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Abstract We conducted a systematic review and meta-analysis of randomized control trials to formally assess the safety and efficacy of autologous whole cell vaccines as immunotherapies for solid tumors. Our primary safety outcome was number, and grade of adverse events. Our primary efficacy outcome was clinical responses. Secondary outcomes included survival metrics and correlative immune assays. We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for studies published between 1946 and August 2020 using any autologous whole cell product in the treatment of any solid tumor. The Cochrane Randomized Controlled Trial risk of bias tool was used to assess risk of bias. Eighteen manuscripts were identified with a total of 714 patients enrolled in control and 808 in vaccine arms. In 698 patients receiving at least one dose of vaccine, treatment was well tolerated with a total of 5 grade III or higher adverse events. Clinical response was reported in a minority (n = 2, 14%) of studies. Autologous cell vaccines were associated with improved overall (HR 1.28, 95% CI 1.01–1.63) and disease-free survival (HR 1.33, 95% CI 1.05–1.67) over thirteen and ten trials respectively. Where reported, immune assays correlated well with clinical outcomes. Our results suggest that autologous whole cell vaccination is safe and efficacious in increasing survival in patients undergoing treatment for solid tumors. Registration: PROSPERO CRD42019140187.

Becoming proficient in scientific discourse such as argumentation or developing explanations can be challenging for students, including neurodivergent students (e.g., autistic students, students with learning disabilities, students with ADHD). Students need to practice developing arguments and explanations as well as sharing their conclusions with others; however, these opportunities do not regularly occur. The use of multimedia technology shows promise in being an engaging and effective way to support student learning and discussion of science topics and phenomena. This study investigated the use of a multimedia presentation called Dialogic Instruction for Argumentative Learning in Science (DIALS) in supporting upper-elementary neurodivergent students to provide complete responses to science questions. DIALS provides a structured inquiry investigation to the student in which they learn about a phenomenon through completing scaffolded animated experiments, explicitly learning how to develop an argument and respond to others conclusions, and learning relevant content information to support their argument and explanation development. An adapted alternating treatments design approach was used in this study. The phenomena explored were counterbalanced between three options: DIALS, PowerPoint comparison lessons, or control probe slides. Results from this study show promise in the use of DIALS in enhancing student complete responding to questions and providing quality claims for why they think phenomena occur. Implications for the findings are discussed.

The ongoing COVID-19 pandemic has led to more than 159 million confirmed cases with over 3.3 million deaths worldwide, but it remains mystery why most infected individuals (∼98%) were asymptomatic or only experienced mild illness. The same mystery applies to the deadly 1918 H1N1 influenza pandemic, which has puzzled the field for a century. Here we discuss dual potential properties of the 1918 H1N1 pandemic viruses that led to the high fatality rate in the small portion of severe cases, while about 98% infected persons in the United States were self-limited with mild symptoms, or even asymptomatic. These variations now have been postulated to be impacted by polymorphisms of the sialic acid receptors in the general population. Since coronaviruses (CoVs) also recognize sialic acid receptors and cause severe acute respiratory syndrome epidemics and pandemics, similar principles of influenza virus evolution and pandemicity may also apply to CoVs. A potential common principle of pathogen/host co-evolution of influenza and CoVs under selection of host sialic acids in parallel with different epidemic and pandemic influenza and coronaviruses is discussed.

There are numerous reasons why students with disabilities struggle in school. A key reason is professionals in the field may not pay enough attention to students' overwhelmed cognitive capacity. Cognitive load theory explains that all humans have limited capacity at any given time to use their auditory, visual, and tactile inputs (independently or collectively) to acquire new information and store it in long-term memory. When available cognition is overwhelmed -- which can be caused by any number of reasons -- learning cannot occur. In this article, we introduce the key aspects of cognitive load theory and give specific examples of how special educators can use this information to shape their instruction to support students' unique needs.

Background: Despite curative intent resection in patients with non-small cell lung cancer (NSCLC), recurrence leading to mortality remains too common. Melatonin has shown promise for the treatment of patients with lung cancer; however, its effect following cancer resection has not been studied. We evaluated if melatonin taken after complete resection reduces lung cancer recurrence and mortality, or impacts quality of life (QOL), symptomatology or immune function. Methods: Participants received melatonin (20 mg) or placebo nightly for one year following surgical resection of primary NSCLC. The primary outcome was two-year disease-free survival (DFS). Secondary outcomes included five-year DFS, adverse events, QOL, fatigue, sleep, depression, anxiety, pain, and biomarkers assessing for immune function/inflammation. This study is registered at https://clinicaltrials.gov NCT00668707. Findings: 709 patients across eight centres were randomized to melatonin (n = 356) versus placebo (n = 353). At two years, melatonin showed a relative risk of 1·01 (95% CI 0·83–1·22), p = 0·94 for DFS. At five years, melatonin showed a hazard ratio of 0·97 (95% CI 0·86–1·09), p = 0·84 for DFS. When stratified by cancer stage (I/II and III/IV), a hazard reduction of 25% (HR 0·75, 95% CI 0·61–0·92, p = 0·005) in five-year DFS was seen for participants in the treatment arm with advanced cancer (stage III/IV). No meaningful differences were seen in any other outcomes. Interpretation: Adjuvant melatonin following resection of NSCLC does not affect DFS for patients with resected early stage NSCLC, yet may increase DFS in patients with late stage disease. Further study is needed to confirm this positive result. No beneficial effects were seen in QOL, symptoms, or immune function. Funding: This study was funded by the Lotte and John Hecht Memorial Foundation and the Gateway for Cancer Research Foundation.

The majority of data on human Natural Killer (NK) cell phenotype and function has been generated using cryopreserved peripheral blood mononuclear cells (PBMCs). However, cryopreservation can have adverse effects on PBMCs. In contrast, investigating immune cells in whole blood can reduce the time, volume of blood required, and potential artefacts associated with manipulation of the cells. Whole blood collected from healthy donors and cancer patients was processed by three separate protocols that can be used independently or in parallel to assess extracellular receptors, intracellular signaling protein phosphorylation, and intracellular and extracellular cytokine production in human NK cells. To assess extracellular receptor expression, 200 μL of whole blood was incubated with an extracellular staining (ECS) mix and cells were subsequently fixed and RBCs lysed prior to analysis. The phosphorylation status of signaling proteins was assessed in 500 μL of whole blood following co-incubation with interleukin (IL)-2/12 and an ECS mix for 20 min prior to cell fixation, RBC lysis, and subsequent permeabilization for staining with an intracellular staining (ICS) mix. Cytokine production (IFNγ) was similarly assessed by incubating 1 mL of whole blood with PMA-ionomycin or IL-2/12 prior to incubation with ECS and subsequent ICS antibodies. In addition, plasma was collected from stimulated samples prior to ECS for quantification of secreted IFNγ by ELISA. Results were consistent, despite inherent inter-patient variability. Although we did not investigate an exhaustive list of targets, this approach enabled quantification of representative ECS surface markers including activating (NKG2D and DNAM-1) and inhibitory (NKG2A, PD-1, TIGIT, and TIM-3) receptors, cytokine receptors (CD25, CD122, CD132, and CD212) and ICS markers associated with NK cell activation following stimulation, including signaling protein phosphorylation (p-STAT4, p-STAT5, p-p38 MAPK, p-S6) and IFNγ in both healthy donors and cancer patients. In addition, we compared extracellular receptor expression using whole blood vs. cryopreserved PBMCs and observed a significant difference in the expression of almost all receptors. The methods presented permit a relatively rapid parallel assessment of immune cell receptor expression, signaling protein activity, and cytokine production in a minimal volume of whole blood from both healthy donors and cancer patients.

High mobility group AT-hook 1 (HMGA1) protein is an oncogenic architectural transcription factor that plays an essential role in early development, but it is also implicated in many human cancers. Elevated levels of HMGA1 in cancer cells cause misregulation of gene expression and are associated with increased cancer cell proliferation and increased chemotherapy resistance. We have devised a strategy of using engineered viruses to deliver decoy hyper binding sites for HMGA1 to the nucleus of cancer cells with the goal of sequestering excess HMGA1 at the decoy hyper binding sites due to binding competition. Sequestration of excess HMGA1 at the decoy binding sites is intended to reduce HMGA1 binding at the naturally occurring genomic HMGA1 binding sites, which should result in normalized gene expression and restored sensitivity to chemotherapy. As proof of principle, we engineered the replication defective adenovirus serotype 5 genome to contain hyper binding sites for HMGA1 composed of six copies of an individual HMGA1 binding site, referred to as HMGA-6. A 70%–80% reduction in cell viability and increased sensitivity to gemcitabine was observed in five different pancreatic and liver cancer cell lines 72 hr after infection with replication defective engineered adenovirus serotype 5 virus containing the HMGA-6 decoy hyper binding sites. The decoy hyper binding site strategy should be general for targeting overexpression of any double-stranded DNA-binding oncogenic transcription factor responsible for cancer cell proliferation. Keywords: adenovirus, cancer therapy, oncogenic transcription factor, chemotherapy resistance, high mobility group A protein, decoy binding site, pancreatic cancer, liver cancer, HMGA1, neoadjuvant therapy

Abstract Background Cancer surgery can promote tumour metastases and worsen prognosis, however, the effect of perioperative complications on metastatic disease remains unclear. In this study we sought to evaluate the effect of common perioperative complications including perioperative blood loss, hypothermia, and sepsis on tumour metastases in a murine model. Methods Prior to surgery, pulmonary metastases were established by intravenous challenge of CT26LacZ colon cancer cells in BALB/c mice. Surgical stress was generated through partial hepatectomy (PH) or left nephrectomy (LN). Sepsis was induced by puncturing the cecum to express stool into the abdomen. Hemorrhagic shock was induced by removal of 30% of total blood volume (i.e. stage 3 hemorrhage) via the saphenous vein. Hypothermia was induced by removing the heating apparatus during surgery and lowering core body temperatures to 30 °C. Lung tumour burden was quantified 3 days following surgery. Results Surgically stressed mice subjected to stage 3 hemorrhage or hypothermia did not show an additional increase in lung tumour burden. In contrast, surgically stressed mice subjected to intraoperative sepsis demonstrated an additional 2-fold increase in the number of tumour metastases. Furthermore, natural killer (NK) cell function, as assessed by YAC-1 tumour cell lysis, was significantly attenuated in surgically stressed mice subjected to intraoperative sepsis. Both NK cell-mediated cytotoxic function and lung tumour burden were improved with perioperative administration of polyI:C, which is a toll-like receptor (TLR)-3 ligand. Conclusions Perioperative sepsis alone, but not hemorrhage or hypothermia, enhances the prometastatic effect of surgery in murine models of cancer. Understanding the cellular mechanisms underlying perioperative immune suppression will facilitate the development of immunomodulation strategies that can attenuate metastatic disease.

Pentapeptide repeat proteins (PRPs) are found abundantly in cyanobacteria, numbering in the dozens in some genomes, e.g. in Nostoc sp. PCC 7120. PRPs, comprised of a repeating consensus sequence of five amino acids, adopt a distinctive right-handed quadrilateral β-helical structure, also referred to as a repeat five residue (Rfr) fold, made up of stacks of coils formed by four consecutive pentapeptide repeats. The right-handed quadrilateral β-helical PRP structure is constructed by repeating β turns at each of four corners in a given coil, each causing a 90° change in direction of the polypeptide chain. Until now, all PRP structures have consisted either of type II and IV β turns or exclusively of type II β turns. Here, we report the first structure of a PRP comprised of type I and II β turns, Alr5209 from Nostoc sp. PCC 7120. The alr5209 gene encodes 129 amino acids containing 16 tandem pentapeptide repeats. The Alr5209 structure was analyzed in comparison to all other PRPs to determine how type I β turns can be accommodated in Rfr folds and the consequences of type I β turns on the right-handed quadrilateral β-helical structure. Given that Alr5209 represents the first PRP structure containing type I β turns, the PRP consensus sequence was reevaluated and updated. Despite a growing number of PRP structural investigations, their function remains largely unknown. Genome analysis indicated that alr5209 resides in a five-gene operon (alr5208-alr5212) with Alr5211 annotated to be a NADH dehydrogenase indicating Alr5209 may be involved in oxidative phosphorylation. Keywords: Pentapeptide repeat protein, Repeat five residue fold, Beta turns, Cyanobacteria, Protein crystal structure, Nostoc sp. PCC 7120

Student achievement disparities in inclusive science classrooms are concerning, as knowledge about science, technology, engineering, and mathematics (STEM) is increasingly important for upward mobility. When students identify with multiple marginalized sociocultural groups, progress becomes more troubling, as the interplay among these factors is rarely accounted for in quantitative intervention research. The purpose of the present study, therefore, was to evaluate performance on measures of science vocabulary and general science knowledge among students with intersectional identities (i.e., students with disabilities from marginalized racial/ethnic groups, n = 33; and students with disabilities from low SES households, n = 167) following teacher participation in a multimedia professional development (PD) process. Using a series of multilevel models, results suggest students who learned from teachers who participated in the multimedia professional development process experienced greater gains than peers with the same intersectional identities in comparison classrooms across all measures. Implications and future directions are discussed.

Understanding science allows students with and without developmental and behavioral-based (DB) disabilities to better appreciate the world around them as well as prepare them for the growing science-related job market. However, students in the United States consistently underperform on science achievement tests compared to students from other nations. This underperformance could be attributed, in part to science having many specialized vocabulary terms that are not often taught explicitly, leaving students with incomplete or inaccurate understandings of word meanings. Improving science vocabulary instructional practices may support students with and without DB disabilities in enhancing their science achievement. To address this need, researchers implemented multicomponent multimedia professional development (PD) to support middle-school science teachers in delivering high-quality vocabulary instruction in inclusive settings. In this paper, data collected from a study evaluating the efficacy of the PD were analyzed to determine the influence on student outcomes using ANOVA and multilevel modeling methodologies. Though initial results indicate a promising impact on teacher instructional practices, little is known whether teacher participation in the PD affected student science vocabulary and content knowledge growth. Using multilevel modeling, student science knowledge growth was evaluated following their teachers' exposure to the PD. The findings from this study indicate having indirect exposure to PD had a positive effect on science content knowledge for students with and without DB disabilities (N = 980). In addition, the authors found students with DB disabilities whose teachers had access to PD showed a larger gain in science knowledge than general education students whose teachers did not have access to the PD.

The pentapeptide repeat protein (PRP) superfamily, identified in 1998, has grown to nearly 39,000 sequences from over 3300 species. PRPs, recognized as having at least eight contiguous pentapeptide repeats (PRs) of a consensus pentapeptide sequence, adopt a remarkable structure, namely, a right-handed quadrilateral β-helix with four consecutive PRs forming a single β-helix coil. Adjacent coils join together to form a β-helix “tower” stabilized by β-ladders on the tower faces and type I, type II, or type IV β-turns facilitating an approximately −90° redirection of the polypeptide chain joining one coil face to the next. PRPs have been found in all branches of life, but they are predominantly found in cyanobacteria. Cyanobacteria have existed on earth for more than two billion years and are thought to be responsible for oxygenation of the earth’s atmosphere. Filamentous cyanobacteria such as Nostoc sp. strain PCC 7120 may also represent the oldest and simplest multicellular organisms known to undergo cell differentiation on earth. Knowledge of the biochemical function of these PRPs is essential to understanding how ancient cyanobacteria achieved functions critical to early development of life on earth. PRPs are predicted to exist in all cyanobacteria compartments including thylakoid and cell-wall membranes, cytoplasm, and thylakoid periplasmic space. Despite their intriguing structure and importance to understanding ancient cyanobacteria, the biochemical functions of PRPs in cyanobacteria remain almost completely unknown. The precise biochemical function of only a handful of PRPs is currently known from any organisms, and three-dimensional structures of only sixteen PRPs or PRP-containing multidomain proteins from any organism have been reported. In this review, the current knowledge of the structures and functions of PRPs is presented and discussed.

As K-12 classrooms in the U.S. grow in linguistic diversity, there is a need to develop and evaluate the effects of instructional approaches that build knowledge of academic vocabulary for multilingual learners. While multimedia vocabulary instruction may represent a promising avenue for improving word learning for linguistically diverse classrooms of upper-elementary students, there is a dearth of empirical evidence on this topic, with no research on multimedia vocabulary instruction having been conducted with linguistically diverse populations in rural contexts. This randomized control trial evaluated the effects of a multimedia vocabulary instructional approach (CAP-S), relative to business-as-usual (BAU) vocabulary instruction on researcher-developed and standardized measures of word knowledge for a linguistically diverse sample of Grade 5 students learning in rural schools (n = 418). The intervention took place over 8 weeks; CAP-S and BAU teachers addressed the same target set of academic words. Hierarchical linear modeling indicated statistically significant and meaningful effects on a custom measure of word learning, as well as small but statistically significant effects on a standardized assessment of word knowledge. On the custom vocabulary measure, ELs benefited more than non-ELs from CAP-S instruction, relative to their counterparts in the BAU condition. Findings suggest the potential advantages of employing efficient, feasible multimedia vocabulary approaches to serve diverse, multilingual student groups in rural, upper-elementary classrooms.

Cancer surgery while necessary for primary tumor removal, has been shown to induce immune suppression and promote metastases in preclinical models and human cancer surgery patients. Activating the immune system and reversing immunosuppression have emerged as promising ways to treat cancer and they can be safely employed in the perioperative period. In this study, we evaluated the immunotherapeutic potential of phosphodiesterase-5 (PDE-5) inhibitors to target surgery-induced myeloid-derived suppressor cells (MDSC) and restore natural killer (NK) cell function in the clinically relevant perioperative period. Immunocompetent murine tumor models of major surgery were used to characterize the functional suppression of surgery-induced MDSC and to assess the in vivo efficacy of perioperative PDE5 inhibition. In cancer surgery patients with abdominal malignancies, we assessed postoperative NK cell function following co-culture with MDSC and PDE5 inhibition. Perioperative PDE5 inhibition reverses surgery-induced immunosuppression. In particular, sildenafil reduces surgery-derived granulocytic-MDSC (gMDSC) function through downregulation of arginase 1 (ARG1), IL4Ra and reactive oxygen species (ROS) expression, enabling NK cell antitumor cytotoxicity and reducing postoperative disease recurrence. By removing surgery-derived immunosuppressive mechanisms of MDSCs, sildenafil can be combined with the administration of perioperative influenza vaccination which targets NK cells to reduce postoperative metastasis. Importantly, sildenafil reverses MDSC suppression in cancer surgery patients. These findings demonstrate that PDE5 inhibitors reduce postoperative metastasis by their ability to inhibit surgery-induced MDSC. Further clinical studies are warranted to investigate the immunotherapeutic role of PDE5 inhibitors in combination with cancer surgery.

It has been highlighted that the original manuscript [1] contains a typesetting error in Fig. 1 and the Fig. 1c panel gas been inadvertently duplicated in panel Fig. 1d. This does not affect the results and conclusions of the article. The correct version of Fig. 1 is included with this Correction. The original article has been updated.

Metabolic profiling of cell line and tissue extracts involves sample processing that includes a drying step prior to re-dissolving the cell or tissue extracts in a buffer for analysis by GC/LC-MS or NMR. Two of the most commonly used drying techniques are centrifugal evaporation under vacuum (SpeedVac) and lyophilization. Here, NMR spectroscopy was used to determine how the metabolic profiles of hydrophilic extracts of three human pancreatic cancer cell lines, MiaPaCa-2, Panc-1 and AsPC-1, were influenced by the choice of drying technique. In each of the three cell lines, 40−50 metabolites were identified as having statistically significant differences in abundance in redissolved extract samples depending on the drying technique used during sample preparation. In addition to these differences, some metabolites were only present in the lyophilized samples, for example, n-methyl-α-aminoisobutyric acid, n-methylnicotimamide, sarcosine and 3-hydroxyisovaleric acid, whereas some metabolites were only present in SpeedVac dried samples, for example, trimethylamine. This research demonstrates that the choice of drying technique used during the preparation of samples of human cell lines or tissue extracts can significantly influence the observed metabolome, making it important to carefully consider the selection of a drying method prior to preparation of such samples for metabolic profiling.