Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8α+ conventional dendritic cells

Although CD103-expressing dendritic cells (DCs) are widely present in nonlymphoid tissues, the transcription factors controlling their development and their relationship to other DC subsets remain unclear. Mice lacking the transcription factor Batf3 have a defect in the development of CD8α(+) conventional DCs (cDCs) within lymphoid tissues. We demonstrate that Batf3(−/−) mice also lack CD103(+)CD11b(−) DCs in the lung, intestine, mesenteric lymph nodes (MLNs), dermis, and skin-draining lymph nodes. Notably, Batf3(−/−) mice displayed reduced priming of CD8 T cells after pulmonary Sendai virus infection, with increased pulmonary inflammation. In the MLNs and intestine, Batf3 deficiency resulted in the specific lack of CD103(+)CD11b(−) DCs, with the population of CD103(+)CD11b(+) DCs remaining intact. Batf3(−/−) mice showed no evidence of spontaneous gastrointestinal inflammation and had a normal contact hypersensitivity (CHS) response, despite previous suggestions that CD103(+) DCs were required for immune homeostasis in the gut and CHS. The relationship between CD8α(+) cDCs and nonlymphoid CD103(+) DCs implied by their shared dependence on Batf3 was further supported by similar patterns of gene expression and their shared developmental dependence on the transcription factor Irf8. These data provide evidence for a developmental relationship between lymphoid organ–resident CD8α(+) cDCs and nonlymphoid CD103(+) DCs

Multicenter development of a PET-based risk assessment tool for product-specific outcome prediction in large B-cell lymphoma patients undergoing CAR T-cell therapy

Purpose: The emergence of chimeric antigen receptor (CAR) T-cell therapy fundamentally changed the management of individuals with relapsed and refractory large B-cell lymphoma (LBCL). However, real-world data have shown divergent outcomes for the approved products. The present study therefore set out to evaluate potential risk factors in a larger cohort. Methods: Our analysis set included 88 patients, treated in four German university hospitals and one Italian center, who had undergone 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (PET) before CAR T-cell therapy with tisagenlecleucel or axicabtagene ciloleucel. We first determined the predictive value of conventional risk factors, treatment lines, and response to bridging therapy for progression-free survival (PFS) through forward selection based on Cox regression. In a second step, the additive potential of two common PET parameters was assessed. Their optimal dichotomizing thresholds were calculated individually for each CAR T-cell product. Results: Extra-nodal involvement emerged as the most relevant of the conventional tumor and patient characteristics. Moreover, we found that inclusion of metabolic tumor volume (MTV) further improves outcome prediction. The hazard ratio for a PFS event was 1.68 per unit increase of our proposed risk score (95% confidence interval [1.20, 2.35], P = 0.003), which comprised both extra-nodal disease and lymphoma burden. While the most suitable MTV cut-off among patients receiving tisagenlecleucel was 11 mL, a markedly higher threshold of 259 mL showed optimal predictive performance in those undergoing axicabtagene ciloleucel treatment. Conclusion: Our analysis demonstrates that the presence of more than one extra-nodal lesion and higher MTV in LBCL are associated with inferior outcome after CAR T-cell treatment. Based on an assessment tool including these two factors, patients can be assigned to one of three risk groups. Importantly, as shown by our study, metabolic tumor burden might facilitate CAR T-cell product selection and reflect the individual need for bridging therapy

Targeting of B and T lymphocyte associated (BTLA) prevents graft-versus-host disease without global immunosuppression

One-time treatment with an antibody against BTLA provides long-term protection against graft-versus-host disease without affecting effector T cell responses to tumors or pathogens

Short-Term Incentive Effects of a Reduction in the NOL Carryback Period

ABSTRACT We examine whether the Taxpayer Relief Act of 1997 (TRA 1997), which reduced the net operating loss (NOL) carryback period from three to two years, created a short-term incentive effect to shift income to accelerate loss recognition in the tax year 1997. We find that our sample of NOL firms in the treatment year of 1997 display higher (lower) levels of income-decreasing (-increasing) earnings management, compared to a control sample of loss firms. When we focus strictly on the NOL firms in the transition year, we find that firms with higher reported income tax expense in fiscal year 1995 display greater income shifting to accelerate loss recognition. We also find that income shifting is greater for treatment NOL firms that expect to report losses in the post-TRA 1997 regime. Overall, our study highlights how changes in tax law provisions (as opposed to tax rate changes) affect firms' reporting behavior.</jats:p

Screening for Cervical Cancer - Minimise Risks - Maximise Benefits. Need for Adaptation in Germany in Light of the European Guidelines and Their Objectives

The national cancer plan calls for adjustment of the early detection scheme for cervical cancer to the quality requirements of the "European guidelines for quality assurance in cervical cancer screening". The existing scheme should be further developed and carried out in an organized, population- based framework. The objective is to lower the incidence and mortality of cervical cancer while minimising the risks and optimising the benefits of the scheme. The self-determined choice of the patients should be respected. The competence for this task falls in the medical field of activity. The adaptation includes an organisational further development and, in part, re-organisation of the established early detection scheme for cervical cancer. If the national cancer plan is considered as a concept for the discursive further development of the healthcare, the experts from different areas of the system are encouraged to participate. To go to a new version of the national directive for early detection of cancer that will define the procedure in the Federal Republic in future first requires a consensus of the fields of action with regard to the specified objectives of the transformation. The heterogeneity of the approaches in Europe ( even within individual countries) as well as the results clearly show that Germany has to find and define its own pathway. The presented overview of the pending fields of action could serve as a basis for the development process and the work of a multisectoral task force in the field of gynaecology

Cervical Cancer Screening: Defining the Need for Research

With the development of a National Cancer Plan published in 2012, Germany has followed the recommendations of the WHO and the EU. The first area of action listed in Germanyʼs National Cancer Plan is improving the early detection of cancer. Both citizens and medical specialists are encouraged to take responsibility themselves and contribute to the efforts being made to meet the challenge of cancer. Screening for cervical cancer has long been an integral part of the German Directive for the Early Detection of Cancer and now – following the recommendations given in the European Guideline – an organised screening approach shall be developed to maximise the benefits and minimise the risks through a partial reorganisation of existing structures. Before this can be rolled out nationwide, it will be necessary to check the feasibility and suitability of new contents and organisational structures. The Federal Joint Committee which is largely responsible for the process according to the draft law on the implementation of the National Cancer Plan has emphasised the importance of evidence-based medicine and of collaboration between the autonomous governing bodies within the healthcare system to obtain viable results. For medical specialists, the follow-on question is which areas will need more research in future. New process steps need to be developed and verified to see whether they offer evidence which will support defined approaches or whether such evidence needs to be newly compiled, e.g. by testing invitation procedures for screening in trial schemes. The experience gained during the implementation of the existing directive on early detection of cancer should be integrated into the new process. Research initiated by specialists could encourage the development of a new version of the Directive for the Early Detection of Cancer suitable for the Germanyʼs healthcare system