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MicroRNAs (miRNAs) are commonly deregulated in acute myeloid leukemia (AML), affecting critical genes not only through direct targeting, but also through modulation of downstream effectors. Homeobox (Hox) genes balance self-renewal, proliferation, cell death, and differentiation in many tissues and aberrant Hox gene expression can create a predisposition to leukemogenesis in hematopoietic cells. However, possible linkages between the regulatory pathways of Hox genes and miRNAs are not yet fully resolved. We identified miR-708 to be upregulated in Hoxa9/Meis1 AML inducing cell lines as well as in AML patients. We further showed Meis1 directly targeting miR-708 and modulating its expression through epigenetic transcriptional regulation. CRISPR/Cas9 mediated knockout of miR-708 in Hoxa9/Meis1 cells delayed disease onset in vivo, demonstrating for the first time a pro-leukemic contribution of miR-708 in this context. Overexpression of miR-708 however strongly impeded Hoxa9 mediated transformation and homing capacity in vivo through modulation of adhesion factors and induction of myeloid differentiation. Taken together, we reveal miR-708, a putative tumor suppressor miRNA and direct target of Meis1, as a potent antagonist of the Hoxa9 phenotype but an effector of transformation in Hoxa9/Meis1. This unexpected finding highlights the yet unexplored role of miRNAs as indirect regulators of the Hox program during normal and aberrant hematopoiesis.

We investigated the clinical and functional role of the miR-106a-363 cluster in adult acute myeloid leukemia (AML). LAML miRNA-Seq TCGA analyses revealed that high expression of miR-106a-363 cluster members was associated with inferior survival, and miR-106a-5p and miR-20b-5p levels were significantly elevated in patients with adverse risk AML. Overexpression of the miR-106a-363 cluster and its individual members in a murine AML model significantly accelerated leukemogenesis. Proteomics analysis of leukemic bone marrow cells from these models emphasized the deregulation of proteins involved in intracellular transport, protein complex organization and mitochondrial function, driven predominantly by miR-106a-5p. These molecular alterations suggested mitochondrial activation as a potential mechanism for the observed increase in leukemogenicity. High-resolution respirometry and STED microscopy confirmed that miR-106a-5p enhances mitochondrial respiratory activity and increases mitochondrial volume. These findings demonstrate that the miR-106a-363 cluster, and particularly miR-106a-5p, contribute to AML progression through modulation of mitochondrial function and deregulation of mitochondria-coordinated pathways.

We investigated the clinical and functional role of the miR-106a-363 cluster in adult acute myeloid leukemia (AML). LAML miRNA-Seq TCGA analyses revealed that high expression of miR-106a-363 cluster members was associated with inferior survival, and miR-106a-5p and miR-20b-5p levels were significantly elevated in patients with adverse risk AML. Overexpression of the miR-106a-363 cluster and its individual members in a murine AML model significantly accelerated leukemogenesis. Proteomics analysis of leukemic bone marrow cells from these models emphasized the deregulation of proteins involved in intracellular transport, protein complex organization and mitochondrial function, driven predominantly by miR-106a-5p. These molecular alterations suggested mitochondrial activation as a potential mechanism for the observed increase in leukemogenicity. High-resolution respirometry and STED microscopy confirmed that miR-106a-5p enhances mitochondrial respiratory activity and increases mitochondrial volume. These findings demonstrate that the miR-106a-363 cluster, and particularly miR-106a-5p, contribute to AML progression through modulation of mitochondrial function and deregulation of mitochondria-coordinated pathways.

The abundances of fungi and bacteria in soil are used as simple predictors for carbon dynamics, and represent widely available microbial traits. Soil biomarkers serve as quantitative estimates of these microbial groups, though not quantifying microbial biomass per se. The accurate conversion to microbial carbon pools, and an understanding of its comparability among soils is therefore needed. We refined conversion factors for classical fungal biomarkers, and evaluated the application of quantitative PCR (qPCR, rDNA copies) as a biomarker for soil fungi. Based on biomarker contents in pure fungal cultures of 30 isolates tested here, combined with comparable published datasets, we propose average conversion factors of 95.3 g fungal C g −1 ergosterol, 32.0 mg fungal C µmol −1 PLFA 18:2ω6,9 and 0.264 pg fungal C ITS1 DNA copy −1. As expected, interspecific variability was most pronounced in rDNA copies, though qPCR results showed the least phylogenetic bias. A modeling approach based on exemplary agricultural soils further supported the hypothesis that high diversity in soil buffers against biomarker variability, whereas also phylogenetic biases impact the accuracy of comparisons in biomarker estimates. Our analyses suggest that qPCR results cover the fungal community in soil best, though with a variability only partly offset in highly diverse soils. PLFA 18:2ω6,9 and ergosterol represent accurate biomarkers to quantify Ascomycota and Basidiomycota. To conclude, the ecological interpretation and coverage of biomarker data prior to their application in global models is important, where the combination of different biomarkers may be most insightful.

Menstrual complaints are widespread but often stigmatized. The most common is dysmenorrhea, or menstrual cramps, which manifests as mild to severe pain during menstruation and affects >40% of women throughout their reproductive lifespan. Dysmenorrhea is often endured silently or managed through self-medication. Consequently, a vast majority of patients with dysmenorrhea may not be found in medical practices, highlighting the need for direct-to-patient communication to reach a broad and diverse patient population. Primarily, this study aims to reveal the diagnosis status, pain levels, comorbidities, eligibility, and willingness to participate in clinical trials of women affected by dysmenorrhea and menstrual discomfort, based on a broad patient population not necessarily reached in medical practices. Second, this study attempts to test the effectiveness of direct-to-patient communication via online campaigns in engaging patients affected by dysmenorrhea or conditions that may benefit from direct-to-patient communication. Women experiencing menstrual pain were reached through a targeted online campaign using Google Ads (Google LLC) and Facebook (Meta Platforms, Inc) in Germany, Austria, and Poland and were surveyed from April to June 2023. This study is observational. We surveyed 3546 women, 94.6% (3230/3413) of whom reported symptoms consistent with dysmenorrhea, highlighting the high specificity of the Google and Facebook campaigns. Of the affected women in Germany and Austria, 88.5% (874/988) reported pain levels of 6 or higher on a scale of 0 to 10, with even higher pain levels observed in Poland. Elevated pain levels were correlated with dysmenorrhea symptoms but not with premenstrual syndrome (PMS) symptoms. Notably, of the 3230 women reporting symptoms consistent with dysmenorrhea, only 4.6% (n=149) reported being diagnosed with the condition, regardless of elevated pain levels. This can be attributed to two factors: (1) 90.3% (3065/3395) of surveyed women did not seek medical advice, were uncertain about their diagnosis, or their menstrual-related symptoms were not recognized as pathological and (2) among the 9.7% (330/3395) diagnosed, only half of DYS-affected women (149/318, 46.9%) were diagnosed with dysmenorrhea. The other 53.1% (169/318) were diagnosed with PMS but not dysmenorrhea despite regularly experiencing dysmenorrhea symptoms. The situation was better for PMS. Among the 330 diagnosed women, 77.3% (n=255) were diagnosed with PMS, in line with the 80.1% (2729/3409) PMS prevalence in the survey population. Overall, about 8.6% (235/2729) of women with PMS symptoms reported having been diagnosed with PMS, nearly double the diagnosis rate reported for dysmenorrhea. The data reveal a significant diagnostic gap for dysmenorrhea, but not necessarily for PMS, even in high-income countries, as observed in Germany, Austria, and Poland. In these 3 countries, most dysmenorrhea-affected women do not seek medical advice, and up to half of dysmenorrhea diagnoses might be missed. Thus, most affected women might not be found in medical settings (doctors' offices and clinics) despite experiencing significant pain. Online campaigns are shown to effectively reach individuals with menstrual complaints, including those who are undiagnosed or not seeking medical care.

Recent computational studies indicate that the molecular noise of a cellular process may be a rich source of information about process dynamics and parameters. However, accessing this source requires stochastic models that are usually difficult to analyze. Therefore, parameter estimation for stochastic systems using distribution measurements, as provided for instance by flow cytometry, currently remains limited to very small and simple systems. Here we propose a new method that makes use of low-order moments of the measured distribution and thereby keeps the essential parts of the provided information, while still staying applicable to systems of realistic size. We demonstrate how cell-to-cell variability can be incorporated into the analysis obviating the need for the ubiquitous assumption that the measurements stem from a homogeneous cell population. We demonstrate the method for a simple example of gene expression using synthetic data generated by stochastic simulation. Subsequently, we use time-lapsed flow cytometry data for the osmo-stress induced transcriptional response in budding yeast to calibrate a stochastic model, which is then used as a basis for predictions. Our results show that measurements of the mean and the variance can be enough to determine the model parameters, even if the measured distributions are not well-characterized by low-order moments only—e.g., if they are bimodal.

Background: Intramedullary metastases are rare and bear a dismal prognosis. Limited data are available on the treatment of such lesions. As surgery may be the mainstay of treatment for patients with resectable and localized metastatic spread, previous case reports and case series suggest radiosurgery to be another viable treatment modality. This multicenter study analyzes the efficacy and safety of robotic radiosurgery (RRS) for intramedullary metastases. Methods: Patients who received RRS for the treatment of at least one intramedullary metastasis were included. Results: Thirty-three patients with 46 intramedullary metastases were treated with a median dose of 16 Gy prescribed to a median isodose of 70%. The local control was 79% after a median follow-up of 8.5 months. The median overall survival (OS) was 11.7 months, with a 12- and 24-month OS of 47 and 31%. The 12-month progression-free survival was 42% and at 24 months 25%. In addition, 57% of patients showed either an improved or stable neurological function after treatment delivery. Systemic disease progression was the main cause of death. No significant treatment-related toxicities were observed. Conclusions: RRS appears to be a safe, time-saving and effective treatment modality for intramedullary metastases, especially for patients with unresectable lesions and high burden of disease.

Background: Foramen magnum meningiomas (FMMs) represent a considerable neurosurgical challenge given their location and potential morbidity. Stereotactic radiosurgery (SRS) is an established non-invasive treatment modality for various benign and malignant brain tumors. However, reports on single-session or multisession SRS for the management and treatment of FMMs are exceedingly rare. We report the largest FMM SRS series to date and describe our multicenter treatment experience utilizing robotic radiosurgery. Methods: Patients who underwent SRS between 2005 and 2020 as a treatment for a FMM at six different centers were eligible for analysis. Results: Sixty-two patients met the inclusion criteria. The median follow-up was 28.9 months. The median prescription dose and isodose line were 14 Gy and 70%, respectively. Single-session SRS accounted for 81% of treatments. The remaining patients received three to five fractions, with doses ranging from 19.5 to 25 Gy. Ten (16%) patients were treated for a tumor recurrence after surgery, and thirteen (21%) underwent adjuvant treatment. The remaining 39 FMMs (63%) received SRS as their primary treatment. For patients with an upfront surgical resection, histopathological examination revealed 22 World Health Organization grade I tumors and one grade II FMM. The median tumor volume was 2.6 cubic centimeters. No local failures were observed throughout the available follow-up, including patients with a follow-up ≥ five years (16 patients), leading to an overall local control of 100%. Tumor volume significantly decreased after treatment, with a median volume reduction of 21% at the last available follow-up (p < 0.01). The one-, three-, and five-year progression-free survival were 100%, 96.6%, and 93.0%, respectively. Most patients showed stable (47%) or improved (21%) neurological deficits at the last follow-up. No high-grade adverse events were observed. Conclusions: SRS is an effective and safe treatment modality for FMMs. Despite the paucity of available data and previous reports, SRS should be considered for selected patients, especially those with subtotal tumor resections, recurrences, and patients not suitable for surgery.

Soils, just like all other ecosystem compartments, change over time and, consequently, conditions for soil‐inhabiting organisms are also changing, affecting their composition and diversity. Soil biodiversity is a critical component of ecosystems that supports many essential ecosystem functions and services, such as nutrient cycling, carbon sequestration, water regulation and biomass production for food, fodder, fibre and energy. However, and despite the importance of soil biodiversity for ecosystem health and human well‐being, neither current state, drivers, potential consequences for ecosystem services nor options for sustainable governance of soil biodiversity are well understood. Here, we provide a framework for and argue that conducting a national assessment of soil biodiversity, albeit being a complex endeavour, is fundamental to building a baseline to understand the current state and trends of soil biodiversity, but also to identify the main drivers of change, the impacts of soil biodiversity loss and the potential pathways for conservation and sustainable governance of soil biodiversity.

Background and Aims Acute necrotising pancreatitis carries high mortality, especially if infected necrosis occurs. While percutaneous drainage may be required when internal drainage is not feasible, reliable guidelines for managing percutaneous drains are lacking. This study aimed to assess the common practice of percutaneous drainage therapy for infected pancreatic necrosis. Methods This retrospective study among 29 tertiary care centres included all patients hospitalised for necrotising acute pancreatitis from 01/2016 until 12/2022 with at least one percutaneous drain. The length of hospital stay was the primary endpoint, with mortality as the secondary endpoint. Between‐group comparisons were conducted using the ratio of restricted mean survival time (RMST) after adjusting for confounders. Results 585 patients (67% male) from 29 tertiary care centres in 15 countries in Europe, Canada and Bolivia were included in the analysis. Length of hospitalisation or mortality did not differ between the flushed (n = 398) and non‐flushed groups (RMST ratio 1.04, p‐value = 0.42 and RMST ratio 1.05, p‐value = 0.1 respectively). Mortality was significantly lower in those patients who received a combination of percutaneous and internal drains (dual‐modality drainage, n = 243) as compared to those who received percutaneous drains only (RMST ratio 1.05, p‐value = 0.01). Flushing with antibiotics as compared to saline was not associated with shorter length of hospital stay or lower mortality (RMST ratio 0.98, p‐value = 0.78 and 0.97, p‐value = 0.48 respectively). Conclusions This study reveals notable differences in therapeutic concepts and flushing management for percutaneous drains. While flushing itself was not associated with a shorter length of hospitalisation or lower in‐hospital mortality, a lower mortality was observed when internal and percutaneous drainage were used in combination. Clinical Trial Registration The study was prospectively registered in the German Clinical Trials Register (Deutsches Register Klinischer Studien, DRKS) under the registration number DRKS00032231. Key Summary Summarise the established knowledge on this subject ◦ Percutaneous drainage as well as endoscopic drainage can be used for the treatment of necrotic collections in pancreatitis ◦ Management of percutaneous drains, including flushing and combination with endoscopic drains, is unclear What are the significant and/or new findings of this study? ◦ Very heterogeneous therapeutic regimens across participating pancreas centres ◦ No differences in hospitalisation or mortality for flushing versus no flushing ◦ No differences in hospitalisation or mortality for flushing with antibiotics versus saline ◦ Lower mortality in patients with dual‐modality drainage