Explore the vast range of titles available.

Adaptive radiotherapy (ART) was introduced in the late 1990s to improve the accuracy and efficiency of therapy and minimize radiation-induced toxicities. ART combines multiple tools for imaging, assessing the need for adaptation, treatment planning, quality assurance, and has been utilized to monitor inter- or intra-fraction anatomical variations of the target and organs-at-risk (OARs). Ethos™ (Varian Medical Systems, Palo Alto, CA), a cone beam computed tomography (CBCT) based radiotherapy treatment system that uses artificial intelligence (AI) and machine learning to perform ART, was introduced in 2020. Since then, numerous studies have been done to examine the potential benefits of Ethos™ CBCT-guided ART compared to non-adaptive radiotherapy. This review will explore the current trends of Ethos™, including improved CBCT image quality, a feasible clinical workflow, daily automated contouring and treatment planning, and motion management. Nevertheless, evidence of clinical improvements with the use of Ethos™ are limited and is currently under investigation via clinical trials.

Complement receptor 3 (CR3, CD11b/CD18) is a major macrophage phagocytic receptor. The biochemical pathways through which CR3 regulates immunologic responses have not been fully characterized. Francisella tularensis is a remarkably infectious, facultative intracellular pathogen of macrophages that causes tularemia. Early evasion of the host immune response contributes to the virulence of F. tularensis and CR3 is an important receptor for its phagocytosis. Here we confirm that efficient attachment and uptake of the highly virulent Type A F. tularensis spp. tularensis strain Schu S4 by human monocyte-derived macrophages (hMDMs) requires complement C3 opsonization and CR3. However, despite a>40-fold increase in uptake following C3 opsonization, Schu S4 induces limited pro-inflammatory cytokine production compared with non-opsonized Schu S4 and the low virulent F. novicida. This suggests that engagement of CR3 by opsonized Schu S4 contributes specifically to the immune suppression during and shortly following phagocytosis which we demonstrate by CD11b siRNA knockdown in hMDMs. This immune suppression is concomitant with early inhibition of ERK1/2, p38 MAPK and NF-κB activation. Furthermore, TLR2 siRNA knockdown shows that pro-inflammatory cytokine production and MAPK activation in response to non-opsonized Schu S4 depends on TLR2 signaling providing evidence that CR3-TLR2 crosstalk mediates immune suppression for opsonized Schu S4. Deletion of the CD11b cytoplasmic tail reverses the CR3-mediated decrease in ERK and p38 activation during opsonized Schu-S4 infection. The CR3-mediated signaling pathway involved in this immune suppression includes Lyn kinase and Akt activation, and increased MKP-1, which limits TLR2-mediated pro-inflammatory responses. These data indicate that while the highly virulent F. tularensis uses CR3 for efficient uptake, optimal engagement of this receptor down-regulates TLR2-dependent pro-inflammatory responses by inhibiting MAPK activation through outside-in signaling. CR3-linked immune suppression is an important mechanism involved in the pathogenesis of F. tularensis infection.

Mycobacterium tuberculosis ( M.tb) infection infects human alveolar macrophages (HAMs). In freshly isolated HAMs from 28 healthy adults, we observe large inter-individual differences in bacterial uptake and growth, with tenfold variation in M.tb load by 72 h. While M.tb infection triggers expression changes of numerous host mRNAs, we examined which genes are most variably expressed (VE genes) between donors, as potential biomarkers of individual tuberculosis (TB) risk. The HAM RNA transcriptome following infection revealed thousands of differentially expressed (DE) genes and differential secretion of 25/27 proteins. Yet only 324 DE genes represent VE genes detected exclusively among DE genes in infected cells. Of 36 DE genes detected at all time points (2, 24, and 72 h), 14 are VE genes, indicating early emergence of the VE gene profile. 9/27 DE proteins following infection were encoded by VE genes. Systems analysis of VE RNAs identified a top-scoring network anchored by IL1B, involved in TB immune response. Independent M.tb -HAM transcriptome results from a TB-endemic region show significant overlap in DE genes, including VE genes identified in the main study. Thus, we identify a VE gene network activated upon M.tb- HAM infection with high inter-person variability, guiding studies on determining individual risk of M.tb infection and/or disease. Mycobacterium tuberculosis ( M.tb ) infection of human alveolar macrophages reveals a variably expressed gene network with inter-individual variability, guiding future studies to determine individual risk of M.tb infection and tuberculosis disease.

Human monocyte inflammatory responses differ between virulent and attenuated Francisella infection. A mixed infection model showed that the virulent F. tularensis Schu S4 can attenuate inflammatory cytokine responses to the less virulent F. novicida in human monocytes. F. tularensis dampens inflammatory response by an active process. This suppression may contribute to enhanced pathogenicity of F. tularensis. Francisella tularensis is a Gram-negative facultative bacterium that can cause the disease tularemia, even upon exposure to low numbers of bacteria. One critical characteristic of Francisella is its ability to dampen or subvert the host immune response. Previous work has shown that monocytes infected with highly virulent F. tularensis subsp. tularensis strain Schu S4 responded with a general pattern of quantitatively reduced pro-inflammatory signaling pathway genes and cytokine production in comparison to those infected with the less virulent related F. novicida. However, it has been unclear whether the virulent Schu S4 was merely evading or actively suppressing monocyte responses. By using mixed infection assays with F. tularensis and F. novicida, we show that F. tularensis actively suppresses monocyte pro-inflammatory responses. Additional experiments show that this suppression occurs in a dose-dependent manner and is dependent upon the viability of F. tularensis. Importantly, F. tularensis was able to suppress pro-inflammatory responses to earlier infections with F. novicida. These results lend support that F. tularensis actively dampens human monocyte responses and this likely contributes to its enhanced pathogenicity.

Background Autophagy has been shown recently to play an important role in the intracellular survival of several pathogenic bacteria. In this study, we investigated the effect of a novel small-molecule autophagy-inducing agent, AR-12, on the survival of Francisella tularensis , the causative bacterium of tularemia in humans and a potential bioterrorism agent, in macrophages. Methods and results Our results show that AR-12 induces autophagy in THP-1 macrophages, as indicated by increased autophagosome formation, and potently inhibits the intracellular survival of F. tularensis (type A strain, Schu S4) and F. novicida in macrophages in association with increased bacterial co-localization with autophagosomes. The effect of AR-12 on intracellular F. novicida was fully reversed in the presence of the autophagy inhibitor, 3-methyl adenine or the lysosome inhibitor, chloroquine. Intracellular F. novicida were not susceptible to the inhibitory activity of AR-12 added at 12 h post-infection in THP-1 macrophages, and this lack of susceptibility was independent of the intracellular location of bacteria. Conclusion Together, AR-12 represents a proof-of-principle that intracellular F. tularensis can be eradicated by small-molecule agents that target innate immunity.

is a remarkably infectious facultative intracellular bacterium of macrophages that causes tularemia. Early evasion of host immune responses contributes to the success of as a pathogen. entry into human monocytes and macrophages is mediated by the major phagocytic receptor, complement receptor 3 (CR3, CD11b/CD18). We recently determined that despite a significant increase in macrophage uptake following C3 opsonization of the virulent Type A spp. Schu S4, this phagocytic pathway results in limited pro-inflammatory cytokine production. Notably, MAP kinase/ERK activation is suppressed immediately during C3-opsonized Schu S4-CR3 phagocytosis. A mathematical model of CR3-TLR2 crosstalk predicted early involvement of Ras GTPase-activating protein (RasGAP) in immune suppression by CR3. Here, we link CR3-mediated uptake of opsonized Schu S4 by human monocytes and macrophages with inhibition of early signal 1 inflammasome activation, evidenced by limited caspase-1 cleavage and IL-18 release. This inhibition is due to increased RasGAP activity, leading to a reduction in the Ras-ERK signaling cascade upstream of the early inflammasome activation event. Thus, our data uncover a novel signaling pathway mediated by CR3 following engagement of opsonized virulent to limit inflammasome activation in human phagocytic cells, thereby contributing to evasion of the host innate immune system.

Mycobacteria-infected macrophages are poor responders to interferon-γ (IFN-γ), resulting in decreased expression of IFN-γ-induced genes. In the present study, we examined the inhibition of IFN-γ-induced gene expression by Mycobacterium tuberculosis and four different Mycobacterium avium strains in mouse RAW264.7 macrophages. Gamma-irradiated M. tuberculosis inhibited mRNA expression of a panel of six different IFN-γ-induced genes. All four of the M. avium strains completely inhibited IFN-γ-induced expression of MHC class II Aα and Eβ mRNA. However, the Mac101 strain, which is serovar 1, inhibited IFN-γ induction of IFN regulatory factor-1 (IRF-1) and guanylate-binding protein-1 (GBP-1) mRNA to a greater extent than the otherM. avium strains, which are serovar 2. In this study, we also show that mycobacteria inhibit gene expression by both toll-like receptor 2 (TLR2)-dependent and independent pathways. The inhibition of IFN-γ-induced gene expression by M. avium was reduced but not completely blocked in macrophages from TLR2–/– mice. IFN-γ-induced gene expression was also inhibited by mycobacteria in RAW264.7 cells expressing dominantnegative TLR2 or myeloid differentiation factor 88 (MyD88), further indicating the existence of a pathway independent of TLR2 and MyD88. These data suggest that mycobacteria inhibit IFN-γ-induced gene expression by multiple pathways involving both TLR2 and non-TLR receptors.

Although parastomal hernias have a high incidence in the general population, involvement of the stomach remains rare due to the numerous suspensory structures tethering this organ in its anatomical location. This case details a 75-year-old lady with a painless onset of a gastric parastomal hernia with progressive incarceration over a two-week period. The deteriorating clinical condition of the patient following weeks of stability indicated that the cause of symptoms is likely sinister. Imaging confirmed incarceration of the stomach within a parastomal hernia. Although this has been reported previously, there is little to suggest this condition exists with an insidious onset. Patients who are at high risk of gastric herniation and who fit this clinical vignette with a known parastomal hernia should be offered prompt investigations to ascertain the diagnosis and facilitate further management.

A central tenet of feminist pedagogies is to engage students in dialogue, rather than a teacher-centered lecturing method that is commonly used in college classrooms (Chow et al. 2003, Friere 1970, hooks 1994). This possibility is complicated by faculty's charge to impart a particular body of discipline-specific knowledge for each class taught. How can faculty impart this knowledge in such a way as to incite dialogue rather than perpetuate monologue? How shall faculty attempt to get students interested in a subject (and maintain their own excitement for the material) when we have no idea where each student's personal connection with the material lies? In this article, I outline two student-centered pedagogical methods—lecturing with questions and student-centered assignments—in which the goal is to incite students and faculty to full engagement and to think reflexively throughout the classroom experience.