Shared germline genomic variants in two patients with double primary gastrointestinal stromal tumours (GISTs).

BACKGROUND: Gastrointestinal stromal tumours (GISTs) are prevalent mesenchymal tumours of the gastrointestinal tract, commonly exhibiting structural variations in KIT and PDGFRA genes. While the mutational profiling of somatic tumours is well described, the genes behind the susceptibility to develop GIST are not yet fully discovered. This study explores the genomic landscape of two primary GIST cases, aiming to identify shared germline pathogenic variants and shed light on potential key players in tumourigenesis. METHODS: Two patients with distinct genotypically and phenotypically GISTs underwent germline whole genome sequencing. CNV and single nucleotide variant (SNV) analyses were performed. RESULTS: Both patients harbouring low-risk GISTs with different mutations (PDGFRA and KIT) shared homozygous germline pathogenic deletions in both CFHR1 and CFHR3 genes. CNV analysis revealed additional shared pathogenic deletions in other genes such as SLC25A24. No particular pathogenic SNV shared by both patients was detected. CONCLUSION: Our study provides new insights into germline variants that can be associated with the development of GISTs, namely, CFHR1 and CFHR3 deep deletions. Further functional validation is warranted to elucidate the precise contributions of identified germline mutations in GIST development.

First Report of Pantoea ananatis causing leaf streak disease on wheat (Triticum aestivum) in the United States of America.

Wheat (Triticum aestivum) loses 21.5% yield to pests and diseases annually (Savary et al. 2019). Among the wheat diseases, bacterial leaf streak (BLS) is a growing problem, costing $78.5 million in losses (https://cropprotectionnetwork.org/). In July 2022, we sampled winter wheat leaf samples at Volga (44.30, -96.92), South Dakota, USA with an estimated disease incidence of 40% (n=100). The typical symptoms were water-soaking with large necrotic and chlorotic streaks extending the length of the leaves and were strikingly similar to BLS. To isolate the pathogen, leaves were cut lengthwise into 1 cm pieces and surface-sterilized using a 10% NaOCl solution for 3 min, followed by 70% ethanol for 3 min, and then rinsed with sterile distilled water and placed in 500 ul of sterile distilled water for 5 min and using a sterile loop the water was streaked over a plate of Nutrient Agar (NA). Following Duveiller et al. (1997), the streaked plate was incubated in the dark at 28℃ for 48 h. Observed single colonies were sub-cultured thrice onto fresh NA plates to obtain a pure culture. We named the culture SD101. Bacteria were found to be gram-negative with a colony morphology initially raised, smooth, and white that later turned yellow. DNA was extracted using the Wizard HMW DNA Extraction Kit (Promega, Madison, WI) following the manufacturer's protocol, and sequenced using Nanopore MinION R9.4 (Oxford Nanopore Technology). We used the Rapid Annotation Using Subsystems Technology approach (Aziz eal. 2008) to extract the 16S rDNA, DNA gyrase subunit B (gyrB), and translation initiation factor IF-2 (infB) gene sequences that were deposited in GenBank under accession numbers PP329908.1 for 16S rDNA, PP496481 for infB, and PP328920.1 for gyrB. Homology analysis using CLC Genomics Workbench 22.0.2 (QIAGEN) and BLASTn against the GenBank nucleotide database resulted in a 99.74% match (1543/ 1547 bp) of the 16S sequence, 99.59% match (2674/ 2685 bp) of the infB sequence, and 99.42% match (2396/ 2410 bp) of the gyrB sequence with Pantoea ananatis strain AJ13355 (AP012032). To test pathogenicity, seeds of spring wheat breeding line SD4892 were planted in 30 cm × 30 cm pots in a greenhouse under a 16 h light photoperiod. The inoculum was prepared from 48-h-old NA plates of SD101 rinsed with 1X Phosphate Buffer Saline (PBS buffer), adjusted to an OD600 = 1.0, and amended with two drops of Tween 20 (polyoxyethylene sorbitol ester, Millipore Sigma). PBS with Tween 20 was used as a negative control. The inoculum was sprayed on 15 replicates of 15-day-old seedlings, kept at 95% relative humidity for 48 h, then moved to the greenhouse at 23 to 25°C. The symptoms appeared as water soaking that later turned to necrotic streaks with surrounding chlorosis on all 15 inoculated plants while control plants remained healthy. The pathogen was re-isolated from the leaves as described above. The 16S rDNA, infB, and gyrB sequences amplified and sequenced were identical to the gene sequences from the whole genome sequencing. The experiment was repeated with the same results, completing Koch's postulates. Although P. ananatis is pathogenic on corn, rice, and other plant species in the United States (Coutinho et al. 2009), and was reported pathogenic on wheat in Poland (Krawczyk et al. 2020), this is the first report of its pathogenicity on wheat in the United States. The prevalence, and incidence of BLS disease caused by P. ananatis in wheat is needed to estimate its threat to wheat production and to develop management strategies.

Impact of Inherited Thrombophilia in Women with Obstetric Antiphospholipid Syndrome: A Single-Center Study and Literature Review.

Inherited thrombophilia (IT) has been implicated as a potential causal factor of adverse pregnancy outcomes (APOs), including recurrent miscarriage with and without the presence of antiphospholipid syndrome (APS). The aim of this study was to assess the prevalence and impact of IT on fetal-maternal outcomes and thrombotic risk in women within the spectrum of obstetric APS. Three hundred and twenty-eight women with APS-related obstetric morbidity ever pregnant were included. Of these, 74 met the APS classification criteria, 169 were non-criteria (NC)-APS, and 85 were seronegative (SN)-APS. Patients with other autoimmune diseases were excluded. APOs included early pregnancy loss, fetal death, preeclampsia, abruptio placentae, and preterm birth. Successful pregnancy was defined as the achievement of a live newborn. A literature search was also performed. The mean age of the overall group was 33.9 ± 5.3 years, and the patients were followed up for 35 (11-79) months. During the study period, there were 1332 pregnancies. Nearly 14% of the patients had an associated IT. IT patients more frequently received the standard-of-care (SoC) therapy. The presence of IT was not associated with worse maternal-fetal outcomes in patients treated with SoC treatment. Overall, IT patients had a lower frequency of newborns without treatment, especially those without definite APS. In addition, IT did not increase the risk of thrombosis during pregnancy or the postpartum period. A detailed analysis of the literature review identified only four publications related to our study and did not show conclusive evidence of the impact of IT on patients with obstetric APS. The group of women with APS-related obstetric morbidity and IT who did not receive treatment, especially those without definite APS, had a worse prognosis in terms of a live birth. However, with SoC therapy, the prognosis is similar in those patients without IT. The association of IT with APS does not seem to predispose to the development of thrombosis during pregnancy and/or the postpartum period.

Effect of 6,6'-Substituents on Bipyridine-Ligated Ni Catalysts for Cross-Electrophile Coupling.

A family of 4,4'-tBu2-2,2'-bipyridine (tBubpy) ligands with substituents in either the 6-position, 4,4'-tBu2-6-Me-bpy (tBubpyMe), or 6 and 6'-positions, 4,4'-tBu2-6,6'-R2-bpy (tBubpyR2; R = Me, iPr, sBu, Ph, or Mes), was synthesized. These ligands were used to prepare Ni complexes in the 0, I, and II oxidation states. We observed that the substituents in the 6 and 6'-positions of the tBubpy ligand impact the properties of the Ni complexes. For example, bulkier substituents in the 6,6'-positions of tBubpy better stabilized (tBubpyR2)NiICl species and resulted in cleaner reduction from (tBubpyR2)NiIICl2. However, bulkier substituents hindered or prevented coordination of tBubpyR2 ligands to Ni0(cod)2. In addition, by using complexes of the type (tBubpyMe)NiCl2 and (tBubpyR2)NiCl2 as precatalysts for different XEC reactions, we demonstrated that the 6 or 6,6' substituents lead to major differences in catalytic performance. Specifically, while (tBubpyMe)NiIICl2 is one of the most active catalysts reported to date for XEC and can facilitate XEC reactions at room temperature, lower turnover frequencies were observed for catalysts containing tBubpyR2 ligands. A detailed study on the catalytic intermediates (tBubpy)Ni(Ar)I and (tBubpyMe2)Ni(Ar)I revealed several factors that likely contributed to the differences in catalytic activity. For example, whereas complexes of the type (tBubpy)Ni(Ar)I are low spin and relatively stable, complexes of the type (tBubpyMe2)Ni(Ar)I are high-spin and less stable. Further, (tBubpyMe2)Ni(Ar)I captures primary and benzylic alkyl radicals more slowly than (tBubpy)Ni(Ar)I, consistent with the lower activity of the former in catalysis. Our findings will assist in the design of tailor-made ligands for Ni-catalyzed transformations.

Osteomesopyknosis associated with a novel ALOX5 variant that impacts the RANKL pathway.

BACKGROUND: Bone tissue homeostasis relies on the coordinated activity of the bone-forming osteoblasts and bone-resorbing osteoclasts. Osteomesopyknosis is considered a distinctive rare sclerosing skeletal disorder of unelucidated pathophysiology and presumably autosomal dominant transmission. However, the causal genes are unknown. METHODS: We present a case report encompassing clinical assessments, imaging studies, and whole-exome sequencing analysis, complemented by functional in vitro experiments. RESULTS: This new case of osteomesopyknosis was associated with a missense ALOX5 variant predicted to induce protein misfolding and proteasomal degradation. Transfection experiments demonstrated that the variant was associated with reduced protein levels restored by proteasomal inhibition with bortezomib. Likewise, gene expression analysis showed that the mutated gene was associated with a decreased RANKL/OPG ratio, which is a critical driver of osteoclast precursor differentiation. CONCLUSION: Our data indicate impaired bone resorption as the underlying mechanism of this rare osteosclerosis, implicating ALOX5 pathogenic variants as potential etiological factors.

HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) study.

HMGA1 is a structural epigenetic chromatin factor that has been associated with tumor progression and drug resistance. Here, we reported the prognostic/predictive value of HMGA1 for trabectedin in advanced soft-tissue sarcoma (STS) and the effect of inhibiting HMGA1 or the mTOR downstream pathway in trabectedin activity. The prognostic/predictive value of HMGA1 expression was assessed in a cohort of 301 STS patients at mRNA (n = 133) and protein level (n = 272), by HTG EdgeSeq transcriptomics and immunohistochemistry, respectively. The effect of HMGA1 silencing on trabectedin activity and gene expression profiling was measured in leiomyosarcoma cells. The effect of combining mTOR inhibitors with trabectedin was assessed on cell viability in vitro studies, whereas in vivo studies tested the activity of this combination. HMGA1 mRNA and protein expression were significantly associated with worse progression-free survival of trabectedin and worse overall survival in STS. HMGA1 silencing sensitized leiomyosarcoma cells for trabectedin treatment, reducing the spheroid area and increasing cell death. The downregulation of HGMA1 significantly decreased the enrichment of some specific gene sets, including the PI3K/AKT/mTOR pathway. The inhibition of mTOR, sensitized leiomyosarcoma cultures for trabectedin treatment, increasing cell death. In in vivo studies, the combination of rapamycin with trabectedin downregulated HMGA1 expression and stabilized tumor growth of 3-methylcholantrene-induced sarcoma-like models. HMGA1 is an adverse prognostic factor for trabectedin treatment in advanced STS. HMGA1 silencing increases trabectedin efficacy, in part by modulating the mTOR signaling pathway. Trabectedin plus mTOR inhibitors are active in preclinical models of sarcoma, downregulating HMGA1 expression levels and stabilizing tumor growth.

Comparison of quality of life after radical treatment in prostate cancer: radical prostatectomy versus external radiotherapy.

OBJECTIVE: To assess and compare the functional and quality of life results in patients treated with curative intent for localized prostate cancer during 2015 in our hospital. METHOD: 77 patients treated by radical prostatectomy or external radiotherapy with androgen deprivation were prospective enrolled. Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP) questionnaire at 3-year follow-up and Spanish Questionnaire on Quality of Life in Patients with Prostate Cancer (CAVIPRES-30) at diagnosis and at 3-year follow-up were registered. RESULTS: 68 patients were included, 39 patients treated by radical prostatectomy and 29 received external radiotherapy with androgen deprivation. Among the operated patients, 61.5% were dry and 17.9% use three or more daily pads, compared to 72.4% and 6.8%, respectively, in the radiotherapy group. 48.7% of prostatectomized patients reported very poor or no capacity to have a sufficiently rigid erection, compared to 69% of the radiated group. After surgery, 43.6% considered bad or very bad quality-of-life, compared to 68.9% in the radiotherapy group. In the comparison of the data of the pre- and post-treatment questionnaire can be seen that the patients had a superior perception before the procedure. CONCLUSIONS: Patients treated by surgery have a better perception of quality-of-life compared to those treated by radiotherapy.

OBJETIVO: Determinar y comparar los resultados funcionales y de calidad de vida de pacientes con cáncer de próstata tratados con intención curativa durante el año 2015 en nuestro centro. MÉTODO: Se incluyeron 77 pacientes sometidos a prostatectomía radical (PR) o radioterapia externa con terapia de deprivación androgénica (TDA). Se realizaron el Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP) tras 3 años de seguimiento y el Cuestionario Español de Calidad de Vida en Pacientes con Cáncer de Próstata (CAVIPRES-30) al diagnóstico y a los 3 años. RESULTADOS: Se incluyeron 68 pacientes, 39 con PR y 29 con radioterapia más TDA. De los pacientes intervenidos, el 61.5% están secos y el 17.9% usan tres o más compresas, diarias frente al 72.4% y el 6.8%, respectivamente, en el grupo de radioterapia. El 48.7% de los prostatectomizados refieren erecciones muy malas o ninguna, frente al 69% de los radiados. Tras la cirugía, el 43.6% refieren mala o muy mala calidad de vida, frente al 68.9% de los radiados. En la comparación de los datos del cuestionario pre- y postratamiento, los pacientes tenían una percepción superior antes del procedimiento. CONCLUSIONES: Los pacientes tratados mediante cirugía tienen una mejor percepción de su calidad de vida relacionada con la salud que los radiados.

Long-range electrostatic effects from intramolecular Lewis acid binding influence the redox properties of cobalt-porphyrin complexes.

A CoII-porphyrin complex (1) with an appended aza-crown ether for Lewis acid (LA) binding was synthesized and characterized. NMR spectroscopy and electrochemistry show that cationic group I and II LAs (i.e., Li+, Na+, K+, Ca2+, Sr2+, and Ba2+) bind to the aza-crown ether group of 1. The binding constant for Li+ is comparable to that observed for a free aza-crown ether. LA binding causes an anodic shift in the CoII/CoI couple of between 10 and 40 mV and also impacts the CoIII/CoII couple. The magnitude of the anodic shift of the CoII/CoI couple varies linearly with the strength of the LA as determined by the pKa of the corresponding metal-aqua complex, with dications giving larger shifts than monocations. The extent of the anodic shift of the CoII/CoI couple also increases as the ionic strength of the solution decreases. This is consistent with electric field effects being responsible for the changes in the redox properties of 1 upon LA binding and provides a novel method to tune the reduction potential. Density functional theory calculations indicate that the bound LA is 5.6 to 6.8 Å away from the CoII ion, demonstrating that long-range electrostatic effects, which do not involve changes to the primary coordination sphere, are responsible for the variations in redox chemistry. Compound 1 was investigated as a CO2 reduction electrocatalyst and shows high activity but rapid decomposition.

Post-COVID-19 syndrome, inflammation and insulin resistance: a retrospective cohort study.

BACKGROUND: COVID-19-induced diabetes is a novel and enigmatic disease. Our aim was to evaluate a possible relationship between post-COVID-19 syndrome (PCS) and increased insulin resistance (IR) in non-diabetic outpatients after mild COVID-19. METHODS: Repeated measures design. Three evaluations [1E (pre-COVID, baseline), 2E (3 months post-COVID) and 3E (21 months post-COVID)] were performed, directed to PCS+ and PCS- subjects. Triglyceride-glucose (TyG) index ≥8.74 was considered IR, and albumin-to-globulin ratio (AGR) <1.50, inflammation. RESULTS: We analyzed 112 individuals (median [IQR] age=44 [20] years, 58% women, 36 PCS+, 76 PCS-). PCS+ with very low basal IR (TyG <7.78, lowest quartile) showed a reduced inflammatory burden (basal AGR=1.81 [0.4] vs. 1.68 [0.2] in 2E; P=0.23), and increased TyG across evaluations (from basal 7.62 [0.2] to 8.29 [0.5]; P=0.018]. Conversely, PCS+ subjects with high basal TyG (TyG ≥8.65, highest quartile) did not show significant variations in TyG, but a greater inflammatory load (basal AGR=1.69 [0.3] vs. 1.44 [0.3] in 2E; P=0.10). In multivariable models addressing groups with reduced basal IR (TyG <8.01), PCS has been a consistent predictor for TyG, after adjusting for confounders. Partial correlation and multivariable analyses showed similarities involving acute polysymptomatic COVID-19 and PCS regarding IR. CONCLUSIONS: PCS was associated with increased IR, being more evident when the baseline degree of IR was very low. PCS and increased IR were separately associated with inflammation. Acute polysymptomatic COVID-19 and PCS could be clinical expressions of underlying inflammatory state, which in turn may also trigger IR.

Impact of COVID-19 on pre-existing liver disease.

Patients with chronic liver disease of any etiology who become infected with SARS-CoV-2 have been found to have a higher risk of mortality compared to those patients who do not have chronic liver disease. A literature review was conducted in the relationship between COVID 19 and preexistence of liver disease. The proportion of COVID-19 patients with abnormal liver function on admission ranged from 40 % to 75 % and the proportion with liver injury was close to 30%. Current studies show an important association between preexisting liver disease and COVID-19. The presence of cirrhosis is now an independent predictor of severity for COVID-19 and prolonged hospitalization in this group of patients. Patients with cirrhosis have a higher mortality rate, and this rate rises with increasing severity.

Pacientes con enfermedad hepática crónica de cualquier etiología que se infectan con SARS-CoV-2 tienen un mayor riesgo de mortalidad en comparación con aquellos pacientes que no tienen enfermedad hepática crónica. Se llevó a cabo una revisión de la literatura en relación a lo publicado de COVID 19 y enfermedad hepática pre-existente. La proporción de pacientes con COVID-19 con función hepática anormal al ingreso osciló entre el 40 % y el 75 % y la proporción con daño hepático fue cercana al 30 %. Los estudios actuales muestran una asociación importante entre la enfermedad hepática preexistente y la COVID-19. La presencia de cirrosis es ahora un predictor independiente de gravedad para COVID-19 y hospitalización prolongada en este grupo de pacientes. Los pacientes con cirrosis tienen una mayor tasa de mortalidad y esta tasa se incrementa con el aumento de la gravedad de la enfermedad hepática.

Photoelectrochemical CO2 Reduction to CO Enabled by a Molecular Catalyst Attached to High-Surface-Area Porous Silicon.

A high-surface-area p-type porous Si photocathode containing a covalently immobilized molecular Re catalyst is highly selective for the photoelectrochemical conversion of CO2 to CO. It gives Faradaic efficiencies of up to 90% for CO at potentials of -1.7 V (versus ferrocenium/ferrocene) under 1 sun illumination in an acetonitrile solution containing phenol. The photovoltage is approximately 300 mV based on comparisons with similar n-type porous Si cathodes in the dark. Using an estimate of the equilibrium potential for CO2 reduction to CO under optimized reaction conditions, photoelectrolysis was performed at a small overpotential, and the onset of electrocatalysis in cyclic voltammograms occurred at a modest underpotential. The porous Si photoelectrode is more stable and selective for CO production than the photoelectrode generated by attaching the same Re catalyst to a planar Si wafer. Further, facile characterization of the porous Si-based photoelectrodes using transmission mode FTIR spectroscopy leads to highly reproducible catalytic performance.

The Role of Gut Microbiome in the Pathogenesis and the Treatment of Inflammatory Bowel Diseases.

Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is a chronic condition characterized by inflammation of the gastrointestinal tract. Its exact cause is unknown, but it's thought to result from a dysregulated immune response influenced by various factors, including changes in the intestinal microbiota, diet, lifestyle, and genetics. The gut microbiome, consisting of diverse microorganisms, plays a crucial role in maintaining physiological balance, with its disruption leading to inflammatory responses typical of IBD. Treatments primarily aim at symptom control, employing immunomodulators, corticosteroids, and newer approaches like probiotics, prebiotics, fecal transplants, and dietary modifications, all focusing on leveraging the microbiota's potential in disease management. These strategies aim to restore the delicate balance of the gut microbiome, typically altered in IBD, marked by a decrease in beneficial bacteria and an increase in harmful pathogens. This review underscores the importance of the gut microbiome in the pathogenesis and treatment of IBD, highlighting the shift towards personalized medicine and the necessity for further research in understanding the complex interactions between the gut microbiota, immune system, and genetics in IBD. It points to the potential of emerging treatments and the importance of a multifaceted approach in managing this complex and challenging disease.

STAT6-targeting antisense oligonucleotides against solitary fibrous tumor.

Solitary fibrous tumor (SFT) is a rare, non-hereditary soft tissue sarcoma thought to originate from fibroblastic mesenchymal stem cells. The etiology of SFT is thought to be due to an environmental intrachromosomal gene fusion between NGFI-A-binding protein 2 (NAB2) and signal transducer and activator protein 6 (STAT6) genes on chromosome 12, wherein the activation domain of STAT6 is fused with the DNA-binding domain of NAB2 resulting in the oncogenesis of SFT. All NAB2-STAT6 fusion variations discovered in SFTs contain the C-terminal of STAT6 transcript, and thus can serve as target site for antisense oligonucleotides (ASOs)-based therapies. Indeed, our in vitro studies show the STAT6 3' untranslated region (UTR)-targeting ASO (ASO 993523) was able to reduce expression of NAB2-STAT6 fusion transcripts in multiple SFT cell models with high efficiency (half-maximal inhibitory concentration: 116-300 nM). Encouragingly, in vivo treatment of SFT patient-derived xenograft mouse models with ASO 993523 resulted in acceptable tolerability profiles, reduced expression of NAB2-STAT6 fusion transcripts in xenograft tissues (21.9%), and, importantly, reduced tumor growth (32.4% decrease in tumor volume compared with the untreated control). Taken together, our study established ASO 993523 as a potential agent for the treatment of SFTs.

High Frequencies of Genetic Variants in Patients with Atypical Femoral Fractures.

This study explores the genetic factors associated with atypical femoral fractures (AFF), rare fractures associated with prolonged anti-resorptive therapy. AFF are fragility fractures that typically appear in the subtrochanteric or diaphyseal regions of the femur. While some cases resemble fractures in rare genetic bone disorders, the exact cause remains unclear. This study investigates 457 genes related to skeletal homeostasis in 13 AFF patients by exome sequencing, comparing the results with osteoporotic patients (n = 27) and Iberian samples from the 1000 Genomes Project (n = 107). Only one AFF case carried a pathogenic variant in the gene set, specifically in the ALPL gene. The study then examined variant accumulation in the gene set, revealing significantly more variants in AFF patients than in osteoporotic patients without AFF (p = 3.7 × 10-5), particularly in ACAN, AKAP13, ARHGEF3, P4HB, PITX2, and SUCO genes, all of them related to osteogenesis. This suggests that variant accumulation in bone-related genes may contribute to AFF risk. The polygenic nature of AFF implies that a complex interplay of genetic factors determines the susceptibility to AFF, with ACAN, SUCO, AKAP13, ARHGEF3, PITX2, and P4HB as potential genetic risk factors. Larger studies are needed to confirm the utility of gene set analysis in identifying patients at high risk of AFF during anti-resorptive therapy.

Circulating TNF-RII, IP-10 and HGF are associated with severity of COVID-19 in oncologic patients.

The COVID-19 patients showed hyperinflammatory response depending on the severity of the disease but little have been reported about this response in oncologic patients that also were infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Sixty-five circulating cytokines/chemokines were quantified in 15 oncologic patients, just after SARS-CoV-2 infection and fourteen days later, and their levels were compared in patients who required hospitalisation by COVID-19 versus non-hospitalised patients. A higher median age of 72 years (range 61-83) in oncologic patients after SARS-CoV-2 infection was associated with hospitalisation requirement by COVID-19 versus a median age of 49 years (20-75) observed in the non-hospitalised oncologic patients (p = 0.008). Moreover, oncologic patients at metastatic stage or with lung cancer were significantly associated with hospitalisation by COVID-19 (p = 0.044). None of these hospitalised patients required ICU treatment. Higher basal levels of tumour necrosis factor receptor II (TNF-RII), interferon-γ (IFNγ)-induced protein 10 (IP-10) and hepatocyte growth factor (HGF) in plasma were significantly observed in oncologic patients who required hospitalisation by COVID-19. Higher TNF-RII, IP-10 and HGF levels after the SARS-CoV-2 infection in oncologic patients could be used as biomarkers of COVID-19 severity associated with hospitalisation requirements.

Delays in diagnosis and surgery of sarcoma patients during the COVID-19 outbreak in Spain.

Background and objectives: Social distancing and quarantine implanted during the COVID-19 outbreak could have delayed the accession of oncologic patients to hospitals and treatments. This study analysed the management of sarcoma patients during this period in five Spanish hospitals. Design and methods: Clinical data from adult sarcoma patients, soft tissue and bone sarcomas, managed during the COVID-19 outbreak, from 15 March to 14 September 2020 (Covid cohort), were retrospectively collected and time for diagnosis, surgery and active treatments were compared with sarcoma patients managed during the same pre-pandemic period in 2018 (Control cohort). Results: A total of 126 and 182 new sarcoma patients were enrolled in the Covid and Control cohorts, respectively, who were mainly diagnosed as soft tissue sarcomas (81.0% and 80.8%) and at localized stage (80.2% and 79.1%). A diagnostic delay was observed in the Covid cohort with a median time for the diagnosis of 102.5 days (range 6-355) versus 83 days (range 5-328) in the Control cohort (p = 0.034). Moreover, a delay in surgery was observed in cases with localized disease from the Covid cohort with a median time of 96.0 days (range 11-265) versus 54.5 days (range 2-331) in the Control cohort (p = 0.034). However, a lower delay for neoadjuvant radiotherapy was observed in the Covid cohort with a median time from the diagnosis to the neoadjuvant radiotherapy of 47 days (range 27-105) versus 91 days (range 27-294) in the Control cohort (p = 0.039). No significant differences for adjuvant radiotherapy, neoadjuvant/adjuvant chemotherapy and neoadjuvant/adjuvant palliative chemotherapy were observed between both cohorts. Neither progression-free survival (PFS) nor overall survival (OS) was significantly different. Conclusion: Delays in diagnosis and surgery were retrospectively observed in sarcoma patients during the COVID-19 outbreak in Spain, while the time for neoadjuvant radiotherapy was reduced. However, no impact on the PFS and OS was observed.

Antifungal Activity Enhancement of Cell-Free Streptomyces griseus Extract Obtained by Fermentation with Magnetic Manganese Ferrite Nanoparticles.

The present study aims to obtain manganese ferrite nanoparticles functionalized with chitosan (C-MNP) or ethylenediamine (E-MNP) by coprecipitation and polyol one-step methods, characterize their interaction with S. griseus demonstrating cell immobilization, and evaluate the antimicrobial activity of the free cell extracts obtained from immobilized S. griseus fermentation in the presence of different concentrations of MNP. The adsorption isotherms were analyzed mathematically using Langmuir and Freundlich models. The highest coefficient of determination (R2) for the S. griseus cell adsorption isotherm with C-MNP was observed with a linear function of the Langmuir model. The adsorption isotherm of S. griseus cells with E-MNP was better fitted to the Freundlich model. Cell immobilization by adsorption on magnetic nanoparticles was demonstrated in both cases. Different concentrations of C-MNP and E-MNP were used in fermentations to prepare cell-free extracts with antifungal activity. The best results were obtained with E-MNP, with a 91.5% inhibition of radial fungal growth. Magnetic nanoparticles offer potential applications in different fields and easy biomass separation.

Polygenic risk of bone fractures in Spanish women with osteoporosis / Riesgo poligénico de fracturas óseas en mujeres españolas con osteoporosis

Background: osteoporosis is a highly polygenic trait characterized by low bone mineral density (BMD) and/or fragility frac-tures. Over the past decade, polygenic risk scores (PRS) are an emerging tool to try to predict the risk of complex disorderswith a genetic component.Objective: to analyze the capacity of different PRSs to predict osteoporosis in the Spanish population.Material and methods: our dataset consisted of two differentiated groups. The first group included osteoporosis casesdiagnosed and treated at the Marques de Valdecilla University Hospital (n = 304; 293 women) while the second groupconsisted of people from the overall Spanish population (n = 3199; 1458 women). Four previously generated PRSs werecompared with generalized linear models.Results: the osteoporosis group showed a significantly higher genetic risk compared to the control group in 3 PRSs (PRS-1p = 1e-7; PRS-2 p = 1.87e-15; PRS-3 p = 0.1477; PRS-4 p = 8.98e-9). In addition, in these PRSs, the individuals in the upperquartile of risk had a significantly higher risk of osteoporosis, compared to those individuals in the other quartiles (PRS-1OR, 1.83; PRS-2 OR, 2.11; PRS-3 OR, 0.96; PRS-4 OR, 1.72).Conclusions: in summary, the application of PRSs shows significant differences between the overall Spanish populationand patients with osteoporosis, which is suggestive of its utility within strategies for the identification of subjects at riskbased on clinical-genetic criteria.(AU)

Hepatitis aguda grave de origen desconocido / Severe acute hepatitis of unknown origin

Resumen A inicios de 2022, en Reino Unido, y posteriormente en varios países europeos, se informó sobre un grupo de pacientes pediátricos que desarrollaron hepatitis aguda de origen desconocido hasta ahora. Los datos clínicos consisten en náusea, vómito, ictericia y falla hepática; algunos pacientes necesitan trasplante hepático. La población afectada es menor a los 10 años. El agente etiológico probable es el adenovirus genotipo F41 y se han descartado factores tóxicos, así como la relación con COVID-19. Existen varias teorías para explicar este fenómeno, las cuales se están investigando.

Abstract At the beginning of 2022, in the United Kingdom, and later in several European countries, a group of pediatric patients who developed acute hepatitis of so far unknown origin was reported. Clinical data include nausea, vomiting, jaundice, and liver failure; some patients require liver transplantation. The affected population is younger than 10 years of age. The probable etiological agent is adenovirus genotype F41, and toxic factors have been ruled out, as well as a relationship with COVID-19. There are several theories to explain this phenomenon, which are being investigated.