Type I interferon signaling induces a delayed antiproliferative response in respiratory epithelial cells during SARS-CoV-2 infection.

ABSTRACT: Disease progression during SARS-CoV-2 infection is tightly linked to the fate of lung epithelial cells, with severe cases of COVID-19 characterized by direct injury of the alveolar epithelium and an impairment in its regeneration from progenitor cells. The molecular pathways that govern respiratory epithelial cell death and proliferation during SARS-CoV-2 infection, however, remain unclear. We now report a high-throughput CRISPR screen for host genetic modifiers of the survival and proliferation of SARS-CoV-2-infected Calu-3 respiratory epithelial cells. The top four genes identified in our screen encode components of the same type I interferon (IFN-I) signaling complex­IFNAR1, IFNAR2, JAK1, and TYK2. The fifth gene, ACE2, was an expected control encoding the SARS-CoV-2 viral receptor. Surprisingly, despite the antiviral properties of IFN-I signaling, its disruption in our screen was associated with an increase in Calu-3 cell fitness. We validated this effect and found that IFN-I signaling did not sensitize SARS-CoV-2-infected cultures to cell death but rather inhibited the proliferation of surviving cells after the early peak of viral replication and cytopathic effect. We also found that IFN-I signaling alone, in the absence of viral infection, was sufficient to induce this delayed antiproliferative response in both Calu-3 cells and iPSC-derived type 2 alveolar epithelial cells. Together, these findings highlight a cell autonomous antiproliferative response by respiratory epithelial cells to persistent IFN-I signaling during SARS-CoV-2 infection. This response may contribute to the deficient alveolar regeneration that has been associated with COVID-19 lung injury and represents a promising area for host-targeted therapeutic development.

A specific EMC subunit supports Dengue virus infection by promoting virus membrane fusion essential for cytosolic genome delivery.

Dengue virus (DENV) represents the most common human arboviral infection, yet its cellular entry mechanism remains unclear. The multi-subunit endoplasmic reticulum membrane complex (EMC) supports DENV infection, in part, by assisting the biosynthesis of viral proteins critical for downstream replication steps. Intriguingly, the EMC has also been shown to act at an earlier step prior to viral protein biogenesis, although this event is not well-defined. Here we demonstrate that the EMC subunit EMC4 promotes fusion of the DENV and endosomal membranes during entry, enabling delivery of the viral genome into the cytosol which is then targeted to the ER for viral protein biosynthesis. We also found that EMC4 mediates ER-to-endosome transfer of phosphatidylserine, a phospholipid whose presence in the endosome facilitates DENV-endosomal membrane fusion. These findings clarify the EMC-dependent DENV early entry step, suggesting a mechanism by which an ER-localized host factor can regulate viral fusion at the endosome.

Identification of cell type specific ACE2 modifiers by CRISPR screening.

SARS-CoV-2 infection is initiated by binding of the viral spike protein to its receptor, ACE2, on the surface of host cells. ACE2 expression is heterogeneous both in vivo and in immortalized cell lines, but the molecular pathways that govern ACE2 expression remain unclear. We now report high-throughput CRISPR screens for functional modifiers of ACE2 surface abundance. In liver-derived HuH7 cells, we identified 35 genes whose disruption was associated with a change in the surface abundance of ACE2. Enriched among these ACE2 regulators were established transcription factors, epigenetic regulators, and functional networks. We further characterized individual HuH7 cell lines with disruption of SMAD4, EP300, PIAS1, or BAMBI and found these genes to regulate ACE2 at the mRNA level and to influence cellular susceptibility to SARS-CoV-2 infection. Orthogonal screening of lung-derived Calu-3 cells revealed a distinct set of ACE2 modifiers comprised of ACE2, KDM6A, MOGS, GPAA1, and UGP2. Collectively, our findings clarify the host factors involved in SARS-CoV-2 entry, highlight the cell type specificity of ACE2 regulatory networks, and suggest potential targets for therapeutic development.

Development of a Novel Protocol for Germline Testing in Pancreatic Cancer.

BACKGROUND: Guidelines now recommend universal germline genetic testing (GGT) for all pancreatic ductal adenocarcinoma (PDAC) patients. Testing provides information on actionable pathogenic variants and guides management of patients and family. Since traditional genetic counseling (GC) models are time-intensive and GC resources are sparse, new approaches are needed to comply with guidelines without overwhelming available resources. METHODS: A novel protocol was developed for physician-led GGT. Completed test kits were delivered to the GC team, who maintained a prospective database and mailed all orders. If results revealed pathogenic variants for PDAC, patients were offered comprehensive GC, whereas negative and variant of uncertain significance (VUS) test results were reported to patients via brief calls. RESULTS: During protocol implementation between January 2020 and December 2022, 310 (81.5%) patients underwent GGT, with a physician compliance rate of 82.6% and patient compliance rate of 98.7%. Of 310 patients tested, 44 (14.2%) patients had detection of pathogenic variants, while 83 (26.8%) patients had VUS. Pathogenic variants included BRCA1/BRCA2/PALB2 (n = 18, 5.8%), ATM (n = 9, 2.9%), CFTR (n = 4, 1.3%), EPCAM/MLH1/MSH2/MSH6/PMS2 (n = 3, 1.0%), and CDKN2A (n = 2, 0.7%). The GC team successfully contacted all patients with pathogenic variants to discuss results and offer comprehensive GC. CONCLUSION: Our novel protocol facilitated GGT with excellent compliance despite limited GC resources. This framework for GGT allocates GC resources to those patients who would benefit most from GC. As we continue to expand the program, we seek to implement methods to ensure compliance with cascade testing of high-risk family members.

Multidisciplinary Delphi Consensus on Safety of Combining Transarterial Radioembolization with Yttrium-90 Microspheres with Systemic Anticancer Agents for the Treatment of Liver Malignancy.

PURPOSE: To provide guidance, via multidisciplinary consensus statements, on the safety interactions between systemic anticancer agents (such as radiosensitizing chemotherapy, immunotherapy, targeted therapy, and peptide receptor radionuclide therapy) and transarterial radioembolization (TARE) with yttrium-90 (90Y)-labeled microspheres in the treatment of primary and metastatic liver malignancies. MATERIALS AND METHODS: A literature search identified 59 references that informed 26 statements on the safety of 90Y TARE combined with systemic therapies. Modified Delphi method was used to develop consensus on statements through online anonymous surveys of the 12 panel members representing the fields of interventional radiology, medical oncology, surgical oncology, hepatology, and pharmacy, focusing on hepatocellular carcinoma (HCC), metastatic colorectal cancer (mCRC), neuroendocrine tumors, metastatic breast cancer, and intrahepatic cholangiocarcinoma. RESULTS: High-level evidence was limited. Level 1 data in patients with mCRC suggest that some radiosensitizing chemotherapies (eg, oxaliplatin) require temporary dose reduction when used concomitantly with 90Y TARE, and some targeted therapies (eg, vascular endothelial growth factor inhibitors and antiangiogenic tyrosine kinase inhibitors) should be avoided for at least 4 weeks before 90Y TARE. In patients with HCC, the feasibility of 90Y TARE and immunotherapy has been demonstrated with Level 4 evidence. Data are more limited for other primary and secondary liver malignancies, and consensus statements were driven by expert opinion (Level 5). CONCLUSIONS: Given the absence of evidence-based guidelines on the safety of 90Y TARE in combination with systemic anticancer therapy, these consensus statements provide expert guidance on the potential risks when considering specific combinations.

A robust evaluation of 49 high-dose-rate prostate brachytherapy treatment plans including all major uncertainties.

BACKGROUND: Uncertainties in radiotherapy cause deviation from the planned dose distribution and may result in delivering a treatment that fails to meet clinical objectives. The impact of uncertainties is unique to the patient anatomy and the needle locations in HDR prostate brachytherapy. Evaluating this impact during treatment planning is not common practice, relying on margins around the target or organs-at-risk to account for uncertainties. PURPOSE: A robust evaluation framework for HDR prostate brachytherapy treatment plans was evaluated on 49 patient plans, measuring the range of possible dosimetric outcomes to the patient due to 14 major uncertainties. METHODS: Patient plans were evaluated for their robustness to uncertainties by simulating probable uncertainty scenarios. Five-thousand probabilistic and 1943 worst-case scenarios per patient were simulated by changing the position and size of structures and length of dwell times from their nominal values. For each uncertainty scenario, the prostate D90 and maximum doses to the urethra, D0.01cc , and rectum, D0.1cc , were calculated. RESULTS: The D90 was an average 1.16 ± 0.51% (mean ± SD) below nominal values for the probabilistic scenarios; the D0.01cc metric was 2.24 ± 0.90% higher; and D0.1cc was greater by 0.48 ± 0.30%. The D0.01cc and D90 metrics were more sensitive to uncertainties than D0.1cc , with a median of 79.0% and 84.9% of probabilistic scenarios passing the constraints, compared to 96.5%. The median pass-rate for scenarios that passed all three metrics simultaneously was 63.4%. CONCLUSIONS: Assessing treatment plan robustness improves plan quality assurance, is achievable in less than 1-min, and identifies treatment plans with poor robustness, allowing re-optimization before delivery.

Effect of Previous Transarterial Chemoembolization on Survival and Toxicity after Yttrium-90 Transarterial Radioembolization of Hepatocellular Carcinoma in the Radiation-Emitting SIR-Spheres in Nonresectable Liver Tumor Registry.

PURPOSE: To determine overall survival (OS), best response, and toxicities in patients with hepatocellular carcinoma (HCC) previously treated with chemoembolization (TACE+) or yttrium-90 resin transarterial radioembolization (TARE) compared with those of TACE-naïve (T-N) participants. MATERIALS AND METHODS: In this prospective, observational study, 262 adult participants with HCC were divided into TACE+ (n = 93, 35%) or T-N (n = 169, 65%) groups, included from 36 centers in the United States. Overall survival (OS) was assessed using Kaplan-Meier analysis from the date of TARE. Best response at 6 months was evaluated using modified Response Evaluation Criteria in Solid Tumors. Six-month toxicities were reported using Common Terminology Criteria for Adverse Events, version 5. RESULTS: Median OS for patients in the TACE+ and T-N groups was 22.3 months (95% CI: 17.2 to not reachable) and 21.5 months (95% confidence interval [CI]: 14.9-29.9), respectively (P = .6). Imaging at 6 months ± 2 weeks was available in 156 of 262 (60%) participants. Partial or complete response was seen in 27 of 55 patients (49%) in the TACE+ group and 65 of 101 patients (64%) in the T-N group (P = .2). Six-month toxicities were available in 69 of 93 patients (74%) in the TACE+ group and 135 of 167 patients (81%) in the T-N group. Attributable Grade 3 or greater liver function toxicities were similar between the study groups (all P > .05). CONCLUSIONS: OS and imaging response at 6 months in the TACE+ group was similar to that in the T-N group with similar toxicities. Radioembolization is an acceptable treatment option for patients with HCC previously treated with TACE.

Survival and Toxicities after Yttrium-90 Transarterial Radioembolization of Cholangiocarcinoma in the RESiN Registry.

PURPOSE: To report outcomes in patients with intrahepatic cholangiocarcinoma treated with yttrium-90 resin microspheres (transarterial radioembolization [TARE]) from a multicenter, prospective observational registry. MATERIALS AND METHODS: Ninety-five patients (median age, 67 years [interquartile range {IQR}, 59-74]; 50 men) were treated in 27 centers between July 2015 and August 2020. Baseline demographic characteristics included imaging findings, performance status, and previous systemic or locoregional treatments. Dosimetry method was tracked. Overall survival (OS) and progression-free survival were calculated using the Kaplan-Meier method. The best imaging response was calculated using the Response Evaluation Criteria in Solid Tumors v1.1. Grade ≥3 toxicities were assessed using Common Terminology Criteria for Adverse Events v5. Cox regression analysis was performed. RESULTS: Fifty-two of 86 (60%) patients had multifocal tumors, and 24/89 (27%) had extrahepatic tumors. The median index tumor diameter was 7.0 cm (IQR, 4.9-10 cm). The activity calculation method was reported in 59/95 (62%) patients, with body surface area being the most frequently used method (45/59, 76%). Median OS for the cohort was 14 months (95% confidence interval, 12-22). OS at 3, 6, 12, and 24 months was 94%, 80%, 63%, and 34%, respectively. Median OS was longer in patients without cirrhosis (19.1 vs 12.2 months, P = .05). Cirrhosis, previous chemotherapy (OS, 19.1 vs 10.6 months for treatment-naïve; P = .07), and imaging response at 6 months (OS, 16.4 vs 9.5 months for no response; P = .06) underwent regression analysis. Imaging response predicted OS at regression (hazard ratio, 0.39; P = .008). Grade 3-4 bilirubin toxicities were noted in 5 of 72 (7%) patients. Grade 3 albumin toxicity was noted in 1 of 72 (1.4%) patients. CONCLUSIONS: Objective response at 6 months predicted longer OS after TARE for intrahepatic cholangiocarcinoma. The incidence of liver function toxicity was <10%.

Survival and Toxicities after 90Y Transarterial Radioembolization of Metastatic Colorectal Cancer in the RESIN Registry.

Background Patients with unresectable, chemorefractory hepatic metastases from colorectal cancer have considerable mortality. The role of transarterial radioembolization (TARE) with yttrium 90 (90Y) microspheres is not defined because most reports are from a single center with limited patient numbers. Purpose To report outcomes in participants with colorectal cancer metastases treated with resin 90Y microspheres from a prospective multicenter observational registry. Materials and Methods This study treated enrolled adult participants with TARE using resin microspheres for liver-dominant metastatic colorectal cancer at 42 centers, with enrollment from July 2015 through August 2020. TARE was used as the first-, second-, or third-line therapy or beyond. Overall survival (OS), progression-free survival (PFS), and toxicity outcomes were assessed by line of therapy by using Kaplan-Meier analysis for OS and PFS and Common Terminology Criteria for Adverse Events, version 5, for toxicities. Results A total of 498 participants (median age, 60 years [IQR, 52-69 years]; 298 men [60%]) were treated. TARE was used in first-line therapy in 74 of 442 participants (17%), second-line therapy in 180 participants (41%), and third-line therapy or beyond in 188 participants (43%). The median OS of the entire cohort was 15.0 months (95% CI: 13.3, 16.9). The median OS by line of therapy was 13.9 months for first-line therapy, 17.4 months for second-line therapy, and 12.5 months for third-line therapy (χ2 = 9.7; P = .002). Whole-group PFS was 7.4 months (95% CI: 6.4, 9.5). The median PFS by line of therapy was 7.9 months for first-line therapy, 10.0 months for second-line therapy, and 5.9 months for third-line therapy (χ2 = 8.3; P = .004). TARE-attributable grade 3 or 4 hepatic toxicities were 8.4% for bilirubin (29 of 347 participants) and 3.7% for albumin (13 of 347). Grade 3 and higher toxicities were greater with third-line therapy for bilirubin (P = .01) and albumin (P = .008). Conclusion Median overall survival (OS) after transarterial radioembolization (TARE) with yttrium 90 microspheres for liver-dominant metastatic colorectal cancer was 15.0 months. The longest OS was achieved when TARE was part of second-line therapy. Grade 3 or greater hepatic function toxicity rates were less than 10%. Clinical trial registration no. NCT02685631 Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Liddell in this issue.

Long-term outcomes following 90Y Radioembolization of neuroendocrine liver metastases: evaluation of the radiation-emitting SIR-spheres in non-resectable liver tumor (RESiN) registry.

BACKGROUND: The goal of this study was to evaluate efficacy and safety of 90Y radioembolization for neuroendocrine liver metastases (NELM) in a multicenter registry. METHODS: One hundred-seventy patients with NELM were enrolled in the registry (NCT02685631). Prior treatments included hepatic resection (n = 23, 14%), arterial therapy (n = 62, 36%), octreotide (n = 119, 83%), cytotoxic chemotherapy (n = 58, 41%), biologic therapy (n = 49, 33%) and immunotherapy (n = 10, 6%). Seventy-seven (45%) patients had extrahepatic disease. Seventy-eight (48%), 61 (37%), and 25 (15%) patients were Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or ≥ 2. Tumor grade was known in 81 (48%) patients: 57 (70%) were well-, 12 (15%) moderate-, and 12 (15%) poorly-differentiated. Kaplan-Meier analysis and log rank tests were performed to compare overall and progression-free survival (OS/PFS) by tumor location and grade. Toxicities were reported using Common Terminology Criteria for Adverse Events v.5. Cox Proportional Hazards were calculated for pancreatic primary, performance status, extrahepatic disease at treatment, unilobar treatment, baseline ascites, and > 25% tumor burden. RESULTS: One, 2, and 3-year OS rates were 75, 62 and 46%, respectively. Median OS was 33 months [(95% CI: 25-not reached (NR)]. The longest median OS was in patients with pancreatic (42 months, 95% CI: 33-NR) and hindgut 41 months, 95% CI: 12-NR) primaries. The shortest OS was in foregut primaries (26 months; 95% CI: 23-NR; X2 = 7, p = 0.1). Median OS of well-differentiated tumors was 36 months (95% CI: 10-NR), compared to 44 (95% CI: 7-NR) and 25 (95% CI: 3-NR) months for moderate and poorly differentiated tumors. Median progression-free survival (PFS) was 25 months with 1, 2, and 3-year PFS rates of 70, 54, and 35%, respectively. Thirteen patients (7.6%) developed grade 3 hepatic toxicity, most commonly new ascites (n = 8, 5%) at a median of 5.5 months. Performance status of ≥2 (HR 2.7, p = 0.01) and baseline ascites (HR 2.8, P = 0.049) predicted shorter OS. DISCUSSION: In a population with a high incidence of extrahepatic disease, 90Y was effective and safe in treatment of NELM, with median OS of 41 months for well differentiated tumors. Grade 3 or greater hepatic toxicity was developed in 7.6% of patients. TRIAL REGISTRATION: NCT02685631 .

Overall survival and toxicity of Y90 radioembolization for hepatocellular carcinoma patients in Barcelona Clinic Liver Cancer stage C (BCLC-C).

INTRODUCTION: National Comprehensive Cancer Network HCC guidelines recommend Y90 to treat BCLC-C patients only in select cases given the development of systemic regimens. We sought to identify ideal candidates for Y90 by assessing survival and toxicities in this patient group. MATERIALS AND METHODS: The Radiation-Emitting Selective Internal radiation spheres in Non-resectable tumor registry is a prospective observational study (NCT: 02,685,631). Patients with advanced HCC were stratified into 3 groups based on tumor location, Eastern Cooperative Oncology Group (ECOG) performance status, and liver function. Group 1: liver isolated HCC, ECOG 0 and Child Pugh (CP) A (n = 12, 16%), Group 2: liver isolated HCC, ECOG ≥ 1 or CP B/C (n = 37, 49%), and Group 3: extrahepatic HCC with any ECOG or CP score (n = 26, 35%). Patients in any group could have macrovascular invasion. Overall survival (OS) and progression-free survival (PFS) with 95% confidence intervals (95% CI) were calculated. Grade 3 + toxicities were tracked using Common Terminology Criteria for Adverse Events v5. Cox proportional hazard model was performed to determine factors affecting OS. RESULTS: Seventy-five BCLC-C patients treated between 2015 and 2019 were reviewed. The groups were similar in age, sex, race, and ethnicity (all p > 0.05). Bilobar disease was least common in Group 1 (p < 0.001). Median OS of the entire cohort was 13.6 (95% CI 7.5-16.1) months. Median OS of Groups 1-3 were 21.8, 13.1 and 11.5 months respectively (p = 0.6). Median PFS for the cohort was 6.3 (4.8-14.7) months. Median PFS for group 1 was not reached. Mean PFS for Group 1 was 17.3 ± 4.8 months. Median PFS for Groups 2 and 3 was 6.8 and 5.9 months (X2 = 1.5, p = 0.5). Twenty-four Grade 3 or greater toxicities developed, most commonly hyperbilirubinemia (8/75, 11%) and thrombocytopenia (2/75, 3%). The incidence of toxicities between groups was similar (all p > 0.05). Cox Proportional Hazard analysis predicted shorter OS with CP class B/C (X2 = 6.7, p = 0.01), while macrovascular invasion (X2 = 0.5, p = 0.5) and ECOG score of ≥ 1 (X2 = 2.1, p = 0.3) was not associated with OS. CONCLUSIONS: OS of CPA patients with advanced HCC and performance status of 0 was 21.8 months following Y90. CP A cirrhosis is the best predictor of prolonged OS in advanced (BCLC-C) HCC.

International recommendations for personalised selective internal radiation therapy of primary and metastatic liver diseases with yttrium-90 resin microspheres.

PURPOSE: A multidisciplinary expert panel convened to formulate state-of-the-art recommendations for optimisation of selective internal radiation therapy (SIRT) with yttrium-90 (90Y)-resin microspheres. METHODS: A steering committee of 23 international experts representing all participating specialties formulated recommendations for SIRT with 90Y-resin microspheres activity prescription and post-treatment dosimetry, based on literature searches and the responses to a 61-question survey that was completed by 43 leading experts (including the steering committee members). The survey was validated by the steering committee and completed anonymously. In a face-to-face meeting, the results of the survey were presented and discussed. Recommendations were derived and level of agreement defined (strong agreement ≥ 80%, moderate agreement 50%-79%, no agreement ≤ 49%). RESULTS: Forty-seven recommendations were established, including guidance such as a multidisciplinary team should define treatment strategy and therapeutic intent (strong agreement); 3D imaging with CT and an angiography with cone-beam-CT, if available, and 99mTc-MAA SPECT/CT are recommended for extrahepatic/intrahepatic deposition assessment, treatment field definition and calculation of the 90Y-resin microspheres activity needed (moderate/strong agreement). A personalised approach, using dosimetry (partition model and/or voxel-based) is recommended for activity prescription, when either whole liver or selective, non-ablative or ablative SIRT is planned (strong agreement). A mean absorbed dose to non-tumoural liver of 40 Gy or less is considered safe (strong agreement). A minimum mean target-absorbed dose to tumour of 100-120 Gy is recommended for hepatocellular carcinoma, liver metastatic colorectal cancer and cholangiocarcinoma (moderate/strong agreement). Post-SIRT imaging for treatment verification with 90Y-PET/CT is recommended (strong agreement). Post-SIRT dosimetry is also recommended (strong agreement). CONCLUSION: Practitioners are encouraged to work towards adoption of these recommendations.

Multicenter Evaluation of Survival and Toxicities of Hepatocellular Carcinoma following Radioembolization: Analysis of the RESiN Registry.

PURPOSE: To determine overall survival (OS), progression-free survival (PFS), and toxicity in patients with hepatocellular carcinoma (HCC) in a multicenter, real-world data registry using transarterial radioembolization (TARE) with resin microspheres. MATERIALS AND METHODS: A total of 448 patients with HCC were treated at 36 centers between 2015 and 2019. Treatment history, baseline laboratory and imaging, and treatment goal were assessed. OS and PFS were stratified using Barcelona Clinic Liver Cancer (BCLC) and Child-Pugh (CP) classifications. Kaplan-Meier analyses compared OS and PFS with 95% confidence intervals. Transplants were tracked. Toxicities were assessed using Common Terminology Criteria for Adverse Events v5. Cox proportional hazard of baseline demographics assessed factors affecting survival. RESULTS: Prior chemoembolization and systemic therapy were used in 107 (26%) and 68 (16%) patients, respectively. Using the BCLC staging system, 66 patients (19%) were BCLC A and 202, 51, and 26 were BCLC B, C, and D, respectively. Median OS for patients with BCLC A disease was not achieved at 30 months. Median OS for patients with BCLC B, C, and D disease were 19.5, 13.6, and 11.5 months, respectively (P = .0006). Median PFS for patients with BCLC A, B, C, and D were 19.8, 10.0, 6.3, and 5.9 months, respectively (P = .003). Twenty patients underwent transplantation, representing 14 of 43 (33%) and 6 of 28 (21%) patients who underwent bridging and downstaging therapy, respectively. Common Grade 3 toxicities were encephalopathy (11/448, 2.5%), hyperbilirubinemia (10/448, 2.2%), and ascites (9/448, 2.0%). Factors predicting longer survival included CP A (χ2 = 4.2, P = .04) and BCLC A (χ2 = 5.2, P = .02). CONCLUSIONS: In a frequently pretreated patient cohort with disease burden in 81% beyond the Milan criteria, TARE with resin microspheres provided OS comparable to other studies in this multicenter registry.

Storm Waves May Be the Source of Some "Tsunami" Coastal Boulder Deposits.

Coastal boulder deposits (CBD) provide what are sometimes the only remaining signatures of wave inundation on rocky coastlines; in recent decades, CBD combined with initiation of motion (IoM) analyses have repeatedly been used as primary evidence to infer the existence of ancient tsunamis. However, IoM storm wave heights inferred by these studies have been shown to be highly inaccurate, bringing some inferences into question. This work develops a dimensionless framework to relate CBD properties with storm-wave hindcasts and measurements, producing data-driven relations between wave climate and boulder properties. We present an elevation-density-size-inland distance-wave height analysis for individual storm-transported boulders which delineates the dynamic space where storm-wave CBD occur. Testing these new relations against presumed tsunami CBD demonstrates that some fall well within the capabilities of storm events, suggesting that some previous studies might be fruitfully reexamined within the context of this new framework.

Critical Appraisal of the Impact of Oesophageal Stents in the Management of Oesophageal Anastomotic Leaks and Benign Oesophageal Perforations: An Updated Systematic Review.

INTRODUCTION: Endoscopic placement of oesophageal stents may be used in benign oesophageal perforation and oesophageal anastomotic leakage to control sepsis and reduce mortality and morbidity by avoiding thoracotomy. This updated systematic review aimed to assess the safety and effectiveness of oesophageal stents in these two scenarios. METHODS: A systematic literature search of all published studies reporting use of metallic and plastic stents in the management of post-operative anastomotic leaks, spontaneous and iatrogenic oesophageal perforations were identified. Primary outcomes were technical (deploying ≥ 1 stent to occlude site of leakage with no evidence of leakage of contrast within 24-48 h) and clinical success (complete healing of perforation or leakage by placement of single or multiple stents irrespective of whether the stent was left in situ or was removed). Secondary outcomes were stent migration, perforation and erosion, and mortality rates. Subgroup analysis was performed for plastic versus metallic stents and anastomotic leaks versus perforations separately. RESULTS: A total of 66 studies (n = 1752 patients) were included. Technical and clinical success rates were 96% and 87%, respectively. Plastic stents had significantly higher migration rates (24% vs 16%, p = 0.001) and repositioning (11% vs 3%, p < 0.001) and lower technical success (91% vs 95%, p = 0.032) than metallic stents. In patients with anastomotic leaks, plastic stents were associated with higher stent migration (26% vs 15%, p = 0.034), perforation (2% vs 0%, p = 0.013), repositioning (10% vs 0%, p < 0.001), and lower technical success (95% vs 100%, p = p = 0.002). In patients with perforations only, plastic stents were associated with significantly lower technical success (85% vs 99%, p < 0.001). CONCLUSIONS: Covered metallic oesophageal stents appear to be more effective than plastic stents in the management of oesophageal perforation and anastomotic leakage. However, quality of evidence of generally poor and high-quality randomised trial is needed to further evaluate best management option for oesophageal perforation and anastomotic leakage.

Drugging the methylome: DNA methylation and memory.

Over the past decade, since epigenetic mechanisms were first implicated in memory formation and synaptic plasticity, dynamic DNA methylation reactions have been identified as integral to long-term memory formation, maintenance, and recall. This review incorporates various new findings that DNA methylation mechanisms are important regulators of non-Hebbian plasticity mechanisms, suggesting that these epigenetic mechanisms are a fundamental link between synaptic plasticity and metaplasticity. Because the field of neuroepigenetics is so young and the biochemical tools necessary to probe gene-specific questions are just now being developed and used, this review also speculates about the direction and potential of therapeutics that target epigenetic mechanisms in the central nervous system and the unique pharmacokinetic and pharmacodynamic properties that epigenetic therapies may possess. Mapping the dynamics of the epigenome in response to experiential learning, even a single epigenetic mark in isolation, remains a significant technical and bioinformatic hurdle facing the field, but will be necessary to identify changes to the methylome that govern memory-associated gene expression and effectively drug the epigenome.

DNA methylation and its implications and accessibility for neuropsychiatric therapeutics.

In this review, we discuss the potential pharmacological targeting of a set of powerful epigenetic mechanisms: DNA methylation control systems in the central nervous system (CNS). Specifically, we focus on the possible use of these targets for novel future treatments for learning and memory disorders. We first describe several unique pharmacological attributes of epigenetic mechanisms, especially DNA cytosine methylation, as potential drug targets. We then present an overview of the existing literature regarding DNA methylation control pathways and enzymes in the nervous system, particularly as related to synaptic function, plasticity, learning and memory. Lastly, we speculate upon potential categories of CNS cognitive disorders that might be amenable to methylomic targeting.

High-throughput cellular RNA device engineering.

Methods for rapidly assessing sequence-structure-function landscapes and developing conditional gene-regulatory devices are critical to our ability to manipulate and interface with biology. We describe a framework for engineering RNA devices from preexisting aptamers that exhibit ligand-responsive ribozyme tertiary interactions. Our methodology utilizes cell sorting, high-throughput sequencing and statistical data analyses to enable parallel measurements of the activities of hundreds of thousands of sequences from RNA device libraries in the absence and presence of ligands. Our tertiary-interaction RNA devices performed better in terms of gene silencing, activation ratio and ligand sensitivity than optimized RNA devices that rely on secondary-structure changes. We applied our method to build biosensors for diverse ligands and determine consensus sequences that enable ligand-responsive tertiary interactions. These methods advance our ability to develop broadly applicable genetic tools and to elucidate the underlying sequence-structure-function relationships that empower rational design of complex biomolecules.

Prevention and treatment of complications of selective internal radiation therapy: Expert guidance and systematic review.

Selective internal radiation therapy (or radioembolization) by intra-arterial injection of radioactive yttrium-90-loaded microspheres is increasingly used for the treatment of patients with liver metastases or primary liver cancer. The high-dose beta-radiation penetrates an average of only 2.5 mm from the source, thus limiting its effects to the site of delivery. However, the off-target diversion of yttrium-90 microspheres to tissues other than the tumor may lead to complications. The most prominent of these complications include radiation gastritis and gastrointestinal ulcers, cholecystitis, radiation pneumonitis, and radioembolization-induced liver disease, which may occur despite careful pretreatment planning. Thus, selective internal radiation therapy demands an expert multidisciplinary team approach in order to provide comprehensive care for patients. This review provides recommendations to multidisciplinary teams on the optimal medical processes in order to ensure the safe delivery of selective internal radiation therapy. Based on the best available published evidence and expert opinion, we recommend the most appropriate strategies for the prevention, early diagnosis, and management of potential radiation injury to the liver and to other organs. (Hepatology 2017;66:969-982).

Autosomal dominant retinitis pigmentosa rhodopsin mutant Q344X drives specific alterations in chromatin complex gene transcription.

Purpose: Epigenetic and transcriptional mechanisms have been shown to contribute to long-lasting functional changes in adult neurons. The purpose of this study was to identify any such modifications in diseased retinal tissues from a mouse model of rhodopsin mutation-associated autosomal dominant retinitis pigmentosa (ADRP), Q344X, relative to age-matched wild-type (WT) controls. Methods: We performed RNA sequencing (RNA-seq) at poly(A) selected RNA to profile the transcriptional patterns in 3-week-old ADRP mouse model rhodopsin Q344X compared to WT controls. Differentially expressed genes were determined by DESeq2 using the Benjamini & Hochberg p value adjustment and an absolute log2 fold change cutoff. Quantitative western blots were conducted to evaluate protein expression levels of histone H3 phosphorylated at serine 10 and histone H4. qRT-PCR was performed to validate the expression patterns of differentially expressed genes. Results: We observed significant differential expression in 2151 genes in the retina of Q344X mice compared to WT controls, including downregulation in the potassium channel gene, Kcnv2, and differential expression of histone genes, including the H1 family histone member, H1foo; the H3 histone family 3B, H3f3b; and the histone deacetylase 9, Hdac9. Quantitative western blots revealed statistically significant decreased protein expression of both histone H3 phosphorylated at serine 10 and histone H4 in 3-week-old Q344X retinas. Furthermore, qRT-PCR performed on select differentially expressed genes based on our RNA-seq results revealed matched expression patterns of up or downregulation. Conclusions: These findings provide evidence that transcriptomic alterations occur in the ADRP mouse model rhodopsin Q344X retina and that these processes may contribute to the dysfunction and neurodegeneration seen in this animal model.