in sickle cell disease (SCD) patients [1]. In the acute setting, SCD patients may have painful crises that require hospitalization [2]. However, these patients also ...
Introduction: The role of methanogenic archaea is becoming more widely recognized in a variety of gastrointestinal symptoms, including bloating and constipation along with systemic effects. Higher methanogenesis has been reported with aging (Takakura W et al. sci rep.2020). We aimed to characterize demographics of patients with intestinal methanogen overgrowth (IMO) in a large database. Methods: A retrospective chart review was conducted among patients evaluated at Cedars-Sinai Medical Center with lactulose breath tests from 2005-2022. Patients undergoing their first lactulose breath test were included. A value of ≥10ppm in exhaled breath was considered positive for IMO and a rise of hydrogen ≥20ppm from baseline within 90 minutes was considered positive for hydrogen-predominant small intestinal bacterial overgrowth (SIBO). Patients were categorized by age grouping. Maximal and baseline methane production were compared among those with positive IMO. Results: We assessed a database of 18,482 lactulose breath tests, of which 16,505 patients (70.7% female; age 47.75 ± 18.53 years, range 2-100 years) were included in analysis after excluding repeat breath tests. Patients with IMO were older than non-IMO patients (Table 1). Prevalence of all IMO increases with age with odds of IMO increasing by 1.8% (OR 1.018; 95%CI 1.016-1.020) (Figure 1A). Male sex was associated with a slight higher risk of IMO (OR 1.095, 95%CI 1.007-1.190). Age is associated with higher maximum methane level (r = 0.15, P < 0.0001) and a higher baseline methane (r = 0.12, P < 0.0001) (Figure 1B). Conclusion: This database represents the largest analysis of SIBO and IMO to date and further supports that IMO positivity increases with age. Additionally, baseline and maximal methane levels increase with age, suggesting a higher burden of methanogen overgrowth as patients age. Association of the phenomenon with aging warrants future mechanistic studies. Reference Takakura W, Oh SJ, Singer-Englar T, et al. Comparing the rates of methane production in patients with and without appendectomy: results from a large-scale cohort. Sci Rep. 2020;10(1):867. Published 2020 Jan 21.Figure 1.: A. Breath tests positive for either IMO alone or both SIBO and IMO as a percentage of total breath tests acquired for each age group. Total number of breath tests for each group are included above each group. B. Average methane baseline and maximum in all patients with IMO (regardless of SIBO positivity) per age group with standard error bars. Table 1. - Baseline characteristics of enrolled patients n Mean Age ± SD (yrs) Sex (% F) Maximum Methane ± SD (ppm) Baseline Methane ± SD (ppm) Maximum H2 ± SD (ppm) Baseline H2 ± SD (ppm) Non-IMO/SIBO 6361 47.23 ± 18.48 71.4% 1.08 ± 2.20 0.56± 1.41 11.39 ± 10.22 4.49 ± 7.28 IMO Alone 2156 52.77 ± 17.87 67.6% 48.77 ± 40.50 26.15 ± 18.98 9.25 ± 9.93 4.28 ± 8.0 IMO And SIBO 1272 51.93 ± 19.15 71.3% 33.56 ± 29.68 14.32 ± 16.49 61.52 ± 36.62 6.67 ± 10.98 SIBO Alone 6716 45.84 ± 18.26 70.9% 0.94 ± 2.40 0.24 ± 0.87 47.06 ± 22.98 3.98 ± 4.92 Total 16505 47.75 ± 18.53 70.7% 9.76 ± 24.28 4.84 ± 12.29 27.49 ± 27.49 4.42 ± 56.95
Abstract Diffuse midline gliomas (DMGs) are responsible for a large proportion of childhood brain tumor deaths. Currently, radiation therapy is thought to be one of the most effective treatment options, but more than 90% of children still die within 2 years of diagnosis. DMGs are defined by somatic histone 3 K27M (H3K27M) mutations that have been shown to promote the G0/G1 to S cell cycle transition. The majority of DMGs also contain loss-of-function mutations in TP53. Prior research demonstrated that orthotopic xenograft and primary mouse models of non-H3K27M-mutated gliomas with inactivation of p53 are preferentially radiosensitized by inactivation of Ataxia Telangiectasia Mutated (ATM), a kinase that mediates DNA repair in response to DNA damage caused by radiation. The high frequency of mutations that deregulate p53 in DMGs raises the possibility that H3K27M-mutant DMGs may also be radiosensitized by ATM inhibition, representing a unique therapeutic opportunity. Here, we hypothesize that H3K27M-mutant DMGs that have loss of function of p53 will be radiosensitized by loss of ATM. To test this hypothesis, we used the RCAS-TVA viral gene delivery system to generate genetically-faithful primary mouse models of H3K27M-mutant DMG with p53 deletion, and we used Cre recombinase to delete Atm in the tumor cells of these mice and generated littermate controls that retained Atm. Mice were imaged weekly via luciferase-based bioluminescence to track tumor development and irradiated with three daily fractions of 10 Gy after tumor detection. We subsequently quantified the survival of mice without neurological decline following irradiation. In separate cohorts, we collected primary tumors after irradiation to verify H3K27M expression and to assess cell cycle arrest and mechanisms of cell death. These studies will elucidate mechanisms by which ATM inactivation can radiosensitize H3K27M-mutant DMGs with nonfunctioning p53, which will guide the design of clinical trials testing ATM inhibitors in DMG patients.
