Chimeric antigen receptor (CAR) T-cell therapies have shown impressive results in patients with hematological malignancies; however, little success has been achieved in the treatment of solid tumors. Recently, macrophages (MΦs) were identified as an additional candidate for the CAR approach, and initial proof of concept studies using peripheral blood-derived monocytes showed antigen-redirected activation of CAR MΦs. However, some patients may not be suitable for monocyte-apheresis, and prior cancer treatment regimens may negatively affect immune cell number and functionality. To address this problem, we here introduce primary human hematopoietic stem and progenitor cells (HSPCs) as a cell source to generate functional CAR MΦs ex vivo. Our data showed successful CAR expression in cord blood (CB)-derived HSPCs, with considerable cell expansion during differentiation to CAR MΦs. HSPC-derived MΦs showed typical MΦ morphology, phenotype, and basic anti-bacterial functionality. CAR MΦs targeting the carcinoembryonic antigen (CEA) and containing either a DAP12- or a CD3ζ-derived signaling domain showed antigen redirected activation as they secreted pro-inflammatory cytokines specifically upon contact with CEA⁺ target cells. In addition, CD3ζ-expressing CAR MΦs exhibited significantly enhanced phagocytosis of CEA⁺ HT1080 cells. Our data establish human HSPCs as a suitable cell source to generate functional CAR MΦs and further support the use of CAR MΦs in the context of solid tumor therapy.

Background: Preeclampsia (PE), a hypertensive disorder of pregnancy affects 2-8% of women and is associated with increased cardiovascular disease (CVD) risk later in life. There is little information about the knowledge of obstetrician-gynecologists in German outpatient care setting regarding the future health risk of PE and knowledge of the current guidelines on treatment and counseling patients post PE. This study aimed to assess whether obstetrician-gynecologists are aware of PE’s association with maternal long-term adverse outcomes and providing appropriate counseling. Methods: A random sample of 500 obstetrician-gynecologists in the federal state of Lower Saxony was mailed a survey and a reminder with a second copy of the survey. The questionnaire elicited both personal information, and knowledge on future disease risks, e.g. cardiovascular disease (CVD) and current guidelines as well as on counseling practice. Descriptive analysis was used to analyze the responses. Results: A total of 212 obstetrician-gynecologists (42.4%) responded to the questionnaire. A large proportion of physicians stated that PE was associated with a higher risk for the development for hypertension (86.6%), stroke (78.5%) and kidney disease (78.0%). Of the participants 75.8% reported that women after PE have a shorter life expectancy. Respondents with knowledge of the current guidelines of the German Association of Obstetrics and Gynecology concerning follow up and risk management of PE (45.2%) were more often aware of the development of CVD and stroke and counseled patients on self -blood-pressure measurement, meaning and long-term-risks of PE and attached importance to family history of PE compared to physicians with no knowledge of the guidelines. Conclusion: Although the majority of obstetrician-gynecologists were aware of higher CVD risk after PE, weaknesses exist in the follow up care and counseling of these patients. These deficiencies would be amendable to directed educational activities to improve the implementation of current guidelines.

This article presents contemporary opinion on the role of alpha-fetoprotein in oncologic diagnostics and treatment. This role stretches far beyond the already known one—that of the biomarker of hepatocellular carcinoma. The turn of the 20th and 21st centuries saw a significant increase in knowledge about the fundamental role of AFP in the neoplastic processes, and in the induction of features of malignance and drug resistance of hepatocellular carcinoma. The impact of AFP on the creation of an immunosuppressive environment for the developing tumor was identified, giving rise to attempts at immunotherapy. The paper presents current and prospective therapies using AFP and its derivatives and the gene therapy options. We directed our attention to both the benefits and risks associated with the use of AFP in oncologic therapy.

Following allogeneic hematopoietic stem cell transplantation (HSCT), interferon (IFN)-gamma levels in the recipient’s body can strongly influence the clinical outcome. Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) are lucrative as biological tolerance-inducers in HSCT settings. Hence, we studied the molecular mechanism of how UC-MSCs influence natural killer (NK) cell-mediated IFN-gamma production. Allogeneic NK cells were cultured in direct contact with UC-MSCs or cell free supernatants from MSC cultures (MSC conditioned media). We found that soluble factors secreted by UC-MSCs strongly suppressed IL-12/IL-18-induced IFN-gamma production by NK cells by reducing phosphorylation of STAT4, NF-kB as well as T-bet activity. UC-MSCs secreted considerable amounts of Activin-A, which could suppress IFN-gamma production by NK cells. Neutralisation of Activin-A in MSC-conditioned media significantly abrogated their suppressive abilities. Till date, multiple groups have reported that prostaglandin (PG)-E2 produced by MSCs can suppress NK cell functions. Indeed, we found that inhibition of PGE2 production by MSCs could also significantly restore IFN-gamma production. However, the effects of Activin-A and PGE2 were not cumulative. To the best of our knowledge, we are first to report the role of Activin-A in MSC-mediated suppression of IFN-gamma production by NK cells.

The early fetal ultrasound assessment at 11 – 13⁺⁶ weeks of gestation remains the cornerstone of care despite the progress in diagnosing fetal chromosomal defects using cell-free fetal DNA (cffDNA) from the maternal circulation. The measurement of nuchal translucency (NT) allows the risk calculation for the fetal trisomies 21, 18 and 13 but also gives information on those fetal chromosomal defects which are at present unable to be detected using cffDNA. Nuchal translucency is the only auditable parameter at 11 – 13⁺⁶ weeks and gives thus information on the quality of the first trimester anomaly scan. In addition it gives indirect information on the risks for fetal defects and for cardiac anomalies. Also the chances for a healthy live baby can be estimated. As experience with first trimester anomaly scanning increases, and the resolution of the ultrasound equipment has increased substantially, more and more details of the fetal anatomy become accessible at the first trimester scan. Therefore fetal anatomical defects and complex anomalies have become amenable to examination in the first trimester. This guideline describes compulsory and optional parameters for investigation at the first trimester scan and outlines a structured method of examining a first trimester fetus at 11 – 13⁺⁶ weeks of gestation. Die frühe Ultraschalluntersuchung zwischen 11 – 13⁺⁶ Schwangerschaftswochen stellt trotz der Fortschritte in der molekularen Diagnostik von Chromosomenstörungen aus dem Blut der Mutter (cffDNA) die Grundlage für Diagnostik und Therapie sowie des Schwangerschaftsmanagement dar. Die Messung der fetalen Nackentransparenz (NT) ermöglicht die Risikoberechnung für die fetalen Trisomien 21, 18 und 13 und liefert auch Informationen über solche fetalen Chromosomenstörungen, welche gegenwärtig durch cffDNA nicht erkannt werden können. Die fetale Nackentransparenzmessung ist der einzige auditierbare Parameter zwischen 11 – 13⁺⁶ SSW und gibt so Auskunft über die Qualität der Ersttrimester Fehlbildungsdiagnostik. Zusätzlich liefert sie indirekte Informationen über die Risiken für Fehlbildungen und Herzfehler. Auch kann die Wahrscheinlichkeit für die Geburt eines lebenden gesunden Babys abgeschätzt werden. Während die Erfahrung mit der Ersttrimester Fehlbildungsdiagnostik steigt und die Auflösung der Ultraschallgeräte substanziell zugenommen hat, werden mehr und mehr Details der fetalen Anatomie einer Untersuchung im ersten Trimenon zugängig. Es werden obligatorische und fakultative Untersuchungsschritte für den Ersttrimester Fehlbildungsultraschall beschrieben und ein strukturierter Untersuchungsgang aufgezeigt, um einen Ersttrimesterfeten zum Zeitpunkt 11 – 13⁺⁶ Schwangerschaftswochen zu untersuchen.

The following AWMF guideline (DGGG/AGG & DEGUM responsible) deals with the diagnosis, screening and management of twins as well as the timing and mode of birth. Twin pregnancies can be classified as dichorionic diamniotic (DC DA), monochorionic diamniotic (MC DA) and monochorionic monoamniotic (MC MA) which are always monochorionic. Twin pregnancies can be concordant (both twins are affected) or discordant (only one twin is affected) for chromosomal defects, malformations, growth restriction and hemodynamic disorders. Chorionicity is the prognostically most significant parameter. Monochorial twins have significantly higher risks of intrauterine morbidity and mortality compared to dichorial twins. In particular, general aspects of twin pregnancies such as dating, determination of chorionicity and amnionicity, the labeling of twin fetuses and the perinatal switch phenomenon are discussed. Routine monitoring of MC and DC twin pregnancies with ultrasound at 11–13^+ 6 weeks of gestation for chromosomal defects, invasive prenatal diagnosis, first-trimester NT or CRL discrepancies, early diagnosis of fetal anatomical defects, and management of twins with abnormalities, including selective fetocide, is described. Second trimester screening and management for preterm birth, intrauterine selective growth restriction (sFGR), classification of monochorial twins with sFGR, and management of the surviving twin after the death of the co-twin are described. Complications exclusively affecting MC twins include Twin to Twin Transfusion Syndrome (TTTS) with the important topics screening, prognosis, complications of laser therapy, timing of delivery, risks for brain abnormalities and delayed neurological development, Twin Anemia-Polycythemia Sequence (TAPS) and Twin Reversed Arterial Perfusion (TRAP) Sequence. This also includes MC MA twins as well as conjoined twins. Finally, the birth mode and time for DC and MC twin pregnancies are described. The information is summarized in 62 recommendations for action, 4 tables and 8 illustrations with comprehensive background texts. The guideline is an international guideline adaptation (ISUOG, NICE) as well as a systematic literature search and is up-to-date. ^* Constantin von Kaisenberg and Philipp Klaritsch share first authorship. Received: 29 May 2020 Accepted: 09 August 2020 Publication Date: 05 October 2020 (online) © 2020. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany