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Oncolytic viral therapy utilizes a tumor-selective replicating virus which preferentially infects and destroys cancer cells and triggers antitumor immunity. The Western Reserve strain of vaccinia virus (VV) is the most virulent strain of VV in animal models and has been engineered for tumor selectivity through two targeted gene deletions (vvDD). We performed the first-in-human phase 1, intratumoral dose escalation clinical trial of vvDD in 16 patients with advanced solid tumors. In addition to safety, we evaluated signs of vvDD replication and spread to distant tumors, pharmacokinetics and pharmacodynamics, clinical and immune responses to vvDD. Dose escalation proceeded without dose-limiting toxicities to a maximum feasible dose of 3 × 109 pfu. vvDD replication in tumors was reproducible. vvDD genomes and/or infectious particles were recovered from injected (n = 5 patients) and noninjected (n = 2 patients) tumors. At the two highest doses, vvDD genomes were detected acutely in blood in all patients while delayed re-emergence of vvDD genomes in blood was detected in two patients. Fifteen of 16 patients exhibited late symptoms, consistent with ongoing vvDD replication. In summary, intratumoral injection of the oncolytic vaccinia vvDD was well-tolerated in patients and resulted in selective infection of injected and noninjected tumors and antitumor activity.

The Palaeocene-Eocene Thermal Maximum ca. 55.93 Ma is considered one of the best geological analogues for worst-case, near-future climate states. During this warming interval, calcareous nannoplankton—critical marine primary producers and important components of the biological pump—experienced significant turnover in community composition, which likely had a major impact on ecosystem function. However, determining the extent of this relationship is complicated by recognized geographic variability in the pattern and magnitude of palaeoecological change, as well as a sampling bias towards lower latitude oceanic sites. In this study, we present new calcareous nannofossil assemblage data from the climatically-sensitive, high latitude south-west Pacific Ocean. Critically, our record shows that major changes in nannoplankton community composition—coincident with a 0.5 ‰ decrease in bulk sediment δ 13 C—preceded the onset of the Palaeocene-Eocene Thermal Maximum by 200 kyr. We suggest this precursor event led to the establishment of a new palaeoecological baseline that caused a relatively muted response of nannofossil assemblages to the main warming event, especially when compared to other high latitude sites. Therefore, our results highlight the importance of examining the influence of local and regional processes on palaeoecological background states when considering geographically heterogenous responses to major global palaeoclimatic events. Localised significant changes in nannofossil assemblage composition took place 200 kyr before the Palaeocene-Eocene Thermal Maximum, according to microfossil analysis from the high-latitude southwest Pacific Ocean.

To fully assess the resilience and recovery of life in response to the Cretaceous–Paleogene (K-Pg) boundary mass extinction ~ 66 million years ago, it is paramount to understand biodiversity prior to the Chicxulub impact event. The peak ring of the Chicxulub impact structure offshore the Yucatán Peninsula (México) was recently drilled and extracted a ~ 100 m thick impact-generated, melt-bearing, polymict breccia (crater suevite), which preserved carbonate clasts with common biogenic structures. We pieced this information to reproduce for the first time the macrobenthic tracemaker community and marine paleoenvironment prior to a large impact event at the crater area by combining paleoichnology with micropaleontology. A variable macrobenthic tracemaker community was present prior to the impact (Cenomanian–Maastrichtian), which included soft bodied organisms such as annelids, crustaceans and bivalves, mainly colonizing softgrounds in marine oxygenated, nutrient rich, conditions. Trace fossil assemblage from these upper Cretaceous core lithologies, with dominant Planolites and frequent Chondrites , corresponds well with that in the overlying post-impact Paleogene sediments. This reveals that the K-Pg impact event had no significant effects (i.e., extinction) on the composition of the macroinvertebrate tracemaker community in the Chicxulub region.

Coccolithophores are a key component of the oceanic food web, and may be sensitive to environmental changes. Modern experiments and an assessment of the fossil record suggest that the response of individual species to a period of ocean acidification in the past may have affected the evolutionary success of these species’ lineages. Coccolithophores—single-celled calcifying phytoplankton—represent an essential footing to marine ecosystems, yet their sensitivity to environmental change, and in particular increases in atmospheric CO 2 , is poorly understood 1 . During the Palaeocene–Eocene Thermal Maximum (PETM), about 56 million years ago, atmospheric CO 2 concentrations rose rapidly and the oceans acidified 2 , 3 , making this an ideal time interval to examine coccolithophore responses to environmental change. Here we compare the results of experiments on modern coccolithophore species with exceptional fossil coccosphere records of the PETM, providing a cellular-level perspective. In modern taxa, we find that during the exponential growth phase of rapid cell division, small cells with few coccoliths are produced, whereas larger cells with more coccoliths are produced during slowed cell division. Applying these diagnostic features to the PETM fossil record, we find that the dominant species exhibited different growth responses to the environmental forcing. Toweius pertusus shows geometry indicative of rapid cell division. In contrast, we suggest that cells of Coccolithus pelagicus grew more slowly during the period of environmental change. In the modern ocean, Emiliania huxleyi , which is closely related to the extinct T. pertusus , is prolific and widespread, whereas C. pelagicus is more limited in range and abundance. We argue that these different responses to environmental change were critical to the post-PETM evolutionary success of the descendants of these taxa.

To compare surgical outcomes in patients undergoing bilateral salpingectomy (salpingectomy group) with those who had partial salpingectomy (partial salpingectomy group) during cesarean delivery. A chart review from July 2015 to November 2016 was performed. We included women who had sterilization during cesarean delivery. We excluded sterilization by occlusive methods. Our primary outcomes were total operative time and a composite score of transfusion rate, internal organ injury, hospital readmission, and endometritis. Secondary outcomes included menstrual abnormalities, pelvic pain, quality of life assessment, and regrets rate. We compared these outcomes between women in the salpingectomy and partial salpingectomy groups. Chi-squared, Fisher's exact, test, and Mann-Whitney were utilized for statistical analysis where appropriate. A <0.05 was considered significant. We included a total of 160 pregnancies. Of these, 41 were in the salpingectomy and 119 in the partial salpingectomy group. The median total operative time was longer for the salpingectomy group (62 [IQR 54, 71] vs 60 minutes [IQR 46, 72]; =0.03). The composite of surgical complications (19.5% vs 12.6%; =0.28) was not significantly different between our study groups. Menstrual irregularities ( ≥0.99), quality of life ( ≥0.99), dyspareunia ( ≥0.99), dysmenorrhea ( =0.36), and regrets ( ≥0.99) were not different between groups. Salpingectomy during cesarean delivery increased the median operative time by 2 minutes and may not be associated with an increased risk of surgical complications. We acknowledge the need for larger multi-center trials to corroborate our outcomes.

We have conducted a phase 1 study of intravenous vvDD, a Western Reserve strain oncolytic vaccinia virus, on 11 patients with standard treatment-refractory advanced colorectal or other solid cancers. The primary endpoints were maximum tolerated dose and associated toxicity while secondary endpoints were pharmacokinetics, pharmacodynamics, immune responses, and antitumor activity. No dose-limiting toxicities and treatment related severe adverse events were observed. The most common adverse events were grades 1/2 flu-like symptoms. Virus genomes were detectable in the blood 15–30 minutes after virus administration in a dose-dependent manner. There was evidence of a prolonged virus replication in tumor tissues in two patients, but no evidence of virus replication in non-tumor tissues, except a healed injury site and an oral thrush. Over 100-fold of anti-viral antibodies were induced in patients' sera. A strong induction of inflammatory and Th1, but not Th2 cytokines, suggested a potent Th1-mediated immunity against the virus and possibly the cancer. One patient showed a mixed response on PET-CT with resolution of some liver metastases, and another patient with cutaneous melanoma demonstrated clinical regression of some lesions. Given the confirmed safety, further trials evaluating intravenous vvDD in combination with therapeutic transgenes, immune checkpoint blockade or complement inhibitors, are warranted.

Calcareous nannoplankton have been one of the dominant primary producers in the surface oceans since the late Triassic. The bolide impact at the Cretaceous/Paleogene (K/Pg) boundary ∼66.0 Ma, led to the elimination of >90% of nannoplankton species: the largest extinction event in their evolutionary history. One of the few nannoplankton genera to survive the K/Pg mass extinction and even thrive in its aftermath was Braarudosphaera, which precipitates pentagonal calcite plates (pentaliths). The only Braarudosphaera species to span the K/Pg boundary (B. bigelowii) is extant and has formed geographically and temporally restricted “blooms” throughout geologic time. Four morphologically and genetically distinct cryptic species of B. bigelowii have been identified in the modern ocean. However, it is uncertain whether these cryptic species have disparate ecophysiological tolerances that have allowed them to adapt to varying environmental conditions. For the first time, we assess changes in the size and shape of Braarudosphaera pentaliths following the K/Pg mass extinction at three geographically and environmentally disparate sites that have early Paleocene Braarudosphaera blooms. Our results show that different Braarudosphaera morphotypes were dominant in the Gulf of Mexico compared with the Tethys Ocean, likely due to regional environmental differences. In addition, we provide evidence that the dominant Braarudosphaera morphotypes shifted in response to changes in upper water column stratification. This ability to rapidly adapt to unstable environments likely helped Braarudosphaera thrive in the aftermath of the K/Pg extinction and explains why this lineage has enjoyed such a long evolutionary history.

Introduction We hypothesized that repeat cytoreductive surgery-hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) for peritoneal metastases (PM) may be associated with suboptimal resection, more frequent postoperative complications, and worse oncologic outcomes. Methods Using a prospectively maintained database, we compared clinicopathologic, perioperative, and oncologic outcome data in patients undergoing single or repeat CRS-HIPEC procedures. The Kaplan–Meier method was used to estimate survival. Multivariate analyses identified associations with perioperative and oncologic outcomes. Results Of the 1294 patients undergoing CRS-HIPEC procedures at our institution, only one CRS-HIPEC procedure (single HIPEC cohort) was performed in 1169 patients (90.3%), whereas 125 patients (9.7%) underwent repeat CRS-HIPEC procedures (repeat HIPEC cohort). Of the 1440 CRS-HIPEC procedures at our institution, a first CRS-HIPEC procedure was performed in 1294 patients (89.9%), whereas subsequent second, third, and fourth CRS-HIPEC procedures were performed in 125 patients (8.7%), 18 patients (1.3%), and 3 patients (0.2%), respectively. Progression-free survival (PFS) following the second CRS-HIPEC procedure was negatively impacted by shorter PFS following the first CRS-HIPEC procedure, independent of other significant variables related to the second procedure, including completeness of cytoreduction and postoperative complications. Patients undergoing multiple CRS-HIPEC procedures were not at higher risk for suboptimal resection or postoperative complications and demonstrated equivalent PFS following each successive procedure compared to the first procedure. Conclusions Repeat CRS-HIPEC procedures for PM were not associated with suboptimal perioperative and oncologic outcomes. Our data confirmed our ability to select patients appropriately for repeat CRS-HIPEC procedures.

BackgroundCRS-HIPEC provides oncologic benefit in well-selected patients with peritoneal carcinomatosis; however, it is a morbid procedure. Decision tools for preoperative patient selection are limited. We developed a risk score to predict severity of 90 day complications for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC).Patients and MethodsAdults who underwent CRS-HIPEC at the University of Pittsburgh Medical Center (March 2001–April 2020) were analyzed as part of this study. Primary endpoint was severe complications within 90 days following CRS-HIPEC, defined using Comprehensive Complication Index (CCI) scores as a dichotomous (determined using restricted cubic splines) and continuous variable. Data were divided into training and test sets. Several machine learning and traditional algorithms were considered.ResultsFor the 1959 CRS-HIPEC procedures included, CCI ranged from 0 to 100 (median 32.0). Adjusted restricted cubic splines model defined severe complications as CCI > 61. A minimum of 20 variables achieved optimal performance of any of the models. Linear regression achieved the highest area under the receiving operator characteristic curve (AUC, 0.74) and outperformed the NSQIP Surgical Risk calculator (AUC 0.80 vs. 0.66). Factors most positively associated with severe complications included peritoneal carcinomatosis index score, symptomatic status, and undergoing pancreatectomy, while American Society of Anesthesiologists 2 class, appendiceal diagnosis, and preoperative albumin were most negatively associated with severe complications.ConclusionsThis study refines our ability to predict severe complications within 90 days of discharge from a hospitalization in which CRS-HIPEC was performed. This advancement is timely and relevant given the growing interest in this procedure and may have implications for patient selection, patient and referring provider comfort, and survival.

The Gulf Stream, a western boundary current transporting warm water into the North Atlantic, plays a key role in climate regulation and oceanographic stability at a regional and global scale as part of the Atlantic Meridional Overturning Circulation (AMOC). Evidence suggests that an ancestral Gulf Stream has existed since the Mesozoic, and it has altered its course repeatedly over Cenozoic times. In this study, we focus on the upper Eocene (Priabonian, ca. 36 Ma) from Ocean Drilling Program Site 1053 on Blake Nose (subtropical North Atlantic). Bulk carbon and oxygen stable isotopes, as well as benthic foraminiferal and calcareous nannofossil assemblages, provide an integrated assessment of the palaeoceanographic changes impacting the area through the water column to the seafloor. Micropaleontological assemblages suggest changes in surface ocean stratification and nutrient supply to the seafloor coeval with a paired negative carbon and oxygen isotope excursion and the return to background conditions higher up in the study section. These transitory changes are compatible with the longitudinal displacement of the proto-Gulf Stream and its related eddies. Our results build on previous work and support the hypothesis that links palaeoceanographic changes in the Blake Nose area with shifts in the proto-Gulf Stream during the middle and late Eocene.