Grand Rapids Community College

Polyaminopathies are a recently described family of rare genetic neurodevelopmental disorders. Polyaminopathies disrupt the biosynthesis of the primary polyamines: putrescine, spermidine, and spermine. Snyder-Robinson syndrome results from hemizygous loss-of-function variants in the spermine synthase (SMS) gene, resulting in decreased or complete loss of spermine synthase enzyme activity. Bachmann-Bupp syndrome results from heterozygous gain-of-function variants in the ornithine decarboxylase 1 (ODC1) gene, resulting in increased ornithine decarboxylase enzyme activity. Faundes-Banka syndrome results from heterozygous loss-of-function variants in the eukaryotic translation initiation factor 5A (EIF5A) gene, impairing eIF5A protein function. DHPS (deoxyhypusine synthase) deficiency is an autosomal recessive disease and results from bi-allelic hypomorphic variants in the deoxyhypusine synthase (DHPS) gene, which results in reduced deoxyhypusine synthase enzyme activity. Finally, DOHH (deoxyhypusine hydroxylase) disorder is an autosomal recessive disorder caused by bi-allelic loss-of-function variants in the deoxyhypusine hydroxylase (DOHH) gene, which causes decreased deoxyhypusine hydroxylase enzyme activity. Snyder-Robinson syndrome was first described in 1969, while the other four syndromes have only been identified in the past 7 years. A comprehensive phenotypic and genotypic description of these five syndromes is needed. We review the clinical and genetic features of these five polyaminopathies to create an inclusive clinical resource. A systematic keyword search strategy was used to identify all published cases in PubMed, Web of Science, and Scopus databases. The five known syndromes associated with the polyamine pathway share many similar clinical phenotypes, and yet patients with each syndrome present with distinctive syndromic features. This review will serve as a valuable resource for clinicians diagnosing and caring for patients with these rare polyaminopathies.

Research suggests fear of sleep (FoS) may be an important consequence of trauma that increases risk for posttraumatic stress disorder (PTSD), especially among patients experiencing ongoing threat after their trauma has ended. Community violence exposure may reinforce perceptions of threat, compounding the pathogenic effect of FoS after trauma. The current study investigated whether FoS increases within the acute aftermath of trauma, and if such increases in FoS predict future PTSD severity. Further, we tested whether community violence exposure moderates the prospective relationship between FoS and PTSD. We recruited patients from an urban Level I trauma center (N = 88; Mage = 39.53 ± SD 14.31, 67.0% male, 67.0% Black). Patients reported FoS within one week of trauma (T1) and again one month later (T2), and PTSD symptoms two months later (T3). We operationalized community violence exposure as the frequency of hearing gunshots in the 90 days prior to trauma. FoS significantly increased from T1 (M = 8.80) to T2 (M = 11.98), p = 0.015, g = 0.28. Change in FoS significantly predicted PTSD symptoms at T3, and this effect was most pronounced among patients who frequently heard gunshots in their community (β = 0.61, SE = 0.35, p = 0.005). Exploratory analyses in a subsample of patients revealed preliminary associations between skin conductance reactivity and sleep fears at T1, tentatively suggesting heightened sympathetic activation as a corollary of fear of sleep. This study provides novel evidence that FoS increases in response to acute trauma exposure and, in turn, predicts future PTSD severity. Moreover, patients exposed to community violence may be especially vulnerable to these effects, perhaps due in part to continued threats to safety. Acute trauma patients who develop sleep fears may be vulnerable to PTSD, particularly those returning to neighborhoods marked by high levels of community violence.

Antigen presentation by major histocompatibility complex class I (MHC-I) is critical for tumor cell killing by CD8+ T cells. Accordingly, tumor cells downregulate MHC-I expression through multiple mechanisms, thereby evading the immune response. Importantly, lower levels of MHC-I are associated with poor responses to immune checkpoint inhibitor therapy. Our recent study has shown that the human papillomavirus (HPV) oncoproteins induce MHC-I protein ubiquitination by membrane-associated Ring-CH-type finger 8 (MARCHF8) in HPV-positive head and neck cancer (HPV+ HNC). However, the mechanism by which ubiquitinated MHC-I is degraded remains elusive. By performing genome-wide CRISPR screens, we identified components of the ULK1 and PIK3C3 complexes for autophagy initiation complexes among the top negative regulators of cell-surface MHC-I expression in HPV+ HNC cells. We show that MHC-I is recruited from the ER to autophagosomes by the cargo receptor NDP52, decreasing MHC-I levels. Further, inhibiting the initiation or nucleation steps of autophagy before autophagosome formation is critical for restoring MHC-I levels on the cell surface. Finally, genetic inhibition of autophagy initiation suppresses HPV+ HNC tumor growth in vivo and enhances the CD8+ T cell-mediated antitumor response. Our findings suggest that autophagic degradation of MARCHF8-ubiquitinated MHC-I is a key immune evasion mechanism in HPV+ HNC.

Introduction: Secondary injury, marked by delayed tissue damage hours to days after traumatic brain injury (TBI), influences outcome. A better understanding of the metabolic pathways and cellular damage that occurs during this phase could lead to therapeutic options. The Warburg Effect is an increase in cellular glucose uptake and lactate synthesis in the presence of Oxygen. We hypothesize that the energetic forces driving the immune responses are predominantly glycolytic persisting despite resuscitation and oxygen availability. Methods: After IRB approval (CHW 2021-096) and informed consent, pediatric patients (17 TBI with GCS ≤ 8, and 10 controls) aged ≥ 1 and ≤ 21 years were enrolled. Blood samples were collected at three timepoints after initial injury: 24±12 hours, 48±12 hours and on hospital day 9±12 hours, along with clinical variables from medical record. RNA was analyzed as paired-end 150 base pair reads of around 30 million reads per sample. Reads were aligned to the human transcriptome Gencode 45. Enriched pathways from significant genes determined using STRING. MiXCR mapped data processed using ImmunArch. We employed Nuclear Magnetic Resonance (NMR) to profile plasma. All data were combined using a variety of machine learning modalities. Results: Clinical data revealed a mean lactic acidemia of 3.2±2mmol/L and a serum glucose of 164.4±57mg/dL, white cell counts (WBC) of 16861±7425/uL, and absolute neutrophil count (ANC) at 11515±5194/uL upon admission. At day 2, WBC: 10949±4409/uL and ANC: 7447±2185/uL. Day 8, WBC: 10815±4534/uL and ANC: 6760±1356/uL. At admission, TBI patients had high-confidence transcripts elevated that returned to control levels by day 8. Glycolysis genes SLC2A3, HK3, HMGb2, HIF1A, LDHA, PKM and HK2 show statistically significant gene expression over controls. High lactate pyruvate (LP) ratios are indicative of increased glycolysis and we found LP ratios were elevated at 24.4 (P< 0.05) in TBI patients in the first 24 hours compared to 15.1 in control and 14.5 later. Conclusions: In severe TBI, RNA from circulatory WBC revealed increased glycolysis with those transcripts being elevated. This was further associated with an increased serum LP ratio. However, confounders such as hypoxia during resuscitation and tissue hypoxia secondary to local effects could confound findings.

Pelvic radiation therapy is an essential treatment for several pelvic malignancies, but it can lead to radiation cystitis (RC), a severe progressive inflammatory bladder disorder lacking effective diagnosis and therapeutic options. RC evolves through acute, latent, and chronic phases, ultimately resulting in bladder fibrosis, vascular damage, and hematuria. Here, we characterize the molecular and immunological features associated with RC progression using a preclinical mouse model. Building on a prior analysis of the acute and chronic phases, we examined the previously unanalyzed latent phase and integrated transcriptomics, immune cell profiling, inflammatory protein measurements, and bladder function assessments across all stages. Acute radiation injury was marked by the strong activation of apoptotic pathways, whereas latent and chronic phases were dominated by inflammatory signaling with distinct cytokine and chemokine signatures. The persistent upregulation of Cdkn1a (P21) was consistent with sustained senescence-associated signaling, while reductions in IL-27 and shifts in the granulocyte-lymphocyte-enriched immune population during the latent phase were consistent with altered immune regulatory states. At chronic stages, increased SASP-associated proteins and matrix remodeling mediators coincided with bladder functional decline. Together, these findings support a model in which radiation-induced senescence, coupled with immune dysregulation during the latent phase, are coordinated features accompanying inflammation, tissue remodeling, and bladder dysfunction in RC.

Patients with postradical prostatectomy (RP) prostate-specific antigen (PSA) persistence (PPP) have been grouped with patients experiencing biochemical recurrence (BCR) in guidelines and clinical trials, potentially masking their distinct, unfavorable outcomes. The objective of this study was to determine whether patients with PPP constitute a unique, high-risk population. The authors conducted a retrospective study of patients with prostate cancer undergoing RP (between January l, 2013 and June 30, 2024) using the Michigan Urological Surgery Improvement Collaborative (MUSIC) registry. Post-RP status was defined as no evidence of disease (NED; never developed detectable PSA), PPP (first PSA remained detectable), and BCR (initially undetectable PSA with PSA ≥0.2 ng/mL later). The following differences were quantified: (1) pre-RP characteristics, (2) pathologic characteristics at RP, (3) subsequent treatment patterns, and (4) differences in mortality outcomes based on postoperative PSA status. Of 15,390 patients with who had a follow-up of 4.0 years (interquartile range, 2.4-4.6 years), 11,019 still had NED, 1919 had PPP, and 2452 developed BCR. Patients who had PPP demonstrated a higher risk pre-RP and post-RP characteristics compared with those who had NED or BCR on unadjusted and adjusted comparisons, with differences that were both statistically significant and clinically meaningful. Patients who had PP had significantly higher PSA values before secondary treatment compared with those who had BCR (median PSA, 0.73 vs. 0.28 ng/mL, respectively; p<.001). The 5-year all-cause mortality rate was 2.5% (95% confidence interval, 2.1%-2.9%) for patients with initially undetectable PSA (NED and BCR combined) and 5.7% (95% confidence interval, 4.3%-5.7%) for patients with PPP (p<.001). One in eight patients who undergo prostatectomy experience PPP. These patients constitute a unique, high-risk population distinct from patients who have NED and BCR. Clinical trials addressing optimal treatment and intensity for these at-risk patients are critically warranted.

Infertility affects 1 in 6 couples, yet male fertility assessments often rely on semen analysis alone, which has limited predictive value for treatment success. This study evaluates an epigenetic tool for assessing sperm quality, aiming to provide a more comprehensive view of male fertility and improve personalized treatment strategies. De-identified pregnancy outcomes from 537 couples treated at 10 US fertility clinics were analyzed. Partner ages, total motile sperm count, treatment type, and sperm epigenetic quality were considered to assess associations with fertility treatment outcomes. Men with abnormal sperm epigenetic profiles had significantly lower pregnancy success rates with intrauterine insemination (IUI) compared to those with normal profiles, despite similar sperm motility and concentration. In contrast, pregnancy rates did not differ between abnormal and normal profiles among couples undergoing in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI), suggesting that ICSI may overcome sperm epigenetic quality issues. This real-world analysis was limited by the availability of detailed clinical and phenotypic data, which may introduce potential confounders. Nevertheless, the findings highlight the clinical value of epigenetic sperm assessment as part of male fertility evaluation and support its potential to guide more effective, personalized fertility treatment pathways.