Citations

Background: Acute cellular rejection is a major determinant of mortality and retransplantation after heart transplantation. We sought to evaluate the prognostic implications of coronary microcirculatory dysfunction assessed by index of microcirculatory resistance (IMR) for the risk of acute cellular rejection after heart transplantation. Methods: The present study prospectively enrolled 154 heart transplant recipients who underwent scheduled coronary angiography and invasive coronary physiological assessment 1 month after transplantation. IMR is microcirculatory resistance under maximal hyperemia. By measuring hyperemic mean transit time using 3 injections (4 mL each) of room-temperature saline under maximal hyperemia, IMR was calculated as hyperemic distal coronary pressure×hyperemic mean transit time. The primary end point was biopsy-proven acute cellular rejection of grade ≥2R during 2 years of follow-up after transplantation and was compared by using multivariable Cox proportional hazards regression according to IMR. The incremental prognostic value of IMR, in addition to the model with clinical factors, was evaluated by comparison of C-index, net reclassification index, and integrated discrimination index. Results: The mean age of recipients was 51.2±13.1 years (81.2% male), and the cumulative incidence of acute cellular rejection was 19.0% at 2 years. Patients with acute cellular rejection had significantly higher IMR values at 1 month than those without acute cellular rejection (23.1±8.6 versus 16.8±11.1, P =0.002). IMR was significantly associated with the risk of acute cellular rejection (per 5-U increase: adjusted hazard ratio, 1.18 [95% CI, 1.04–1.34], P =0.011) and the optimal cutoff value of IMR to predict acute cellular rejection was 15. Patients with IMR≥15 showed significantly higher risk of acute cellular rejection than those with IMR<15 (34.4% versus 3.8%; adjusted hazard ratio, 15.3 [95% CI 3.6–65.7], P <0.001). Addition of IMR to clinical variables showed significantly higher discriminant and reclassification ability for risk of acute cellular rejection (C-index 0.87 versus 0.74, P <0.001; net reclassification index 1.05, P <0.001; integrated discrimination index 0.20, P <0.001). Conclusions: Coronary microcirculatory dysfunction assessed by IMR measured early after heart transplantation showed significant association with the risk of acute cellular rejection. In addition to surveillance endomyocardial biopsy, early stratification using IMR could be a clinically useful tool to identify patients at higher risk of future acute cellular rejection after heart transplantation. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02798731.

Targeting the main protease of SARS-CoV-2 Inside host cells, the RNA genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is translated into two polyproteins that are cleaved to give the individual viral proteins. The main viral protease, known as Mpro or 3CLpro, plays a key role in these cleavages, making it an important drug target. Drayman et al . identified eight drugs that target 3CLpro from a library of 1900 clinically safe drugs. Because of the challenge of working with SARS-CoV-2, they started by screening for drugs that inhibit the replication of a human coronavirus that causes the common cold. They then evaluated the top hits for inhibiting SARS-CoV-2 replication and for inhibiting 3CLpro. Masitinib, a broad antiviral, inhibited the main proteases of coronaviruses and picornaviruses and was effective in reducing SARS-CoV-2 replication in mice. —VV

AbstractBackgroundPositron emission tomography (PET)‐based measures of baseline total‐body tumor burden may improve risk stratification in intermediate‐risk Hodgkin lymphoma (HL).Materials and methodsEvaluable patients were identified from a cohort treated homogeneously with the same combined modality regimen on the Children's Oncology Group AHOD0031 study. Eligible patients had high‐quality baseline PET scans. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were each measured based on 15 thresholds for every patient. Univariate and multivariable Cox regression and Kaplan–Meier survival analyses assessed for an association of MTV and TLG with event‐free survival (EFS).ResultsFrom the AHOD0031 cohort (n = 1712), 86 patients were identified who (i) were treated with four cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide (ABVE‐PC) chemotherapy followed by involved field radiotherapy, and (ii) had a baseline PET scan that was amenable to quantitative analysis. Based on univariate Cox regression analysis, six PET‐derived parameters were significantly associated with EFS. For each of these, Kaplan–Meier analyses and the log‐rank test were used to compare patients with highest tumor burden (i.e., highest 15%) to the remainder of the cohort. EFS was significantly associated with all six PET parameters (all p < .029). In a multivariable model controlling for important covariates including disease bulk and response to chemotherapy, MTV2BP was significantly associated with EFS (p = .012).ConclusionMultiple baseline PET‐derived volumetric parameters were associated with EFS. MTV2BP was highly associated with EFS when controlling for disease bulk and response to chemotherapy. Incorporation of baseline MTV into risk‐based treatment algorithms may improve outcomes in intermediate‐risk HL.

Background: Previous observational studies have demonstrated that outcomes after OHCA can be significantly improved with therapies such as mild therapeutic hypothermia and percutaneous coronary intervention (PCI). However, the optimal candidate and timing for PCI in OHCA remains unknown. This study aimed to assess the impact of emergent PCI on survival and neurological outcome after OHCA. Methods: This is a prospective observational study from a statewide OHCA database in Arizona. Patients included were greater than 18 years old who received CPR and were admitted to one of 34 recognized cardiac receiving centers. Patients who did not achieve ROSC, died within 2 hours of hospital arrival, and DNAR patients were excluded since the likelihood of PCI impacting outcome in these patients is questionable. An in-hospital post-arrest database, including PCI (Y/N), was linked with an Utstein-style OHCA database. Univariate and multivariate logistic regression were utilized to assess the association between PCI and survival to hospital discharge and neurological outcome. Results: During this study period (1-1-2011-12-31-2013), there were a total of 6,543 adult OHCA patients. After exclusions, 782 patients with suspected cardiac etiology OHCA were analyzed. The median age of patients was 64.0 years (Q1:54.0, Q3:73.0) and 70.2% were male. Among them 458 (58.6%) and 238 (30.4%) patients underwent the emergency coronary angiogram (CAG), and Primary PCI, respectively. Among PCI patients, the rate of survival to hospital discharge was 75.2%, vs. 60.4% for those without PCI (p<0.001) and good cerebral outcome (CPC 1-2) was found in 67.6%, vs. 44.3% of those without PCI (p<0.001). After adjusting for age, gender, initial rhythm, bystander CPR, and hypothermia, the Odds Ratio was 1.2 (95% CI:0.8-1.8) for survival and 2.8 (95% CI:1.5-5.1) for good neurologic outcome (CPC 1-2) among PCI patients. Conclusion: This study shows an association with emergent PCI and good neurologic outcome after OHCA. Further study is necessary to determine a potential causal relationship between PCI and outcome.

Abstract Cisplatin chemotherapy, although efficacious in resolution of cancer, potentiates cognitive impairments (known as chemobrain) affecting approximately 14 million cancer survivors in the United States. Cisplatin is a frontline chemotherapy used to treat ovarian, testicular, breast and brain cancers. Despite the high prevalence of clinical reports of cognitive impairments during and following chemotherapy, there is little information on how learning/memory are detrimentally affected and no known cure. To elucidate the mechanisms by which chemobrain impairs cognition, we implemented a mouse model resembling intermittent cisplatin chemotherapy in humans. Our preliminary studies revealed that repeated intermittent cisplatin treatment detrimentally affects the structure of neuronal brain cells in the hippocampus, a brain region known for its ability to control learning/memory, emotional behaviors and motor function. Although the molecular pathways vulnerable to cisplatin in the brain remain elusive, gene sequencing from the hippocampus of mice administered cisplatin identified the adenosine A2A receptor (Adora2a) protein was concentrated in elevated quantities in this brain region. Importantly, the Adora2a receptor protein is known for its critical role in learning/memory and has been found to play a role in neurodegenerative conditions. To investigate Adora2a functionality in cisplatin-induced chemobrain, we assessed the efficacy of the non-selective Adora2a antagonist caffeine, in preventing cisplatin-induced cognitive dysfunction. Caffeine was selected as a therapeutic due to its safe pharmacological profile, its universal availability, and low cost. Our translational approach employing the non-selective Adora2a antagonist caffeine, protected against cisplatin-induced body weight deficits and motor dysfunction, both of which are common clinical symptoms of chemotherapy. Interestingly, relative to cisplatin alone, mice treated with caffeine in combination with cisplatin exhibited improved dendritic spine densities in the hippocampus, suggesting improved neuronal morphology by caffeine. Given that Adora2a antagonists are known to enhance anti-tumor activity while also showing neuroprotective promise in neurodegenerative conditions, inhibiting Adora2a during cancer treatment may have far-reaching synergistic effects on quality of life improvement for cancer survivors. Citation Format: Alfredo Oliveros, Ana M. Corujo-Ramirez, Ki-Hyun Yoo, Jason Tang, Danielle Brogren, Mohammad A. Rashid, Yuanhang Liu, Mi-Hyeon Jang. Adora2a inhibition via caffeine as a novel therapeutic target for cisplatin-induced chemobrain [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3115.

Although hepatitis B virus (HBV) integration into the cellular genome is well known in HCC (hepatocellular carcinoma) patients, its biological role still remains uncertain. This study investigated the patterns of HBV integration and correlated them with TERT (telomerase reverse transcriptase) alterations in paired tumor and non-tumor tissues. Compared to those in non-tumors, tumoral integrations occurred less frequently but with higher read counts and were more preferentially observed in genic regions with significant enrichment of integration into promoters. In HBV-related tumors, TERT promoter was identified as the most frequent site (38.5% (10/26)) of HBV integration. TERT promoter mutation was observed only in tumors (24.2% (8/33)), but not in non-tumors. Only 3.00% (34/1133) of HBV integration sites were shared between tumors and non-tumors. Within the HBV genome, HBV breakpoints were distributed preferentially in the 3’ end of HBx, with more tumoral integrations detected in the preS/S region. The major genes that were recurrently affected by HBV integration included TERT and MLL4 for tumors and FN1 for non-tumors. Functional enrichment analysis of tumoral genes with integrations showed enrichment of cancer-associated genes. The patterns and functions of HBV integration are distinct between tumors and non-tumors. Tumoral integration is often enriched into both human-virus regions with oncogenic regulatory function. The characteristic genomic features of HBV integration together with TERT alteration may dysregulate the affected gene function, thereby contributing to hepatocarcinogenesis.

Introduction: Left ventricular assist device (LVAD) is known to extend survival in patients with advanced heart failure but it is associated with intracranial cranial hemorrhage (ICH). In the last decade, the use of LVAD substantially increased along with advances in LVAD technology, but there is limited data regarding the trends of ICH risk and predictors in patients with LVAD. Methods: We included the patients aged≥18 years with primary diagnosis of LVAD hospitalized in the US from 2005 to 2014 using the National Inpatient Sample. We computed the survey weighted percentages with ICH across the 10-year study period and assessed whether the proportions changed over time. Predictors of ICH were evaluated using the multivariable logistic regression model. All analyses were appropriately adjusted for the survey design variables to account for the complex survey design. Results: Of 33,246 hospitalizations, 568 (1.7%) had ICH. The number of LVAD placement has increased from 873 in year 2005 to 5,175 in year 2014. However, the risk of ICH remained largely unchanged from 1.7% to 2.3% (linear trend: p=0.604). The adjusted odds of ICH was increased with the presence one of the following variables: female sex (odds ratio [OR]: 1.58, 95% confidence interval [CI] 1.03-2.43), history of ischemic stroke (OR: 3.13, 95% CI 1.86-5.28), and Charlson Comorbidity Index (CCI) of ≥3 (OR: 77.40, 95% CI 10.03-597.60). Conclusions: Despite advances in LVAD technology and its increased use in patients with advanced heart failure, the risk of ICH has remained relatively unchanged. High CCI and history of ischemic stroke were associated with higher odds of ICH in patients with LVAD. With the advent of magnetically levitated centrifugal-flow LVAD, future trend of ICH may change and further research efforts are needed to prevent ICH in patients with LVAD.

Gastric cancer (GC) is the fifth most common cancer globally. Secreted frizzled-related proteins (SFRP) are important elements associated with the Wnt signaling pathway, and its dysregulated expression is found in multiple cancers. However, the function of distinct SFRPs in GC remains poorly understood. We investigated the differential expression, prognostic value, and immune cell infiltration of SFRPs in gastric cancer patients from the Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, Kaplan–Meier plotter, cBioPortal, STRING, Gene-MANIA, DAVID, MethSurv, and TIMER databases. We found that the expression levels of SFRP2 and SFRP4 were significantly increased in GC tissues, whereas the SFRP1 and SFRP5 expressions were reduced. SFRP1, SFRP2, and SFRP5 were significantly correlated with the clinical cancer stage in GC patients. Higher expression of SFRPs was associated with short overall survival (OS) in GC patients. Besides, high SFRPs methylation showed favorable OS in GC patients. The functions of SFRPs were primarily related to the Wnt signaling pathway, immune system development, and basal cell carcinoma. The expression of SFRPs was strongly correlated with immune infiltrating cells, including CD4+ T cells and macrophages in GC. Our study indicated that SFRPs could be potential targets of precision therapy and prognostic biomarkers for the survival of GC patients.