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Proteolysis-targeting chimeras (PROTACs) describe compounds that bind to and induce degradation of a target by simultaneously binding to a ubiquitin ligase. More generally referred to as bifunctional degraders, PROTACs have led the way in the field of targeted protein degradation (TPD), with several compounds currently undergoing clinical testing. Alongside bifunctional degraders, single-moiety compounds, or molecular glue degraders (MGDs), are increasingly being considered as a viable approach for development of therapeutics, driven by advances in rational discovery approaches. This review focuses on drug discovery with respect to bifunctional and molecular glue degraders within the ubiquitin proteasome system, including analysis of mechanistic concepts and discovery approaches, with an overview of current clinical and pre-clinical degrader status in oncology, neurodegenerative and inflammatory disease.

This retrospective chart review study investigated the clinical burden of adult patients with chronic-phase chronic myeloid leukemia (CP-CML) treated at three centers in France (2006-2021) who failed on two or more tyrosine kinase inhibitors (TKIs; third-line [3L]+ cohort) or harbored the BCR::ABL1 T315I mutation (T315I cohort). In the 3L+ cohort (N = 157; median age at diagnosis, 56 years), TKIs received in 3L (median duration: 17 months) were dasatinib (32%), nilotinib (19%), imatinib (18%), ponatinib (17%), and bosutinib (14%). Of the 145 patients with documented responses in 3L, 42% experienced major molecular response (MMR) at 12 months. Median event-free survival [95% confidence interval] was 53.6 [44.0, 67.5] months, and median progression-free survival and overall survival (OS) were not reached. Achieving MMR in 3L was associated with a decreased mortality risk. In the T315I cohort (N = 17; 52 years), 41% of patients received five or more lines of therapy. Following identification of the T315I mutation, ponatinib was the most common TKI used (59%); the median [interquartile range] OS was 5 [3-10] years. The most common adverse events were infections (3L+ cohort) and thrombocytopenia (T315I cohort) (both 18%). Well-tolerated therapies that achieve durable responses are needed in 3L or earlier to improve CP-CML prognosis.

Background-The purpose of this study was to investigate the bone resorption, as well as the vascular and immune microenvironment, of jaw osteosarcomas (JO) and to correlate these features with patient clinical outcomes. Methods-We studied 50 JO biopsy samples by immunohistochemical analysis of tissue microarrays (TMAs). We investigated the bone remodeling markers RANK/RANKL/OPG, the endothelial glycoprotein CD146, and biomarkers of the immune environment (CD163 and CD68 of macrophages, CD4+ and CD8+ of tumor-infiltrating lymphocytes (TILs), and an immune checkpoint PD-1/PD-L1). The biomarkers were analyzed for their influence on progression (recurrence and metastasis), overall survival (OS), and disease-free survival (DFS). Results-A strong and significant correlation has been found between CD163 staining and lower OS and DFS. The level of CD4+ and CD8+ staining was low and non-significantly associated with survival outcomes. High levels of RANK and RANKL were found in the tumor samples and correlated with lower DFS. Conclusion-Our findings suggest that CD163+ TAMs represent markers of poor prognosis in JO. Targeting TAMs could represent a valuable therapeutic strategy in JO.

The Sphingosine kinase-1/Sphingosine 1-Phosphate (SphK1/S1P) signaling pathway is overexpressed in various cancers, and is instrumental for the adaptation to hypoxia in a number of solid tumor models, but no data are available in osteosarcoma. Here we report that SphK1 and the S1P 1 receptor are involved in HIF-1α accumulation in hypoxic osteosarcoma cells. FTY720 (Fingolimod), which targets SphK1 and S1P 1, prevented HIF-1α accumulation, and also inhibited cell proliferation in both normoxia and hypoxia unlike conventional chemotherapy. In human biopsies, a significant increase of SphK1 activity was observed in cancer compared with normal bones. In all sets of TMA samples (130 cases of osteosarcoma), immunohistochemical analysis showed the hypoxic marker GLUT-1, SphK1 and S1P 1 were expressed in tumors. SphK1 correlated with the GLUT-1 suggesting that SphK1 is overexpressed and correlates with intratumoral hypoxia. No correlation was found between GLUT-1 or SphK1 and response to chemotherapy, but a statistical difference was found with increased S1P 1 expression in patients with poor response in long bone osteosarcomas. Importantly, multivariate analyses showed that GLUT-1 was associated with an increased risk of death in flat bone, whereas SphK1 and S1P 1 were associated with an increased risk of death in long bones.

Biological and histopathological techniques identified osteoclasts and macrophages as targets of zoledronic acid (ZA), a therapeutic agent that was detrimental for patients in the French OS2006 trial. Conventional and multiplex immunohistochemistry of microenvironmental and OS cells were performed on biopsies of 124 OS2006 patients and 17 surgical ("OSNew") biopsies respectively. CSF-1R (common osteoclast/macrophage progenitor) and TRAP (osteoclast activity) levels in serum of 108 patients were correlated to response to chemotherapy and to prognosis. TRAP levels at surgery and at the end of the protocol were significantly lower in ZA+ than ZA- patients (p adj = 0.0011; 0.0132). For ZA+-patients, an increase in the CSF-1R level between diagnosis and surgery and a high TRAP level in the serum at biopsy were associated with a better response to chemotherapy ( p = 0.0091; p = 0.0251). At diagnosis, high CD163+ was associated with good prognosis, while low TRAP activity was associated with better overall survival in ZA- patients only. Multiplex immunohistochemistry demonstrated remarkable bipotent CD68+/CD163+ macrophages, homogeneously distributed throughout OS regions, aside osteoclasts (CD68+/CD163-) mostly residing in osteolytic territories and osteoid-matrix-associated CD68-/CD163+ macrophages. We demonstrate that ZA not only acts on harmful osteoclasts but also on protective macrophages, and hypothesize that the bipotent CD68+/CD163+ macrophages might present novel therapeutic targets., Competing Interests: The authors declare no conflict of interest.

Ribonucleotide reductase (RNR) is the rate-limiting enzyme in the synthesis of deoxyribonucleotides and the target of multiple chemotherapy drugs, including gemcitabine. We previously identified that inhibition of RNR in Ewing sarcoma tumors upregulates the expression levels of multiple members of the activator protein-1 (AP-1) transcription factor family, including c-Jun and c-Fos, and downregulates the expression of c-Myc. However, the broader functions and downstream targets of AP-1, which are highly context- and cell-dependent, are unknown in Ewing sarcoma tumors. Consequently, in this work, we used genetically defined models, transcriptome profiling, and gene-set -enrichment analysis to identify that AP-1 and EWS-FLI1, the driver oncogene in most Ewing sarcoma tumors, reciprocally regulate the expression of multiple extracellular-matrix proteins, including fibronectins, integrins, and collagens. AP-1 expression in Ewing sarcoma cells also drives, concurrent with these perturbations in gene and protein expression, changes in cell morphology and phenotype. We also identified that EWS-FLI1 dysregulates the expression of multiple AP-1 proteins, aligning with previous reports demonstrating genetic and physical interactions between EWS-FLI1 and AP-1. Overall, these results provide novel insights into the distinct, EWS-FLI1-dependent features of Ewing sarcoma tumors and identify a novel, reciprocal regulation of extracellular-matrix components by EWS-FLI1 and AP-1. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal neuroendocrine neoplasms (GI-NENs) represent a diverse group of tumors, with surgical resection being the gold standard for treatment. Materials and Methods: A retrospective analysis was conducted on 63 patients (32 women, 31 men) who underwent surgery for GI-NENs at the Department of Digestive Tract Surgery from January 2013 to June 2023. Tumors were classified by stage (localized, regionally advanced, metastatic). Results: Clinical symptoms were reported by 42 (66.7%) patients, with abdominal pain being the most common symptom, affecting 28 (44.4%) patients. The majority of tumors (44, 69.8%) originated in the midgut. The most frequently performed surgery was right hemicolectomy, carried out on 33 (52.4%) patients. Radical tumor resection was performed in 35 (55.6%) patients. Postoperative complications occurred in 12 (19%) patients, with male gender identified as an independent predictive factor for complications (p = 0.04). Non-functioning tumors were more common (33, 52.4%), and most tumors were classified as grade 1 histopathologically (49, 77.8%). Distant metastases were present in 29 (46%) patients. The overall two-year survival rate was 94.9%, with a five-year survival rate also estimated at 94.9%. Conclusions: GI-NENs are often diagnosed at advanced stages, frequently with distant or lymph node metastases, and predominantly arise in the midgut. Despite low postoperative morbidity and mortality, male gender may be a predictor of postoperative complications. Overall, the prognosis for GI-NENs is favorable, reflected in high overall survival rates. [ABSTRACT FROM AUTHOR]

Simple Summary: The medical field is increasingly interested in using machine learning (ML) to analyse data, sparking a debate on whether ML is better than traditional statistical modelling. The aim of our retrospective study was to investigate the use of statistical models versus ML to predict survival in patients with osteosarcoma using low-dimensional data from the EURAMOS-1 trial. Results showed that ML did not add much value in this context, which involved data from nearly 2000 patients and eight predictors. Traditional statistical models worked well without needing extensive complex training, unlike ML, and they showed better effectiveness overall because they are easy to understand and use. The article helps healthcare researchers assess different prediction models in similar low-dimensional contexts. Since the mid-1980s, there has been little progress in improving survival of patients diagnosed with osteosarcoma. Survival prediction models play a key role in clinical decision-making, guiding healthcare professionals in tailoring treatment strategies based on individual patient risks. The increasing interest of the medical community in using machine learning (ML) for predicting survival has sparked an ongoing debate on the value of ML techniques versus more traditional statistical modelling (SM) approaches. This study investigates the use of SM versus ML methods in predicting overall survival (OS) using osteosarcoma data from the EURAMOS-1 clinical trial (NCT00134030). The well-established Cox proportional hazard model is compared to the extended Cox model that includes time-varying effects, and to the ML methods random survival forests and survival neural networks. The impact of eight variables on OS predictions is explored. Results are compared on different model performance metrics, variable importance, and patient-specific predictions. The article provides comprehensive insights to aid healthcare researchers in evaluating diverse survival prediction models for low-dimensional clinical data. [ABSTRACT FROM AUTHOR]

Simple Summary: Osteosarcoma (OS) is the most frequently occurring malignant bone tumor in children. Although advances in chemotherapy and surgery have gradually improved OS prognosis, no improvement has been reported over the past two decades. Recently, tumor microenvironment (TME) has attracted attention as a novel therapeutic target. The TME includes peritumoral immune cells, blood vessels, extracellular matrix, fibroblasts, lymphocytes, bone marrow-derived inflammatory cells, platelets, and signaling molecules, which create an environment that promotes tumor growth, metastasis, and anticancer drug resistance. Research on the TME is particularly important because tumor-associated macrophages (TAMs) are a major component of this microenvironment, and the interaction between tumors and TAMs contributes towards tumor aggressiveness. However, our knowledge of the interaction between OS and TAMs is limited. In this review, we aim to describe the characteristics of TAMs in the OS TME. Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Prognosis is improving with advances in multidisciplinary treatment strategies, but the development of new anticancer agents has not, and improvement in prognosis for patients with pulmonary metastases has stalled. In recent years, the tumor microenvironment (TME) has gained attention as a therapeutic target for cancer. The immune component of OS TME consists mainly of tumor-associated macrophages (TAMs). They exhibit remarkable plasticity, and their phenotype is influenced by the TME. In general, surface markers such as CD68 and CD80 show anti-tumor effects, while CD163 and CD204 show tumor-promoting effects. Surface markers have potential value as diagnostic and prognostic biomarkers. The cytokines and chemokines produced by TAMs promote tumor growth and metastasis. However, the role of TAMs in OS remains unclear to date. In this review, we describe the role of TAMs in OS by focusing on TAM surface markers and the TAM-produced cytokines and chemokines in the TME, and by comparing their behaviors in other carcinomas. We found contrary results from different studies. These findings highlight the urgency for further research in this field to improve the stalled OS prognosis percentages. [ABSTRACT FROM AUTHOR]

Simple Summary: Intramedullary primary spinal cord tumors represent a heterogeneous group of very rare tumors. In cases of recurrence or high-grade tumors, radiotherapy, chemotherapy, or targeted therapies can be indicated. The purpose of this review is to clarify the actual knowledge about intramedullary primary spinal cord tumors in light of the latest progress made in their classification. Intramedullary primary spinal cord tumors are rare in adults and their classification has recently evolved. Their treatment most frequently relies on maximal safe surgical resection. Herein, we review, in light of the WHO 2021 classification of central nervous system tumors, the knowledge regarding the role of radiotherapy and systemic treatments in spinal ependymomas, spinal astrocytomas (pilocytic astrocytoma, diffuse astrocytoma, spinal glioblastoma IDH wildtype, diffuse midline glioma H3-K27M altered, and high-grade astrocytoma with piloid features), neuro-glial tumors (ganglioglioma and diffuse leptomeningeal glioneuronal tumor), and hemangioblastomas. In spinal ependymomas, radiotherapy is recommended for incompletely resected grade 2 tumors, grade 3 tumors, and recurrent tumors not amenable to re-surgery. Chemotherapy is used in recurrent cases. In spinal astrocytomas, radiotherapy is recommended for incompletely resected grade 2 astrocytomas and grade 3 or 4 tumors as well as recurrent tumors. Chemotherapy is indicated for newly diagnosed high-grade astrocytomas and recurrent cases. In hemangioblastomas not amenable to surgery, radiotherapy is an effective alternative option. Targeted therapies are playing an increasingly important role in the management of some intramedullary primary spinal cord tumor subtypes. BRAF and/or MEK inhibitors have demonstrated efficacy in pilocytic astrocytomas and glioneuronal tumors, belzutifan in von Hippel–Lindau-related hemangioblastomas, and promising results have been reported with ONC201 in diffuse midline glioma H3-K27M altered. [ABSTRACT FROM AUTHOR]

In this paper, a novel deep learning approach based on conditional FLOW is proposed for sea clutter augmentation. Sea clutter data augmentation is important for testing detection algorithms for maritime remote sensing and surveillance due to the expensive and time-consuming nature of sea clutter data acquisition. Whereas the conventional parametric methods face challenges in finding appropriate distributions and modeling time correlations of sea clutter data, the proposed deep learning approach, GCC-FLOW, can learn the data distribution from the data without explicitly defining a mathematical model. Furthermore, unlike the existing generative deep learning approaches, the proposed GCC-FLOW is able to synthesize sea clutter data of arbitrary length with the stable autoregressive structure using conditional FLOW. In addition, the proposed algorithm generates sea clutter data not only with the same characteristics of the training data, but also with the interpolated characteristics of different training data by introducing a global condition variable corresponding to the target characteristic, such as sea state. Experimental results demonstrate the effectiveness of the proposed GCC-FLOW in generating sea clutter data of arbitrary length under different sea state conditions. [ABSTRACT FROM AUTHOR]

Salt-affected soils are a prevalent issue globally, resulting in a severe degradation of soil sustainability and plant productivity, reducing the area of agricultural land, and affecting food security. Therefore, eco-solutions and remediation approaches are needed. The needed remediation for salt-affected soil can be addressed via engineering, physical, chemical, or biological techniques. Salt-tolerant crops are normally used for the remediation of slight and moderate saline soil conditions. However, no crops, including salt-tolerant crops, can be cultivated in areas with extreme salinity levels (ECe 8–16 dS/m). Therefore, the aim of this study was to investigate the effect of vermicompost and organic amendment on the cultivation of salt-tolerant crops (Sesbania rostrata) in severely salt-affected soil under field conditions in order to improve saline soil and crop productivity. The design of the experiment followed a randomized complete block design (RCBD) with three treatments and four replications: T1, severely salt-affected soil (control); T2, severely salt-affected soil + vermicompost at a ratio of 25:75; T3, severely salt-affected soil + vermicompost + rice husk biochar + coconut coir at a ratio of 25:25:25:25. The results found that using vermicompost and organic amendment improved the soil quality, increased the soil fertility (organic matter and plant nutrients N, P, and K), and reduced the soil salinity. Sesbania rostrate could not grow in severely salt-affected soil (T1) alone, but could grow in the treatments with vermicompost and organic amendments (T2 and T3). The percentage of Sesbania survival per plot was also high in the treatments with vermicompost and organic amendments (T2 and T3). The highest growth rate, flower production, biomass, and root morphology of Sesbania rostrata were found in T3, with severely salt-affected soil + vermicompost + rice husk biochar + coconut coir at a ratio of 25:25:25:25 with a statistically significant difference (p < 0.05). Moreover, the Sesbania flowers treated with vermicompost and organic amendments have a higher nutritional value due to their minerals and vitamins than Sesbania flowers grown without using vermicompost and organic amendments. This study's findings suggest that incorporating vermicompost and organic amendments is a feasible and economical method for enhancing the quality of salt-affected soils in a sustainable manner. The results of this study demonstrate that utilizing vermicompost and organic amendments is a sustainable and economical strategy for enhancing the quality of salt-affected soils and improving yields in severely salt-affected areas, thereby increasing crop production and the nutritional value of the plants as well as helping to increase farmers' income. [ABSTRACT FROM AUTHOR]

RNA-based next-generation sequencing (RNA-seq) represents the gold standard for detecting gene fusion in non-small cell lung cancer (NSCLC). Despite this, RNA instability makes the management of tissue samples extremely complex, resulting in a significant number of test failures with missing data or the need to switch to other techniques. In the present study, we analyzed pre-analytical variables in 140 tumor tissue samples from patients affected by NSCLC to detect features that increase the chances of successful RNA-seq. We found that the success rate of the analysis positively correlates with the RNA concentration and fragmentation index. Interestingly, small biopsies were more suitable samples than surgical specimens and cell blocks. Among surgical specimens, wedge resections demonstrated better results than lobectomy. Moreover, samples stored for less than 30 days (1 month) had a better chance of success than older samples. Defining the role of pre-analytical variables in RNA-seq allows the detection of more suitable samples for analysis and more effective planning of molecular-based diagnostic approaches in NSCLC. [ABSTRACT FROM AUTHOR]

Synovial sarcoma (SS) is a rare soft-tissue tumor characterized by a monomorphic blue spindle cell histology and variable epithelial differentiation. Morphologically, SSs may be confused with other sarcomas. Systemic treatment is more effective for patients with high-risk SSs, patients with advanced disease, and younger patients. However, further studies are required to find new prognostic biomarkers. Herein, we describe the morphological, molecular, and clinical findings, using a wide immunohistochemical panel, of a series of SS cases. We studied 52 cases confirmed as SSs by morphological diagnosis and/or molecular studies. Clinical data (gender, age, tumor size, tumor location, resection margins, adjuvant treatment, recurrences, metastasis, and survival) were also retrieved for each patient. All the available H&E slides were examined by four pathologists. Three tissue microarrays (TMAs) were constructed for each of the tumors, and a wide immunohistochemical panel was performed. For time-to-event variables, survival analysis was performed using Kaplan–Meier curves and log-rank testing, or Cox regression. Statistical significance was considered at p < 0.05. The mean age of our patients was 40.33, and the median was 40.5 years. We found a predominance of males versus females (1.7:1). The most frequent morphological subtype was monophasic. TRPS1, SS18-SSX, and SSX-C-terminus were positive in 96% of cases. GLI1 expression was strong in six and focal (cytoplasmic) in twenty patients. Moreover, BCOR was expressed in more than half of SSs. Positive expression of both proteins, BCOR and GLI1, was correlated with a worse prognosis. Multivariate analysis was also performed, but only BCOR expression appeared to be significant. The combination of GLI1 and BCOR antibodies can be used to group SSs into three risk groups (low, intermediate, and high risk). We hypothesize that these findings could identify which patients would benefit from receiving adjuvant treatment and which would not. Moreover, these markers could represent therapeutic targets in advanced stages. However, further, larger series of SSs and molecular studies are necessary to corroborate our present findings. [ABSTRACT FROM AUTHOR]

In this work, electrical resistivity tomography was carried out together with physical hydrogeology techniques to evaluate the karst aquifer in the northwest region of the Yucatán Peninsula in a study area near the western edge of the Ring of Cenotes of the Chicxulub Crater. In addition, based on a systematic compilation of open-access data of water levels reported for the peninsular aquifer, maps of groundwater isolines and groundwater flows were generated using IDW interpolation, Empirical Bayesian Kriging, and the Flow Net method. From these results, a shallow aquifer is observed, with the presence of heterogeneities such as possible dissolution conduits and/or flooded caverns, approximately 20 m below ground level, formed by the dissolution processes of limestone rocks. On a regional scale, the geomorphological influence of the Ring of Cenotes on groundwater flows was observed. In general, the flow directions observed from these maps coincide with those conceptualized for this region of the peninsular aquifer. Nevertheless, some differences were observed depending on the interpolation method used. Our results contribute to hydrogeological studies carried out in the periphery of this ring, where the vulnerability of the aquifer to anthropogenic contamination has been highlighted due to the intrinsic features of the karst environment. [ABSTRACT FROM AUTHOR]

Simple Summary: Simultaneous positron emission tomography/magnetic resonance imaging (PET-MRI) combines the high sensitivity of PET with the high specificity of MRI. Here, we aimed to evaluate whether a combined PET-MRI exam may give more information than conventional exams at the time of diagnosis in a series of patients presenting with a neuroendocrine tumor in the pancreas or within the gastrointestinal tract. We also investigated if the procedure could influence survival. In 71 patients, we performed a PETMRI at the baseline and in 50 patients the follow-up was based on PET-MRI performed every 6–12 months. The results show that the hybrid exam yielded new information at the baseline and during the follow-up, but had no impact on the survival. Introduction and aim: Simultaneous positron emission tomography/magnetic resonance imaging (PET-MRI) combines the high sensitivity of PET with the high specificity of MRI and is a tool for the assessment of gastroenteropancreatic neuroendocrine neoplasms (G-NENs). However, it remains poorly evaluated with no clear recommendations in current guidelines. Thus, we evaluated the prognostic impact of PET-MRI in G-NEN patients. Methods: From June 2017 to December 2021, 71 G-NEN patients underwent whole-body PET-MRI for staging and/or follow-up purposes. A whole-body emission scan with 18F-6-fluoro-L-dihydroxyphenylalanine (18FDOPA, n = 30), 18F-fluoro-2-deoxy-D-glucose (18FDG, n = 21), or 68Ga-(DOTA(0)-Phe(1)-Tyr(3))-octreotide (68Ga-DOTATOC, n = 20) with the simultaneous acquisition of a T1-Dixon sequence and diffusion-weighed imaging (DWI), followed by a dedicated step of MRI sequences with a Gadolinium contrast was performed. The patients underwent PET-MRI every 6–12 months during the follow-up period until death. Over this period, 50 patients with two or more PET-MRI were evaluated. Results: The mean age was 61 [extremes, 31–92] years. At the baseline, PET-MRI provided new information in 12 cases (17%) as compared to conventional imaging: there were more metastases in eight, an undescribed location (myocardia) in two, and an unknown primary location in two cases. G grading at the baseline influenced overall survival. During the follow-up (7–381 months, mean 194), clinical and therapy managements were influenced by PET-MRI in three (6%) patients due to new metastases findings when neither overall, nor disease-free survivals in these two subgroups (n = 12 vs. n = 59), were different. Conclusion: Our study suggests that using PET/MRI with the appropriate radiotracer improves the diagnostic performance with no benefit on survival. Further studies are warranted to evaluate the cost-effectiveness of this procedure. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuroendocrine neoplasms (NENs) are occurring more frequently worldwide. Data from the UK cancer database (National Cancer Registration and Analysis Service (NCRAS)) showed that female patients have better survival with neuroendocrine neoplasms. This study used the U.S. cancer database (Surveillance, Epidemiology, and End Results Program (SEER)) to validate and compare these findings. Sixty-months survival for NENs were calculated for both male and female patients from NCRAS and SEER. The findings from NCRAS were confirmed by the findings from SEER that females survive more than males with NENs, mainly with lung and stomach NENs. The reason behind this is unclear and remains unexplained. Background: Neuroendocrine neoplasms (NENs) are increasing in incidence globally. Previous analysis of the UK cancer database (National Cancer Registration and Analysis Service (NCRAS)) showed a notable female survival advantage in most tumour sites. This study aims to compare NCRAS to the Surveillance, Epidemiology, and End Results Program (SEER) to validate these results using the same statistical methods. Methods: A total of 14,834 and 108,399 patients with NENs were extracted from NCRAS and SEER, respectively. Sixty-months survival for both males and females for each anatomical site of NENs were calculated using restricted mean survival time (RMST) and Kaplan–Meier Survival estimates. The sixty-month RMST female survival advantage (FSA) was calculated. Results: FSA was similar in NCRAS and SEER. The highest FSA occurred in lung and stomach NENs. Conclusions: The data from SEER confirm the findings published by NCRAS. Female survival advantage remains unexplained. [ABSTRACT FROM AUTHOR]

Simple Summary: Treatment for osteosarcoma (OS) has remained largely unchanged over the past 25 years. This is due in part to the low incidence of the disease, which makes the design of and recruitment to clinical trials challenging. The aim of our ongoing study is to establish a platform for the recruitment of newly diagnosed OS patients across the UK, with corresponding collection of clinical and patient-reported outcome (PRO) data, as well as biospecimen sample collection. In Stage 1 of the study, we established the feasibility of patient recruitment and patient data and sample collection. In Stage 2, biological and clinical data will be correlated with outcomes to develop prognostic biomarkers and inform the development of future clinical trials. There has been little change to the standard treatment for osteosarcoma (OS) over the last 25 years and there is an unmet need to identify new biomarkers and novel therapeutic approaches if outcomes are to improve. Furthermore, there is limited evidence on the impact of OS treatment on patient-reported outcomes (PROs). ICONIC (Improving Outcomes through Collaboration in Osteosarcoma; NCT04132895) is a prospective observational cohort study recruiting newly diagnosed OS patients across the United Kingdom (UK) with matched longitudinal collection of clinical, biological, and PRO data. During Stage 1, which assessed the feasibility of recruitment and data collection, 102 patients were recruited at 22 sites with representation from patient groups frequently excluded in OS studies, including patients over 50 years and those with less common primary sites. The feasibility of collecting clinical and biological samples, in addition to PRO data, has been established and there is ongoing analysis of these data as part of Stage 2. ICONIC will provide a unique, prospective cohort of newly diagnosed OS patients representative of the UK patient population, with fully annotated clinical outcomes linked to molecularly characterised biospecimens, allowing for comprehensive analyses to better understand biology and develop new biomarkers and novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms presenting unique challenges in diagnosis and management. Traditional markers such as chromogranin A (CgA), pancreatic polypeptide (PP), and neuron-specific enolase (NSE) have limitations in terms of specificity and sensitivity. Specific circulating markers such as serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) and various gastrointestinal hormones such as gastrin, glucagon, somatostatin, and vasoactive intestinal peptide (VIP) have a role in identifying functional NENs. Recent advances in molecular and biochemical markers, also accounting for novel genomic and proteomic markers, have significantly improved the landscape for the diagnosis and monitoring of NENs. This review discusses these developments, focusing on both traditional markers such as CgA and NSE, as well as specific hormones like gastrin, insulin, somatostatin, glucagon, and VIP. Additionally, it covers emerging genomic and proteomic markers that are shaping current research. The clinical applicability of these markers is highlighted, and their role in improving diagnostic accuracy, predicting surgical outcomes, and monitoring response to treatment is demonstrated. The review also highlights the need for further research, including validation of these markers in larger studies, development of standardized assays, and integration with imaging techniques. The evolving field of biochemical markers holds promise for improving patient outcomes in the treatment of NENs, although challenges in standardization and validation remain. [ABSTRACT FROM AUTHOR]

Simple Summary: Chondroblastoma is a rare benign aggressive primary bone tumor, with susceptibility to local recurrence and metastasis, mainly to the lungs. However, various metastatic locations have been described, such as bone, soft tissue, and liver. Metastatic chondroblastoma treatment involves various approaches including surgical resection, radiotherapy, chemotherapy, and palliative treatment. The expression of RANKL in chondroblastoma cells has opened new avenues for treatment with denosumab, which shows effectiveness in controlling both local and metastatic tumors. Hence, there is a greater need to enhance our understanding of this rare tumor's biology and refine therapeutic approaches to improve patient outcomes, reduce recurrence rates, and better manage metastatic cases. Chondroblastoma metastasis, though rare, represents a clinically significant and notably important aspect of bone tumors. Understanding its epidemiological characteristics, pathological features, and treatment modalities, despite its infrequency, is imperative for comprehensive patient management. This review aims to elucidate the epidemiology, molecular mechanisms, diagnostic challenges, and therapeutic strategies associated with chondroblastoma metastasis. The patterns, prognostic factors, and treatment outcomes were explored through an analysis of case studies and clinical reports. Notably, we highlighted emerging therapeutic perspectives aimed at improving patient outcomes. To the best of our knowledge, there has been no previous review addressing these matters cumulatively, highlighting a significant gap in the existing scholarly literature. By shedding light on the nuances of chondroblastoma metastasis, this review contributes to the advancement of knowledge in this field and informs clinical decision-making for improved patient care. [ABSTRACT FROM AUTHOR]

Simple Summary: The immune microenvironment surrounding a growing tumor is complex and diverse. Understanding this complexity is crucial for predicting prognosis and response to cancer therapy. Various immune cells, signaling molecules, and extracellular matrix components within this microenvironment interact intricately, influencing tumor progression and treatment effectiveness. A deeper understanding of these interactions can lead to better prognostic markers and more effective, personalized therapeutic strategies. Compared to adults, the pediatric tumor immune microenvironment is less studied. Research on different pediatric tumors has shown that regulatory signaling networks between tumors and surrounding immune cells are critical in shifting the balance between pro- and anti-tumor immune responses. Therefore, gaining insights into the tumor immune composition is key to improving the efficacy of various pediatric cancer therapies, particularly immunotherapies that enhance host anti-tumor immunity. The tumor immune microenvironment is pivotal in cancer initiation, advancement, and regulation. Its molecular and cellular composition is critical throughout the disease, as it can influence the balance between suppressive and cytotoxic immune responses within the tumor's vicinity. Studies on the tumor immune microenvironment have enriched our understanding of the intricate interplay between tumors and their immunological surroundings in various human cancers. These studies illuminate the role of significant components of the immune microenvironment, which have not been extensively explored in pediatric tumors before and may influence the responsiveness or resistance to therapeutic agents. Our deepening understanding of the pediatric tumor immune microenvironment is helping to overcome challenges related to the effectiveness of existing therapeutic strategies, including immunotherapies. Although in the early stages, targeted therapies that modulate the tumor immune microenvironment of pediatric solid tumors hold promise for improved outcomes. Focusing on various aspects of tumor immune biology in pediatric patients presents a therapeutic opportunity that could improve treatment outcomes. This review offers a comprehensive examination of recent literature concerning profiling the immune microenvironment in various pediatric tumors. It seeks to condense research findings on characterizing the immune microenvironment in pediatric tumors and its impact on tumor development, metastasis, and response to therapeutic modalities. It covers the immune microenvironment's role in tumor development, interactions with tumor cells, and its impact on the tumor's response to immunotherapy. The review also discusses challenges targeting the immune microenvironment for pediatric cancer therapies. [ABSTRACT FROM AUTHOR]

The presented manuscript focuses on the influence of process parameters of abrasive water jet technology on the creation of non-transient erosive grooves. The processed stainless steel SS 316L is additively manufactured using the selective laser melting (SLM) method. Due to the distinct mechanical properties of this material resulting from the production process, the material was machined in two planes according to the direction of the printing layers. The experimental part employed a planned experiment utilizing the DoE (Design of Experiment) method. Experiments aimed at varying process parameters (traverse speed, standoff distance, abrasive mass flow) were conducted at a water pressure of 50 MPa, assessing the parameters' impact on the removed material and the properties of the resulting non-transient erosion groove. The properties of the erosion groove, such as shape and the material removal (area of erosion groove), were evaluated. The influences of process parameters on the observed parameters were assessed using the analysis of variance (ANOVA) method. Experiment preparation and setup were based on a thorough theoretical analysis of the machining process with the abrasive water jet (AWJ) method. The experiment also highlights the diverse properties of the SS 316L material prepared using the SLM method when machined with AWJ technology. [ABSTRACT FROM AUTHOR]

This paper addresses the problem of removing 3D effects as one of the most challenging problems related to 2D electrical resistivity tomography (ERT) monitoring of embankment structures. When processing 2D ERT monitoring data measured along linear profiles, it is fundamental to estimate and correct the distortions introduced by the non-uniform 3D geometry of the embankment. Here, I adopt an iterative 3D correction plus 2D inversion procedure to correct the 3D effects and I test the validity of the proposed algorithm using both synthetic and real data. The modelled embankment is inspired by a critical section of the Parma River levee in Colorno (PR), Italy, where a permanent ERT monitoring system has been in operation since November 2018. For each model of the embankment, reference synthetic data were produced in Res2dmod and Res3dmod for the corresponding 2D and 3D models. Using the reference synthetic data, reference 3D effects were calculated to be compared with 3D effects estimated by the proposed algorithm at each iteration. The results of the synthetic tests showed that even in the absence of a priori information, the proposed algorithm for correcting 3D effects converges rapidly to ideal corrections. Having validated the proposed algorithm through synthetic tests, the method was applied to the ERT monitoring data in the study site to remove 3D effects. Two real datasets from the study site, taken after dry and rainy periods, are discussed here. The results showed that 3D effects cause about ±50% changes in the inverted resistivity images for both periods. This is a critical artifact considering that the final objective of ERT monitoring data for such studies is to produce water content maps to be integrated in alarm systems for hydrogeological risk mitigation. The proposed algorithm to remove 3D effects is thus a rapid and validated solution to satisfy near-real-time data processing and to produce reliable results. [ABSTRACT FROM AUTHOR]

In the last few decades, the traditional paradigm of teleonomy, in which the amino acid sequence of a protein is tightly associated with its structure and, in turn, with its function, has been partially undermined. The idea of a protein as a two-state object has been superseded by that of understanding it as a multistate object. Indeed, some proteins, or portions of a protein, display intrinsically disordered regions (IDRs), which means that they lack stable secondary or tertiary structures. While we are aware that IDRs are present in almost half of the total human proteins, we are still quite far away from understanding their contextual-specific functions and figuring out how they mechanistically work. In the present perspective article, we will attempt to summarize the role/s of IDRs in ubiquitin–proteasome system (UPS)-mediated protein quality control (PQC) at different levels, ranging from ubiquitination to protein degradation through the proteasome machinery up to their role in decoding the complex ubiquitin code. Ultimately, we will critically discuss the future challenges we are facing to gain insights into the role of IDRs in regulating UPS-mediated PQC. [ABSTRACT FROM AUTHOR]

Introduction: Osteosarcomas of the jaw (OSJs) are rare tumors with distinct characteristics from osteosarcomas affecting other bones. This study aims to analyze the clinical, pathological, and therapeutic characteristics of OSJs. Methods: A retrospective, descriptive cross-sectional study including patients diagnosed with OSJ registered at the "La Paz" University Hospital, Madrid, was performed. Results: Data of eight patients with a diagnosis of OSJ were obtained during the study period of 22 years (2002–2024). The mean age of the patients was 41 years. The distribution was 1:1 between the maxilla and mandible. Painful inflammation was the most frequent clinical manifestation. Conventional osteoblastic osteosarcoma was the most predominant histological type. Survival rate at 5 years was 50%, which decreased to 25% at 10 years. Conclusions: OSJs differ from conventional osteosarcomas of long tubular bones. Surgery continues to be the mainstay of treatment. However, more studies are needed through which more standardized protocols can be proposed for adjuvant therapeutic management. [ABSTRACT FROM AUTHOR]

Neuroendocrine neoplasms (NENs) are a diverse group of tumors with varying clinical behaviors. Their incidence has risen due to increased awareness, improved diagnostics, and aging populations. The 2019 World Health Organization classification emphasizes integrating radiology and histopathology to characterize NENs and create personalized treatment plans. Imaging methods like CT, MRI, and PET/CT are crucial for detection, staging, treatment planning, and monitoring, but each of them poses different interpretative challenges and none are immune to pitfalls. Treatment options include surgery, targeted therapies, and chemotherapy, based on the tumor type, stage, and patient-specific factors. This review aims to provide insights into the latest developments and challenges in NEN imaging, diagnosis, and management. [ABSTRACT FROM AUTHOR]

In the past two decades, several floods have affected people and their properties in Burkina Faso, with unprecedented flooding occurring in Ouagadougou in September 2009. So far, most studies have focused on Ouagadougou and surrounding localities and have paid little attention to other flood-prone regions in Burkina Faso. Consequently, there is a data and knowledge gap regarding flood risk in the Haut-Bassins region, which in turn hinders the development of mitigation strategies and risk reduction measures in affected communities. This study demonstrates how data collected at the household level can be used to understand flood risk and its components at the village level in this data-scarce region. Using an indicator-based method, we analyzed both flood risk and flood risk perception at the village level. Moreover, we determined the factors influencing flood risk perception at the household level using an ordered logit model. We found that 12 out of the 14 villages in our sample group had experienced high levels of flood risk. The management of runoff from the nearest urban areas as well as poorly designed civil engineering infrastructures, such as roads, were highlighted by households as significant factors that increased their vulnerability. Additionally, we found that the perceived flood risk consistently exceeds the estimated flood risk, with an insignificant positive correlation between both risk indices. Regression results indicate that flood risk perception is mainly influenced by informational and behavioral factors of households. The findings of this study can provide valuable information to municipal and regional authorities involved in disaster risk management within the study area. Moreover, our/this method is transferable to other data-scarce regions. [ABSTRACT FROM AUTHOR]

Simple Summary: Sufferers of neuroendocrine neoplasms (NENs) of unknown primary origin are a poor prognostic group with largely unmet clinical needs. In the absence of standard therapeutic algorithms, treatment should be based on tumor clinical-pathological characteristics, disease burden, and patient conditions. The aim of this review is to explore the evidence relating to available treatment options for NENs of unknown primary and to offer insights into future perspectives. Particular attention is given to molecular characterization and genomic profiling of NENs with potential therapeutic implications, mainly through the identification of druggable targets for agnostic treatments. Moreover, a treatment algorithm for both well-differentiated and poorly differentiated NENs of unknown primary is proposed. Among neuroendocrine neoplasms (NENs), a non-negligible proportion (9–22%) is represented by sufferers of NENs of unknown primary origin (UPO), a poor prognostic group with largely unmet clinical needs. In the absence of standard therapeutic algorithms, current guidelines suggest that the treatment of UPO-NENs should be based on tumor clinical-pathological characteristics, disease burden, and patient conditions. Chemotherapy represents the backbone for the treatment of high-grade poorly differentiated UPO-NENs, usually providing deep but short-lasting responses. Conversely, the spectrum of available systemic therapy options for well-differentiated UPO-NENs may range from somatostatin analogs in indolent low-grade tumors, to peptide receptor radioligand therapy, tyrosine kinase inhibitors (TKIs), or chemotherapy for more aggressive tumors or in case of high disease burden. In recent years, molecular profiling has provided deep insights into the molecular landscape of UPO-NENs, with both diagnostic and therapeutic implications. Although preliminary, interesting activity data have been provided about upfront chemoimmunotherapy, the use of immune checkpoint inhibitors (ICIs), and the combination of ICIs plus TKIs in this setting. Here, we review the literature from the last 30 years to examine the available evidence about the treatment of UPO-NENs, with a particular focus on future perspectives, including the expanding scenario of targeted agents in this setting. [ABSTRACT FROM AUTHOR]

The morphodynamics of the Leucate double-crescent bar system was studied over twenty years using bathymetric data supplemented by satellite images and video monitoring. Eleven different bar typologies were identified, mostly based on existing beach state classifications (Low-Tide Terrace, Transverse Bar and Rip, Rhythmic Bar and Beach), also including new heterogeneous typologies (TBR/LTT, RBB HP/RBB, TBR/RBB). The inner bar shows greater variability, with 10 different typologies observed, while the outer bar shows only three different typologies. Summer low-energy periods are dominated by TBR/LTT and TBR typologies, while RBB, although common throughout the year, dominates winter periods along with disrupted bar configurations. The return to less energetic periods in spring is associated with the establishment of heterogeneous typologies. The outer bar has a fairly stable position, although breaches at the embayments and slight movements of its horns can occur following particularly energetic episodes. The inner bar, on the other hand, is much more dynamic, with more common breaches at the embayments and significant cross-shore movement of the horns. Seasonal changes in bar typology do not lead to bar renewal through destruction/reconstruction. Overall, the morphological and typological characteristics of the bar system described here seem somewhat unique compared to the existing literature. [ABSTRACT FROM AUTHOR]

Remote video imagery using shoreline edge detection is widely used in coastal monitoring in order to acquire measurements of nearshore and swash features. Some of these systems are constrained by their long setup time, positioning requirements and considerable hardware costs. As such, there is a need for an autonomous low-cost system (~EUR 500), such as Timex cameras, that can be rapidly deployed in the field, while still producing the outcomes required for coastal monitoring. This research presents an assessment of the effect of the sampling strategy (time-lapse intervals) on the precision of shoreline detection for two low-cost cameras located in a remote coastal area in western Ireland, overlooking a dissipative beach–dune system. The analysis shows that RMSD in the detected shoreline is similar to other studies for sampling intervals ranging between 1 s and 30 s (i.e., RMSDmean for Camera 1 = 1.4 m and Camera 2 = 0.9 m), and an increase in the sampling interval from 1 s to 30 s had no significant adverse effect on the precision of shoreline detection. The research shows that depending on the intended use of the detected shorelines, the current standard of 1 s image sampling interval when using Timex cameras can be increased up to 30 s without any significant loss of accuracy. This positively impacts battery life and memory storage, making the systems more autonomous; for example, the battery life increased from ~10 days to ~100 days when the sampling interval was increased from 1 to 5 s. [ABSTRACT FROM AUTHOR]

Giant cell tumor of soft tissue (GCTST) is a locally aggressive mesenchymal neoplasm of intermediate malignancy that predominantly occurs in the superficial soft tissue of the extremities. It is histologically similar to a giant cell tumor of bone (GCTB) and shows a mixture of round to oval mononuclear cells and osteoclast-like multinucleated giant cells. Currently, immunohistochemistry plays a very limited role in the diagnosis of GCTST. Primary or secondary malignant GCTST has recently been described and tumors exhibiting high-grade histological features demonstrate higher rates of distant metastasis. GCTST lacks the H3-3A gene mutations that are identified in the vast majority of GCTBs, suggesting a different pathogenesis. Surgery is the standard treatment for localized GCTST. Incomplete surgical resection is usually followed by local recurrence. Radiation therapy may be considered when the close proximity of critical structures prevents microscopically negative surgical margins. The systemic treatment options for advanced or metastatic disease are very limited. This review provides an updated overview of the clinicoradiological features, pathogenesis, histopathology, and treatment for GCTST. In addition, we will discuss the differential diagnosis of this peculiar neoplasm. [ABSTRACT FROM AUTHOR]

Simple Summary: Epidermal growth factor receptors (EGFRs) have been suggested as prognostic markers and potential therapeutic targets in several neoplasms in both human and veterinary medicine, among these is human cutaneous melanoma. The aim of this study was to evaluate the immunohistochemical expression of human epidermal growth factor receptors HER-2 and HER-3 in canine melanomas and correlate their expression to clinicopathological parameters. HER-2 expression was observed in 48.6% of the samples and HER-3 expression in 18.9%, while the coexpression of the two receptors was detected in 13.5% of the samples. The expression of both markers was significantly correlated to the presence of ulceration in oral melanomas. A statistically significant association (p < 0.05) was observed between the expression of HER-2 and HER-3 and the presence of ulceration in oromucosal tumors. This work confirmed the expression of HER-2 and HER-3 in canine melanomas. Further studies are necessary to investigate the prognostic and therapeutic role of EGFR family receptors in canine melanomas. Canine melanoma is a malignant and aggressive neoplasm showing clinical, histological, and molecular features similar to the human counterpart. In human medicine, epidermal growth factor receptors (EGFRs) have already been suggested as prognostic markers and potential therapeutic targets in cutaneous melanoma. The aim of this study was to evaluate the expression of HER-2 and HER-3 in canine melanomas by immunohistochemistry and correlate their expression to the clinicopathological parameters of the examined tumors. Thirty-seven canine melanoma samples were recruited. Data regarding signalment and clinical parameters were also collected. The population was composed of 18 cutaneous, 16 oral/mucosal, and three digital/foot pad melanomas. Histopathological investigations were carried out to analyze histological type, ulceration, and mitotic count. On each sample, immunohistochemistry was performed using an anti-Melan-A or anti-Melanoma antigen, i.e., anti-HER-2 and anti-HER-3 antibodies. HER-2 and HER-3 positivity were classified using already established scoring criteria and a statistical analysis was carried out. The results highlighted that HER-2 expression was observed in 48.6% of the samples and HER-3 expression in 18.9%. The highest HER 2 score (3+) was recorded in 16.2% of the samples, while the coexpression of the two receptors was detected in 13.5% of the samples. A statistically significant association (p < 0.05) was observed between the expression of HER-2 and HER-3 and the presence of ulceration in oromucosal tumors. This work confirms the expression of HER-2 and HER-3 in canine melanomas and suggests a putative association with negative prognostic parameters. Further studies are necessary to strengthen these data by increasing the samples size and combining pathological examinations with molecular biology in the investigation of EGFR family receptors. [ABSTRACT FROM AUTHOR]

Primary cardiac tumours are relatively uncommon (75% are benign). Across the other 25%, representing malignant neoplasia, sarcomas account for 75–95%, and primary cardiac intimal sarcoma (PCIS) is one of the rarest findings. We aimed to present a comprehensive review and practical considerations from a multidisciplinary perspective with regard to the most recent published data in the specific domain of PCIS. We covered the issues of awareness amid daily practice clinical presentation to ultra-qualified management in order to achieve an adequate diagnosis and prompt intervention, also emphasizing the core role of MDM2 immunostaining and MDM2 genetic analysis. An additional base for practical points was provided by a novel on-point clinical vignette with MDM2-positive status. According to our methods (PubMed database search of full-length, English publications from January 2021 to March 2023), we identified three studies and 23 single case reports represented by 22 adults (male-to-female ratio of 1.2; male population with an average age of 53.75 years, range: 35–81; woman mean age of 55.5 years, range: 34–70) and a 4-year-old child. The tumour-related clinical picture was recognized in a matter of one day to ten months on first admission. These non-specific data (with a very low index of suspicion) included heart failure at least NYHA class II, mitral regurgitation and pulmonary hypertension, acute myocardial infarction, ischemic stroke, obstructive shock, and paroxysmal atrial fibrillation. Awareness might come from other complaints such as (most common) dyspnoea, palpitation, chest pressure, cough, asthenia, sudden fatigue, weakness, malaise, anorexia, weight loss, headache, hyperhidrosis, night sweats, and epigastric pain. Two individuals were initially misdiagnosed as having endocarditis. A history of prior treated non-cardiac malignancy was registered in 3/23 subjects. Distant metastasis as the first step of detection (n = 2/23; specifically, brain and intestinal) or during follow-up (n = 6/23; namely, intestinal, brain and bone, in two cases for each, and adrenal) required additional imagery tools (26% of the patients had distant metastasis). Transoesophageal echocardiography, computed tomography (CT), magnetic resonance imagery, and even 18F-FDG positronic emission tomography-CT (which shows hypermetabolic lesions in PCIS) represent the basis of multimodal tools of investigation. Tumour size varied from 3 cm to ≥9 cm (average largest diameter of 5.5 cm). The most frequent sites were the left atrium followed by the right ventricle and the right atrium. Post-operatory histological confirmation was provided in 20/23 cases and, upon tumour biopsy, in 3/23 of them. The post-surgery maximum free-disease interval was 8 years, the fatal outcome was at the earliest two weeks since initial admission. MDM2 analysis was provided in 7/23 subjects in terms of MDM2-positive status (two out of three subjects) at immunohistochemistry and MDM2 amplification (four out of five subjects) at genetic analysis. Additionally, another three studies addressed PCISs, and two of them offered specific MDM2/MDM2 assays (n = 35 patients with PCISs); among the provided data, we mention that one cohort (n = 20) identified a rate of 55% with regard to MDM2 amplification in intimal sarcomas, and this correlated with a myxoid pattern; another cohort (n = 15) showed that MDM2-positive had a better prognostic than MDM2-negative immunostaining. To summarize, MDM2 amplification and co-amplification, for example, with MDM4, CDK4, HMGA3, CCND3, PDGFRA, TERT, KIT, CCND3, and HDAC9, might improve the diagnosis of PCIS in addition to MDM2 immunostaining since 10–20% of these tumours are MDM2-negative. Further studies are necessary to highlight MDM2 applicability as a prognostic factor and as an element to be taken into account amid multi-layered management in an otherwise very aggressive malignancy. [ABSTRACT FROM AUTHOR]

Coral reef health is tightly connected to the coral holobiont, which is the association between the coral animal and a diverse microbiome functioning as a unit. The coral holobiont depends on key services such as nitrogen and sulfur cycling mediated by the associated bacteria. However, these microbial services may be impaired in response to environmental changes, such as thermal stress. A perturbed microbiome may lead to coral bleaching and disease outbreaks, which have caused an unprecedented loss in coral cover worldwide, particularly correlated to a warming ocean. The response mechanisms of the coral holobiont under high temperatures are not completely understood, but the associated microbial community is a potential source of acquired heat-tolerance. Here we investigate the effects of increased temperature on the taxonomic and functional profiles of coral surface mucous layer (SML) microbiomes in relationship to coral–algal physiology. We used shotgun metagenomics in an experimental setting to understand the dynamics of microbial taxa and genes in the SML microbiome of the coral Pseudodiploria strigosa under heat treatment. The metagenomes of corals exposed to heat showed high similarity at the level of bacterial genera and functional genes related to nitrogen and sulfur metabolism and stress response. The coral SML microbiome responded to heat with an increase in the relative abundance of taxa with probiotic potential, and functional genes for nitrogen and sulfur acquisition. Coral–algal physiology significantly explained the variation in the microbiome at taxonomic and functional levels. These consistent and specific microbial taxa and gene functions that significantly increased in proportional abundance in corals exposed to heat are potentially beneficial to coral health and thermal resistance. [ABSTRACT FROM AUTHOR]

The integumentary system of the leatherback sea turtle (Dermochelys coriacea) is the most visible and defining difference of the species, with its smooth and waxy carapace and finely scaled skin, distinguishing it from the other six sea turtle species. The skin is the body's largest organ and serves as a primary defense against the outside world and is thus essential to health. To date, we have begun to understand that the microorganisms located on the skin aid in these functions. However, many host–microbial interactions are not yet fully defined or understood. Prior to uncovering these crucial host–microbial interactions, we must first understand the communities of microorganisms present and how they differ through life-stage classes and across the body. Here, we present a comprehensive bacterial microbial profile on the skin of leatherbacks. Using next-generation sequencing (NGS), we identified the major groups of bacteria on the skin of neonates at emergence, neonates at 3–4 weeks of age (i.e., post-hatchlings), and nesting females. These data show that the predominant bacteria on the skin of the leatherback are different at each life-stage class sampled. This suggests that there is a shift in the microbial communities of the skin associated with life-stage class or even possibly age. We also found that different sample locations on the nesting female (i.e., carapace and front appendages = flipper) have significantly different communities of bacteria present. This is likely due to differences in the microhabitats of these anatomic locations and future studies should explore if this variation also holds true for neonates. These data define baseline skin microbiota on the leatherback and can serve as a foundation for additional work to broaden our understanding of the leatherbacks' host–microbial interactions, the impacts of environmental changes or stressors over time, and even the pathogenicity of disease processes. [ABSTRACT FROM AUTHOR]

Soil amendments such as humic acid (HA), a biochar-based microbial agent (M), and vermicompost (V) can improve soil quality and promote crop growth. However, it remains unclear whether the co-application of the three soil amendments (HMV) has a synergistic effect on alleviating soil quality deterioration obstacles caused by dry sowing and wet emergence technology in Xinjiang cotton fields. A three-year field experiment was conducted in saline–alkali soils using plastic-film-mulched drip irrigation in Xinjiang, China. Through the orthogonal experiment method, the application amounts of HA, M and V were 75 kg ha−1, 75 kg ha−1 and 225 kg ha−1 respectively in 2021. In 2022, three application amount gradients were used for HA, M and V: 60 kg ha−1, 90 kg ha−1 and 120 kg ha−1 respectively. In 2023, the application amounts of HA, M, and V were 60 kg ha−1, 120 kg ha−1, and 120 kg ha−1. It should be pointed out that V contains HA in the range of 20–35%. This study aimed to explore the improvement effect of a single or combined application of HA, M, and V on soil quality and cotton emergence rate using dry sowing and wet emergence technology in Xinjiang cotton fields. The results showed that the single and combined applications of HA, M, and V improved the soil quality and water–heat–salt environment of the cultivated layer. In the combined application, the cotton seedling emergence rate and yield increased by 1.9–22.8% and 7.0–54.1%. Therefore, it is recommended to jointly apply HA, M, and V to promote cotton seedling emergence and increase yield using dry sowing and wet emergence technology in Xinjiang cotton fields. [ABSTRACT FROM AUTHOR]

Bone regeneration using Bone Morphogenetic Proteins (BMPs) alongside various engineered scaffolds has attracted considerable attention over the years. The field has seen extensive research in preclinical animal models, leading to the approval of two products and guiding the quest for new materials. Natural and synthetic polymers, ceramics, and composites have been used to fabricate the necessary porous 3D scaffolds and delivery systems for BMPs. Interestingly, all reported applications in the literature are triumphant. Evaluation of the results is typically based on histologic assessment after appropriate staining and radiological modalities, providing morphological identification of the newly formed bone and describing cells and the organic compound. Remarkably, while these evaluation methods illustrate mineralization, they are not capable of identifying hydroxyapatite crystals, the mineral component of the bone, which are crucial for its mechanical properties, structure, integrity, and long-term stability of regenerated bone tissue. This review aims to focus on the different scaffolds used in bone tissue engineering applications and underline the pressing need for techniques that could recognize the presence of hydroxyapatite crystals as well as their characteristics in bone tissue engineering, which will provide a more complete and comprehensive assessment of the successful results. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we investigate the availability and access to orphan drugs for rare cancers in Bulgaria, aiming to address the urgent need for improved treatment access for this vulnerable population. By comparing data from European and national sources, we aimed to assess the availability, delays, and budgetary impact of these drugs. Our findings reveal significant disparities in their access and highlight the pressing need for targeted policies to address these inequalities. This research contributes valuable insights into the challenges faced by rare cancer patients and we call for focused efforts at both the European and national levels to ensure equitable access to treatment. Rare cancers are defined by an annual incidence of fewer than 6 per 100,000. Bearing similarities to rare diseases, they are associated with substantial health inequalities due to diagnostic complexity and delayed access to innovative therapies. This situation is further aggravated in Southeastern European countries like Bulgaria, where limited public resources and expertise underscore the need for additional policy and translational research on rare cancers. This study aimed to explore the availability and access to orphan drugs for rare cancers in Bulgaria for the period of 2020–2023. We cross-compared data from both the European Union and national public sources to evaluate the number of available and accessible orphan drugs for rare cancers, the delay from market authorization to reimbursement, the dynamics of public expenditures, and regional disparities in access across the country. We juxtaposed the main characteristics of oncological and non-oncological orphan drugs as well. Only 15 out of 50 oncological orphan drugs that were authorized by the European Medicine Agency were accessible for rare cancer patients in Bulgaria. The median delay between market authorization and inclusion in the Bulgarian Positive Drug List was 760 days. The total expenditures for all orphan drugs for rare cancers amounted to EUR 74,353,493 from 2020 to 2023. The budgetary impact of this group rose from 0.24% to 3.77% of total public medicinal product expenditures for the study period. Rare cancer patients represent a vulnerable population that often faces limited to no access to treatment. We call for targeted European and national policies to address this major inequality. [ABSTRACT FROM AUTHOR]

A clean environment is an essential component of sustainable development, which is based on a comprehensive understanding of the behavior of water, soil, and air. The soil water retention (SWR) curve is a crucial function that describes how soil retains water, playing a fundamental role in irrigation and drainage, soil conservation, as well as water and contaminant transport in the vadose zone. This study evaluates the accuracy, performance, and prediction capabilities of 15 SWR models. A total of 140 soil samples were collected from different sites, covering all textural classes. Standard suction tests, using both hanging column and ceramic pressure plate extractors, were conducted to compile the SWR databank. 15 SWR models were selected and fitted to the SWR data points. Soil texture, bulk density, and organic matter were used to determine their effect on the performance of the SWR models. The results indicate that the Tani and Russo models exhibit the lowest levels of accuracy and performance among the selected models. Based on the Akaike and Bayesian information criteria analysis, the van Genuchten model exhibits the lowest values among the selected models, with poor prediction capabilities in estimating the SWR curve. The significance test at the 0.05 level (95% confidence interval) shows that according to the calculated p-values for the Pearson correlation coefficient between RMSE and texture, the Brooks-Corey and van Genuchten models are poorly influenced by soil properties. The performance of the models is not significantly affected by the soil organic matter. Similarly, bulk density does not significantly affect model performance except for the Brooks–Corey, van Genuchten, Tani, and Russo models. Among the SWR models considered, the double exponential, Groenevelt and Grant, and Khlosi et al. models demonstrate superior accuracy and performance in predicting the SWR curve. This is supported by lower values for RMSE, Akaike, and Bayesian information criteria. [ABSTRACT FROM AUTHOR]

Simple Summary: The quality of resection after unplanned excision of soft tissue sarcoma (STS) performed outside of a reference center or at second resection potentially impacts local and metastatic recurrence and survival. The French cohort NETSARC prospectively collected data from patients with unplanned excision outside reference centers from 2010 to 2019 and reported survival in patients reexcised (RE) or not (No-RE). Patients who would most benefit from RE need to be identified. A total of 2371 patients had unplanned excision for STS outside reference centers, including 1692 patients with no multidisciplinary board review (RE: 913; No-RE: 779). Discrepancies in RE/No-RE subgroups were observed regarding age, tumor site, size, depth, grade and histotype. R0 final resection associated with better MFS; R1 initial resection showed better MFS than R0 initial resection. The study identified RE as an independent favorable factor for MFS (HR 0.7, 95% CI 0.53–0.93; p = 0.013). All subgroups except patients > 70 years, and patients with large tumors (>10 cm) showed better MFS with RE. RE in patients with STS of limb or trunk after macroscopic complete resection out of NETSARC reference center, and also in R0 resections to improve LRFS and MFS. Systematic RE should not be advocated for patients ≥ 70 years, or tumor size ≥ 10 cm. Background: Whether re-excision (RE) of a soft tissue sarcoma (STS) of limb or trunk should be systematized as adjuvant care and if it would improve metastatic free survival (MFS) are still debated. The impact of resection margins after unplanned macroscopically complete excision (UE) performed out of a NETSARC reference center or after second resection was further investigated. Methods: This large nationwide series used data from patients having experienced UE outside of a reference center from 2010 to 2019, collected in a French nationwide exhaustive prospective cohort NETSARC. Patient characteristics and survival distributions in patients reexcised (RE) or not (No-RE) are reported. Multivariate Cox proportional hazard model was conducted to adjust for classical prognosis factors. Subgroup analysis were performed to identify which patients may benefit from RE. Results: Out of 2371 patients with UE for STS performed outside NETSARC reference centers, 1692 patients were not reviewed by multidisciplinary board before treatment decision and had a second operation documented. Among them, 913 patients experienced re-excision, and 779 were not re-excised. Characteristics were significantly different regarding patient age, tumor site, size, depth, grade and histotype in patients re-excised (RE) or not (No-RE). In univariate analysis, final R0 margins are associated with a better MFS, patients with R1 margins documented at first surgery had a better MFS as compared to patients with first R0 resection. The study identified RE as an independent favorable factor for MFS (HR 0.7, 95% CI 0.53–0.93; p = 0.013). All subgroups except older patients (>70 years) and patients with large tumors (>10 cm) had superior MFS with RE. Conclusions: RE might be considered in patients with STS of limb or trunk, with UE with macroscopic complete resection performed out of a reference center, and also in originally defined R0 margin resections, to improve LRFS and MFS. Systematic RE should not be advocated for patients older than 70 years, or with tumors greater than 10 cm. [ABSTRACT FROM AUTHOR]

The breeding of laying hens and broilers in China has increased tremendously. Wet organic fertilizer prepared from hen manure using high-temperature container fermentation preserves high levels of nutrients and a diverse microbial community. We applied low doses of organic fertilizer to peanuts in the black soil area of China's northeastern region. Based on the calculation of nitrogen content, treatments were set as follows: chemical fertilizer (PCF), organic fertilizer (POF, 4500 kg·ha−1), and replacement of 50% chemical fertilizer with organic fertilizer (PR, 2250 kg·ha−1). Compared to the plots with chemical fertilizers, the use of organic fertilizer and replacing 50% of the chemical fertilizers with organic fertilizer significantly increased peanut yields. Both the organic fertilizer and replacing 50% of the chemical fertilizers with organic fertilizer did not significantly affect the activities of the most tested soil enzymes related to carbon transformation and the absolute abundance of microorganisms. However, they did significantly enhance soil dehydrogenase and α-glucosidase. The community abundance ratio of fungi/bacteria trended downward, leading to soil with a high-fertility bacterial composition. The replacement of 50% chemical fertilizer with organic fertilizer significantly enhanced the species richness and diversity of the bacterial and fungal communities. Organic fertilizer treatment significantly increased the relative abundance of Gemmatimonas and Sphingomonas. The relative abundance of Mycobacterium in the treatment where 50% of the chemical fertilizers were replaced with organic fertilizer was significantly lower than that in the organic fertilizer treatment. PCoA results showed that the low-dose organic fertilizer treatment, replacing 50% of the chemical fertilizers with organic fertilizer, had a significant impact on the composition of soil bacterial communities. [ABSTRACT FROM AUTHOR]

Giant cell tumor of bone (GCTB) is characterized by uncertain biological behavior due to its local aggressiveness and metastasizing potential. In this study, we conducted a meta-analysis of the contemporary literature to evaluate all management strategies for GCTB metastases. A combination of the terms "lung metastases", "giant cell tumor", "bone", "treatment", and "oncologic outcomes" returned 133 patients meeting our inclusion criteria: 64 males and 69 females, with a median age of 28 years (7–63), at the onset of primary GCTB. Lung metastases typically occur at a mean interval of 26 months (range: 0–143 months) after treatment of the primary site, commonly presenting as multiple and bilateral lesions. Various treatment approaches, including surgery, chemotherapy, radiotherapy, and drug administration, were employed, while 35 patients underwent routine monitoring only. Upon a mean follow-up of about 7 years (range: 1–32 years), 90% of patients were found to be alive, while 10% had died. Death occurred in 25% of patients who had chemotherapy, whereas 96% of those not treated or treated with Denosumab alone were alive at a mean follow-up of 6 years (range: 1–19 years). Given the typically favorable prognosis of lung metastases in patients with GCTB, additional interventions beyond a histological diagnosis confirmation may not be needed. Denosumab, by reducing the progression of the disease, can play a pivotal role in averting or delaying lung failure. [ABSTRACT FROM AUTHOR]

Curettage is recommended for the treatment of Campanacci stages 1–2 giant cell tumor of bone (GCTB) in the extremities, pelvis, sacrum, and spine, without preoperative denosumab treatment. In the distal femur, bone chips and plate fixation are utilized to reduce damage to the subchondral bone and prevent pathological fracture, respectively. For local recurrence, re-curettage may be utilized when feasible. En bloc resection is an option for very aggressive Campanacci stage 3 GCTB in the extremities, pelvis, sacrum, and spine, combined with 1–3 doses of preoperative denosumab treatment. Denosumab monotherapy once every 3 months is currently the standard strategy for inoperable patients and those with metastatic GCTB. However, in case of tumor growth, a possible malignant transformation should be considered. Zoledronic acid appears to be as effective as denosumab; nevertheless, it is a more cost-effective option. Therefore, zoledronic acid may be an alternative treatment option, particularly in developing countries. Surgery is the mainstay treatment for malignant GCTB. [ABSTRACT FROM AUTHOR]

The parameters of the GR4J-CemaNeige coupling model (GR4neige) are typically treated as constants. However, the maximum capacity of the production store (parX1) exhibits time-varying characteristics due to climate variability and vegetation coverage change. This study employed differentiable parameter learning (dPL) to identify the time-varying parX1 in the GR4neige across 671 catchments within the United States. We built two types of dPL, including static and dynamic parameter networks, to assess the advantages of the time-varying parameter. In the dynamic parameter network, we evaluated the impact of potential evapotranspiration (PET), precipitation (P), temperature (T), soil moisture (SM), and normalized difference vegetation index (NDVI) datasets on the performance of dPL. We then compared dPL with the empirical functional method (fm). The results demonstrated that the dynamic parameter network outperformed the static parameter network in streamflow estimation. There were differences in streamflow estimation among the dynamic parameter network driven by various input features. In humid catchments, simultaneously incorporating all five factors, including PET, P, T, SM, and the NDVI, achieved optimal streamflow simulation accuracy. In arid catchments, it was preferable to introduce PET, T, and the NDVI separately for improved performance. dPL significantly outperformed the empirical fm in estimating streamflow and uncalibrated intermediate variables, like evapotranspiration (ET). Both the derived parX1 from dPL and the empirical fm exhibited significant spatiotemporal variation across 671 catchments. Notably, compared to parX1 obtained through the empirical fm, parX1 derived from dPL exhibited a distinct spatial clustering pattern. This study highlights the potential of dPL in enhancing model accuracy and contributes to understanding the spatiotemporal variation characteristics of parX1 under the influence of climate factors, soil conditions, and vegetation change. [ABSTRACT FROM AUTHOR]

Non-conventional processes are considerably important for the machining of hard-to-cut alloys in various demanding applications. Given that the surface quality and integrity, dimensional accuracy, and productivity are important considerations in industrial practice, the prediction of the outcome of the material removal process should be able to be conducted with sufficient accuracy, taking into consideration the computational cost and difficulty of implementation of the relevant models. In the case of AWJ, various types of approaches have been already proposed, both relying on analytical or empirical models and developed by solving partial differential equations. As the creation of a model for AWJ pocket milling is rather demanding, given the number of parameters involved, in the present work, it is intended to compare the use of three different types of efficient modeling approaches for the prediction of the dimensions of pockets milled by AWJ technology. The models are developed and evaluated based on experimental results of AWJ pocket milling of a titanium workpiece by an eco-friendly walnut shell abrasive. The results indicate that a semi-empirical approach performs better than a two-step hybrid analytical/semi-empirical method regarding the selected cases, but both methods show promising results regarding the realistic representation of the pocket shape, which can be further improved by a probabilistic approach. [ABSTRACT FROM AUTHOR]

This document provides a comprehensive analysis of subterranean biodiversity, specifically focusing on caves and other subterranean habitats. The authors identify and document 28 subterranean biodiversity hotspots worldwide, with a concentration in Europe and North America. The document discusses different approaches to identifying and categorizing subterranean species, as well as challenges in defining them. It also explores the distribution and richness of species in different hotspots and highlights the need for further research. The document also discusses the vulnerabilities of subterranean fauna and various protection strategies. Additionally, the document includes tables that provide information on cave systems, troglobionts, and the distribution of arachnids and beetles in hotspot caves. [Extracted from the article]

Introduction: The goal of this study is to compare the prognostic performance of NETPET scores, based on gallium-68 DOTANOC (68Ga-DOTANOC) and fluorine-18 fluorodeoxyglucose (18F-FDG) Positron Emission Tomography-Computed Tomography (PET-CT), and PET-CT metabolic parameters in metastatic gastrointestinal neuroendocrine tumors (GI-NET), while constructing and validating a nomogram derived from dual-scan PET-CT. Methods: In this retrospective study, G1–G3 GI-NET patients who underwent 68Ga-DOTANOC and 18F-FDG PET scans were enrolled and divided into training and internal validation cohorts. Three grading systems were constructed based on NETPET scores and standardized uptake value maximum (SUVmax). LASSO regression selected variables for a multivariable Cox model, and nomograms predicting progression-free survival (PFS) and overall survival (OS) were created. The prognostic performance of these systems was assessed using time-dependent receiver-operating characteristic (ROC) curves, concordance index (C-index), and other methods. Nomogram evaluation involved calibration curves, decision curve analysis (DCA), and the aforementioned methods in both cohorts. Results: In this study, 223 patients (130 males; mean age ±  SD: 52.6 ± 12 years) were divided into training (148) and internal validation (75) cohorts. Dual scans were classified based on NETPET scores (D1–D3). Single 68Ga-DOTANOC and 18F-FDG PET-CT scans were stratified into S1-S3 and F1-F3 based on SUVmax. The NETPET score-based grading system demonstrated the best OS and PFS prediction (C-index, 0.763 vs. 0.727 vs. 0.566). Nomograms for OS and PFS exhibited superior prognostic performance in both cohorts (all AUCs > 0.8). Conclusions: New classification based on NETPET score predicts patient OS/PFS best. PET-CT-based nomograms show accurate OS/PFS forecasts. [ABSTRACT FROM AUTHOR]

This study aims to investigate the impact of spatial rainfall distribution scenarios from ground observation stations on runoff simulation using hydrological modeling specific to the Rainfall-Runoff-Inundation (RRI) model. The RRI model was applied with six different spatial distribution scenarios of input rainfall, including Inverse Distance Weight (IDW), Thiessen polygon (TSP), Surface Polynomial (SPL), Simple kriging (SKG), and Ordinary kriging (OKG), to simulate the runoff of a 13,000 km2 watershed, namely the Nan River Basin in Thailand. This study utilized data from the 2014 storm event, incorporating temporal information from 28 rainfall stations to estimate rainfall in the spatial distribution scenarios. The six statistics, Volume Bias, Peak Bias, Root Mean Square Error, Correlation, and Mean Bias, were used to determine the accuracy of the estimated rainfall and runoff. Overall, the Simple kriging (SKG) method outperformed the other scenarios based on the statistical values to validate with measured rainfall data. Similarly, SKG demonstrated the closest match between simulated and observed runoff, achieving the highest correlation (0.803), the lowest Root Mean Square Error (164.48 cms), and high Nash-Sutcliffe Efficiency coefficient (0.499) values. This research underscores the practical significance of spatial interpolation methods, such as SKG, in combination with digital elevation models (DEMs) and landuse/soil type datasets, in delivering reliable runoff simulations considering the RRI model on the river basin scale. [ABSTRACT FROM AUTHOR]

Our knowledge regarding the role of the microbiome in fish health has been steadily increasing in the last decade, especially for species of commercial interest. Conversely, relatively few studies focus on the microbiomes of wild fish, especially apex predators like sharks, due to lower economic interest and greater difficulty in obtaining samples. Studies investigating microbiome differences between diverse anatomical locations of sharks are limited, and the majority of the available studies are focused on the microbial diversity present on shark teeth, with the aim of preventing infections due to bites of these animals or evaluating the presence of certain pathogens in healthy or diseased specimens. Here, we investigated the skin, mouth, gills, and cloaca microbiomes of five individuals of two phylogenetically distant species of sharks (Prionace glauca and Somniosus rostratus) to obtain a better understanding of the diversity regarding the microbiomes of these animals, how they change throughout different body parts, and how much they are influenced and determined by the ecology and evolutionary relationship between host and microbiome. To confirm the taxonomy of the sharks under study, we barcoded the specimens by sequencing the mtDNA COI from a biopsy of their skin. Microbial diversity based on the 16S rRNA gene reveals that partially overlapping microbiomes inhabit different body parts of each shark species, while the communities are distinct between the two species. Our results suggest that sharks' microbiome species-specific differences are controlled by the ecology of the shark species. This is the first study comparatively analyzing the microbiome diversity of different anatomical locations in two shark species of the Mediterranean Sea. [ABSTRACT FROM AUTHOR]