Hematopoietic aging is characterized by diminished stem cell regenerative capacity and an increased risk of hematologic dysfunction. We previously identified that the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) regulates hematopoietic stem cell activity. Here, we expand on this work and demonstrate that in aged mice, (1) 15-PGDH expression and activity remain conserved in the bone marrow and spleen, suggesting it remains a viable therapeutic target in aging, (2) prolonged PGDH inhibition (PGDHi) significantly increases the frequency and number of phenotypic hematopoietic stem and progenitor cells across multiple compartments, with transcriptional changes indicative of enhanced function, (3) PGDHi-treated bone marrow enhances short-term hematopoietic recovery following transplantation, leading to improved peripheral blood output and accelerated multilineage reconstitution, and (4) PGDHi confers a competitive advantage in primary hematopoietic transplantation while mitigating age-associated myeloid bias in secondary transplants. Notably, these effects occur without perturbing steady-state blood production, suggesting that PGDHi enhances hematopoiesis under regenerative conditions while maintaining homeostasis. Our work identifies PGDHi as a translatable intervention to rejuvenate aged HSCs and mitigate hematopoietic decline. Significance Statement We identify 15-hydroxyprostaglandin dehydrogenase inhibition (PGDHi) as a strategy to enhance hematopoietic stem cell function in aging. In aged mice, PGDHi expands stem and progenitor populations, accelerates hematopoietic recovery after transplantation, and reduces myeloid bias while maintaining steady-state blood production. These findings highlight a potential therapeutic approach to restore hematopoietic resilience and improve regenerative outcomes in aging. Graphical Abstract 15-prostaglandin dehydrogenase inhibition ameliorates multiple facets of age-related hematopoietic decline. Schematic made using BioRender.com. ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. [1]: pending:yes

Hematopoietic stem cells (HSCs) play a crucial role in generating all blood cell types, vital for a functional immune system and oxygen transport. Maintaining this balance throughout life involves a tight regulation of self-renewal, differentiation, and quiescence, influenced by both intrinsic and extrinsic signals. Although the influence of many HSC progeny on HSC decisions is known, the role of mast cells (MCs) has remained unexplored. MCs, known for their immunomodulatory functions through secretion of various factors, including histamine, present a novel avenue for understanding HSC regulation. In this study, we uncover a novel role for MC-derived histamine in modulating HSC behavior. Our hypothesis posits that MCs act as negative regulators of HSCs. We observed that genetically MC-deficient “SASH” mice exhibit increased hematopoietic output and bone marrow (BM) HSCs, characterized by an enhanced quiescent signature that increases chemoresistance. The SASH microenvironment also shows elevated frequencies of HSC-supportive cell types and increased expression of genes conducive to HSC maintenance, providing a functional advantage when wild-type BM is transplanted into this microenvironment. Moreover, we found that the genetic loss of MCs correlates with lower serum histamine levels in SASH mice, and the augmented hematopoietic phenotype can be reversed by administering exogenous histamine. Subsequent experiments with US Food and Drug Administration (US FDA)-approved antihistamines in wild-type mice revealed that cetirizine, an H1R inverse agonist, notably increased HSC frequency in the BM. We have also shown that cetirizine treatment posttransplant leads to an accelerated HSC and peripheral blood recovery. Overall, our findings highlighted MCs as negative regulators of HSCs, laying the groundwork for future studies to unravel the underlying mechanisms and explore the therapeutic potential of cetirizine.

Alzheimer's disease (AD) and traumatic brain injury (TBI) are currently untreatable neurodegenerative disorders afflicting millions of people worldwide. These conditions are pathologically related, and TBI is one of the greatest risk factors for AD. Although blood-brain barrier (BBB) disruption drives progression of both AD and TBI, strategies to preserve BBB integrity have been hindered by lack of actionable targets. Here, we identify 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that catabolizes eicosanoids and other anti-inflammatory mediators, as a therapeutic candidate that protects the BBB. We demonstrate that 15-PGDH is enriched in BBB-associated myeloid cells and becomes markedly elevated in human and mouse models of AD and TBI, as well as aging, another major risk factor for AD. Pathological increase in 15-PGDH correlates with pronounced oxidative stress, neuroinflammation, and neurodegeneration, alongside profound BBB structural degeneration characterized by astrocytic endfeet swelling and functional impairment. Pharmacologic inhibition or genetic reduction of 15-PGDH in AD and TBI models strikingly mitigates oxidative damage, suppresses neuroinflammation, and restores BBB integrity. Most notably, inhibiting 15-PGDH not only halts neurodegeneration but also preserves cognitive function at levels indistinguishable from healthy controls. Remarkably, these neuroprotective effects in AD are achieved without affecting amyloid pathology, underscoring a noncanonical mechanism for treating AD. In a murine microglia cell line exposed to amyloid beta oligomer, major protection was demonstrated by multiple anti-inflammatory substrates that 15-PGDH degrades. Thus, our findings position 15-PGDH inhibition as a broad-spectrum strategy to protect the BBB and thereby preserve brain health and cognition in AD and TBI.

Background:Screening efforts for Barrett's Esophagus (BE) predominantly focus on performing upper endoscopy (EGD) on patients with gastroesophageal reflux disease (GERD) symptoms who have additional risk factors for BE. However, cost and invasiveness preclude EGD in those who have no prior GERD symptoms, despite having other risk factors, representing missed opportunities for BE screening in individuals who account for approximately 40% of the patients who eventually develop esophageal adenocarcinoma (EAC). Aim:The aim of this study was to evaluate if non-endoscopic methods can enable BE detection in an at-risk population without GERD symptoms. Methods:Patients presenting for colonoscopy who had not undergone previous EGD plus had ≥3 BE risk factors (from among age ≥50 years, male sex, white race, smoking history, family history of BE/EAC, or central obesity) without chronic GERD symptoms were prospectively recruited for non-endoscopic screening. Trained nurses administered the EsoCheck (Lucid Diagnostics) encapsulated balloon. Samples were assayed with the EsoGuard BE detection methylated DNA marker panel (Lucid Diagnostics). Patients with a positive result were offered standard-of-care EGD, while patients with a negative EG result were offered free of cost research EGD. Positive predictive value (PPV), negative predictive value (NPV), and BE prevalence were calculated. Results:The mean age of the 132 study subjects was 60.7 years, 129 (98%) were white, 124 (94%) were male, 71 (54%) had a prior smoking history, 46 (35%) were centrally obese, and 5 (4%) reported a family history. EsoCheck was successfully administered in 124 (94%) and the EsoGuard methylated DNA marker panel could be assayed in 120 (97%) of the samples. Thirty-four assays were positive of which 27 underwent a follow-up EGD and BE was identified in 9, PPV = 33% [17%, 54%] subjects. EGD was also performed in 22 of the 86 subjects whose assays were negative and none of them had BE, NPV = 100% [85%, 100%]. A logistic regression model fitted to impute the presence of BE estimated the PPV as 27% [13%, 44%], NPV as 98% [92%, 100%], and BE prevalence as 8.4% [4.5%, 14.3%]. Conclusion:Patients without chronic GERD who have ≥3 BE risk factors have a moderately high prevalence of BE. Non-endoscopic detection can effectively identify BE, enabling expansion of screening to this larger at-risk population. Those with a negative EG assay have a low likelihood of BE.

Patients with ulcerative colitis (UC) face a cumulative risk of developing colitis-associated cancer (CAC) that is significantly higher than that of the general population. This increased risk is directly associated with the inflammatory process that occurs throughout the disease, creating the appropriate environment for the development of neoplastic lesions and impacting treatment decisions for these patients. Therefore, developing a drug capable of both mitigating the inflammatory response associated with ulcerative colitis and preventing tumor development would be an ideal therapeutic approach for UC patients. Using the murine dextran sulfate sodium (DSS) model of acute colitis, the Markowitz lab has previously demonstrated that inhibition of 15-PGDH, the primary enzyme responsible for PGE2 degradation, can markedly enhance tissue repair capacity in the colon as well as multiple additional organs (Science, 2015. PMID: 26068857). We demonstrated that treatment with (+)-SW033291 (‘291), a small molecule 15-PGDH inhibitor, increased the levels of tissue PGE2, near completely reversed colitis mucosal damage and promoted mucosal regeneration by sustaining colonocyte proliferation. We now aim to evaluate the safety of this 15-PGDH inhibitor in the context of CAC by testing ‘291 efficacy in the azoxymethane (AOM)/DSS model. Colon carcinogenesis was induced by a single dose of AOM (10 mg/kg) on day 1 of the experiment followed by 7 days of DSS treatment in drinking water (from days 8 to 15). Animals were treated with daily injections of ‘291 (10 mg/kg, twice daily, i.p.) or it is vehicle for 15 days (from days 8 to 22) and were monitored for signs of disease. Euthanasia occurred on day 47 of the experiment. At the time of sacrifice, colons were isolated and analyzed for the presence of macroscopic lesions and then fixed for histopathology and IHC staining (analyses that are in progress). Macroscopic evaluation of the colons demonstrated that inhibiting 15-PGDH reduced tumor number and tumor burden in the ‘291-treated mice when compared to vehicle controls by 50 and 60%, respectively. Additionally, treatment with ‘291 prevented body weight loss (p=0.02) during the disease course. This data indicates that ‘291 can not only reverse epithelial damage after DSS-induced colitis, but also be an effective strategy in preventing the development of colitis-associated dysplastic lesions in the AOM/DSS model. This data reinforces the rationale for developing a 15-PGDH inhibitor therapeutic to be used for patients with UC with the ultimate goal of mitigating colitis symptoms and preventing neoplastic lesion formation. Mariana Franco Fragoso, Filip Goshevski, Stephen P. Fink, Won Jin Ho, Sanford D. Markowitz. Inhibition of 15-PGDH prevents tumor development in the AOM/DSS model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6341.

Hematopoietic aging is characterized by diminished stem cell regenerative capacity and an increased risk of hematologic dysfunction. We previously identified that the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) regulates hematopoietic stem cell (HSC) activity. Here, we expand on this work and demonstrate that in aged mice: (1) 15-PGDH expression and activity remain conserved in the bone marrow (BM) and spleen, suggesting that it remains a viable therapeutic target in aging; (2) prolonged PGDH inhibition (PGDHi) significantly increases the frequency and number of phenotypic hematopoietic stem and progenitor cells across multiple compartments, with transcriptional changes indicative of enhanced function; (3) PGDHi-treated BM enhances short-term hematopoietic recovery following transplantation, leading to improved peripheral blood output and accelerated multilineage reconstitution; and (4) PGDHi confers a competitive advantage in primary hematopoietic transplantation while mitigating age-associated myeloid bias in secondary transplants. Notably, these effects occur without perturbing steady-state blood production, suggesting that PGDHi enhances hematopoiesis under regenerative conditions while maintaining homeostasis. Our work identifies PGDHi as a translatable intervention to rejuvenate aged HSCs and mitigate hematopoietic decline.

ABSTRACTHematopoietic stem cells (HSCs) are essential for generating all blood cell types and maintaining immune function and oxygen transport. This requires tight regulation of self-renewal, differentiation, and quiescence, driven by intrinsic and extrinsic signals. While the influence of many HSC progeny on HSC decisions are recognized, the role of mast cells (MCs) remain understudied. MCs are known for their immunomodulatory functions through the secretion of factors such as histamine and could offer new insights into HSC regulation. In this study, we describe a novel role for MC-derived histamine in modulating HSC behavior. We observed that genetically MC-deficient “SASH” mice exhibit increased hematopoietic output and bone marrow (BM) HSCs, characterized by an enhanced quiescent signature that increases resistance to myeloablative chemotherapy. The SASH microenvironment also contained increased frequencies of HSC-supportive cell types and expression of genes conducive to HSC maintenance, which together accelerated HSC engraftment when wild-type BM was transplanted into SASH recipients. Moreover, we found lower serum histamine levels in SASH mice, and that the enhanced hematopoietic phenotype observed in these mice could be reversed by administering exogenous histamine. Subsequent experiments with FDA-approved antihistamines in wild-type mice revealed that cetirizine, an H1R inverse agonist, notably increased HSC frequency in the BM. Overall, our findings implicate MCs are negative regulators of HSC function. This lays the groundwork for future studies to elucidate the underlying mechanisms and explore the therapeutic potential of modulating histamine signaling to promote hematopoiesis.

INTRODUCTION:Upper endoscopy (EGD) is generally recommended in those with chronic gastroesophageal reflux disease (GERD). To evaluate nonendoscopic screening in those without GERD symptoms. METHODS:EsoCheck/Esoguard (LucidDx) was performed in recruited patients without chronic GERD who had ≥3 other BE risk factors. RESULTS:The EsoGuard assay was positive in 34 of 120 patients. BE was identified in 9 of 27 who had follow-up EGD, positive predictive value = 33% (17%-54%). EGD performed in 22 of 86 subjects with negative assays found no BE, negative predictive value = 100% (85%-100%). DISCUSSION:Nonendoscopic BE detection is effective in patients without chronic GERD.

α-Sulfinyl esters can be readily prepared through thiol substitution of α-bromo esters followed by oxidation to the sulfoxide. Enzymatic resolution with lipoprotein lipase provides both the unreacted esters and corresponding α-sulfinyl carboxylic acids in high yields and enantiomeric ratios. Subsequent decarboxylative halogenation, dihalogenation, trihalogenation and cross-coupling gives rise to functionalized sulfoxides. The method has been applied to the asymmetric synthesis of a potent inhibitor of 15-prostaglandin dehydrogenase.

INTRODUCTION:Preliminary data suggest that an encapsulated balloon (EsoCheck), coupled with a 2 methylated DNA biomarker panel (EsoGuard), detects Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) with high accuracy. The initial assay requires sample freezing upon collection. The purpose of this study was to assess a next-generation EsoCheck sampling device and EsoGuard assay in a much-enlarged multicenter study clinically enhanced by using a Clinical Laboratory Improvement Amendments of 1988-compliant assay and samples maintained at room temperature. METHODS:Cases with nondysplastic BE (NDBE), dysplastic BE (indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia), EAC, junctional adenocarcinoma, plus endoscopy controls without esophageal intestinal metaplasia, were prospectively enrolled. Medical assistants at 6 institutions delivered the encapsulated balloon per orally with inflation in the stomach. The inflated balloon sampled the distal 5 cm of the esophagus and then was deflated and retracted into the capsule, preventing sample contamination. EsoGuard bisulfite sequencing assayed levels of methylated vimentin and methylated cyclin A1. RESULTS:A total of 243 evaluable patients-88 cases (median age 68 years, 78% men, 92% White) and 155 controls (median age 57 years, 41% men, 88% White)-underwent adequate EsoCheck sampling. The mean procedural time was approximately 3 minutes. Cases included 31 with NDBE, 16 with indefinite for dysplasia/low-grade dysplasia, 23 with high-grade dysplasia, and 18 with EAC/junctional adenocarcinoma. Thirty-seven NDBE and dysplastic BE cases (53%) were short-segment BE (<3 cm). Overall sensitivity was 85% (95% confidence interval 0.78-0.93) and specificity was 85% (95% confidence interval 0.79-0.90). Sensitivity for NDBE was 84%. EsoCheck/EsoGuard detected 100% of cancers (n = 18). DISCUSSION:EsoCheck/EsoGuard demonstrated high sensitivity and specificity in detecting BE and BE-related neoplasia.

Hematopoietic stem cells (HSCs) play a crucial role in generating all blood cell types, vital for a functional immune system and oxygen transport. Maintaining this balance throughout life involves a tight regulation of self-renewal, differentiation, and quiescence, influenced by both intrinsic and extrinsic signals. While the influence of many HSC progeny on HSC decisions is known, the role of mast cells (MCs) has remained unexplored. MCs, known for their immunomodulatory functions through secretion of various factors including histamine, present a novel avenue for understanding HSC regulation. In this study, we uncover a novel role for MC-derived histamine in modulating HSC behavior. Our hypothesis posits that MCs act as negative regulators of HSCs. We observed that genetically MC-deficient “SASH” mice exhibit increased hematopoietic output and bone marrow (BM) HSCs, characterized by an enhanced quiescent signature that increases chemoresistance. The SASH microenvironment also shows elevated frequencies of HSC-supportive cell types and increased expression of genes conducive to HSC maintenance, providing a functional advantage when wild-type BM is transplanted into this microenvironment. Moreover, we found that the genetic loss of MCs correlates with lower serum histamine levels in SASH mice, and the augmented hematopoietic phenotype can be reversed by administering exogenous histamine. Subsequent experiments with FDA-approved antihistamines in wild-type mice revealed that cetirizine, an H1R inverse agonist, notably increased HSC frequency in the BM. Overall, our findings highlight MCs as negative regulators of HSCs, laying the groundwork for future studies to unravel the underlying mechanisms and explore the therapeutic potential of cetirizine.

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

Supplementary Table 3 from A Segregation Analysis of Barrett's Esophagus and Associated Adenocarcinomas

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

Supplementary Methods of imputation of age and estimating the parameters of the prediction model. Supplementary Table S1 Missing rates on the 8 covariates in the training and validation datasets. Supplementary Table S2 Stepwise removal of covariates in the MLM model on the basis of LRT tests and AIC. Supplementary Table S3. Description of the eight predictor covariates. Supplementary Table S4 Number of informative pedigrees without missing covariate data.

BACKGROUND:We previously reported an encapsulated balloon (EsoCheck TM , EC), which selectively samples the distal esophagus, that coupled with a two methylated DNA biomarker panel (EsoGuard TM , EG), detected Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), with a sensitivity and specificity of 90.3% and 91.7%, respectively. This previous study utilized frozen EC samples.AIM:To assess a next generation EC sampling device and EG assay that utilizes a room temperature sample preservative to enable office-based testing.METHODS:Cases with nondysplastic (ND) and dysplastic (indefinite=IND, low grade dysplasia = LGD, high grade dysplasia = HGD) BE, EAC, junctional adenocarcinoma (JAC) and controls with no intestinal metaplasia (IM) were included. Nurses or physician assistants at six institutions, who were trained in EC administration, delivered the encapsulated balloon per orally and inflated it in the stomach. The inflated balloon was pulled back to sample 5 cm of the distal esophagus, then deflated and retracted into the EC capsule to prevent sample contamination from proximal esophagus. Nextgen EG sequencing assays performed on bisulfite-treated DNA extracted from EC samples determined levels of methylated Vimentin (mVIM) and methylated Cyclin A1 (mCCNA1) in a CLIA-certified laboratory, blinded to patients' phenotypes.RESULTS:A total of 243 evaluable patients - 88 cases (median age 68 years, 78% men, 92% white) and 155 controls (median age 57 years, 41% men, 88% white) - underwent adequate EC sampling. Mean time for EC sampling was just over 3 minutes. The cases included 31 NDBE, 16 IND/LGD, 23 HGD, and 18 EAC/JAC. Thirty-seven (53%) of the non-dysplastic and dysplastic BE cases were short-segment BE (SSBE; < 3 cm). Overall sensitivity for detecting all cases was 85% (95% CI= 0.78-0.93) and specificity was 85% (95% CI=0.79-0.90). Sensitivity for NDBE was 84% (n=37). The EC/EG test detected 100% of cancers.CONCLUSION:The next-generation EC/EG technology has been both successfully updated to incorporate a room temperature sample collection preservative and successfully implemented in a CLIA certified laboratory. When performed by trained personnel, EC/EG detects non-dysplastic BE, dysplastic BE, and cancer with high sensitivity and specificity, replicating the operating characteristics of the initial pilot study of this technology. Future applications utilizing EC/EG to screen broader populations at risk for developing cancer are proposed.SIGNIFICANCE:This multi-center study demonstrates the successful performance of a commercially available clinically implementable non-endoscopic screening test for BE in the U.S., as recommended in the most recent ACG Guideline and AGA Clinical Update. It transitions and validates a prior academic laboratory-based study of frozen research samples over to a CLIA laboratory, one that also integrates a clinically practical room temperature method for sample acquisition and storage, enabling office-based screening.

Supplemental Table S1. Clinical Characteristics of Samples