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To determine the pattern of and factors associated with changes in nutritional status in early infancy in a resource-poor setting. Methods: A cohort study in Lagos, Nigeria, in which the nutritional status at birth was compared with status at the first postnatal check-up routinely scheduled for 6–8 weeks based on the World Health Organization's multicenter growth reference and the Centers for Disease Control and Prevention 2000 growth charts. Factors associated with improved, worsened or steady nutritional status at follow-up based on z-scores for weight-for-age, length-for-age and weight-for-length were determined with multinomial regression analysis. Results: The mean length-for-age and weight-for-length based on the Centers for Disease Control and Prevention for the 445 full-term singletons studied were higher than the corresponding World Health Organization's multicenter growth reference values at birth and at follow-up, while mean weight-for-age was lower at birth but higher subsequently. Some 20.7% of infants were undernourished by at least one nutritional measure initially, which declined to 16.4% at follow-up. Also 8.1% of the infants remained undernourished, 8.3% became undernourished, and 5.6% became well-nourished at follow-up. Low birthweight full-term infants were significantly likely to remain undernourished (p

Metabolite accumulation in the tumor microenvironment fosters immune evasion and limits the efficiency of immunotherapeutic approaches. Methylthioadenosine phosphorylase (MTAP), which catalyzes the degradation of 5'-deoxy-5'methylthioadenosine (MTA), is downregulated in many cancer entities. Consequently, MTA accumulates in the microenvironment of MTAP-deficient tumors, where it is known to inhibit tumor-infiltrating T cells and NK cells. However, the impact of MTA on other intra-tumoral immune cells has not yet been fully elucidated. To study the effects of MTA on dendritic cells (DCs), human monocytes were maturated into DCs with (MTA-DC) or without MTA (co-DC) and analyzed for activation, differentiation, and T cell-stimulating capacity. MTA altered the cytokine secretion profile of monocytes and impaired their maturation into dendritic cells. MTA-DCs produced less IL-12 and showed a more immature-like phenotype characterized by decreased expression of the co-stimulatory molecules CD80, CD83, and CD86 and increased expression of the monocyte markers CD14 and CD16. Consequently, MTA reduced the capability of DCs to stimulate T cells. Mechanistically, the MTA-induced effects on monocytes and DCs were mediated by a mechanism beyond adenosine receptor signaling. These results provide new insights into how altered polyamine metabolism impairs the maturation of monocyte-derived DCs and impacts the crosstalk between T and dendritic cells.

D-2-hydroxyglutarate (D-2-HG) accumulates in patients with acute myeloid leukemia (AML) with mutated isocitrate dehydrogenase (IDH) and in other malignancies. D-2-HG suppresses antitumor T-cell immunity but little is known about potential effects on non-malignant myeloid cells. Here we show that D-2-HG impairs human but not murine dendritic cell differentiation, resulting in a tolerogenic phenotype with low major histocompatibility class II expression. In line with this, IDH-mutated AML blasts exhibited lower expression of HLA-DP and were less susceptible to lysis by HLA-DP-specific T cells. Interestingly, besides its expected impact on DNA demethylation, D-2-HG reprogrammed metabolism towards increased lactate production in dendritic cells and AML. Vitamin C accelerated DNA demethylation, but only the combination of vitamin C and glycolytic inhibition lowered lactate levels and supported major histocompatibility complex class II expression. Our results indicate an unexpected link between the immunosuppressive metabolites 2-HG and lactic acid and suggest a potentially novel therapeutic strategy with combinations of anti-glycolytic drugs and epigenetic modulators (hypomethylating agents) or other therapeutics for the treatment of AML.

Obesity is an emerging public health problem. Chronic low-grade inflammation is considered a major promotor of obesity-induced secondary diseases such as cardiovascular and fatty liver disease, type 2 diabetes mellitus, and several cancer entities. Most preliminary studies on obesity-induced immune responses have been conducted in male rodents. Sex-specific differences between men and women in obesity-induced immune dysregulation have not yet been fully outlined but are highly relevant to optimizing prevention strategies for overweight-associated complications. In this study, we fed C57BL/6 female vs. male mice with either standard chow or an obesity-inducing diet (OD). Blood and spleen immune cells were isolated and analyzed by flow cytometry. Lean control mice showed no sex bias in systemic and splenic immune cell composition, whereas the immune responses to obesity were significantly distinct between female and male mice. While immune cell alterations in male OD mice were characterized by a significant reduction in T cells and an increase in myeloid-derived suppressor cells (MDSC), female OD mice displayed preserved T cell numbers. The sex-dependent differences in obesity-induced T cell dysregulation were associated with varying susceptibility to body weight gain and fatty liver disease: Male mice showed significantly more hepatic inflammation and histopathological stigmata of fatty liver in comparison to female OD mice. Our findings indicate that sex impacts susceptibility to obesity-induced T cell dysregulation, which might explain sex-dependent different incidences in the development of obesity-associated secondary diseases. These results provide novel insights into the understanding of obesity-induced chronic inflammation from a sex-specific perspective. Given that most nutrition, exercise, and therapeutic recommendations for the prevention of obesity-associated comorbidities do not differentiate between men and women, the data of this study are clinically relevant and should be taken into consideration in future trials and treatment strategies.

Vitamin D3 regulates a variety of biological processes irrespective of its well-known importance for calcium metabolism. Epidemiological and animal studies indicate a role in immune regulation, intestinal barrier function and microbiome diversity. Here, we analyzed the impact of different vitamin D3- containing diets on C57BL/6 and BALB/c mice, with a particular focus on gut homeostasis and also investigated effects on immune cells in vitro . Weak regulatory effects were detected on murine T cells. By trend, the active vitamin D3 metabolite 1,25-dihydroxyvitamin D3 suppressed IFN, GM-CSF and IL-10 cytokine secretion in T cells of C57BL/6 but not BALB/c mice, respectively. Using different vitamin D3-fortified diets, we found a tissue-specific enrichment of mainly CD11b+ myeloid cells but not T cells in both mouse strains e.g. in spleen and Peyer's Patches. Mucin Reg3γ and Batf expression, as well as important proteins for gut homeostasis, were significantly suppressed in the small intestine of C57BL76 but not BALB/c mice fed with a high-vitamin D3 containing diet. Differences between both mouse stains were not completely explained by differences in vitamin D3 receptor expression which was strongly expressed in epithelial cells of both strains. Finally, we analyzed gut microbiome and again an impact of vitamin D3 was detected in C57BL76 but not BALB/c. Our data suggest strain-specific differences in vitamin D3 responsiveness under steady state conditions which may have important implications when choosing a murine disease model to study vitamin D3 effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Schreiber, Ghimire, Hiergeist, Renner, Althammer, Babl, Peuker, Schoenhammer, Hippe, Gessner, Albrecht, Pielmeier, Büttner-Herold, Bruns, Hoffmann, Herr, Holler, Peter, Kreutz and Matos.)

Extracranial arteriovenous malformations (AVMs) are regarded as rare diseases and are prone to complications such as pain, bleeding, relentless growth, and high volume of shunted blood. Due to the high vascular pressure endothelial cells of AVMs are exposed to mechanical stress. To control symptoms and lesion growth pharmacological treatment strategies are urgently needed in addition to surgery and interventional radiology. AVM cells were isolated from three patients and exposed to cyclic mechanical stretching for 24 h. Thalidomide and bevacizumab, both VEGF inhibitors, were tested for their ability to prevent the formation of circular networks and proliferation of CD31 + endothelial AVM cells. Furthermore, the effect of thalidomide and bevacizumab on stretched endothelial AVM cells was evaluated. In response to mechanical stress, VEGF gene and protein expression increased in patient AVM endothelial cells. Thalidomide and bevacizumab reduced endothelial AVM cell proliferation. Bevacizumab inhibited circular network formation of endothelial AVM cells and lowered VEGF gene and protein expression, even though the cells were exposed to mechanical stress. With promising in vitro results, bevacizumab was used to treat three patients with unresectable AVMs or to prevent regrowth after incomplete resection. Bevacizumab controlled bleeding, pulsation, and pain over the follow up of eight months with no patient-reported side effects. Overall, mechanical stress increases VEGF expression in the microenvironment of AVM cells. The monoclonal VEGF antibody bevacizumab alleviates this effect, prevents circular network formation and proliferation of AVM endothelial cells in vitro. The clinical application of bevacizumab in AVM treatment demonstrates effective symptom control with no side effects., (© 2023. The Author(s).)

The intended or unintentional transport of soil material contaminated with weed seeds is one of the most important drivers in the spreading dynamics of invasive alien plants (IAPs). This phenomenon can be observed at any kind of construction site. Typical transfer of soil contaminated with IAP seeds can be observed along with road construction (soil translocation) or road maintenance services (deposit of mown plant biomass). Thus, an effective inactivation of these seeds by heating can avoid the spread of IAPs substantially. In the present study, the effects of various thermal control techniques (dry air heating and wet heating with hot steam, hot water, and hot foam) on seed survival of the widespread European IAPs common ragweed ( Ambrosia artemisiifolia ), narrow-leaved ragwort ( Senecio inaequidens ), and giant hogweed ( Heracleum mantegazzianum ) are discussed. Dry and wet seeds which were either uncovered or covered with soil were tested for survival at different treatment temperatures and different exposure times. Results revealed that particularly dry seeds of all three species could withstand temperatures of 100 °C for at least 6 h in climate chambers. Dry seeds of common ragweed and narrow-leaved ragwort survived exposure times of up to 48 h. Wet seeds were significantly more susceptible to heat treatments. Giant hogweed seeds were completely killed after 12 h at 70 °C. The exposure of IAP seeds to hot water was generally more effective than the treatment with hot steam. The treatment with hot foam was only effective when seeds were lying unprotected on the soil surface. Dry seeds of all the three species survived hot foam application in the field when they were covered by vegetation and leaf litter or soil. Due to the robustness of the seeds, a preventive management of IAPs by an efficient control before seeds formation is substantial to avoid their further dispersal.

Background & Aims: Intratumoral lactate accumulation and acidosis impair T-cell function and antitumor immunity. Interestingly, expression of the lactate transporter monocarboxylate transporter (MCT) 4, but not MCT1, turned out to be prognostic for the survival of patients with rectal cancer, indicating that single MCT4 blockade might be a promising strategy to overcome glycolysis-related therapy resistance., Methods: To determine whether blockade of MCT4 alone is sufficient to improve the efficacy of immune checkpoint blockade (ICB) therapy, we examined the effects of the selective MCT1 inhibitor AZD3965 and a novel MCT4 inhibitor in a colorectal carcinoma (CRC) tumor spheroid model co-cultured with blood leukocytes in vitro and the MC38 murine CRC model in vivo in combination with an antibody against programmed cell death ligand-1(PD-L1)., Results: Inhibition of MCT4 was sufficient to reduce lactate efflux in three-dimensional (3D) CRC spheroids but not in two-dimensional cell-cultures. Co-administration of the MCT4 inhibitor and ICB augmented immune cell infiltration, T-cell function and decreased CRC spheroid viability in a 3D co-culture model of human CRC spheroids with blood leukocytes. Accordingly, combination of MCT4 and ICB increased intratumoral pH, improved leukocyte infiltration and T-cell activation, delayed tumor growth, and prolonged survival in vivo. MCT1 inhibition exerted no further beneficial impact., Conclusions: These findings demonstrate that single MCT4 inhibition represents a novel therapeutic approach to reverse lactic-acid driven immunosuppression and might be suitable to improve ICB efficacy., Competing Interests: Competing interests: The study was conducted in close collaboration with Merck. A.S-H., T.H., and C.H. are employees of Merck. R.F. is an employee of EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. S.R. was an employee of EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA at the time the research was conducted., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immune checkpoint inhibition (ICI) has revolutionized cancer therapy. However, response to ICI is often limited to selected subsets of patients or not durable. Tumors that are non-responsive to checkpoint inhibition are characterized by low anti-tumoral immune cell infiltration and a highly immunosuppressive tumor microenvironment. Exercise is known to promote immune cell circulation and improve immunosurveillance. Results of recent studies indicate that physical activity can induce mobilization and redistribution of immune cells towards the tumor microenvironment (TME) and therefore enhance anti-tumor immunity. This suggests a favorable impact of exercise on the efficacy of ICI. Our review delivers insight into possible molecular mechanisms of the crosstalk between muscle, tumor, and immune cells. It summarizes current data on exercise-induced effects on anti-tumor immunity and ICI in mice and men. We consider preclinical and clinical study design challenges and discuss the role of cancer type, exercise frequency, intensity, time, and type (FITT) and immune sensitivity as critical factors for exercise-induced impact on cancer immunosurveillance.

Communication through airborne volatile organic compounds (VOCs) and root exudates plays a vital role in the multifarious interactions of plants. Common ragweed ( Ambrosia artemesiifolia L.) is one of the most troublesome invasive alien species in agriculture. Below- and aboveground chemical interactions of ragweed with crops might be an important factor in the invasive species' success in agriculture. In laboratory experiments, we investigated the contribution of intra- and interspecific airborne VOCs and root exudates of ragweed to its competitiveness. Wheat, soybean, and maize were exposed to VOCs emitted from ragweed and vice versa, and the adaptation response was measured through plant morphological and physiological traits. We observed significant changes in plant traits of crops in response to ragweed VOCs, characterized by lower biomass production, lower specific leaf area, or higher chlorophyll contents. After exposure to ragweed VOCs, soybean and wheat produced significantly less aboveground dry mass, whereas maize did not. Ragweed remained unaffected when exposed to VOCs from the crops or a conspecific. All crops and ragweed significantly avoided root growth toward the root exudates of ragweed. The study shows that the plant response to either above- or belowground chemical cues is highly dependent on the identity of the neighbor, pointing out the complexity of plant-plant communication in plant communities.

Glucose limitation and increased lactic acid levels are consequences of the elevated glycolytic activity of tumor cells, and constitute a metabolic barrier for the function of tumor infiltrating effector immune cells. The immune-suppressive functions of regulatory T cells (Tregs) are unobstructed in lactic-acid rich environments. However, the impact of lactic acid on the induction of Tregs remains unknown. We observed increased TGFβ-mediated induction of Forkhead box P3 + (FoxP3 + ) cells in the presence of extracellular lactic acid, in a glycolysis-independent, acidity-dependent manner. These CD4 + FoxP3 + cells expressed Treg-associated markers, including increased expression of CD39, and were capable of exerting suppressive functions. Corroborating these results in vivo, we observed that neutralizing the tumor pH by systemic administration of sodium bicarbonate (NaBi) decreased Treg abundance. We conclude that acidity augments Treg induction and propose that therapeutic targeting of acidity in the tumor microenvironment (TME) might reduce Treg-mediated immune suppression within tumors., (© 2023 Wiley-VCH GmbH.)

Decreased walking speed is associated with impaired physical performance and function in older adults. Following total ankle arthroplasty (TAA), walking speed continues to be slower than age matched controls. The purpose of this study was to determine if patients 1 year post-TAA can achieve walking speed benchmarks and investigate if gait metrics are predictive of achieved benchmarks. 191 TAA patients were recruited and assessed pre-TAA and 1 year post-TAA. Kinetic and kinematic data were collected during seven self-selected speed barefoot walking trials along a 30-m walkway. Receiver operator curves were generated for each variable to determine threshold values needed to achieve walking speeds of 0.8, 0.9, 1.1, and 1.3 m/s. Each variable's predictive ability was classified according to the area under the curve. Ninety one percent of participants achieved a walking speed > 0.8 m/s, 85.3% achieved ≥0.9 m/s, 64.9% walked at ≥1.1 m/s, and 24.1% achieved a walking speed of 1.3 m/s by 1 year post-TAA. Walking speed pre-TAA was the strongest predictor with ankle moment, power and GRF data showing mixed results. Clinical Significance: 75.9% of participants were unable to walk at 1.3 m/s-a speed indicative of safely crossing a street. Variables predictive of postoperative walking speed benchmarks could be useful in developing interventions for the TAA population. The strongest predictor across all walking speed benchmarks was preoperative walking speed. A walking speed > 0.71 m/s was predictive of achieving 0.8 m/s 1 year post-TAA, while >1.09 m/s predicted 1.3 m/s 1 year post-TAA., (© 2022 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Following the novel weapon hypothesis, the invasiveness of non-native species, such as common ragweed ( Ambrosia artemisiifolia L.) can result from a loss of natural competitors due to the production of chemical compounds, which negatively affect native communities. Particularly the genus Ambrosia produces several types of organic compounds, which have the potential to inhibit germination and growth of other plants. Subsequent to an assessment of the chemical content of three different ragweed extracts (aqueous shoot and root extracts, as well as essential oil), two different trials on the effects of different concentrations of these extracts, as well as ragweed residues, were conducted on two different mediums (Petri dish vs. soil). In addition, we investigated the impact on the infection potential of Bradyrhizobium japonicum on soybean roots in three different soil types (arable soil, potting soil, and sand). The results showed that the exposure to common ragweed extracts and residues induced changes in the biomass and root production of crops and ragweed itself. Even though crops and ragweed differed in their response behavior, the strongest negative impact on all crops and ragweed was observed with ragweed residues, leading to reductions in biomass and root growth of up to 90%. Furthermore, we found a decrease in the number of rhizobial nodules of up to 48% when soybean was exposed to ragweed root extract.