julilili42/papers huggingface dataset:
Perioperative Observations and Outcome in Surgical Treatment of Malignant Peripheral Nerve Sheath Tumors
2024-11-07

Background/Objectives: This retrospective observational study aimed to investigate the perioperative outcome in Malignant Peripheral Nerve Sheath Tumors (MPNSTs) with and without relation to Neurofibromatosis Type 1 (NF1) and to detect possible influencing factors. Methods: Clinical reports, histopathological evaluations, imaging, and treatment characteristics were reviewed in 35 operated MPNSTs in 33 patients. Possible predictive valuables included disease type, preoperative tumor volume, SUV and MIB-1 proliferation index, resection margins, the presence of metastasis, and whether radio-/chemotherapy was received. Results: Patients with NF1 were younger (mean age: 29 ± 13, 8–54 years) than sporadic cases (mean age: 45 ± 13, 24–67 years) and exhibited significantly larger preoperative tumor volumes (mean 299 vs. 18 cm3, p = 0.048). Most tumors were located in the facial/cervical/neck area (34%, n = 12), followed by the trunk (31%, n = 11), lower extremity (17%, n = 6), upper extremity (14%, n = 5), and intraspinal area (3%, n = 1). NF1-associated MPNSTs appeared predominantly on the trunk (39%) and sporadically in the facial/cervical/neck area (50%). Complete resection was possible in 66% and an improvement in or stability of function was achieved in most cases (motor 69%, sensory 74%), as well as a decrease in pain intensity (63%). NF1-associated MPNSTs exhibited more severe pain scores (median VRS scale 2, p = 0.002) compared to sporadic tumors (median VRS scale 0.5). Sporadic MPNSTs located at the head/facial/brachial plexus and upper extremities exhibited better preoperative functions compared to those on the lower extremities. In 12 cases with available [18F]FDG PET, the mean preoperative SUV (9.8 ± 7.2) positively correlated with the mean maximum MIB-1 index (34 ± 26%, p = 0.005) and the mean preoperative tumor volume (474.7 ± 68.6 cm3, p = 0.047). The overall survival (OS) was significantly longer in tumors with higher resection extents (R0, p = 0.01) and without accompanying metastasis (p = 0.046), and tended to be longer, but not significantly so, in sporadic MPNSTs. In six and seven tumors, with R1/R2 resection margins and present metastasis, respectively, solid or combined neo-/adjuvant radio-/chemotherapy led to a significantly shorter OS (p = 0.014). Conclusions: NF1-associated MPNSTs have larger tumor volumes, higher SUVs and MIB-1 proliferation indices, and a shorter overall survival period. Nevertheless, surgery can improve symptoms, particularly medication-resistant pain, and should also be considered in advanced disease for symptom control/improvement.
Multicomponent Syntheses Enable the Discovery of Novel Quisinostat-Derived Chemotypes as Histone Deacetylase Inhibitors
2024-11-07

Epigenetic drug targets have become an important focus in drug discovery. One of the key mechanisms in epigenetics is the acetylation and deacetylation of histone proteins. In this study, we synthesized and evaluated novel histone deacetylase (HDAC) inhibitors derived from the clinical candidate quisinostat. A library of 16 compounds categorized in three novel chemotypes was rapidly generated using multicomponent reactions (MCRs), enabling efficient structure-activity relationship studies. The compounds were evaluated for their activity against Plasmodium falciparum, the main malaria parasite, and solid cancer cell lines. The antiplasmodial activity was assessed against P. falciparum strains 3D7 and Dd2, identifying compound 18b of the type C series as the most potent. It demonstrated low nanomolar IC50 values (IC50 (3D7) = 0.023 μM; IC50 (Dd2) = 0.047 μM) and high parasite selectivity (SIMRC-5/Pf3D7 &gt; 2174). Docking studies suggested distinct binding modes of 18b with P. falciparum and human HDAC1. The in vitro anticancer activity was also evaluated in the Cal27 and HepG2 cell lines and compounds 9b, 9d, and 13f showed potent antiproliferative activity. Compound 9d significantly induced caspase 3/7-mediated apoptosis and caused hyperacetylation of histone H3 and α-tubulin, indicating robust cellular target engagement. Overall, in this work we have identified several promising HDAC inhibitors with antimalarial and anticancer activities, providing valuable leads for further drug development efforts aimed at creating derivatives with reduced cytotoxicity compared to quisinostat.
Case report: Pulmonary Ewing sarcoma disguised as non-small cell lung cancer
2024-11-07

Ewing sarcoma is the second most common primary malignant bone cancer in children and adolescents. This rare type of cancer is characterized by its high malignancy and therefore high risk of metastases. Typically, Ewing sarcomas originate from bones. However, extraosseous Ewing sarcoma such as pulmonary Ewing sarcoma can also be found. In this case report, we present a 55-year old male patient who was initially diagnosed with non-small cell lung cancer at his local district hospital. However, the diagnosis was changed to one of pulmonary Ewing sarcoma after subsequent histopathological and molecular pathological analysis performed in a reference pathology laboratory. After patient referral to a certified (according to the German Cancer Society) high-volume sarcoma center, multimodal chemotherapy was initiated based on recently published clinical data as opposed to the more commonly used treatment regimen in Europe. The patient responded well to treatment and underwent a complete surgical tumor resection followed by radiotherapy. In summary, this case report highlights the importance of a rigorous and timely histopathological examination of biopsy samples by a specialized cancer center to enable a correct diagnosis of the cancer type. Additionally, molecular pathology plays a crucial part in this analysis and allows the necessary differentiation between cancer types. Up to now, there is no international treatment guideline available for the treatment of Ewing sarcoma. Patients should be referred to specialist centers to allow the best possible treatment of the cancer type in view of current published clinical data. In the case of Ewing sarcoma, and in accordance with the most recent research, patients should be treated with vincristine, doxorubicin and cyclophosphamide plus ifosfamide and etoposide in combination with local treatment such as surgery and/or radiotherapy because this has been demonstrated to be the more effective therapy.
ECM Proteins Nidogen‐1 and Decorin Restore Functionality of Human Islets of Langerhans upon Hypoxic Conditions
2024-11-07

Abstract Transplantation of donor islets of Langerhans is a potential therapeutic approach for patients with diabetes mellitus; however, its success is limited by islet death and dysfunction during the initial hypoxic conditions at the transplantation site. This highlights the need to support the donor islets in the days post‐transplantation until the site is vascularized. It was previously demonstrated that the extracellular matrix (ECM) proteins nidogen‐1 (NID1) and decorin (DCN) improve the functionality and survival of the β‐cell line, EndoC‐βH3, and the viability of human islets post‐isolation. To advance the use of these ECM proteins toward a clinical application and elucidate the mechanisms of action in primary islets, the study assesses the effects of ECM proteins NID1 and DCN on isolated human donor islets cultured in normoxic and hypoxic conditions. NID1‐ and DCN‐treatment restore β‐cell functionality of human donor islets in a hypoxic environment through upregulation of genes involved in glycolytic pathways and reducing DNA fragmentation in hypoxic conditions comparable to normoxic control islets. The results demonstrate that the utilization of NID1 or DCN with islets of Langerhans may have the potential to overcome the hypoxia‐induced cell death observed post‐transplantation and improve transplant outcomes.
Neural Representation of Time across Complementary Reference Frames
2024-11-07

Abstract Humans conceptualize time in terms of space, allowing flexible time construals from various perspectives. We can travel internally through a timeline to remember the past and imagine the future (i.e., mental time travel) or watch from an external standpoint to have a panoramic view of history (i.e., mental time watching). However, the neural mechanisms that support these flexible temporal construals remain unclear. To investigate this, we asked participants to learn a fictional religious ritual of 15 events. During fMRI scanning, they were guided to consider the event series from either an internal or external perspective in different tasks. Behavioral results confirmed the success of our manipulation, showing the expected symbolic distance effect in the internal-perspective task and the reverse effect in the external-perspective task. We found that the activation level in the posterior parietal cortex correlated positively with sequential distance in the external-perspective task but negatively in the internal-perspective task. In contrast, the activation level in the anterior hippocampus positively correlated with sequential distance regardless of the observer’s perspectives. These results suggest that the hippocampus stores the memory of the event sequences allocentrically in a perspective-agnostic manner. Conversely, the posterior parietal cortex retrieves event sequences egocentrically from the optimal perspective for the current task context. Such complementary allocentric and egocentric representations support both the stability of memory storage and the flexibility of time construals.
Strong Kleene Logics as a Tool for Modelling Formal Epistemic Norms
2024-11-07

In this paper, we present two ways of modelling every epistemic formal conditional commitment that involves (at most) three key epistemic attitudes: acceptance, rejection and neither acceptance nor rejection. The first one consists of adopting the plurality of every mixed Strong Kleene logic (along with an epistemic reading of the truth-values), and the second one involves the use of a unified system of six-sided inferences, named 6SK, that recovers the validities of each mixed Strong Kleene logic. We also introduce a sequent calculus that is sound and complete with respect to both approaches. We compare both accounts, and finally, we suggest that the plurality of Strong Kleene logic as well as the general framework 6SK are linked to formal epistemic norms via bridge principles.
A cereblon (CRBN) molecular glue degrader of NIMA-related kinase 7 (NEK7) reveals a context-dependent role in NLRP3 inflammasome activation
2024-11-08

Summary The NLRP3 (NACHT-, leucine-rich repeat [LRR]- and pyrin domain [PYD]- containing protein 3) inflammasome is a cytoplasmic signaling complex that promotes inflammation in response to signals from infection and cellular damage. Increased activation of the NLRP3 inflammasome is linked to numerous diseases including gout, osteoarthritis, cardiovascular disease, neuroinflammatory diseases and cancer, which has prompted the search for therapeutics that can inhibit the NLRP3 pathway. Recent work suggested that NIMA-related kinase 7 (NEK7) may be required for proper assembly and activation of the NLRP3 inflammasome independent of its kinase activity, and that hence reduction of NEK7 protein levels may block NLRP3 activation. Since NEK7 contains a glycine beta hairpin loop structural degron found in many targets of cereblon (CRBN) molecular glue degraders, we used this strategy to degrade NEK7 and inhibit the NLRP3 inflammasome. We identified NK7-902, a CRBN glue degrader of NEK7. NK7-902 potently and selectively degraded NEK7 in human primary monocytes, peripheral blood mononuclear cells (PBMCs) and whole blood. Unexpectedly, full NEK7 degradation led to only partial blockade of NLRP3-dependent interleukin-1β (IL-1β) release in these cells under different stimulation conditions, with the extent of IL-1β inhibition varying greatly across donors. Unlike most CRBN glue degraders, NK7-902 degraded NEK7 in mouse cells and efficiently inhibited NLRP3-dependent IL-1β release in a mouse cryopyrin-associated syndrome (CAPS) model. By contrast, oral administration of NK7-902 in non-human primates led to profound and long lasting NEK7 degradation but only transiently blocked IL-1β production in blood. Collectively, our data suggest that NEK7 is involved but may not be strictly required for NLRP3 activation in primates and humans. Highlights Identification of NK7-902, a CRBN molecular glue degrader of NEK7 NK7-902 fully degrades NEK7 in human primary monocytes and whole blood but only partially inhibits NLRP3-dependent IL-1β production Unlike most CRBN glue degraders, NK7-902 shows activity in murine systems In vivo oral administration of NK7-902 in non-human primates leads to profound and long-lasting NEK7 degradation but only transiently blocks NLRP3 inflammasome activation
The rise of cochlear gene therapy
2024-11-08

Recent evidence provides strong support for the safe and effective use of gene therapy in humans with hearing loss. By means of a single local injection of a set of adeno-associated virus (AAV) vectors, hearing was partially restored in several children with neurosensory nonsyndromic autosomal recessive deafness 9 (DFNB9), harboring variants in the OTOF gene. Current research focuses on refining endoscopic and transmastoid injection procedures to reduce risks of side effects, as emerging evidence suggests bidirectional fluid exchanges between the ear and the brain. Moreover, gene editing approaches and novel AAV capsids are successfully tested in animal models and will likely lead to enhanced targeting of the cochlea. Here, we cover the recent advances in cochlear gene therapy, provide an overview of the translational potential of these new approaches for existing and future clinical trials, and highlight the translational implications that remain to be determined for their application in humans.
Multicomponent syntheses enable the discovery of novel quisinostat-derived chemotypes as histone deacetylase inhibitors
2024-11-08

In this study, we synthesized and evaluated novel histone deacetylase (HDAC) inhibitors derived from the clinical candidate quisinostat. A library of 16 compounds categorized in three novel chemotypes was rapidly generated using multicomponent reactions (MCRs), enabling efficient structure-activity relationship studies. First, the compounds were evaluated for their activity against the Plasmodium falciparum strains 3D7 and Dd2, the main malaria-causing parasite, identifying compound 18b of the type C series as the most potent. It demonstrated low nanomolar IC<sub>50</sub> values (IC<sub>50</sub> (3D7) = 0.023 μM; IC<sub>50</sub> (Dd2) = 0.047 μM) and high parasite selectivity (SI<sup>MRC-5/Pf3D7</sup> > 2174). HDAC inhibition assays confirmed substantial inhibition of the P. falciparum enzyme PfHDAC1 (IC<sub>50</sub> = 0.037 μM) as well as of human HDAC1 (IC<sub>50</sub> = 0.021 μM) and HDAC6 (IC<sub>50</sub> = 0.25 μM). Docking studies suggested distinct binding modes of 18b in P. falciparum and human HDAC1. Additionally, the in vitro anticancer activity was evaluated in Cal27 (head-neck carcinoma), HepG2 (hepatocellular carcinoma), A2780 (ovarian carcinoma), and U87 (glioblastoma) cell lines. Compounds 9b, 9d, and 13f showed potent antiproliferative activity and caspase 3/7 activation, in contrast to 18b. Furthermore, these compounds caused hyperacetylation of histone H3 and α-tubulin, indicating robust cellular target engagement. Overall, in this work we have identified the HDAC inhibitor 18b with selective antiplasmodial and 9b, 9d, and 13f with selective anticancer activities, providing valuable hits for further drug development efforts aimed at creating derivatives with reduced cytotoxicity against non-cancer cells compared to quisinostat.
Gallium Methylene Ga8(CH2)12 on Mesoporous Silica
2024-11-09

Abstract Gallium methylene Ga 8 (CH 2 ) 12 was grafted onto large‐pore mesoporous silica SBA‐15 500 and silica MCM‐41 500 with smaller mesopores, each thermally pretreated at 500 °C. For comparability reasons, trimethylgallium was employed as a grafting reagent. The hybrid materials Ga 8 (CH 2 ) 12 @SBA‐15 500 , GaMe 3 @SBA‐15 500 , Ga 8 (CH 2 ) 12 @MCM‐41 500 and GaMe 3 @MCM‐41 500 were characterized by ICP‐OES, N 2 physisorption, elemental analysis, solid‐state 1 H/ 13 C/ 29 Si NMR spectroscopy and diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy. To gain further insight into potential surface species, the molecular compound Ga 8 (CH 2 ) 12 was treated with excess (eight equivalents) of HOSi(O t Bu) 3 , which gave the dimeric species [Me 2 Ga{OSi(O t Bu) 3 }] 2 , being isolable also from the reaction of GaMe 3 with one equivalent of silanol. The hybrid materials revealed high metal contents and surface species with intact Ga−CH 2 −Ga linkages as proposed by NMR spectroscopy and their reactivity toward benzophenone.
Simulatio/dissimulatio – Stellung/Verstellung: Rhetorik, höfische Verhaltenslehre, Ethik (mit Überlegungen zur Rezeption von Balthasar Graciáns Handorakel in Deutschland)
2024-11-09

Abstract Early modern manuals of courtly conduct offer advice on successful behavior and communication for courtiers, emphasizing masquerade and the concealment of intentions through dissimulatio and simulatio as rhetorical key techniques of the courtier. Important works include Castiglione’s Libro del Cortegiano , Machiavelli’s Principe , and Gracián’s Oráculo manual . Their reception in the German early Enlightenment, especially by Thomasius and Müller, demonstrates the development and recontextualization of these ideas within practical philosophy.
The need for general adaptive capacity—Discussing resilience with complex adaptive systems theory
2024-11-10

Abstract The concept of resilience intrinsically links with both complexity and adaptive capacity. Scholars from different fields agree on this. Still, the detailed relations between resilience, complexity, and adaptive capacity need a more thorough theoretical analysis. This article analyses resilience with the help of assumptions from complex adaptive systems (CAS) theory to answer two questions in more detail: What is the relation between resilience and complexity? How can adaptive capacity contribute to resilience? By applying basic ideas from CAS theory to the resilience discourse, the article deduces that complexity of a system is a necessary condition for resilience because complex systems consist of agents that possess adaptive capacity, whereas simple systems consist of mere elements that cannot adapt to unexpected disruptions. The relation between complexity and resilience is multidimensional. Growing complexity leads to a growing need for resilience because the chances for severe, unexpected disruptions increase. The analysis of adaptive capacities revealed that systems and the agents they consist of can possess of specialized and general adaptive capacity. General adaptive capacity is the core feature of resilience because it enables systems to cope with unexpected disruptions. System design principles such as diversity within functional groups and redundancy help to increase general adaptive capacity. The same is true on the community level for social capital and on the individual level for disaster preparedness measures because they increase coping capacities independent of specific hazards.
ComFB, a new widespread family of c-di-NMP receptor proteins
2024-11-10

ABSTRACT Cyclic dimeric GMP (c-di-GMP) is a widespread bacterial second messenger that controls a variety of cellular functions, including protein and polysaccharide secretion, motility, cell division, cell development, and biofilm formation, and contributes to the virulence of some important bacterial pathogens. While the genes for diguanylate cyclases and c-di-GMP hydrolases (active or mutated) can be easily identified in microbial genomes, the list of c-di-GMP receptor domains is quite limited, and only two of them, PliZ and MshEN, are found across multiple bacterial phyla. Recently, a new c-di-GMP receptor protein, named CdgR or ComFB, has been identified in cyanobacteria and shown to regulate their cell size and, more recently, natural competence. Sequence and structural analysis indicated that CdgR is part of a widespread ComFB protein family, named after the “late competence development protein ComFB” from Bacillus subtilis . This prompted the suggestion that ComFB and ComFB-like proteins could also be c-di-GMP receptors. Indeed, we revealed that ComFB proteins from Gram-positive B. subtilis and Thermoanaerobacter brockii were able to bind c-di-GMP with high-affinity. The ability to bind c-di-GMP was also demonstrated for the ComFB proteins from clinically relevant Gram-negative bacteria Vibrio cholerae and Treponema denticola . These observations indicate that the ComFB family serves as yet another widespread family of bacterial c-di-GMP receptors. Incidentally, some ComFB proteins were also capable of c-di-AMP binding, identifying them as a unique family of c-di-NMP receptor proteins. The overexpression of comFB in B. subtilis, combined with an elevated concentration of c-di-GMP, suppressed motility, attesting to the biological relevance of ComFB as a c-di-GMP binding protein. IMPORTANCE The cellular content of the bacterial second messenger c-di-GMP is controlled by c-di-GMP synthases (GGDEF domains) and hydrolases (EAL or HD-GYP domains), whose activities, in turn, respond to the signals perceived by their upstream sensory domains. Cyclic-di-GMP transmits the signals to a variety of its targets, which may contain inactivated GGDEF, EAL, or HD-GYP domains, widespread PilZ or MshEN domains, or various lineage-specific c-di-GMP receptors. Many organisms encode multiple GGDEF domains but few c-di-GMP-binding proteins, suggesting the existence of still unidentified c-di-GMP receptors. Here, we demonstrate that the ComFB family proteins, which include the recently characterized cyanobacterial CdgR/ComFB, constitute yet another widespread family of bacterial c-di-NMP receptors. We additionally show that ComFB controls bacillar motility in a c-di-GMP-dependent manner.
ROSIE: AI generation of multiplex immunofluorescence staining from histopathology images
2024-11-11

Abstract Hematoxylin and eosin (H&amp;E) is a common and inexpensive histopathology assay. Though widely used and information-rich, it cannot directly inform about specific molecular markers, which require additional experiments to assess. To address this gap, we present ROSIE, a deep-learning framework that computationally imputes the expression and localization of dozens of proteins from H&amp;E images. Our model is trained on a dataset of over 1000 paired and aligned H&amp;E and multiplex immunofluorescence (mIF) samples from 20 tissues and disease conditions, spanning over 16 million cells. Validation of our in silico mIF staining method on held-out H&amp;E samples demonstrates that the predicted biomarkers are effective in identifying cell phenotypes, particularly distinguishing lymphocytes such as B cells and T cells, which are not readily discernible with H&amp;E staining alone. Additionally, ROSIE facilitates the robust identification of stromal and epithelial microenvironments and immune cell subtypes like tumor-infiltrating lymphocytes (TILs), which are important for understanding tumor-immune interactions and can help inform treatment strategies in cancer research.