Search

The exceptionally high positive charge of the histones, concentrated in the N- and C-terminal tails, is believed to contribute to the stability of the nucleosome by neutralizing the negative charge of the nucleosomal DNA. We find, on the contrary, that the high positive charge contributes to instability, performing an essential function in chromatin remodeling. We show that the tails are required for removal of the histone octamer by the RSC chromatin remodeling complex, and this function is not due to direct RSC–tail interaction. We also show that the tails are required for histone octamer transfer from nucleosomes to DNA, and this activity of the tails is a consequence of their positive charge. Thus, the histone tails, intrinsically disordered protein regions, perform a critical role in chromatin structure and transcription, unrelated to their well-known role in regulation through posttranscriptional modification.

Figure S4

Supplementary Data

PD-1 immune checkpoint inhibitors have produced encouraging results in patients with hepatocellular carcinoma (HCC). However, what determines resistance to anti–PD-1 therapies is unclear. We created a novel genetically engineered mouse model of HCC that enables interrogation of how different genetic alterations affect immune surveillance and response to immunotherapies. Expression of exogenous antigens in MYC;Trp53−/− HCCs led to T cell–mediated immune surveillance, which was accompanied by decreased tumor formation and increased survival. Some antigen-expressing MYC;Trp53−/− HCCs escaped the immune system by upregulating the β-catenin (CTNNB1) pathway. Accordingly, expression of exogenous antigens in MYC;CTNNB1 HCCs had no effect, demonstrating that β-catenin promoted immune escape, which involved defective recruitment of dendritic cells and consequently impaired T-cell activity. Expression of chemokine CCL5 in antigen-expressing MYC;CTNNB1 HCCs restored immune surveillance. Finally, β-catenin–driven tumors were resistant to anti–PD-1. In summary, β-catenin activation promotes immune escape and resistance to anti–PD-1 and could represent a novel biomarker for HCC patient exclusion.Significance:Determinants of response to anti–PD-1 immunotherapies in HCC are poorly understood. Using a novel mouse model of HCC, we show that β-catenin activation promotes immune evasion and resistance to anti–PD-1 therapy and could potentially represent a novel biomarker for HCC patient exclusion.See related commentary by Berraondo et al., p. 1003.This article is highlighted in the In This Issue feature, p. 983

Hybrid meat products represent a promising, more sustainable alternative to all-meat formulations. However, differences among plant- and animal-based proteins may alter traditional handling and final product properties. In this study, pork meat was partially replaced with texturized pumpkin seed proteins at 12.5, 25, 37.5, and 50% to obtain dry-cured hybrid meat sausages and their ripening (acidification, drying) during 21 days and final product properties (texture, sensory) were characterized and compared to a control (all-meat formulation). The drying behavior and distribution of moisture and free water of hybrids with extrudate contents of 12.5 and 25% were comparable to the sample made with meat and no significant (p > 0.05) differences in proximate composition were found. In contrast, higher meat replacement levels resulted in distinct changes of compositional and textural attributes i.e. chewiness was decreasing by up to 70%. Results suggested 25% of extrudates as an important threshold in manufacture of hybrid dry-cured sausages due to alterations in their ability to bind or release water. Results may be used to understand the influence of alternative texturized proteins in hybrid formulations and help product developers to understand related process and product relevant changes.

Small molecules that bind in the minor groove of DNA are in clinical use as antibiotics and antitumor drugs. Two members of this class of molecules, netropsin and chromomycin, are shown here to displace DNA from the nucleosome and promote transfer of the histone octamer to an acceptor protein. The effects of these groove-binding molecules are exploited to address an outstanding problem in the mechanism of the RSC chromatin remodeling complex. RSC and other remodeling complexes are DNA translocases, acting near the center of the nucleosomal DNA, but translocation is apparently impossible because DNA cannot slide across the histone surface in the nucleosome. Netropsin and chromomycin promote the release of DNA from the histone surface, enhance the formation of a RSC–nucleosome complex, and synergize with RSC in chromatin remodeling. These findings are in keeping with an involvement of bulge translocation in chromatin remodeling.

Zusammenfassung Hintergrund Schwangerschaft und Schmerzen unterschiedlicher Herkunft sind eine ungünstige Kombination, die alle BehandlerInnen vor besondere Herausforderungen stellt. Schmerzen beeinflussen die Homöostase des Menschen negativ. Compliance der Patientin und fundiertes Wissen über Fetotoxizität und Teratogenität von Analgetika sind nötig, um die Balance zwischen Therapie der Mutter und Sicherheit des Ungeborenen zu wahren. Ziel der Arbeit ExpertInnen verschiedener Disziplinen, die mit der Betreuung von schwangeren Schmerzpatientinnen betraut sind, haben sich zusammengeschlossen, um medikamentöse und nichtmedikamentöse Therapiekonzepte zu erstellen, mit dem Ziel, eine suffiziente Analgesie von schwangeren Schmerzpatientinnen zu ermöglichen. Material und Methode Relevante Fragestellungen wurden durch ExpertInnen formuliert und einer Literatursuche unterzogen. Kombiniert mit weiteren nationalen und internationalen Empfehlungen wurden Behandlungskonzepte entwickelt, interdisziplinär diskutiert und im Anschluss Kernaussagen erstellt, die mit Empfehlungsgraden abgestuft wurden. Ergebnisse Abhängig vom Trimenon können bei Schmerzen Paracetamol, Ibuprofen, Diclofenac, Metamizol und Opioide wohlüberlegt verabreicht werden, besondere Vorsicht ist bei nichtsteroidalen Antirheumatika (NSAR) im letzten Trimenon geboten. COX-2-Hemmer werden nicht empfohlen. Bei neuropathischen Schmerzen gelten Amitriptylin, Duloxetin, Venlafaxin als sicher. Bei starker Migräne kann Sumatriptan zum Einsatz kommen. Nichtmedikamentöse Therapien wie transkutane elektrische Nervenstimulation (TENS-Therapie), Kinesio-Tapes und Akupunktur gelten als sicher. Lymphdrainagen werden bei Ödemen empfohlen, sofern sie nicht durch eine Präeklampsie bedingt sind. Schlussfolgerung Die Therapie sollte mit einer nichtmedikamentösen Behandlung beginnen und eskalierend in einer Kombination aus medikamentösen und nichtmedikamentösen Konzepten enden.

Type-2 cytokines are hypothesized to promote an immune-permissive milieu for cancer to grow. Through scRNAseq and CITEseq on human non-small cell lung cancer (NSCLC) and the krasG12Dp53−/− lung cancer model we previously described a tumor-enriched dendritic cell program of concomitant immunosuppression and activation which we termed the “mregDC,” that was also notable for a strong Th2 immune signature. We subsequently blocked the canonical Th2 cytokine IL-4 in vivo in tumor-bearing mice, and found that this significantly decreased lung tumor burden, which was recapitulated in multiple other tumor models. Furthermore, this effect synergized with PD-L1 blockade. Based on this data, we designed a clinical trial to assess if the addition of dupilumab, an anti-IL-4Ra antibody widely used for treatment of atopic diseases, may rescue responses to checkpoint blockade (NCT05013450). In this Phase 1b/2 trial, up to 21 patients with NSCLC that have progressed on prior anti-PD-(L)1 therapy will be enrolled. Patients continue PD-(L)1 blockade while receiving three doses of dupilumab, administered every three weeks, with initial radiographic assessment of response at 9 weeks. Patients without progression of disease then continue anti-PD-(L)1 alone. The primary endpoint of Phase 1b is safety and tolerability, while the primary endpoint of Phase 2, inclusive of patients from Phase 1b, is efficacy as per RECIST. Patients undergo pre- and on-treatment biopsies, pre-treatment stool collection for microbiome analysis, as well as blood collection at 6 timepoints for PBMCs, plasma and ctDNA. Here we report the Phase 1b portion that has completed accrual in which 6 patients were enrolled in a Phase 1b run-in to confirm safety and tolerability. There were no adverse events attributable to study treatment during Phase 1b in any of the 6 patients treated. Serum proteomic analysis of this cohort revealed that dupilumab treatment induced a profound increase in proinflammatory/tumoricidal immune effector molecules, and reversed a systemic Th2 cytokine signature. Furthermore, mass cytometry of circulating immune populations showed an expansion of cytotoxic lymphocyte populations and a reduction in immunosuppressive myeloid cells. The fourth patient treated on trial who had progressive disease after 9 cycles of consolidation checkpoint blockade following concurrent chemoradiation for squamous NSCLC was enrolled, and had a partial response at 9 weeks, with deepening of the PR at 25 weeks. This patient’s on-treatment biopsy showed a major increase in CD8 T cell tumor infiltration. Histological analysis using spatial transcriptomics and multiplexed imaging from these patients is ongoing, and will be reported at the conference. Based on this promising signal in the initial lead-in, the trial will proceed through Simon’s Two Stage design and enroll a full 21 patients as part of the Phase 2 expansion cohort. This clinical trial is funded entirely through philanthropy support through the Tisch Cancer Institute. Citation Format: Thomas Urban Marron, Nelson M. LaMarche, Matthew D. Park, Samarth Hegde, Bailey Fitzgerald, Clotilde Hennequin, Raphael Mattiuz, Meriem Belabed, Jessica Le Berichel, Barbara Maier, Nicole Hall, Justin Miller, Deborah B. Doroshow, Nicholas Rohs, Rajwanth Veluswamy, Nicholas Venturini, Jorge E. Gomez, Christian Rolfo, David Yankelevitz, Udit Chaddha, Timothy Harkin, Mary B. Beasley, Seunghee Kim-schulze, Sacha Gnjatic, Fred R. Hirsch, Miriam Merad. Rescuing response to ICI by blocking the type-2 immune axis in patients with NSCLC progressing on immunotherapy: A phase 1b/2 trial of dupilumab administered with checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT199.

Checkpoint blockade therapies have improved cancer treatment, but such immunotherapy regimens fail in a large subset of patients. Conventional type 1 dendritic cells (DC1s) control the response to checkpoint blockade in preclinical models and are associated with better overall survival in patients with cancer, reflecting the specialized ability of these cells to prime the responses of CD8+ T cells1–3. Paradoxically, however, DC1s can be found in tumours that resist checkpoint blockade, suggesting that the functions of these cells may be altered in some lesions. Here, using single-cell RNA sequencing in human and mouse non-small-cell lung cancers, we identify a cluster of dendritic cells (DCs) that we name ‘mature DCs enriched in immunoregulatory molecules’ (mregDCs), owing to their coexpression of immunoregulatory genes (Cd274, Pdcd1lg2 and Cd200) and maturation genes (Cd40, Ccr7 and Il12b). We find that the mregDC program is expressed by canonical DC1s and DC2s upon uptake of tumour antigens. We further find that upregulation of the programmed death ligand 1 protein—a key checkpoint molecule—in mregDCs is induced by the receptor tyrosine kinase AXL, while upregulation of interleukin (IL)-12 depends strictly on interferon-γ and is controlled negatively by IL-4 signalling. Blocking IL-4 enhances IL-12 production by tumour-antigen-bearing mregDC1s, expands the pool of tumour-infiltrating effector T cells and reduces tumour burden. We have therefore uncovered a regulatory module associated with tumour-antigen uptake that reduces DC1 functionality in human and mouse cancers. After taking up tumour-associated antigens, dendritic cells in mouse and human tumours upregulate a regulatory gene program that limits dendritic cell immunostimulatory function, and modulating this program can rescue antitumor immunity in mice.

Purpose This is an official S3-guideline of the German Society of Gynaecology and Obstetrics (DGGG), the Austrian Society of Gynaecology and Obstetrics (ÖGGG) and the Swiss Society of Gynaecology and Obstetrics (SGGG). The guideline contains evidence-based information and recommendations on indications, complications, methods and care associated with delivery by caesarean section for all medical specialties involved as well as for pregnant women. Methods This guideline has adapted information and recommendations issued in the NICE Caesarean Birth guideline. This guideline also considers additional issues prioritised by the Cochrane Institute and the Institute for Research in Operative Medicine (IFOM). The evaluation of evidence was based on the system developed by the Scottish Intercollegiate Guidelines Network (SIGN). A multi-part nominal group process moderated by the AWMF was used to compile this S3-level guideline. Recommendations Recommendations on consultations, indications and the process of performing a caesarean section as well as the care provided to the mother and neonate were drawn up.

Macrophages have a key role in shaping the tumour microenvironment (TME), tumour immunity and response to immunotherapy, which makes them an important target for cancer treatment1,2. However, modulating macrophages has proved extremely difficult, as we still lack a complete understanding of the molecular and functional diversity of the tumour macrophage compartment. Macrophages arise from two distinct lineages. Tissue-resident macrophages self-renew locally, independent of adult haematopoiesis3–5, whereas short-lived monocyte-derived macrophages arise from adult haematopoietic stem cells, and accumulate mostly in inflamed lesions1. How these macrophage lineages contribute to the TME and cancer progression remains unclear. To explore the diversity of the macrophage compartment in human non-small cell lung carcinoma (NSCLC) lesions, here we performed single-cell RNA sequencing of tumour-associated leukocytes. We identified distinct populations of macrophages that were enriched in human and mouse lung tumours. Using lineage tracing, we discovered that these macrophage populations differ in origin and have a distinct temporal and spatial distribution in the TME. Tissue-resident macrophages accumulate close to tumour cells early during tumour formation to promote epithelial–mesenchymal transition and invasiveness in tumour cells, and they also induce a potent regulatory T cell response that protects tumour cells from adaptive immunity. Depletion of tissue-resident macrophages reduced the numbers and altered the phenotype of regulatory T cells, promoted the accumulation of CD8+ T cells and reduced tumour invasiveness and growth. During tumour growth, tissue-resident macrophages became redistributed at the periphery of the TME, which becomes dominated by monocyte-derived macrophages in both mouse and human NSCLC. This study identifies the contribution of tissue-resident macrophages to early lung cancer and establishes them as a target for the prevention and treatment of early lung cancer lesions. Single-cell RNA sequencing and imaging of macrophages in human non-small cell lung cancer and in a mouse model of lung adenocarcinoma show that tissue-resident macrophages have a key role in early tumour progression.

Objectives To report clinical data on maternal outcome, mode of delivery and immediate neonatal outcome in women infected with COVID-19. Methods Retrospective data collection. Results A total of 8.6% of the total population of hospitalised SARS-CoV-2 positive pregnant women were admitted to a critical care unit. The premature birth rate for births before 34+0 weeks of gestation among pregnant women who tested positive for SARS-CoV-2 was 7.1%. One newborn (3.6%) tested positive for SARS-CoV-2 two days after birth and showed symptoms. Conclusions Pregnant women with COVID-19 seem to be at higher risk of invasive ventilation, admission to a critical care unit and preterm birth, and should therefore be considered a high-risk-population.

Objectives Report of clinical data on maternal outcomes, mode of delivery and immediate neonatal outcome in women infected with COVID-19, as well as clarifying whether the transmission of SARS-CoV-2 could occur in utero (congenital), intrapartum, and/or postnatally through breastmilk, amniotic fluid or cord blood. Methods Retrospective data collection. Evidence of vertical transmission was assessed by testing for SARS-CoV-2 in amniotic fluid, cord blood, maternal liquor, breast milk and neonatal pharyngeal swab samples. Results 8.9% (n=8) of the total population of hospitalized SARS-CoV-2 positive pregnant women were admitted to a critical care unit, one (0.9%) needed extracorporal membrane oxygenation (ECMO) and one woman died (0.9%). The premature birth rate before 34+0 weeks of gestational age of 8.2% (n=8) among pregnant women who tested positive for SARS-CoV-2, was almost four times higher than among the total population of pregnant women in Austria. Two newborns (2%) were tested positive for SARS-CoV-2 after birth. No SARS-CoV-2 was found in amniotic fluid, cord blood, maternal liquor or breast milk using polymerase chain reaction (PCR). Conclusions Pregnant women with COVID-19 seem to be at a higher risk of invasive ventilation, admission to a critical care unit and pre-term birth and therefore they should be considered as a high-risk population. The risk of congenital or intrapartal infection seems to be insignificant.

Macrophages (MΦ) form a highly heterogenous compartment within tumor lesions. Using lineage tracing, we recently established that advanced NSCLC lesions in both mice and humans are depleted of tissue-resident macrophages (TRM) and are mainly populated by monocyte-derived MΦ (MoMΦ). Here, we show that TREM2+ MoMΦ dominate murine and human NSCLC lesions. Importantly, using mice reconstituted with mixed TREM2-deficient and -proficient bone marrow cells, we identified a cell-intrinsic ability for TREM2 to drive an efferocytosis-associated molecular program that profoundly reduced the expression of immunogenic molecules in tumor-infiltrating MoMΦ. Trem2 deletion significantly dampened this program, reversed MoMΦ immunosuppression, and significantly enhanced the accumulation of activated NK cells and cDC1 in tumor lesions. Notably, Trem2 deletion reduced lung cancer progression in an NK cell-dependent manner. Taken together, our results underscore the potential for therapeutic inhibition of TREM2 to mount a potent anti-tumor immune response by unleashing cooperative NK/cDC1 cell function.

TPS9139 Background: Although tumor microenvironments may contain chronic inflammatory cells, this milieu can lead to immune evasion and may contribute to resistance to immunotherapy. Dendritic cells are one of the most potent cross presenters of tumor antigen, and their function is crucial to tumor-directed adaptive immune responses. In the KP mouse model of lung adenocarcinoma (KrasG12D; Tp53-/-), we recently identified interleukin-4 (IL-4)-driven suppression of tumor-antigen charged dendritic cells, which was similarly seen in human lung cancer lesions (Maier, B., et al., A conserved dendritic-cell regulatory program limits antitumour immunity. Nature, 2020.580[7802]:257-262). In the mouse model IL-4 blockade resulted in an increase in IL-12, IFNg and TNF in CD8+ T cells and decreased tumor burden, and further antitumor activity was seen when combined with PD-L1 blockade. Dupilumab is a fully human monoclonal antibody that blocks the IL-4 receptor alpha subunit which disrupts signaling through receptors for both IL-4 and IL-13; it is FDA approved for patients with multiple atopic conditions, in whom series adverse effects are rare. Based on this pre-clinical data, we hypothesize that the addition of dupilumab to anti PD-(L)1 therapy will be well tolerated, and will rescue the anti-tumor effect of immune checkpoint blockade. Methods: This is a phase Ib/II trial. Patients with relapsed/refractory NSCLC who have received prior anti PD-(L)1 treatment are eligible for enrollment. In a phase Ib safety run-in, six patients will be enrolled in a modified set-dose 3+3 design. If no more than 1 DLT is observed during this phase, the trial will proceed to phase II. Phase II will enroll a further 15 patients in a minimax design with early stopping for futility to a maximum total of 21 patients. Patients will undergo pre-treatment biopsies and peripheral blood sampling prior to receiving 3 doses of dupilumab, administered every three weeks, in conjunction with continuing standard-of-care anti-PD-(L)1 therapy. Patients will undergo repeat biopsies 4 weeks after starting therapy. After completion of dupilumab (at 9 weeks) patients will undergo repeat staging. The primary endpoint of phase 1b is safety as measured by frequency and severity of adverse effects. The primary endpoint of phase II is overall response rate as assessed using RECIST 1.1 criteria at the time of post-dupilumab imaging. Exploratory endpoints include analysis of peripheral blood by CyTOF and O-link, and tissue biopsies will be analyzed by multiplex-IHC and bulk-RNA-sequencing. T cell receptor sequencing will be performed on tumor and matched peripheral blood samples, and circulating tumor DNA will be assessed at multiple time points. Phase 1b is currently enrolling as planned. Clinical trial information: NCT05013450.

Recent studies demonstrate that gut microbiota regulate tumor response to immune checkpoint blockade. Still, the mechanisms by which microbiota control tumor response to immunotherapy remain unclear. We colonized germ-free mice with cultured human-derived microbiota prior to tumor inoculation. While no human donor microbiota altered tumor growth, two distinct gut microbiota inhibited tumor response to anti-PD-L1. Colonization with non-responder microbiota led to reduced tumor immune cell infiltration and modified antigen presenting cell phenotype. RNA sequencing of tumor-infiltrating CD8+ T cells revealed enrichment for stem cell-like genes in non-responders and reduced effector-like expression conferring cytotoxic potential. Antibiotic depletion and microbiota transplant restored anti-PD-L1 response in non-responders, with expansion of effector cells and cytotoxicity. Concomitant blockade of TNFα similarly improved response to anti-PD-L1 and increased cytotoxicity. These results demonstrate inhibitory roles for the microbiota in checkpoint blockade and reveal the potential for microbiota transplant and TNF blockade to overcome microbiota-mediated resistance.

SUMMARYImmunotherapy is becoming a mainstay in the treatment of NSCLC. While tumor mutational burden (TMB) has been shown to correlate with response to immunotherapy, little is known about the relation of the baseline immune response with the tumor genotype. Here, we profiled 35 early stage NSCLC lesions using multiscale single cell sequencing. Unsupervised clustering identified in a subset of patients a key cellular module consisting of PDCD1+ CXCL13+ activated T cells, IgG+ plasma cells, and SPP1+ macrophages, referred to as the lung cancer activation module (LCAMhi). Transcriptional data from two NSCLC cohorts confirmed a subset of patients with LCAMhi enrichment, which was independent of overall immune cell content. The LCAMhi module strongly correlated with TMB, expression of cancer testis antigens, and with TP53 mutations in smokers and non-smokers. These data establish LCAM as a key mode of immune cell activation associated with high tumor antigen load and driver mutations.

We dissect metabolic variability of mononuclear phagocyte (MNP) subpopulations across different tissues through integrative analysis of three large scale datasets. Specifically, we introduce ImmGen MNP Open Source dataset that profiled 337 samples and extended previous ImmGen effort which included 202 samples of mononuclear phagocytes and their progenitors. Next, we analysed Tabula Muris Senis dataset to extract data for 51,364 myeloid cells from 18 tissues. Taken together, a compendium of data assembled in this work covers phagocytic populations found across 38 different tissues. To analyse common metabolic features, we developed novel network-based computational approach for unbiased identification of key metabolic subnetworks based on cellular transcriptional profiles in large-scale datasets. Using ImmGen MNP Open Source dataset as baseline, we define 9 metabolic subnetworks that encapsulate the metabolic differences within mononuclear phagocytes, and demonstrate that these features are robustly found across all three datasets, including lipid metabolism, cholesterol biosynthesis, glycolysis, and a set of fatty acid related metabolic pathways, as well as nucleotide and folate metabolism. We systematically define major features specific to macrophage and dendritic cell subpopulations. Among other things, we find that cholesterol synthesis appears particularly active within the migratory dendritic cells. We demonstrate that interference with this pathway through statins administration diminishes migratory capacity of the dendritic cells in vivo. This result demonstrates the power of our approach and highlights importance of metabolic diversity among mononuclear phagocytes.

The squalene-based oil-in-water emulsion (SE) vaccine adjuvant MF59 has been administered to more than 100 million people in more than 30 countries, in both seasonal and pandemic influenza vaccines. Despite its wide use and efficacy, its mechanisms of action remain unclear. In this study we demonstrate that immunization of mice with MF59 or its mimetic AddaVax (AV) plus soluble antigen results in robust antigen-specific antibody and CD8 T cell responses in lymph nodes and non-lymphoid tissues. Immunization triggered rapid RIPK3-kinase dependent necroptosis in the lymph node which peaked at 6 hr, followed by a sequential wave of apoptosis. Immunization with alum plus antigen did not induce RIPK3-dependent signaling. RIPK3-dependent signaling induced by MF59 or AV was essential for cross-presentation of antigen to CD8 T cells by Batf3-dependent CD8+ DCs. Consistent with this, RIPK3 deficient or Batf3 deficient mice were impaired in their ability to mount adjuvant-enhanced CD8 T cell responses. However, CD8 T cell responses were unaffected in mice deficient in MLKL, a downstream mediator of necroptosis. Surprisingly, antibody responses were unaffected in RIPK3-kinase or Batf3 deficient mice. In contrast, antibody responses were impaired by in vivo administration of the pan-caspase inhibitor Z-VAD-FMK, but normal in caspase-1 deficient mice, suggesting a contribution from apoptotic caspases, in the induction of antibody responses. These results demonstrate that squalene emulsion-based vaccine adjuvants induce antigen-specific CD8 T cell and antibody responses, through RIPK3-dependent and-independent pathways, respectively.

BACKGROUND Pathophysiological changes often result in altered pharmacokinetics of ciprofloxacin in critically ill patients. Although ciprofloxacin clearance (CLCIP) substantially depends on kidney function in healthy volunteers, its relationship to measured creatinine clearance (CLCRM) is weak in critically ill patients. OBJECTIVES To assess the need for dose reductions in isolated or combined kidney and liver dysfunction in critically ill patients and to re-evaluate relationships between kidney parameters, demographics and ciprofloxacin pharmacokinetics. METHODS A population pharmacokinetic model was developed based on 444 ciprofloxacin serum concentrations from 15 critically ill patients with severe infections. CLCIP relationships to parameters reflecting hepatic function, CLCRM, Cockcroft-Gault creatinine clearance (CLCRCG), serum creatinine, sex, weight and age were explored. A simulation study was conducted to integrate knowledge from the new and previously published models. RESULTS Total bilirubin was identified as a hepatic parameter with a clear relationship to CLCIP. A significant relationship between CLCIP and CLCRCG could be attributed to age and sex only. CLCIP was not associated with CLCRM. The predicted risk of potential overexposure (AUC > 250 mg·h/L) was low even with 1200 mg/day ciprofloxacin daily for patients with reduced CLCRCG (

Immunotherapy is a mainstay of non-small cell lung cancer (NSCLC) management. While tumor mutational burden (TMB) correlates with response to immunotherapy, little is known about the relationship between the baseline immune response and tumor genotype. Using single-cell RNA sequencing, we profiled 361,929 cells from 35 early-stage NSCLC lesions. We identified a cellular module consisting of PDCD1(+)CXCL13(+) activated T cells, IgG(+) plasma cells, and SPP1(+) macrophages, referred to as the lung cancer activation module (LCAM(hi)). We confirmed LCAM(hi) enrichment in multiple NSCLC cohorts, and paired CITE-seq established an antibody panel to identify LCAM(hi) lesions. LCAM presence was found to be independent of overall immune cell content and correlated with TMB, cancer testis antigens, and TP53 mutations. High baseline LCAM scores correlated with enhanced NSCLC response to immunotherapy even in patients with above median TMB, suggesting that immune cell composition, while correlated with TMB, may be a nonredundant biomarker of response to immunotherapy.

Objective This study investigates pregnancy- and birth-giving-related fears of women of different risk groups and examines their influence on pregnancy and delivery. Study design Prospective study. Setting Pregnant out-patients were recruited in medical practices in Berlin. Data on perinatal outcome were obtained from the charts of the obstetric units. Participants 589 pregnant women between 16 and 22 weeks of gestation. Methods Pregnant women were interviewed by a semi-standardized questionnaire and related to information from the charts about perinatal outcome of the obstetric units. Results 77 women were at risk of anxiety influencing pregnancy and perinatal outcome due to chronic diseases, 61 had a history of previous miscarriage, 38 had a history of termination of pregnancy. 288 had no risk factors. Women with previous miscarriage had the highest degree of pregnancy-related fears. Their pregnancies were significantly more often complicated by the threat of miscarriage. A relationship between high levels of pregnancy-related fears and pregnancy complications was only found in the group of “low- risk women”. Conclusion Women with a history of miscarriage evidently make use of special care services and social support services. For these women no correlation between pregnancy-related fears and complications was found. Low-risk pregnant women seem to have fewer means of coping with their unreasonable fear.

Sexual dimorphism in the mammalian immune system is manifested as more frequent and severe infectious diseases in males and, on the other hand, higher rates of autoimmune disease in females, yet insights underlying those differences are still lacking. Here we characterize sex differences in the immune system by RNA and ATAC sequence profiling of untreated and interferon-induced immune cell types in male and female mice. We detect very few differentially expressed genes between male and female immune cells except in macrophages from three different tissues. Accordingly, very few genomic regions display differences in accessibility between sexes. Transcriptional sexual dimorphism in macrophages is mediated by genes of innate immune pathways, and increases after interferon stimulation. Thus, the stronger immune response of females may be due to more activated innate immune pathways prior to pathogen invasion., Sexual dimorphism is observed frequently in immune disorders, but the underlying insights are still unclear. Here the authors analyze transcriptome and epigenome changes induced by interferon in various mouse immune cell types, and find only a restricted set of sexual dimorphism genes in innate immunity and macrophages.

Phosphatidylinositol 3-kinase catalytic subunit p110β is involved in tumorigenesis and hemostasis. However, it remains unclear if p110β also regulates platelet-mediated immune responses, which could have important consequences for immune modulation during anti-cancer treatment with p110β inhibitors. Thus, we investigate how platelet p110β affects inflammation and infection. Using a mouse model of Streptococcus pneumoniae-induced pneumonia, we find that both platelet-specific p110β deficiency and pharmacologic inhibition of p110β with TGX-221 exacerbate disease pathogenesis by preventing platelet-monocyte and neutrophil interactions, diminishing their infiltration and enhancing bacterial dissemination. Platelet p110β mediates neutrophil phagocytosis of S. pneumoniae in vitro and curtails bacteremia in vivo. Genetic deficiency or inhibition of platelet p110β also impairs macrophage recruitment in an independent model of sterile peritonitis. Our results demonstrate that platelet p110β dysfunction exacerbates pulmonary infection by impeding leukocyte functions. Thereby, our findings provide important insights into the immunomodulatory potential of PI3K inhibitors in bacterial infection.

Checkpoint blockade therapies have improved cancer treatment, but such immunotherapy regimens fail in a large subset of patients. Conventional type 1 dendritic cells (DC1s) control the response to checkpoint blockade in preclinical models and are associated with better overall survival in patients with cancer, reflecting the specialized ability of these cells to prime the responses of CD8

SUMMARYCaloric restriction is known to improve inflammatory and autoimmune diseases. However, the mechanisms by which reduced caloric intake modulates inflammation are poorly understood. Here we show that short-term fasting reduced monocyte metabolic and inflammatory activity and drastically reduced the number of circulating monocytes. Regulation of peripheral monocyte numbers was dependent on dietary glucose and protein levels. Specifically, we found that activation of the low-energy sensor 5’-AMP-activated protein kinase (AMPK) in hepatocytes and suppression of systemic CCL2 production by peroxisome proliferator-activator receptor alpha (PPARα) reduced monocyte mobilization from the bone marrow. Importantly, while caloric restriction improves chronic inflammatory diseases, fasting did not compromise monocyte emergency mobilization during acute infectious inflammation and tissue repair. These results reveal that caloric intake and liver energy sensors dictate the blood and tissue immune tone and link dietary habits to inflammatory disease outcome.HighlightsFasting reduces the numbers of peripheral pro-inflammatory monocytes in healthy humans and mice.A hepatic AMPK-PPARα energy-sensing axis controls homeostatic monocyte numbers via regulation of steady-state CCL2 production.Fasting reduces monocyte metabolic and inflammatory activity.Fasting improves chronic inflammatory diseases but does not compromise monocyte emergency mobilization during acute infectious inflammation and tissue repair.

PD-1 immune checkpoint inhibitors have produced encouraging results in patients with hepatocellular carcinoma (HCC). However, what determines resistance to anti–PD-1 therapies is unclear. We created a novel genetically engineered mouse model of HCC that enables interrogation of how different genetic alterations affect immune surveillance and response to immunotherapies. Expression of exogenous antigens in MYC;Trp53−/− HCCs led to T cell–mediated immune surveillance, which was accompanied by decreased tumor formation and increased survival. Some antigen-expressing MYC;Trp53−/− HCCs escaped the immune system by upregulating the β-catenin (CTNNB1) pathway. Accordingly, expression of exogenous antigens in MYC;CTNNB1 HCCs had no effect, demonstrating that β-catenin promoted immune escape, which involved defective recruitment of dendritic cells and consequently impaired T-cell activity. Expression of chemokine CCL5 in antigen-expressing MYC;CTNNB1 HCCs restored immune surveillance. Finally, β-catenin–driven tumors were resistant to anti–PD-1. In summary, β-catenin activation promotes immune escape and resistance to anti–PD-1 and could represent a novel biomarker for HCC patient exclusion. Significance: Determinants of response to anti–PD-1 immunotherapies in HCC are poorly understood. Using a novel mouse model of HCC, we show that β-catenin activation promotes immune evasion and resistance to anti–PD-1 therapy and could potentially represent a novel biomarker for HCC patient exclusion. See related commentary by Berraondo et al., p. 1003. This article is highlighted in the In This Issue feature, p. 983

Fixe Erwartungshaltungen sind oft Ursache fur Probleme unter der Geburt, deswegen ist es wichtig, diese in einer guten Geburtsvorbereitung zu thematisieren und realitatsbezogen zu diskutieren. Unbegrundete Angste wie allzu euphorische Vorstellungen (Stichwort: „sanfte Geburt“) fuhren zu Enttauschungen. Eine realistische Vorbereitung auf die Geburt kann Frauen zur vernunftigen Einschatzung und einer aktiven Gestaltung ihrer Geburt verhelfen.

Dass das Neugeborene bei der Geburt keine Tabula rasa ist, sondern sich bereits intrauterin psychosomatisch entwickelt hat, wird aufgrund der Erkenntnisse pranataler Psychologie wie Neurowissenschaften immer deutlicher. Wahrnehmungen der Sinnesorgane wie emotionale Reaktionen werden im Mutterleib bereits eingeubt und sind die Basis postnataler Entwicklungen. Kinder sind pra- wie postnatale Subjekte, so erleben sie auch ihre Geburt. Diesen Erkenntnissen ist auch in Schwangerschafts- und Geburtsbegleitung Rechnung zu tragen.

Die schwangere Frau sollte darauf vorbereitet sein, dass unter der Geburt medizinische Eingriffe notwendig werden konnen. Sie dienen dazu, ihr wie ihrem Kind zu helfen und Schaden von ihr und ihrem Kind abzuwenden. Diese Eingriffe sollten realitatsbezogen und ideologiefrei in der Geburtsvorbereitung thematisiert werden.

Die Anwesenheit des Partners bei der Geburt ist heute Normalitat. Um zu einem positiven Geburtserlebnis in der jungen Familie zu kommen, ist es wichtig, dass auch der Partner in die Geburtsvorbereitung miteinbezogen wird. Ein Zwang zur Partnergeburt sollte aber nicht bestehen.

F. Leboyer hat mit seinem Buch „Naissance sans Violence“ die Geburtshilfe sehr verandert. Der Titel bezog sich aber nicht auf das Gebaren, das immer eine Herausforderung sein wird, sondern auf die liebevolle Versorgung des Kindes nach seiner Geburt, auf das unmittelbare Bonding, das Zusammensein von Mutter und Kind von Anfang an.

Problematik des Gebarens in der Spannbreite zwischen Leid und Lust. Heute ist es fur Frauen leichter denn je, zu einem positiven Geburtserleben zu kommen.

Das Wissen um den Ablauf einer Geburt ist bei vielen Gebarenden und ihren Partnern noch immer sehr beschrankt und von vielen falschen Vorstellungen belastet. Deshalb ist eine gute Geburtsvorbereitung fur das Erleben und die Gestaltung der Geburt besonders wichtig. Realitatsbezogen sollten Frauen und ihre Partner auf das, was moglicherweise bei einer Geburt auf sie zukommen kann, vorbereitet werden.

Fortschritte der Geburtsmedizin haben das Mortalitats- wie Morbiditatsrisiko von Kindern und Muttern drastisch gesenkt. Auch problematische Geburtsverlaufe konnen dank der operativen und anasthesiologischen Moglichkeiten weitgehend verhindert werden. Vor allem ist es moglich geworden, den Schmerz unter der Geburt durch den sogenannten Kreuzstich hintanzuhalten.

Es gibt viele Methoden der Geburtsvorbereitung. Ihnen gemeinsam sind drei Grundpfeiler: Psychoprophylaxe, Atmung, Entspannung. Bedenklich ist eine Geburtsvorbereitung dann, wenn sie Leistungsdruck erzeugt, wenn sie nicht erreichbare fixe Idealvorstellungen vermittelt. Geburtsvorbereitung soll neugierig machen.

In diesem Kapitel werden theoretische wie praktische Anleitungen zum Atmen und Entspannen unter der Geburt vermittelt. Diese konnen als Geburtsvorbereitung in der Schwangerschaft eingeubt werden.

Schwangere wie ihre Partner kommen oft mit unrealistischen Erwartungen zur Geburt. Sie empfinden dann jeden auch noch so notwendigen Eingriff als gewaltsame Intervention in den von ihnen erwarteten physiologischen Ablauf. Systemische Probleme wie zu wenig geburtshilfliches Personal in unseren Kreissalen, keine 1:1-Betreuung (1 Schwangere auf 1 Hebamme) und allzu rasche Interventionen in den Geburtsverlauf, um sich forensisch abzusichern, verstarken diesen Eindruck nicht nur bei Betroffenen. Im Hintergrund bleibt die grose Verantwortung der Geburtshelfern, die fur die Gesundheit von Mutter und Kind verantwortlich sind.