Immunometabolism and Pulmonary Infections: Implications for Protective Immune Responses and Host-Directed Therapies

The biology and clinical efficacy of immune cells from patients with infectious diseases or cancer are associated with metabolic programming. Host immune- and stromal-cell genetic and epigenetic signatures in response to the invading pathogen shape disease pathophysiology and disease outcomes. Directly linked to the immunometabolic axis is the role of the host microbiome, which is also discussed here in the context of productive immune responses to lung infections. We also present host-directed therapies (HDT) as a clinically viable strategy to refocus dysregulated immunometabolism in patients with infectious diseases, which requires validation in early phase clinical trials as adjuncts to conventional antimicrobial therapy. These efforts are expected to be continuously supported by newly generated basic and translational research data to gain a better understanding of disease pathology while devising new molecularly defined platforms and therapeutic options to improve the treatment of patients with pulmonary infections, particularly in relation to multidrug-resistant pathogens

Gamma knife surgery as monotherapy with clinically relevant doses prolongs survival in a Human GBM Xenograft Model

Object. Gamma knife surgery (GKS) may be used for recurring glioblastomas (GBMs). However, patients have then usually undergone multimodal treatment, which makes it difficult to specifically validate GKS independent of established treatments. Thus, we developed an experimental brain tumor model to assess the efficacy and radiotoxicity associated with GKS. Methods. GBM xenografts were implanted intracerebrally in nude rats, and engraftment was confirmed with MRI. The rats were allocated to GKS, with margin doses of 12Gy or 18Gy, or to no treatment. Survival time was recorded, tumor sections were examined, and radiotoxicity was evaluated in a behavioral open field test. Results. In the first series, survival from the time of implantation was 96 days in treated rats and 72 days in controls ( < 0.001). In a second experiment, survival was 72 days in the treatment group versus 54 days in controls ( < 0.006). Polynuclear macrophages and fibrosis was seen in groups subjected to GKS. Untreated rats with GBM xenografts displayed less mobility than GKS-treated animals in the open field test 4 weeks after treatment ( = 0.04). Conclusion.GKS administered with clinically relevant doses prolongs survival in rats harboringGBMxenografts, and the associated toxicity is mild.publishedVersio

Knowledge and perceptions of type 2 diabetes among Ghanaian migrants in three European countries and Ghanaians in rural and urban Ghana: The RODAM qualitative study.

African migrants in Europe and continental Africans are disproportionately affected by type 2 diabetes (T2D). Both groups develop T2D at a younger age, and have higher morbidity and mortality from T2D and complications, compared to European populations. To reduce risk, and avoidable disability and premature deaths, culturally congruent and context specific interventions are required. This study aimed to: (a) assess perceptions and knowledge of T2D among Ghanaian migrants in Europe and their compatriots in Ghana and (b) identify specific perceptions and knowledge gaps that might predispose migrants to higher risk of diabetes. Data was gathered through 26 focus groups with 180 individuals, aged 21 to 70, from Amsterdam, Berlin and London and rural and urban Ashanti Region, Ghana. Thematic analysis of the data was informed by Social Representations Theory, which focuses on the sources, content and functions of social knowledge. Three key insights emerged from analysis. First, there was general awareness, across migrant and non-migrant groups, of T2D as a serious chronic condition with life threatening complications, and some knowledge of biomedical strategies to prevent diabetes (e.g healthy eating) and diabetes complications (e.g medication adherence). However, knowledge of T2D prevention and reduction of diabetes complications was not comprehensive. Secondly, knowledge of biomedical diabetes theories and interventions co-existed with theories about psychosocial and supernatural causes of diabetes and the efficacy of herbal and faith-based treatment of diabetes. Finally, migrants' knowledge was informed by both Ghanaian and European systems of T2D knowledge suggesting enculturation dynamics. We discuss the development of culturally congruent and context-specific T2D interventions for the research communities

Gamma knife surgery as monotherapy with clinically relevant doses prolongs survival in a Human GBM Xenograft Model

Object. Gamma knife surgery (GKS) may be used for recurring glioblastomas (GBMs). However, patients have then usually undergone multimodal treatment, which makes it difficult to specifically validate GKS independent of established treatments. Thus, we developed an experimental brain tumor model to assess the efficacy and radiotoxicity associated with GKS. Methods. GBM xenografts were implanted intracerebrally in nude rats, and engraftment was confirmed with MRI. The rats were allocated to GKS, with margin doses of 12Gy or 18Gy, or to no treatment. Survival time was recorded, tumor sections were examined, and radiotoxicity was evaluated in a behavioral open field test. Results. In the first series, survival from the time of implantation was 96 days in treated rats and 72 days in controls ( < 0.001). In a second experiment, survival was 72 days in the treatment group versus 54 days in controls ( < 0.006). Polynuclear macrophages and fibrosis was seen in groups subjected to GKS. Untreated rats with GBM xenografts displayed less mobility than GKS-treated animals in the open field test 4 weeks after treatment ( = 0.04). Conclusion.GKS administered with clinically relevant doses prolongs survival in rats harboringGBMxenografts, and the associated toxicity is mild

Dural Arteriovenous Fistulas and the Role of Gamma Knife Stereotactic Radiosurgery: The Stockholm Experience

We review the clinical and radiological outcomes of patients with dural arteriovenous fistulae (DAVFs), treated with the Gamma Knife® (GK) in Stockholm. During the period 1972-2008, 73 consecutive patients were treated. Eight were excluded due to lack of follow-up. Thus, the material comprises 65 patients harboring 67 DAVFs subjected to 75 treatments with GK stereotactic radiosurgery (SRS). Fifty-four cases were subjected to upfront GK SRS while 13 followed failed surgery or embolization. Nine patients had been retreated with GK SRS. One was recent and was excluded. Prescription doses varied considerably, but most commonly it was 20-25 Gy to the 40-60% isodose. Target definition was from angiography in all cases. 63 cases had an angiographic follow-up. There were 37 (59%) obliterations and 17 (27%) regressions. Nine lesions were unchanged (14%). If patients with clinical data suggestive of obliteration or magnetic resonance imaging follow-up are included, the numbers differ. Two patients are excluded. As for the 73 remaining cases, there were 46 (63%) obliterations, 17 (23%) regressions and 10 (14%) unchanged. There were 2 posttreatment hemorrhages and 5 minor adverse radiation effects. GK SRS is an effective treatment for DAVFs, with a low incidence of complications. GK SRS is a treatment alternative for patients harboring a DAVF without cortical venous reflux that causes intolerable bruit and to those not amenable to embolization or surgery

Anti-PD-1/PD-L1 therapy for infectious diseases: learning from the cancer paradigm

Objectives: Immune checkpoint pathways regulate optimal host immune responses against transformed cells, induce immunological memory, and limit tissue pathology. Conversely, aberrant immune checkpoint activity signifies a poor prognosis in cancer and infectious diseases. Host-directed therapy (HDT) via immune checkpoint blockade has revolutionized cancer treatment with therapeutic implications for chronic infections, thus laying the foundation for this review. Methods: Online literature searches were performed via PubMed, PubMed Central, and Google using the keywords “immune checkpoint inhibition”; “host-directed therapy”; “T cell exhaustion”; “cancer immunotherapy”; “anti-PD-1 therapy”; “anti-PD-L1 therapy”; “chronic infections”; “antigen-specific cells”; “tuberculosis”; “malaria”; “viral infections”; “human immunodeficiency virus”; “hepatitis B virus”; “hepatitis C virus”; “cytomegalovirus” and “Epstein–Barr virus”. Search results were filtered based on relevance to the topics covered in this review. Results: The use of monoclonal antibodies directed against the antigen-experienced T-cell marker programmed cell death 1 (PD-1) and its ligand PD-L1 in the context of chronic infectious diseases is reviewed. The potential pitfalls and precautions, based on clinical experience from treating patients with cancer with PD-1/PD-L1 pathway inhibitors, are also described. Conclusions: Anti-PD-1/PD-L1 therapy holds promise as adjunctive therapy for chronic infectious diseases such as tuberculosis and HIV, and must therefore be tested in randomized clinical trials