Citations

Abstract Oligodendroglioma is a subtype of diffuse glioma defined by a mutation in the isocitrate dehydrogenase (IDH) genes and a co-deletion of chromosome arms 1p and 19q. These tumors primarily occur in adult patients in their third and fourth decade of life and are universally fatal due to an inevitable recurrence that follows a treatment regimen of surgical resection and an optional combination of alkylating chemotherapy and/or radiation therapy. While initially slow growing, recurrent tumors exhibit increasingly aggressive phenotypes that become progressively more difficult to treat with conventional therapy. Currently, the molecular mechanisms and cellular phenotypes that drive this recurrence remain unknown. To understand these factors, we assembled a cohort of matched initial and recurrent oligodendroglioma samples from over 100 patients and performed whole-genome sequencing and whole-exome sequencing on each of them. To link these molecular profiles to cell state changes, we additionally performed bulk and single-nucleus RNA-sequencing on a subset of these tumor pairs. In nearly 40% of alkylating chemotherapy-treated patients, recurrent tumors presented with hypermutation that corresponded with an increase in neoplastic cell proliferation. Additionally, while individual somatic alterations specific to recurrence were relatively rare, we observed a subset of tumors that acquired deletions in the cell cycle regulator CDKN2A following treatment with radiotherapy. Acquisition of either of these features associated with shorter patient survival and higher grade at recurrence, implicating cell cycle dysregulation as a mechanism of treatment resistance and increased tumor severity. Together, these results indicate that oligodendrogliomas evolve in a treatment-specific manner following chemo- and radiation therapy and highlight key pathways that can be targeted to delay the onset of recurrence.

Abstract Exposure of biological systems to acute or chronic insults triggers a host of molecular and physiological responses to either tolerate, adapt, or fully restore homeostasis; these responses constitute the hallmarks of resilience. Given the many facets, dimensions, and discipline‐specific focus, gaining a shared understanding of “resilience” has been identified as a priority for supporting advances in cardiovascular health. This report is based on the working definition: “ Resilience is the ability of living systems to successfully maintain or return to homeostasis in response to physical, molecular, individual, social, societal, or environmental stressors or challenges ,” developed after considering many factors contributing to cardiovascular resilience through deliberations of multidisciplinary experts convened by the National Heart, Lung, and Blood Institute during a workshop entitled: “ Enhancing Resilience for Cardiovascular Health and Wellness.” Some of the main emerging themes that support the possibility of enhancing resilience for cardiovascular health include optimal energy management and substrate diversity, a robust immune system that safeguards tissue homeostasis, and social and community support. The report also highlights existing research challenges, along with immediate and long‐term opportunities for resilience research. Certain immediate opportunities identified are based on leveraging existing high‐dimensional data from longitudinal clinical studies to identify vascular resilience measures, create a ‘resilience index,’ and adopt a life‐course approach. Long‐term opportunities include developing quantitative cell/organ/system/community models to identify resilience factors and mechanisms at these various levels, designing experimental and clinical interventions that specifically assess resilience, adopting global sharing of resilience‐related data, and cross‐domain training of next‐generation researchers in this field.

Abstract Atherosclerotic renal artery stenosis (ARAS) is associated with irreversible parenchymal renal disease and regenerative stem cell therapies may improve renal outcomes. Hypoxia preconditioning (HPC) may improve the regenerative functions of adipose tissue-derived mesenchymal stem cells (AMSC) by affecting DNA 5-hydroxymethylcytosine (5hmC) marks in angiogenic genes. Here, we investigated using a porcine ARAS model, whether growth of ARAS AMSCs in hypoxia (Hx) versus normoxia (Nx) would enhance renal tissue repair, and comprehensively analyze how HPC modifies DNA hydroxymethylation compared to untreated ARAS and healthy/normal pigs (n=5 each). ARAS pigs exhibited elevated serum cholesterol, serum creatinine and renal artery stenosis, with a concomitant decrease in renal blood flow (RBF) and increased blood pressure (BP) compared to healthy pigs. Renal artery injection of either autologous Nx or Hx AMSCs improved diastolic BP, reduced kidney tissue fibrosis, and inflammation (CD3+ T-cells) in ARAS pigs. In addition, renal medullary hypoxia significantly lowered with Nx but not Hx AMSC treatment. Mechanistically, levels of epigenetic 5hmC marks (which reflect gene activation) estimated using DNA immunoprecipitation technique were elevated in profibrotic and inflammatory genes in ARAS compared with normal AMSCs. HPC significantly reduced 5hmC levels in cholesterol biosynthesis and oxidative stress response pathways in ARAS AMSCs. Thus, autologous AMSCs improve key renovascular parameters and inflammation in ARAS pigs, with HPC mitigating pathological molecular effects on inflammatory and profibrotic genes which may play a role in augmenting regenerative capacity of AMSCs.

BACKGROUND: Several collateral venous pathways exist to assist in cranial venous drainage in addition to the internal jugular veins. The important extrajugular networks (EJN) are often readily identified on diagnostic cerebral angiography. However, the angiographic pattern of venous drainage through collateral EJN has not been previously compared among patients with and without idiopathic intracranial hypertension (IIH). OBJECTIVE: To quantify EJN on cerebral angiography among patients both with and without IIH and to determine whether there is a different EJN venous drainage pattern in patients with IIH. METHODS: Retrospective imaging review of 100 cerebral angiograms (50 IIH and 50 non-IIH patients) and medical records from a single academic medical center was performed by 2 independent experienced neuroendovascular surgeons. Points were assigned to EJN flow from 0 to 6 using an increasing scale (with each patient's dominant internal jugular vein standardized to 5 points to serve as the internal reference). Angiography of each patient included 11 separately graded extrajugular networks for internal carotid and vertebral artery injections. RESULTS: Patients in the IIH group had statistically significant greater flow in several of the extrajugular networks. Therefore, they preferentially drained through EJN compared with the non-IIH group. Right transverse-sigmoid system was most often dominant in both groups, yet there was a significantly greater prevalence of codominant sinus pattern on posterior circulation angiograms. CONCLUSION: Patients with IIH have greater utilization of EJN compared with patients without IIH. Whether this is merely an epiphenomenon or possesses actual cause-effect relationships needs to be determined with further studies.

Abstract Background To evaluate the early functional and oncological outcomes of single-port robot-assisted perineal radical prostatectomy (sp-pRARP) using the da Vinci XI system, and analyze its learning curve using the cumulative sum (CUSUM) method. Methods The clinical data of 50 patients who underwent sp-pRARP for localized prostate cancer between May 2020 and May 2022 in our center by a single surgeon were analyzed retrospectively. Demographic information, preoperative and postoperative variables, complications, early functional and oncological outcomes of patients were recorded. The CUSUM method was used to illustrate the learning curve based on operation time. Results All surgeries were completed without conversion. The median (interquartile range, IQR) operation time was 205.0 (82.5) min, whereas the median (IQR) docking time was 30.0 (15.0) min and the console time was 120.0 (80.5) min. The median (IQR) estimated blood loss (EBL) was 50.0 (137.5) mL. Positive surgical margins were detected in five patients (10.0%). The continence rate was 40.9%, 63.6%, 88.4%, 97.7% at the 1, 3, 6 and 12 months after surgery. According to the CUSUM plot, the inflection points of the learning curve were 20 cases, splitting the case series into "early phase" and "late phase." In "late phase" cases, there was less time spent on each step of the operation and less EBL. Conclusions Sp-pRARP using the da Vinci XI system was verified to be a feasible and reliable surgical approach. According to the CUSUM plot, 20 cases was considered the turning point for surgeons to master the novel technique.

Autophagy eliminates excessive nutrients and maintains homeostasis. Obesity and metabolic syndrome (MetS) dysregulate autophagy, possibly partly due to mitochondria injury and inflammation. Elamipretide (ELAM) improves mitochondrial function. We hypothesized that MetS blunts kidney autophagy, which ELAM would restore. Domestic pigs were fed a control or MetS-inducing diet for 16 weeks. During the 4 last weeks, MetS pigs received subcutaneous injections of ELAM (0.1 mg/kg/day, MetS + ELAM) or vehicle (MetS), and kidneys were then harvested to measure protein expression of autophagy mediators and apoptosis. Systemic and renal venous levels of inflammatory cytokines were measured to calculate renal release. The function of isolated mitochondria was assessed by oxidative stress, energy production, and pro-apoptotic activity. MetS slightly downregulated renal expression of autophagy mediators including p62, ATG5-12, mTOR, and AMPK vs. control. Increased mitochondrial H2O2 production accompanied decreased ATP production, elevated apoptosis, and renal fibrosis. In MetS + ELAM, mito-protection restored autophagic protein expression, improved mitochondrial energetics, and blunted renal cytokine release and fibrosis. In vitro, mitoprotection restored mitochondrial membrane potential and reduced oxidative stress in injured proximal tubular epithelial cells. Our study suggests that swine MetS mildly affects renal autophagy, possibly secondary to mitochondrial damage, and may contribute to kidney structural damage in MetS.

BACKGROUND: Current literature has identified textbook outcome (TO) as a quality metric after cancer surgery. We studied whether TO after pancreatic resection has a stronger association with long-term survival than individual hospital case volume. STUDY DESIGN: Patients undergoing surgery for pancreatic adenocarcinoma from 2010 to 2015 were identified from the National Cancer Database. Hospitals were stratified by volume (low less than 6, medium 6 to 19, and high 20 cases or more per year), and overall survival data were abstracted. We defined TO as adequate lymph node count, negative margins, length of stay less than the 75th percentile, appropriate systemic therapy, timely systemic therapy, and without a mortality event or readmission within 30 days. The association of TO and case volume was assessed using a multivariable Cox regression model for survival. RESULTS: Overall, 7270 patients underwent surgery, with 30.7%, 48.7%, and 20.6% performed at low-, medium-, and high-volume hospitals, respectively. Patients treated at low-volume hospitals were more likely to be Black, be uninsured or on Medicaid, have higher Charlson comorbidity scores, and be less likely to achieve TO (23.4% TO achievement vs 37.5% achievement at high-volume hospitals). However, high hospital volume was no longer associated with overall survival once TO was added to the multivariable model stratified by volume status. Achievement of TO corresponded to a 31% decrease in mortality (hazard ratio 0.69; p < 0.001), independent of hospital volume. CONCLUSIONS: Improved long-term survival after pancreatic resection was associated with TO rather than high hospital volume. Quality improvement efforts focused on TO criteria have the potential to improve outcomes irrespective of case volume.