Macrophages mediate the anti-tumor effects of the oncolytic virus HSV1716 in mammary tumors

Oncolytic viruses (OV) have been shown to activate the anti-tumor functions of specific immune cells like T cells. Here, we show OV can also reprogram TAMs to a less immunosuppressive phenotype. Syngeneic, immunocompetent mouse models of primary breast cancer were established using PyMT-TS1, 4T1 and E0771 cell lines and a metastatic model of breast cancer was established using the 4T1 cell line. Tumor growth and overall survival was assessed following intravenous administration of the OV, HSV1716 (a modified herpes simplex virus). Infiltration and function of various immune effector cells was assessed by NanoString, flow cytometry of dispersed tumors and immunofluorescence analysis of tumor sections. HSV1716 administration led to marked tumor shrinkage in primary mammary tumors and a decrease in metastases. This was associated with a significant increase in the recruitment/activation of cytotoxic T cells, a reduction in the presence of regulatory T cells and the reprograming of TAMs towards a pro-inflammatory, less immunosuppressive phenotype. These findings were supported by in vitro data demonstrating that human monocyte-derived macrophages (MDMs) host HSV1716 replication, and that this led to immunogenic macrophage lysis. These events were dependent on macrophage expression of proliferating cell nuclear antigen (PCNA). Finally, the anti-tumor effect of OV was markedly diminished when TAMs were depleted using clodronate liposomes. Together, our results show that TAMs play an essential role in support of the tumoricidal effect of the OV, HSV1716 - they both host viral replication via a novel, PCNA-dependent mechanism and are reprogramed to express a less immunosuppressive phenotype

Reconciling Apparent Conflicts between Mitochondrial and Nuclear Phylogenies in African Elephants

Conservation strategies for African elephants would be advanced by resolution of conflicting claims that they comprise one, two, three or four taxonomic groups, and by development of genetic markers that establish more incisively the provenance of confiscated ivory. We addressed these related issues by genotyping 555 elephants from across Africa with microsatellite markers, developing a method to identify those loci most effective at geographic assignment of elephants (or their ivory), and conducting novel analyses of continent-wide datasets of mitochondrial DNA. Results showed that nuclear genetic diversity was partitioned into two clusters, corresponding to African forest elephants (99.5% Cluster-1) and African savanna elephants (99.4% Cluster-2). Hybrid individuals were rare. In a comparison of basal forest “F” and savanna “S” mtDNA clade distributions to nuclear DNA partitions, forest elephant nuclear genotypes occurred only in populations in which S clade mtDNA was absent, suggesting that nuclear partitioning corresponds to the presence or absence of S clade mtDNA. We reanalyzed African elephant mtDNA sequences from 81 locales spanning the continent and discovered that S clade mtDNA was completely absent among elephants at all 30 sampled tropical forest locales. The distribution of savanna nuclear DNA and S clade mtDNA corresponded closely to range boundaries traditionally ascribed to the savanna elephant species based on habitat and morphology. Further, a reanalysis of nuclear genetic assignment results suggested that West African elephants do not comprise a distinct third species. Finally, we show that some DNA markers will be more useful than others for determining the geographic origins of illegal ivory. These findings resolve the apparent incongruence between mtDNA and nuclear genetic patterns that has confounded the taxonomy of African elephants, affirm the limitations of using mtDNA patterns to infer elephant systematics or population structure, and strongly support the existence of two elephant species in Africa

Evaluation of prognostic risk models for postoperative pulmonary complications in adult patients undergoing major abdominal surgery: a systematic review and international external validation cohort study

Background Stratifying risk of postoperative pulmonary complications after major abdominal surgery allows clinicians to modify risk through targeted interventions and enhanced monitoring. In this study, we aimed to identify and validate prognostic models against a new consensus definition of postoperative pulmonary complications. Methods We did a systematic review and international external validation cohort study. The systematic review was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched MEDLINE and Embase on March 1, 2020, for articles published in English that reported on risk prediction models for postoperative pulmonary complications following abdominal surgery. External validation of existing models was done within a prospective international cohort study of adult patients (≥18 years) undergoing major abdominal surgery. Data were collected between Jan 1, 2019, and April 30, 2019, in the UK, Ireland, and Australia. Discriminative ability and prognostic accuracy summary statistics were compared between models for the 30-day postoperative pulmonary complication rate as defined by the Standardised Endpoints in Perioperative Medicine Core Outcome Measures in Perioperative and Anaesthetic Care (StEP-COMPAC). Model performance was compared using the area under the receiver operating characteristic curve (AUROCC). Findings In total, we identified 2903 records from our literature search; of which, 2514 (86·6%) unique records were screened, 121 (4·8%) of 2514 full texts were assessed for eligibility, and 29 unique prognostic models were identified. Nine (31·0%) of 29 models had score development reported only, 19 (65·5%) had undergone internal validation, and only four (13·8%) had been externally validated. Data to validate six eligible models were collected in the international external validation cohort study. Data from 11 591 patients were available, with an overall postoperative pulmonary complication rate of 7·8% (n=903). None of the six models showed good discrimination (defined as AUROCC ≥0·70) for identifying postoperative pulmonary complications, with the Assess Respiratory Risk in Surgical Patients in Catalonia score showing the best discrimination (AUROCC 0·700 [95% CI 0·683–0·717]). Interpretation In the pre-COVID-19 pandemic data, variability in the risk of pulmonary complications (StEP-COMPAC definition) following major abdominal surgery was poorly described by existing prognostication tools. To improve surgical safety during the COVID-19 pandemic recovery and beyond, novel risk stratification tools are required. Funding British Journal of Surgery Society

Slow continuous intracorporeal plasmapheresis for acute fluid overload

Intermittent dialysis is still the predominant treatment for acute or chronic renal insufficiency in the USA despite increasing evidence that slower and longer fluid management therapies are more beneficial to the patient. We have investigated the use of slow continuous intracorporeal plasmapheresis (SCIP) as a more efficient and hemodynamically stable alternative means of treating acute fluid overload. In this paper we discuss preliminary observations on the safety of SCIP catheter insertion, fluid removal, extraction and pathology in Yorkshire pigs. SCIP catheters removed plasma for extracorporeal plasma water removal without significant gross or histopathological changes. Blood chemistry and cell counts remained stable during therapy. Toxicological studies indicated no pyrogenicity, hemolysis, cytotoxicity, acute systemic toxicity, delayed-type hypersensitivity, or blood recalcification coagulation inhibition. Intracutaneous extracts caused only mild irritation. SCIP therapy appears to be safe for use in the removal of plasma and plasma water from experimental animals. Copyright (C) 2003 S. Karger AG, Basel

Intravenous catheter for intracorporeal plasma filtration

Future advances in dialysis of end-stage renal disease patients may include improvements in therapeutic continuity and patient mobility. Continuous renal replacement therapies could lead to self-contained, mobile and potentially wearable dialysis units. We investigated an experimental, intravenous slow-continuous plasma separation system (IPSS) as a precursor to direct intravenous hemofiltration. An intracorporeal catheter employs asymmetric hollow fibers to separate blood cells from plasma in vivo. The fibers possess a sieving coefficient of 0.7 mum and remove 99.99% of all platelets. In vivo, catheters sustain an average plasma separation flow rate of 3 ml/min over 22 h, sufficient to remove 2 net liters of water from pigs through an extracorporeal hemofilter. Used catheter fibers are relatively free of protein deposition or clots in situ. In vitro studies suggest that human catheters may perform at 3-4 times the rate of porcine catheters. IPSS is proposed for acute fluid removal in CHF patients refractory to diuretics. Copyright (C) 2002 S. Karger AG, Basel

Slow continuous intravenous plasmapheresis (SCIPTM): Clinical applications and hemostability of extracorporeal ultrafiltration

An intravenous plasmapheresis catheter which excludes > 99.4% of platelets from external ultrafiltration circuits is currently undergoing safety and efficacy trials for fluid removal from NYHA class II-IV congestive heart failure patients resistant to diuretic drug therapy. In animals, the SCIPTM catheter allowed a four fold increase in ultrafiltration efficiency without hemolysis, hermoinstability or external cartridge changes in 72 hours of treatment. Further, systemic anticoagulation was not required. These techniques might be envisioned for treatment of fluid overload in heart failure, surgery or trauma and may have applications in therapeutic apheresis, venous thrombosis, liver disease or autologous tissue engineering. Copyright (c) 2005 S, Karger AG. Hasel