Citations

Abstract Glioblastomas (GBM) are routinely treated with ionizing radiation (IR) but inevitably recur and develop therapy resistance. During treatment, the tissue surrounding tumors is also irradiated. IR potently induces senescence, and senescent stromal cells can promote the growth of neighboring tumor cells by secreting factors that create a senescence-associated secretory phenotype (SASP). Here, we carried out transcriptomic and tumorigenicity analyses in irradiated mouse brains to elucidate how radiotherapy-induced senescence of non-neoplastic brain cells promotes tumor growth. Following cranial irradiation, widespread senescence in the brain occurred, with the astrocytic population being particularly susceptible. Irradiated brains showed an altered transcriptomic profile characterized by upregulation of CDKN1A (p21), a key enforcer of senescence, and several SASP factors, including HGF, the ligand of the receptor tyrosine kinase (RTK) Met. Preirradiation of mouse brains increased Met-driven growth and invasiveness of orthotopically implanted glioma cells. Importantly, irradiated p21−/− mouse brains did not exhibit senescence and consequently failed to promote tumor growth. Senescent astrocytes secreted HGF to activate Met in glioma cells and to promote their migration and invasion in vitro, which could be blocked by HGF-neutralizing antibodies or the Met inhibitor crizotinib. Crizotinib also slowed the growth of glioma cells implanted in preirradiated brains. Treatment with the senolytic drug ABT-263 (navitoclax) selectively killed senescent astrocytes in vivo, significantly attenuating growth of glioma cells implanted in preirradiated brains. These results indicate that SASP factors in the irradiated tumor microenvironment drive GBM growth via RTK activation, underscoring the potential utility of adjuvant senolytic therapy for preventing GBM recurrence after radiotherapy. Significance: This study uncovers mechanisms by which radiotherapy can promote GBM recurrence by inducing senescence in non-neoplastic brain cells, suggesting that senolytic therapy can blunt recurrent GBM growth and aggressiveness.

Abstract While chronological age is one of the most influential determinants of post-stroke outcomes, little is known of the impact of neuroimaging-derived biological brain age. We here first examine whether radiomics analysis of the texture of brain T2-FLAIR MRI images can be used to predict brain age in stroke patients. We then assess the clinical determinants of accelerated brain aging and, finally, its impact on post-stroke functional outcomes. Leveraging a multisite cohort of 4,163 ischemic stroke patients, we show that older-appearing patients have more hypertension, diabetes mellitus, prior strokes, and smoking history and are more likely to develop worse post-stroke outcomes than their younger-appearing counterparts. Our results strengthen the importance of preventive medicine for maintaining brain health in stroke patients as they age and suggest a novel methodology to capture previously undescribed prognostic information available on commonly acquired MRI sequences during routine stroke care.

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.

Objectives We investigated haemodynamics and clinical outcomes according to type of pulmonary hypertension (PH) in patients with constrictive pericarditis (CP). Background As the prevalence of CP with concomitant myocardial disease (mixed CP) grows, PH is more commonly seen in patients with CP. However, haemodynamic and outcome data according to the presence or absence of PH are limited. Methods 150 patients with surgically confirmed CP who underwent echocardiography and cardiac catheterisation within 7 days at two tertiary centres were divided into three groups: no-PH, isolated postcapillary PH (Ipc-PH) and combined postcapillary and precapillary PH (Cpc-PH). Primary outcome was all-cause mortality during follow-up. Result In this retrospective cohort study, 110 (73.3%) had PH (mean pulmonary artery pressure ≥25 mm Hg). Cpc-PH, using defined cut-offs for pulmonary vascular resistance (>3 Wood units) or diastolic pulmonary gradient (≥7 mm Hg), was seen in 18 patients (12%). The Cpc-PH group had a higher prevalence of comorbidities (diabetes and atrial fibrillation) and concomitant myocardial disease as an aetiology of CP than other groups. Pulmonary vascular resistance had a significant direct correlation with medial E/e′ by Doppler echocardiography (r=0.404, p<0.001). Survival rate was significantly lower in the Cpc-PH than the no-PH (p=0.002) and Ipc-PH (p=0.024) groups. On multivariable analysis, age, New York Heart Association functional class IV, medial e′ velocity, Cpc-PH and Ipc-PH were independently associated with long-term mortality. Conclusion Combined postcapillary and precapillary PH develops in a subset of patients with CP and is associated with long-term mortality after pericardiectomy.

Backgrounds: Left ventricular torsion (LVtor) is an integral part of systole and untwisting plays an important role in diastole. The aim of this study was to characterize LVtor and untwisting in different grades of diastolic dysfunction. Methods: We studied 135 patients with normal LV EF with various grades of diastolic dysfunction (40 group1:mild,42 group 2:moderate,and 22 group 3:severe dysfunction) and 31 controls with normal diastolic function. Apical and basal short axis rotations were measured by 2D STE. LVtor was defined as net difference between apical and basal rotation. Results: Age, gender, and EF were similar in 3 groups and control. Mitral annulus early diastolic velocity was reduced in all 3 groups (see table ). Peak LVtor was significantly greater in group 1 compared with control, group 2 and group 3. The time from peak LVtor to Mitral valve opening, and to peak early diastolic velocity were significantly delayed in group 1 compared to control (p=0.0030 and 0.0409, respectively). The twisting rate and untwisting rate were found to be highest in group 1. Conclusions: Systolic torsion and diastolic untwisting are significantly increased in patients with mild diastolic dysfunction. In patients with advanced diastolic dysfunction with increased filling pressure, torsion and untwisting are normalized. Hence, vigorous LV torsion appears to be a compensatory mechanism during an early stage of diastolic dysfunction to maintain normal filling in the setting of reduced longitudinal myocardial motion.

Background: Patients with sinus node dysfunction (SND) are at increased risk of atrial tachyarrhythmias, including atrial fibrillation (AF). Whether the presence of SND is also associated with worse outcomes among those with AF has not been well described. Methods: The ORBIT-AF registry enrolled patients with AF from a range of clinical practices across the US. SND was defined clinically, based on the presence of sinus bradycardia, severe sinus bradycardia, sinus arrest, sinoatrial exit block, or features of tachycardia-bradycardia syndrome. Descriptive statistics and multivariable logistic regression analysis were used to describe treatment patterns and outcomes for patients with and without SND and AF. Results: Overall, 1,710 (17.7%) patients had SND at enrollment. Patients with SND had lower left-ventricular ejection fractions, higher CHA 2 DS 2 -VASc risk scores, and more prior cerebrovascular events. Patients with SND had more severe symptoms (EHRA class IV: 17.5% vs. 13.9%; p=0.007) and poorer quality of life (median AFEQT 77.5 vs. 81.1; p=0.008) as compared to those without. SND patients were more frequently treated with oral anticoagulants (79.2% vs. 75.9%, p=0.004) and had more often received interventional therapy for AF (16.1% vs. 10.5%, p<0.0001). There were no differences in the current AF management strategy between patients with SND and those without [rate control (69.7% vs. 67.7%), rhythm control (30.0% vs. 32.0%); P=0.11]. After adjustment, significantly more patients with SND had progressed from paroxysmal AF at baseline to persistent or permanent AF at any follow-up or persistent AF at baseline to permanent AF at any follow-up than those without (OR 1.23, 95% CI 1.01-1.49, p=0.035). Conclusion: Sinus node dysfunction is associated worse symptoms, lower quality of life, and higher risk of progression to permanent AF. However, SND is not associated with increased risk of all-cause hospitalization, incident stroke, or all-cause death.

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.

OBJECTIVE Scoliosis is common in patients with Chiari malformation type I (CM-I)–associated syringomyelia. While it is known that treatment with posterior fossa decompression (PFD) may reduce the progression of scoliosis, it is unknown if decompression with duraplasty is superior to extradural decompression. METHODS A large multicenter retrospective and prospective registry of 1257 pediatric patients with CM-I (tonsils ≥ 5 mm below the foramen magnum) and syrinx (≥ 3 mm in axial width) was reviewed for patients with scoliosis who underwent PFD with or without duraplasty. RESULTS In total, 422 patients who underwent PFD had a clinical diagnosis of scoliosis. Of these patients, 346 underwent duraplasty, 51 received extradural decompression alone, and 25 were excluded because no data were available on the type of PFD. The mean clinical follow-up was 2.6 years. Overall, there was no difference in subsequent occurrence of fusion or proportion of patients with curve progression between those with and those without a duraplasty. However, after controlling for age, sex, preoperative curve magnitude, syrinx length, syrinx width, and holocord syrinx, extradural decompression was associated with curve progression > 10°, but not increased occurrence of fusion. Older age at PFD and larger preoperative curve magnitude were independently associated with subsequent occurrence of fusion. Greater syrinx reduction after PFD of either type was associated with decreased occurrence of fusion. CONCLUSIONS In patients with CM-I, syrinx, and scoliosis undergoing PFD, there was no difference in subsequent occurrence of surgical correction of scoliosis between those receiving a duraplasty and those with an extradural decompression. However, after controlling for preoperative factors including age, syrinx characteristics, and curve magnitude, patients treated with duraplasty were less likely to have curve progression than patients treated with extradural decompression. Further study is needed to evaluate the role of duraplasty in curve stabilization after PFD.