TXNIP-mediated crosstalk between oxidative stress and glucose metabolism.

Thioredoxin-interacting protein (TXNIP) has emerged as a key player in cancer and diabetes since it targets thioredoxin (TRX)-mediated redox regulation and glucose transporter (GLUT)-mediated metabolism. TXNIP consists of two arrestin (ARR, N-ARR and C-ARR) domains at its amino-terminus and two PPxY (PY) motifs and a di-leucine (LL) motif for endocytosis at its carboxyl-terminus. Here, we report that TXNIP shuffles between TRX and GLUTs to regulate homeostasis of intracellular oxidative stress and glucose metabolism. While TXNIP functions as a gatekeeper of TRX by default, it robustly interacted with class I GLUTs through its C-ARR domain upon increase of intracellular reactive oxygen species. This interaction prompted the surface expression downregulation and lysosomal degradation of GLUTs by its carboxyl-terminal LL endocytic signaling motif to attenuate glucose uptake. Consequently, TXNIP expression significantly limited glucose uptake, leading to the suppression of glycolysis, hexosamine biosynthesis, and the pentose phosphate pathway. Our findings establish a fundamental link between ROS and glucose metabolism through TXNIP and provide a promising target for the drug development against GLUT-related metabolic disorders.

Assessing Adherence to US LI-RADS Follow-up Recommendations in Vulnerable Patients Undergoing Hepatocellular Carcinoma Surveillance.

Purpose To assess adherence to the US Liver Imaging Reporting and Data System (LI-RADS) recommendations for hepatocellular carcinoma (HCC) surveillance and associated patient-level factors in a vulnerable, diverse patient sample. Materials and Methods The radiology report database was queried retrospectively for patients who underwent US LI-RADS-based surveillance examinations at a single institution between June 1, 2020, and February 28, 2021. Initial US and follow-up liver imaging were included. Sociodemographic and clinical data were captured from electronic medical records. Adherence to radiologist recommendation was defined as imaging (US, CT, or MRI) follow-up in 5-7 months for US-1, imaging follow-up in 3-6 months for US-2, and CT or MRI follow-up in 2 months for US-3. Descriptive analysis and multivariable modeling that adjusted for age, sex, race, and time since COVID-19 pandemic onset were performed. Results Among 936 patients, the mean age was 59.1 years; 531 patients (56.7%) were male and 544 (58.1%) were Asian or Pacific Islander, 91 (9.7%) were Black, 129 (13.8%) were Hispanic, 147 (15.7%) were White, and 25 (2.7%) self-reported as other race. The overall adherence rate was 38.8% (95% CI: 35.7, 41.9). The most common liver disease etiology was hepatitis B (60.6% [657 of 936 patients]); 19.7% of patients (183 of 936) had current or past substance use disorder, and 44.8% (416 of 936) smoked. At adjusted multivariable analysis, older age (odds ratio [OR], 1.20; P = .02), male sex (OR, 1.62; P = .003), hepatology clinic attendance (OR, 3.81; P < .001), and recent prior US examination (OR, 2.44; P < .001) were associated with full adherence, while current smoking (OR, 0.39; P < .001) was negatively associated. Conclusion Adherence to HCC imaging surveillance was suboptimal, despite US LI-RADS implementation. Keywords: Liver, Ultrasound, Screening, Abdomen/GI, Cirrhosis, Metabolic Disorders, Socioeconomic Issues Supplemental material is available for this article. © RSNA, 2024.

The art of specimen orientation: Two-dimensional maps for oropharynx squamous cell carcinoma.

The goal of surgical treatment for oropharynx squamous cell carcinoma (SCCa) is resection to negative margins. Current methods of orienting resection specimens often do not give a comprehensive view, especially in oropharynx SCCa where specimens can lack anatomic landmarks. We created standardized two-dimensional maps of oropharynx anatomy drawn to scale to improve communication between surgeons and pathologists. Notes regarding surgery including anatomic landmarks, areas of concern, additional margins, and relevant clinical information were added to the map. The maps guided pathology work-up, and the pathologist could communicate details back to the surgeon on how the specimen was sectioned or locations of microscopic foci to direct future treatment and clinical monitoring. The use of two-dimensional maps for oropharynx SCCa specimens offers a standardized solution to address the challenges of anatomic orientation. These maps summarized key pathological information, preserved clinical details from the specimens, and guided multidisciplinary conferences when planning adjuvant treatment.

DNA methylation biomarkers distinguishing early-stage prostate cancer from benign prostatic hyperplasia.

Background: DNA methylation markers are considered robust diagnostic features in various cancer types, as epigenetic marks are commonly altered during cancer progression. Differentiation between benign prostatic hyperplasia (BPH) and early-stage prostate cancer (PCa) is clinically difficult, relying on the information of the patient's symptoms or levels of prostate-specific antigen. Methods: A total of 42 PCa patients and 11 BPH patients were recruited. Genomic DNA was purified from tissues and used for the library preparation of the target-enriched methylome with enzymatic conversion and a Twist 85 Mbp EM-seq panel. Paired-end sequencing (150 bp) was performed using NovaSeq 6000 or NextSeq 550. After quality control, including adapter trimming and de-duplication of raw sequencing data, differential methylation patterns were analyzed between the BPH and PCa groups. Results: We report DNA methylation patterns existing between BPH and PCa. The major finding is that broad hypermethylation occurred at genic loci in PCa tissues as compared to the BPH. Gene ontology analysis suggested that hypermethylation of genic loci involved in chromatin and transcriptional regulation is involved in cancer progression. We also compared PCa tissues with high Gleason scores to tissues with low Gleason scores. The high-Gleason PCa tissues showed hundreds of focal differentially methylated CpG sites corresponding to genes functioning in cancer cell proliferation or metastasis. This suggests that dissecting early-to-advanced-grade cancer stages requires an in-depth analysis of differential methylation at the single CpG site level. Conclusions: Our study reports that enzymatic methylome sequencing data can be used to distinguish PCa from BPH and advanced PCa from early-stage PCa. The stage-specific methylation patterns in this study will be valuable resources for diagnostic purposes as well as further development of liquid biopsy approaches for the early detection of PCa.

Lung-specific MCEMP1 functions as an adaptor for KIT to promote SCF-mediated mast cell proliferation.

Lung mast cells are important in host defense, and excessive proliferation or activation of these cells can cause chronic inflammatory disorders like asthma. Two parallel pathways induced by KIT-stem cell factor (SCF) and FcεRI-immunoglobulin E interactions are critical for the proliferation and activation of mast cells, respectively. Here, we report that mast cell-expressed membrane protein1 (MCEMP1), a lung-specific surface protein, functions as an adaptor for KIT, which promotes SCF-mediated mast cell proliferation. MCEMP1 elicits intracellular signaling through its cytoplasmic immunoreceptor tyrosine-based activation motif and forms a complex with KIT to enhance its autophosphorylation and activation. Consequently, MCEMP1 deficiency impairs SCF-induced peritoneal mast cell proliferation in vitro and lung mast cell expansion in vivo. Mcemp1-deficient mice exhibit reduced airway inflammation and lung impairment in chronic asthma mouse models. This study shows lung-specific MCEMP1 as an adaptor for KIT to facilitate SCF-mediated mast cell proliferation.

Spectrum of Clinical Presentations, Imaging Findings, and HLA Types in Immune Checkpoint Inhibitor-Induced Hypophysitis.

Context: Hypophysitis is a known immune-related adverse event (irAE) of immune checkpoint inhibitors (CPIs), commonly associated with CTLA-4 inhibitors and less often with PD-1/PD-L1 inhibitors. Objective: We aimed to determine clinical, imaging, and HLA characteristics of CPI-induced hypophysitis (CPI-hypophysitis). Methods: We examined the clinical and biochemical characteristics, magnetic resonance imaging (MRI) of the pituitary, and association with HLA type in patients with CPI-hypophysitis. Results: Forty-nine patients were identified. Mean age was 61.3 years, 61.2% were men, 81.6% were Caucasian, 38.8% had melanoma, and 44.5% received PD-1/PD-L1 inhibitor monotherapy while the remainder received CTLA-4 inhibitor monotherapy or CTLA-4/PD-1 inhibitor combination therapy. A comparison of CTLA-4 inhibitor exposure vs PD-1/PD-L1 inhibitor monotherapy revealed faster time to CPI-hypophysitis (median 84 vs 185 days, P < .01) and abnormal pituitary appearance on MRI (odds ratio 7.00, P = .03). We observed effect modification by sex in the association between CPI type and time to CPI-hypophysitis. In particular, anti-CTLA-4 exposed men had a shorter time to onset than women. MRI changes of the pituitary were most common at the time of hypophysitis diagnosis (55.6% enlarged, 37.0% normal, 7.4% empty or partially empty) but persisted in follow-up (23.8% enlarged, 57.1% normal, 19.1% empty or partially empty). HLA typing was done on 55 subjects; HLA type DQ0602 was over-represented in CPI-hypophysitis relative to the Caucasian American population (39.4% vs 21.5%, P = 0.01) and CPI population. Conclusion: The association of CPI-hypophysitis with HLA DQ0602 suggests a genetic risk for its development. The clinical phenotype of hypophysitis appears heterogenous, with differences in timing of onset, changes in thyroid function tests, MRI changes, and possibly sex related to CPI type. These factors may play an important role in our mechanistic understanding of CPI-hypophysitis.

Outcomes of Early Versus Delayed Completion Thyroidectomy for Malignancy.

PURPOSE: To determine whether time interval between hemi-thyroidectomy and subsequent completion thyroidectomy impacts outcomes. METHODS: Retrospective review of 68 patients having completion thyroidectomy from August 2012 to December 2019. Patients were separated into two groups based on the time interval between surgeries: early (≤10 days) or delayed (≥90 days). RESULTS: Patients who underwent delayed completion thyroidectomy (n = 17) had significantly higher rates of hypocalcemia and/or hypoparathyroidism (P = .03) and higher rates of requiring postoperative hospitalization (P=.07) compared to those who underwent early completion thyroidectomy (n = 51). Delayed completion had significantly lower risk of developing one or more of dysphonia, dysphagia, or vocal cord paresis postoperatively (P=.02). No patients developed hematoma or wound infection. CONCLUSIONS: Delayed completion thyroidectomy is associated with increased rates of hypocalcemia, but lower rates of dysphonia and dysphagia. Given the low risk of long-term complications in both groups, it may be beneficial to perform completion thyroidectomy early in order to expedite cancer treatment.

Unraveling the Transcriptomic Signatures of Homologous Recombination Deficiency in Ovarian Cancers.

Homologous recombination deficiency (HRD) is a crucial driver of tumorigenesis by inducing impaired repair of double-stranded DNA breaks. Although HRD possibly triggers the production of numerous tumor neoantigens that sufficiently stimulate and activate various tumor-immune responses, a comprehensive understanding of the HRD-associated tumor microenvironment is elusive. To investigate the effect of HRD on the selective enrichment of transcriptomic signatures, 294 cases from The Cancer Genome Atlas-Ovarian Cancer project with both RNA-sequencing and SNP array data are analyzed. Differentially expressed gene analysis and network analysis are performed to identify HRD-specific signatures. Gene-sets associated with mitochondrial activation, including enhanced oxidative phosphorylation (OxPhos), are significantly enriched in the HRD-high group. Furthermore, a wide range of immune cell activation signatures is enriched in HRD-high cases of high-grade serous ovarian cancer (HGSOC). On further cell-type-specific analysis, M1-like macrophage genes are significantly enriched in HRD-high HGSOC cases, whereas M2-macrophage-related genes are not. The immune-response-associated genomic features, including tumor mutation rate, neoantigens, and tumor mutation burdens, correlated with HRD scores. In conclusion, the results of this study highlight the biological properties of HRD, including enhanced energy metabolism, increased tumor neoantigens and tumor mutation burdens, and consequent exacerbation of immune responses, particularly the enrichment of M1-like macrophages in HGSOC cases.

Single-cell analysis of Kaposi's sarcoma-associated herpesvirus infection in three-dimensional air-liquid interface culture model.

The oral cavity is the major site for transmission of Kaposi's sarcoma-associated herpesvirus (KSHV), but how KSHV establishes infection and replication in the oral epithelia remains unclear. Here, we report a KSHV spontaneous lytic replication model using fully differentiated, three-dimensional (3D) oral epithelial organoids at an air-liquid interface (ALI). This model revealed that KSHV infected the oral epithelia when the basal epithelial cells were exposed by damage. Unlike two-dimensional (2D) cell culture, 3D oral epithelial organoid ALI culture allowed high levels of spontaneous KSHV lytic replication, where lytically replicating cells were enriched at the superficial layer of epithelial organoid. Single cell RNA sequencing (scRNAseq) showed that KSHV infection induced drastic changes of host gene expression in infected as well as uninfected cells at the different epithelial layers, resulting in altered keratinocyte differentiation and cell death. Moreover, we identified a unique population of infected cells containing lytic gene expression at the KSHV K2-K5 gene locus and distinct host gene expression compared to latent or lytic infected cells. This study demonstrates an in vitro 3D epithelial organoid ALI culture model that recapitulates KSHV infection in the oral cavity, where KSHV undergoes the epithelial differentiation-dependent spontaneous lytic replication with a unique cell population carrying distinct viral gene expression.

DNAJB1-PRKACA in HEK293T cells induces LINC00473 overexpression that depends on PKA signaling.

Fibrolamellar carcinoma (FLC) is a primary liver cancer that most commonly arises in adolescents and young adults in a background of normal liver tissue and has a poor prognosis due to lack of effective chemotherapeutic agents. The DNAJB1-PRKACA gene fusion (DP) has been reported in the majority of FLC tumors; however, its oncogenic mechanisms remain unclear. Given the paucity of cellular models, in particular FLC tumor cell lines, we hypothesized that engineering the DP fusion gene in HEK293T cells would provide insight into the cellular effects of the fusion gene. We used CRISPR/Cas9 to engineer HEK293T clones expressing DP fusion gene (HEK-DP) and performed transcriptomic, proteomic, and mitochondrial studies to characterize this cellular model. Proteomic analysis of DP interacting partners identified mitochondrial proteins as well as proteins in other subcellular compartments. HEK-DP cells demonstrated significantly elevated mitochondrial fission, which suggests a role for DP in altering mitochondrial dynamics. Transcriptomic analysis of HEK-DP cells revealed a significant increase in LINC00473 expression, similar to what has been observed in primary FLC samples. LINC00473 overexpression was reversible with siRNA targeting of PRKACA as well as pharmacologic targeting of PKA and Hsp40 in HEK-DP cells. Therefore, our model suggests that LINC00473 is a candidate marker for DP activity.

Is it Anaplastic Thyroid Cancer, Primary Thyroid Lymphoma, or Rosai Dorfman Disease? An Elusive Histopathologic Diagnosis of a Thyroid Mass.

The aim of this study is to present an elusive case of primary thyroid lymphoma (PTL), initially thought to be anaplastic thyroid carcinoma, then Rosai Dorfman disease, before the final diagnosis of PTL was made. An elderly female with hypothyroidism presented with compressive airway symptoms secondary to an enlarging neck mass. Imaging was suggestive of undifferentiated thyroid cancer. The initial biopsy was unexpectedly consistent with a lymphoproliferative disorder such as Rosai-Dorfman disease. A repeat biopsy with immunohistochemical analysis yielded a diagnosis of diffuse large B-cell lymphoma of germinal center subtype. The patient was spared thyroid surgery and started on appropriate chemotherapy. PTL is within the differential diagnosis that physicians must consider in a patient with a rapidly-enlarging neck mass. A clinical index of suspicion and early accurate diagnosis may spare the patient from unnecessary surgery that is required of most other non-hematopoeitic thyroid malignancies.

Correction: A real-world evaluation of radium-223 in combination with abiraterone or enzalutamide for the treatment of metastatic castration-resistant prostate cancer.

[This corrects the article DOI: 10.1371/journal.pone.0253021.].

Sporadic Primary Hyperparathyroidism.

Sporadic primary hyperparathyroidism is a common endocrinopathy, particularly afflicting postmenopausal women and both African American men and women. Although classic signs and symptoms of the disease are well appreciated and described, because of the ease and availability and low threshold for screening, the disorder often is diagnosed in patients who are minimally symptomatic or asymptomatic. Surgery conducted by experienced endocrine surgeons has a high cure rate, particularly if guided by concordant imaging. In patients who cannot safely undergo surgery or who fail to be cured, medical therapy with the oral calcimimetic cinacalcet is a validated option for controlling serum calcium levels.

Mitochondrial complex II in intestinal epithelial cells regulates T cell-mediated immunopathology.

Intestinal epithelial cell (IEC) damage by T cells contributes to graft-versus-host disease, inflammatory bowel disease and immune checkpoint blockade-mediated colitis. But little is known about the target cell-intrinsic features that affect disease severity. Here we identified disruption of oxidative phosphorylation and an increase in succinate levels in the IECs from several distinct in vivo models of T cell-mediated colitis. Metabolic flux studies, complemented by imaging and protein analyses, identified disruption of IEC-intrinsic succinate dehydrogenase A (SDHA), a component of mitochondrial complex II, in causing these metabolic alterations. The relevance of IEC-intrinsic SDHA in mediating disease severity was confirmed by complementary chemical and genetic experimental approaches and validated in human clinical samples. These data identify a critical role for the alteration of the IEC-specific mitochondrial complex II component SDHA in the regulation of the severity of T cell-mediated intestinal diseases.

Association of Childhood Adversity With Morbidity and Mortality in US Adults: A Systematic Review.

Importance: Childhood adversity (CA) is a powerful determinant of long-term physical and mental health that is associated with elevated risk for chronic disease and psychopathology. However, the degree to which CA contributes to mortality as a preventable driver of ill-health and death is unknown. Objective: To estimate the contribution of CA to health behaviors, including smoking and sedentary behavior, as well as the annual mortality attributable to CA in the US through influences on leading causes of death (eg, cardiovascular disease). Evidence Review: For this systematic review, the PsycINFO and MEDLINE databases were searched on November 15, 2019. The databases were searched for publications from inception (1806 for PsycINFO, 1946 for MEDLINE) to November 15, 2019. Meta-analyses of the associations between CA and morbidity outcomes were included. The population attributable fraction (PAF) was calculated from these associations along with the estimated US prevalence of CA. The PAF was then applied to the number of annual deaths associated with each cause of death to estimate the number of deaths that are attributable to CA. Additionally, the PAF was applied to the incidence of health behaviors to derive the number of cases attributable to CA. Exposure to 1 or more experiences of adversity before the age of 18 years was analyzed, including abuse, neglect, family violence, and economic adversity. Findings: A total of 19 meta-analyses with 20 654 832 participants were reviewed. Childhood adversity accounted for approximately 439 072 deaths annually in the US, or 15% of the total US mortality in 2019 (2 854 838 deaths), through associations with leading causes of death (including heart disease, cancer, and suicide). In addition, CA was associated with millions of cases of unhealthy behaviors and disease markers, including more than 22 million cases of sexually transmitted infections, 21 million cases of illicit drug use, 19 million cases of elevated inflammation, and more than 10 million cases each of smoking and physical inactivity. The greatest proportion of outcomes attributable to CA were for suicide attempts and sexually transmitted infections, for which adversity accounted for up to 38% and 33%, respectively. Conclusions and Relevance: The results of this systematic review suggest that CA is a leading contributor to morbidity and mortality in the US and may be considered a preventable determinant of mortality. The prevention of CA and the intervention on pathways that link these experiences to elevated disease risk should be considered a critical public health priority.

Surgical resection of high-grade nonfunctional pancreatic neuroendocrine carcinoma is associated with improved survival.

BACKGROUND AND OBJECTIVES: The role of surgery in the treatment of nonfunctional pancreatic neuroendocrine carcinomas (PNEC) is not well defined. This study investigated the effect of surgical resection on cause-specific survival compared with nonoperative management. METHODS: The Surveillance, Epidemiology, and End Results Program (SEER) database was utilized to identify patients with nonfunctional pancreatic neuroendocrine carcinoma diagnosed between January 1, 2004 and December 31, 2015. Survival was modeled using Kaplan-Meier analysis and multivariable Cox proportional hazards models. RESULTS: Of the 488 patients identified, 137 (29%) underwent surgical resection of the primary site. Patients who underwent surgery had a median CSS of 31 months compared with 5 months in those who did not (p < 0.01). A survival benefit was observed when the cohort was stratified into local, nodal, and metastatic disease. CONCLUSION: Resection of the primary site in the cohort of PNEC patients compiled by SEER is associated with improved survival. Further consideration be placed on primary surgical resection for PNEC while additional studies that can select specifically for high-grade, poorly differentiated carcinomas need to be undertaken.

A real-world evaluation of radium-223 in combination with abiraterone or enzalutamide for the treatment of metastatic castration-resistant prostate cancer.

INTRODUCTION: Radium-223, abiraterone, and enzalutamide have each been shown to significantly improve survival as monotherapy in patients with metastatic castration-resistant prostate cancer. However, effects of combination radium-223 plus abiraterone or enzalutamide on survival and safety remain unclear. PATIENTS AND METHODS: This single-center retrospective cohort study used electronic health record data of patients with metastatic castration-resistant prostate cancer and bone metastases who were treated with radium-223 between April 1, 2014 and February 19, 2019. Patients who received radium-223 monotherapy were compared to patients who received a combination of radium-223 plus either abiraterone or enzalutamide. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, time to symptomatic skeletal event, symptomatic skeletal event-free survival, and incidence of drug-related adverse events. Time-to-event analyses were estimated by log rank tests using Kaplan-Meier curves. Hazard ratios and 95% confidence intervals were derived from Cox proportional hazards models. Chi-square tests evaluated difference in serious adverse events between the two arms. RESULTS: A total of 60 patients met inclusion criteria (n = 41 in the monotherapy arm, n = 19 in the combination arm). Differences in median overall survival were not observed (12.7 vs. 12.8 months; HR 1.15, 95% CI 0.59-2.23; P = 0.68), but median progression-free survival was significantly longer in the combination arm (7.6 vs. 4.9 months; HR 1.94, 95% CI 1.11-3.40; P = 0.02). Significant differences were not observed in time to first SSE (P = 0.97), SSE-free survival (P = 0.16), or in the overall incidence of serious adverse events (P = 0.45). CONCLUSION: Combination radium-223 plus abiraterone or enzalutamide did not improve overall survival, but prolonged progression-free survival without increasing the incidence of serious adverse events in metastatic castration-resistant prostate cancer patients with bone metastases. However, these results are limited by small numbers and patient selection inherent in retrospective analysis.

Ten-year Thyroid Cancer Incidence in an Integrated Healthcare Delivery System.

INTRODUCTION: The incidence of papillary thyroid cancer (PTC) has increased in recent decades, but data from community-based settings are limited. This study characterizes PTC trends in a large, integrated healthcare system over 10 years. METHODS: The annual incidence of PTC (2006-2015) was examined among Kaiser Permanente Northern California adults aged 21 to 84 years using Cancer Registry data, including tumor size and stage. Incidence estimates were age-adjusted using the 2010 US Census. RESULTS: Of 2990 individuals newly diagnosed with PTC (76.8% female, 52.7% non-Hispanic White), 38.5% and 61.5% were aged < 45 and < 55 years, respectively. At diagnosis, 60.9% had PTC tumors ≤ 2 cm, 9.2% had tumors > 4 cm, and 66.1% had Stage I disease. The annual age-adjusted incidence of PTC increased from 9.4 (95% confidence interval [CI] = 8.1-10.7) to 14.5 (95% CI = 13.1-16.0) per 100,000 person-years and was higher for female patients than for male patients. Incidence tended to be higher in Asian/Pacific Islanders and lower in Black individuals. Increasing incidence was notable for Stage I disease (especially 2006-2012) and evident across a range of tumor sizes (3.0-4.6 for ≤ 1 cm, 2.5-3.5 for 1-2 cm, and 2.4-4.7 for 2-4 cm) but was modest for large tumors (0.9-1.5 for > 4 cm) per 100,000 person-years. DISCUSSION: Increasing PTC incidence over 10 years was most evident for tumors ≤ 4 cm and Stage I disease. Although these findings may be attributable to greater PTC detection, the increase across a range of tumor sizes suggests that PTC burden might also have increased.

RNA-seq of human T cells after hematopoietic stem cell transplantation identifies Linc00402 as a regulator of T cell alloimmunity.

Mechanisms governing allogeneic T cell responses after solid organ and allogeneic hematopoietic stem cell transplantation (HSCT) are incompletely understood. To identify lncRNAs that regulate human donor T cells after clinical HSCT, we performed RNA sequencing on T cells from healthy individuals and donor T cells from three different groups of HSCT recipients that differed in their degree of major histocompatibility complex (MHC) mismatch. We found that lncRNA differential expression was greatest in T cells after MHC-mismatched HSCT relative to T cells after either MHC-matched or autologous HSCT. Differential expression was validated in an independent patient cohort and in mixed lymphocyte reactions using ex vivo healthy human T cells. We identified Linc00402, an uncharacterized lncRNA, among the lncRNAs differentially expressed between the mismatched unrelated and matched unrelated donor T cells. We found that Linc00402 was conserved and exhibited an 88-fold increase in human T cells relative to all other samples in the FANTOM5 database. Linc00402 was also increased in donor T cells from patients who underwent allogeneic cardiac transplantation and in murine T cells. Linc00402 was reduced in patients who subsequently developed acute graft-versus-host disease. Linc00402 enhanced the activity of ERK1 and ERK2, increased FOS nuclear accumulation, and augmented expression of interleukin-2 and Egr-1 after T cell receptor engagement. Functionally, Linc00402 augmented the T cell proliferative response to an allogeneic stimulus but not to a nominal ovalbumin peptide antigen or polyclonal anti-CD3/CD28 stimulus. Thus, our studies identified Linc00402 as a regulator of allogeneic T cell function.

NAD+ depletion by type I interferon signaling sensitizes pancreatic cancer cells to NAMPT inhibition.

Emerging evidence suggests that intratumoral interferon (IFN) signaling can trigger targetable vulnerabilities. A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its extensively reprogrammed metabolic network, in which nicotinamide adenine dinucleotide (NAD) and its reduced form, NADH, are critical cofactors. Here, we show that IFN signaling, present in a subset of PDAC tumors, substantially lowers NAD(H) levels through up-regulating the expression of NAD-consuming enzymes PARP9, PARP10, and PARP14. Their individual contributions to this mechanism in PDAC have not been previously delineated. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD salvage pathway, a dominant source of NAD in cancer cells. We found that IFN-induced NAD consumption increased dependence upon NAMPT for its role in recycling NAM to salvage NAD pools, thus sensitizing PDAC cells to pharmacologic NAMPT inhibition. Their combination decreased PDAC cell proliferation and invasion in vitro and suppressed orthotopic tumor growth and liver metastases in vivo.