Role of environmental variability in the evolution of life history strategies

We reexamine the role of environmental variability in the evolution of life history strategies. We show that normally distributed deviations in the quality of the environment should lead to normally distributed deviations in the logarithm of year-to-year survival probabilities, which leads to interesting consequences for the evolution of annual and perennial strategies and reproductive effort. We also examine the effects of using differing criteria to determine the outcome of selection. Some predictions of previous theory are reversed, allowing distinctions between r and K theory and a theory based on variability. However, these distinctions require information about both the environment and the selection process not required by current theory.     

Safety and biodistribution of 111In-amatuximab in patients with mesothelin expressing cancers using Single Photon Emission Computed Tomography-Computed Tomography (SPECT-CT) imaging

Amatuximab is a chimeric high-affinity monoclonal IgG1/k antibody targeting mesothelin that is being developed for treatment of mesothelin-expressing cancers. Considering the ongoing clinical development of amatuximab in these cancers, our objective was to characterize the biodistribution, and dosimetry of ¹¹¹Indium (¹¹¹In) radiolabelled amatuximab in mesothelin-expressing cancers. Between October 2011 and February 2013, six patients including four with malignant mesothelioma and two with pancreatic adenocarcinoma underwent Single Photon Emission Computed Tomography-Computed Tomography (SPECT/CT) imaging following administration of ¹¹¹In amatuximab. SPECT/CT images were obtained at 2–4 hours, 24–48 hours and 96–168 hours after radiotracer injection. In all patients, tumor to background ratios (TBR) consistently met or exceeded an uptake of 1.2 (range 1.2–62.0) which is considered the minimum TBR that can be visualized. TBRs were higher in tumors of patients with mesothelioma than pancreatic adenocarcinoma. ¹¹¹In-amatuximab uptake was noted in both primary tumors and metastatic sites. The radiotracer dose was generally well-tolerated and demonstrated physiologic uptake in the heart, liver, kidneys and spleen. This is the first study to show tumor localization of an anti-mesothelin antibody in humans. Our results show that ¹¹¹In-amatuximab was well tolerated with a favorable dosimetry profile. It localizes to mesothelin expressing cancers with a higher uptake in mesothelioma than pancreatic cancer.     

Surgical management of hepatocellular carcinoma after Fontan procedure

The Fontan operation has successfully prolonged the lives of patients born with single-ventricle physiology. A long-term consequence of post-Fontan elevation in systemic venous pressure and low cardiac output is chronic liver inflammation and cirrhosis, which lead to an increased risk of hepatocellular carcinoma (HCC). Surgical management of patients with post-Fontan physiology and HCC is challenging, as the requirement for adequate preload in order to sustain cardiac output conflicts with the low central venous pressure (CVP) that minimizes blood loss during hepatectomy. Consequently, liver resection is rarely performed, and most reports describe nonsurgical treatments for locoregional control of the tumors in these patients. Here, we present a multidisciplinary approach to a successful surgical resection of a HCC in a patient with Fontan physiology.     

Hypoxic Preconditioning Alleviates Ethanol Neurotoxicity: The Involvement of Autophagy

Ethanol is a neuroteratogen and neurodegeneration is the most devastating consequence of developmental exposure to ethanol. A sublethal preconditioning has been proposed as a neuroprotective strategy against several central nervous system neurodegenerative diseases. We have recently demonstrated that autophagy is a protective response to alleviate ethanol toxicity. A modest hypoxic preconditioning (1 % oxygen) did not cause neurotoxicity but induced autophagy (Tzeng et al. Free Radic Biol Med 49: 839–846, 2010). We, therefore, hypothesize that the modest hypoxic preconditioning may offer a protection against ethanol-induced neurotoxicity. We showed here that the modest hypoxic preconditioning (1 % oxygen) for 8 h significantly alleviated ethanol-induced death of SH-SY5Y neuroblastoma cells. Under the normoxia condition, cell viability in ethanol-exposed cultures (316 mg/dl for 48 h) was 49 ± 6 % of untreated controls; however, with hypoxic preconditioning, cell viability in the ethanol-exposed group increased to 78 ± 7 % of the controls (p < 0.05; n = 3). Bafilomycin A1, an inhibitor of autophagosome and lysosome fusion, blocked hypoxic preconditioning-mediated protection. Similarly, inhibition of autophagic initiation by wortmannin also eliminated hypoxic preconditioning-mediated protection. In contrast, activation of autophagy by rapamycin further enhanced neuroprotection caused by hypoxic preconditioning. Taken together, the results confirm that autophagy is a protective response against ethanol neurotoxicity and the modest hypoxic preconditioning can offer neuroprotection by activating autophagic pathways.     

Interleukin-7 gene-modified dendritic cells reduce pulmonary tumor burden in spontaneous murine bronchoalveolar cell carcinoma

The antitumor efficiency of dendritic cells transduced with an adenovirus vector expressing interleukin (IL)-7 (DC-AdIL-7) was evaluated in a murine model of spontaneous bronchoalveolar cell carcinoma. These transgenic mice (CC-10 TAg), expressing the SV40 large T antigen under the Clara cell promoter, develop bilateral multifocal pulmonary adenocarcinomas and die at 4 months as a result of progressive pulmonary tumor burden. Injection of DC-AdIL-7 in the axillary lymph node region (ALNR) weekly for 3 weeks led to a marked reduction in tumor burden with extensive lymphocytic infiltration of the tumors and enhanced survival. The antitumor responses were accompanied by the enhanced elaboration of interferon (IFN)-gamma and IL-12 as well as an increase in the antiangiogenic chemokines, IFN-gamma-inducible protein 10 (IP-10/CXCL10) and monokine induced by IFN-gamma (MIG/CXCL9). In contrast, production of the immunosuppressive mediators IL-10, transforming growth factor (TGF)-beta, prostaglandin E(2) (PGE(2)), and the proangiogenic modulator vascular endothelial growth factor (VEGF) decreased in response to DC-AdIL-7 treatment. Significant reduction in tumor burden in a model in which tumors develop in an organ-specific manner provides a strong rationale for further evaluation of DC-AdIL-7 in regulation of tumor immunity and its use in lung cancer genetic immunotherapy.     

SARS-CoV-2 Infections in Vaccinated and Unvaccinated Populations in Camp Lemonnier,Djibouti, from April 2020 to January 2022

The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has highlighted the disparity between developed and developing countries for infectious disease surveillance and the sequencing of pathogen genomes. The majority of SARS-CoV-2 sequences published are from Europe, North America, and Asia. Between April 2020 and January 2022, 795 SARS-CoV-2-positive nares swabs from individuals in the U.S. Navy installation Camp Lemonnier, Djibouti, were collected, sequenced, and analyzed. In this study, we described the results of genomic sequencing and analysis for 589 samples, the first published viral sequences for Djibouti, including 196 cases of vaccine breakthrough infections. This study contributes to the knowledge base of circulating SARS-CoV-2 lineages in the under-sampled country of Djibouti, where only 716 total genome sequences are available at time of publication. Our analysis resulted in the detection of circulating variants of concern, mutations of interest in lineages in which those mutations are not common, and emerging spike mutations.     

Melanoma-Specific Clinical Outcomes of Inpatient Immune Checkpoint Blockade Treatment

BackgroundLittle is known about patient outcomes with advanced melanoma following inpatient initiation or continuation of immune checkpoint blockade (ICB).Methods and ResultsWe conducted a single institution retrospective case series of advanced melanoma patients who initiated ICB as an inpatient (initial inpatient cohort, n = 9), or continued ICB as an inpatient after previously starting as an outpatient (outpatient then inpatient cohort, n = 5). One patient had a partial response to ICB initiated as an inpatient, but ultimately died of melanoma after 13.5 months. Median overall survival for initial inpatient cohort was 1.0 month (95% CI: 0.2-11.2), and 1.4 months (95% CI: 0.4-58.0) for the outpatient then inpatient cohort. Three patients were alive >6 months after inpatient ICB administration.ConclusionDespite overall poor outcomes, some patients may benefit from inpatient ICB. This study provides additional information for clinicians to appropriately counsel patients on expectations following inpatient ICB.