Mycobacterium tuberculosis (Mtb) infection is initiated in the distal airways, but the bacteria ultimately disseminate to the lung interstitium. Although various cell types, including alveolar ...macrophages (AM), neutrophils, and permissive monocytes, are known to be infected with Mtb, the initially infected cells as well as those that mediate dissemination from the alveoli to the lung interstitium are unknown. In this study, using a murine infection model, we reveal that early, productive Mtb infection occurs almost exclusively within airway-resident AM. Thereafter Mtb-infected, but not uninfected, AM localize to the lung interstitium through mechanisms requiring an intact Mtb ESX-1 secretion system. Relocalization of infected AM precedes Mtb uptake by recruited monocyte-derived macrophages and neutrophils. This dissemination process is driven by non-hematopoietic host MyD88/interleukin-1 receptor inflammasome signaling. Thus, interleukin-1-mediated crosstalk between Mtb-infected AM and non-hematopoietic cells promotes pulmonary Mtb infection by enabling infected cells to disseminate from the alveoli to the lung interstitium.
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•Early M. tuberculosis infection primarily targets lung alveolar macrophages (AM)•Mtb-infected AM selectively relocalize from the airways to the lung interstitium•AM interstitial localization precedes Mtb dissemination to other immune cell types•Relocalization of infected AM is dependent on Mtb ESX-1 and host IL-1R signaling
Using a mouse model, Cohen et al. demonstrate that early Mycobacterium tuberculosis infection predominantly targets alveolar macrophages (AM). Infected AM relocalize from the alveolar space to lung interstitium, preceding bacterial dissemination into migratory myeloid populations. Relocalization requires IL-1R and bacterial ESX-1, highlighting the host-pathogen interplay required to establish infection.
Offshore outsourcing to vendors in foreign countries causes unique challenges which need to be understood and managed effectively. This paper explores cultural differences in IS offshoring ...arrangements involving German client organizations that outsource application development activities to Indian vendors. For this purpose, a research framework is developed based on both theoretical considerations and specific empirical observations from multiple case studies. The goal is to (1) explore the nature of cultural differences in offshore outsourcing arrangements in depth and to (2) analyze the relationship between those cultural differences and offshore outsourcing success. Based on the case findings, implications and practices for the management of offshore development projects are outlined. The results indicate that cultural differences in terms of power distance, IS designer values, and an active versus passive working attitude critically affect several dimensions of relationship quality, thereby influencing offshore outsourcing success. A clear definition of roles and mechanisms, strong leadership, and an active management of culture by adapting to either the client’s or the vendor’s national culture appeared to be effective ways to manage cultural differences.
Mycobacterium tuberculosis (MTB) is a highly successful pathogen that infects over a billion people. As with most organisms, MTB adapts to stress by modifying its transcriptional profile. Remodeling ...of the transcriptome requires both altering the transcription rate and clearing away the existing mRNA through degradation, a process that can be directly regulated in response to stress. To understand better how MTB adapts to the harsh environs of the human host, we performed a global survey of the decay rates of MTB mRNA transcripts. Decay rates were measured for 2139 of the ~4000 MTB genes, which displayed an average half-life of 9.5 min. This is nearly twice the average mRNA half-life of other prokaryotic organisms where these measurements have been made. The transcriptome was further stabilized in response to lowered temperature and hypoxic stress. The generally stable transcriptome described here, and the additional stabilization in response to physiologically relevant stresses, has far-ranging implications for how this pathogen is able to adapt in its human host.
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Background: Allogeneic hematopoietic cell transplantation (HCT) provides a potentially curative option for patients (pts) with R/R AML. Disease status at the time of transplant is ...a major determinant of long-term prognosis, with pts typically receiving salvage chemotherapy prior to HCT to induce a remission. However, older and/or heavily pre-treated pts frequently cannot tolerate intensive chemotherapy (IC) or do not obtain adequate disease control to permit an HCT. IVO is an oral, potent, targeted inhibitor of mutant IDH1 (mIDH1) approved for the treatment of adults with newly diagnosed AML ≥75 y of age or ineligible for IC, and those with R/R AML. We assessed HCT outcomes in pts with m IDH1 R/R AML who proceeded to HCT after treatment with IVO in a phase I study (NCT02074839). Methods: Baseline characteristics, clinical response (including CR, CRi/CRp, MLFS), and overall survival (OS) for the subgroup of pts with m IDH1 R/R AML who received IVO 500 mg QD, responded to treatment and then underwent HCT are reported. m IDH1 variant allele frequency (VAF) from bone marrow mononuclear cells was assessed using BEAMing digital PCR (0.02–0.04% VAF detection limit). Results: Among 179 pts with R/R AML treated with IVO, 18 proceeded to HCT: median age, 61.5 y (range 36–68); 56% male; 16.7% had secondary AML; 27.8% had ≥3 prior regimens; 11.1% had a prior HCT. The median duration of IVO treatment prior to HCT was 3.9 mo (range 2.1–15.2). The last reported response prior to HCT was 50.0% CR. Six- and 12-mo post-HCT survival rates were 77.8% and 50.0%; median relapse-free survival post HCT was 7.3 mo (range 2.6–NE). Median OS from start of IVO was 16.8 mo (95% CI 9.2, NE) for HCT pts vs 9.0 mo (95% CI 7.1, 10.2) in the entire study cohort; median follow-up time, 33.2 mo (range 3.2–41.9). Eight HCT pts were censored for OS: 5 are in remission, 2 relapsed and are in survival follow-up, and 1 was lost to follow-up. Median OS was not estimable (95% CI 9.1, NE) for the 12 HCT pts who achieved CR after IVO therapy and was 20.5 mo (95% CI 16.4, NE) for the 31 CR pts who did not undergo HCT. m IDH1 was undetectable in 1/18 (6%) pts; 4/18 (22%) pts had reduction below 1% VAF in ≥1 at the last assessment prior to HCT. Conclusions: IVO monotherapy is a putative treatment option to induce remissions prior to HCT for m IDH1 R/R AML pts who are not considered candidates for intensive salvage therapy. Post-transplant survival rates are encouraging and warrant further investigation of IVO monotherapy or combination salvage therapies prior to HCT. Clinical trial information: NCT02074839 .
Allogeneic HCT provides a potentially curative option for R/R AML. Disease status at transplant is a major determinant of prognosis, with patients typically receiving salvage chemotherapy prior to ...HCT to induce remission. IVO is an oral, targeted inhibitor of mutant IDH1 (mIDH1) approved for the treatment of adults with newly diagnosed AML ≥ 75 years of age or ineligible for IC, and those with R/R AML.
To assess HCT outcomes in patients with mIDH1 R/R AML who proceeded to HCT after responding to IVO 500 mg once daily in a phase 1 study (NCT02074839).
18 patients proceeded to HCT: median age, 61.5 years (range 36–68); 56% male; 16.7% secondary AML; 16.7% had ≥ 3 prior regimens; 11.1% had prior HCT. Median duration on IVO prior to HCT 3.9 months (range 2.1–15.2). Last responses prior to HCT were 50.0% CR, 22.2% CRi/CRp, 11.1% MLFS, 5.6% relapse, and 11.1% response not evaluable. Six- and 12-month post-HCT survival rates were 77.8% and 50.0%; median post-HCT relapse-free survival was 7.3 months (range 2.6–not estimable NE). Median OS from start of IVO was 16.8 months (95% CI 9.2, NE) for HCT patients vs 9.0 months (95% CI 7.1, 10.2) in the entire study cohort; median follow-up time was 33.2 months (range 3.2–41.9). Eight HCT patients were censored for OS: 5 are in remission, 2 relapsed and are in survival follow-up, and 1 was lost to follow-up. Among 43 patients who achieved CR as best response, median OS was NE (95% CI 9.1, NE) for the 12 CR patients who underwent HCT vs 20.5 months (95% CI 16.4, NE) for the 31 CR patients who did not undergo HCT. mIDH1 was undetectable in 1/18 (5.6%) patients (digital PCR; 0.02–0.04% mutation frequency detection limit); 6/18 (33.3%) patients had mIDH1 reduction ≤ 1%.
IVO monotherapy is a potential treatment option to induce remissions prior to HCT for patients with mIDH1 R/R AML who were not previously considered candidates for IC. Post-transplant survival rates are encouraging and warrant further investigation of IVO monotherapy or combinations prior to HCT.
Agios.
In the early 1990s, offshoring of software work to development centers in low wage countries pertained to large Western companies such as IBM and SAP who systematically attempted to take a hold of ...wage differences and resources of a global market. With the rise of the new millennium, former development countries such as India and emerging nations in Eastern Europe began to establish themselves as outsourcing vendors in the global market of IT services, drawing from a growing pool of qualified IS resources (Bode & Mertens, 2006; Hirschheim, George, & Wong, 2004). Given this global supply, offshore outsourcing of IT services has become a widely adopted part of many global organizations' sourcing strategies, especially in the labor-intensive domain of application services. Similar to domestic outsourcing, however, offshore outsourcing is associated with the typical market-based frictions. These frictions pertain to the very nature of systems development and maintenance as services that require a lot of communication and cooperation between the client (e.g., users, business managers, as well as systems analysts and architects) and the vendor (e.g., solutions architects, systems designers and programmers). It is therefore of little surprise that studies on domestic outsourcing have shown that effective relationship management that is aimed at reducing frictions is one of the key challenges and success factors of IS outsourcing (Goles, 2001; Grover, Cheon, & Teng, 1996; Kern, 1997; Lee & Kim, 1999).
Chemokine CXCL12 and receptor CXCR4 control multiple steps in primary tumor growth and metastasis in breast cancer and more than 20 other human malignancies. Mechanisms that regulate availability of ...CXCL12 in tumor microenvironments will substantially impact cancer progression and ongoing efforts to target the CXCL12-CXCR4 pathway for cancer chemotherapy. We used dual luciferase imaging to investigate CXCR7-dependent scavenging of CXCL12 in breast tumors in vivo and quantify effects of CXCR7 on tumor growth and metastasis of a separate population of CXCR4+ breast cancer cells. In a mouse xenograft model of human breast cancer, in vivo imaging showed that malignant cells expressing CXCR7 reduced bioluminescent CXCL12 secreted in the primary tumor microenvironment. Capitalizing on sensitive detection of bioluminescent CXCL12, we also demonstrated that CXCR7+ cells reduced amounts of chemokine released from orthotopic tumors into the circulation. Immunofluorescence staining of human primary breast cancers showed expression of CXCR4 and CXCR7 on malignant cells in ≈30% of cases. In most cases, CXCR4 and CXCR7 predominantly were expressed on separate populations of malignant cells in a tumor. We modeled these cases of human breast cancer by co-implanting tumor xenografts with CXCR4+ breast cancer cells, human mammary fibroblasts secreting CXCL12, and CXCR7+ or control breast cancer cells. Bioluminescence imaging showed that CXCR7+ breast cancer cells enhanced proliferation of CXCR4+ breast cancer cells in orthotopic tumors and spontaneous metastases. Treatment with a small-molecule inhibitor of CXCR7 chemokine limited the growth of CXCR4+ breast cancer cells in tumors that also contained malignant CXCR7+ cells. These studies establish a new in vivo imaging method to quantify chemokine scavenging by CXCR7 in the tumor microenvironment and identify that CXCR7+ cells promote growth and metastasis of CXCR4+ breast cancer cells.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-a new coronavirus that has led to a worldwide pandemic
-has a furin cleavage site (PRRAR) in its spike protein that is absent in other ...group-2B coronaviruses
. To explore whether the furin cleavage site contributes to infection and pathogenesis in this virus, we generated a mutant SARS-CoV-2 that lacks the furin cleavage site (ΔPRRA). Here we report that replicates of ΔPRRA SARS-CoV-2 had faster kinetics, improved fitness in Vero E6 cells and reduced spike protein processing, as compared to parental SARS-CoV-2. However, the ΔPRRA mutant had reduced replication in a human respiratory cell line and was attenuated in both hamster and K18-hACE2 transgenic mouse models of SARS-CoV-2 pathogenesis. Despite reduced disease, the ΔPRRA mutant conferred protection against rechallenge with the parental SARS-CoV-2. Importantly, the neutralization values of sera from patients with coronavirus disease 2019 (COVID-19) and monoclonal antibodies against the receptor-binding domain of SARS-CoV-2 were lower against the ΔPRRA mutant than against parental SARS-CoV-2, probably owing to an increased ratio of particles to plaque-forming units in infections with the former. Together, our results demonstrate a critical role for the furin cleavage site in infection with SARS-CoV-2 and highlight the importance of this site for evaluating the neutralization activities of antibodies.
Unrelated individuals can produce genetically similar clones of antibodies, known as public clonotypes, which have been seen in responses to different infectious diseases, as well as healthy ...individuals. Here we identify 37 public clonotypes in memory B cells from convalescent survivors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or in plasmablasts from an individual after vaccination with mRNA-encoded spike protein. We identify 29 public clonotypes, including clones recognizing the receptor-binding domain (RBD) in the spike protein S1 subunit (including a neutralizing, angiotensin-converting enzyme 2 ACE2-blocking clone that protects in vivo) and others recognizing non-RBD epitopes that bind the S2 domain. Germline-revertant forms of some public clonotypes bind efficiently to spike protein, suggesting these common germline-encoded antibodies are preconfigured for avid recognition. Identification of large numbers of public clonotypes provides insight into the molecular basis of efficacy of SARS-CoV-2 vaccines and sheds light on the immune pressures driving the selection of common viral escape mutants.
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•Public clonotypes are shared among SARS-CoV-2-vaccinated and -infected individuals•Group 3 antibodies share the same binding site as CR3022 but neutralize variants•Germline-revertant forms of public clonotypes bind efficiently to spike protein•Public clonotype responses inform research on new viral variants of concern
Chen et al. describe neutralizing and non-neutralizing public antibodies elicited to SARS-CoV-2 spike in vaccinated and naturally infected individuals. Germline-revertant forms of some public clonotypes bind efficiently to spike protein, suggesting common germline-encoded properties for recognition.
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