Doxorubicin-Trabectedin with Trabectedin Maintenance in Leiomyosarcoma.

BACKGROUND: The addition of trabectedin to doxorubicin, followed by trabectedin maintenance, may have superior efficacy to doxorubicin alone as first-line treatment in patients with advanced leiomyosarcoma. METHODS: We conducted a phase 3 trial involving patients with metastatic or unresectable leiomyosarcoma who had not received chemotherapy previously. Patients were randomly assigned to receive either single-agent doxorubicin (six cycles) or doxorubicin plus trabectedin (six cycles), with continued trabectedin as maintenance therapy in patients in the doxorubicin-trabectedin group who did not have disease progression. Surgery to resect residual disease was allowed in each group after six cycles of therapy. Analyses of progression-free survival (primary end point) and overall survival (secondary end point) were adjusted for two stratification factors: tumor origin site (uterine vs. soft tissue) and disease stage (locally advanced vs. metastatic). The primary end-point results were reported previously. RESULTS: A total of 150 patients underwent randomization. At a median follow-up of 55 months (interquartile range, 49 to 63), a total of 107 patients had died (47 in the doxorubicin-trabectedin group and 60 in the doxorubicin group). The median overall survival was longer in the doxorubicin-trabectedin group (33 months; 95% confidence interval [CI], 26 to 48) than in the doxorubicin group (24 months; 95% CI, 19 to 31); the adjusted hazard ratio for death was 0.65 (95% CI, 0.44 to 0.95). In a finding consistent with earlier reports, progression-free survival was longer in the doxorubicin-trabectedin group (12 months; 95% CI, 10 to 16) than in the doxorubicin group (6 months; 95% CI, 4 to 7); the adjusted hazard ratio for progression or death was 0.37 (95% CI, 0.26 to 0.53). The incidence of adverse events and the percentage of patients with dose reductions were higher with doxorubicin plus trabectedin than with doxorubicin alone. CONCLUSIONS: Combination therapy with doxorubicin and trabectedin induction, followed by trabectedin maintenance, was associated with improved overall survival and progression-free survival, as compared with doxorubicin alone, among patients with metastatic or surgically unresectable uterine or soft-tissue leiomyosarcoma. (Funded by PharmaMar and others; LMS04 ClinicalTrials.gov number, NCT02997358.).

Nanoscale Dodecahedral and Fullerene-Type Organoboroxine and Borazine Cages from Planar Building Units.

Boroxine- and borazine-cage analogs to C20, C60, and C70 were calculated and compared in terms of structure, strain indicators, and physical properties relevant to nanoscale applications. The results show C60 and C70 type cages are less strained than the smaller congener, primarily due to minimized bending in the B-arylene-B segments. The smallest cage calculated has a diameter of 2.4 nm, which increases up to 4.9 nm by either variation of the polyhedron (C20 < C60 < C70-type cage) or organic spacer elongation between boron centers. All calculated cages are porous (apertures ranging from 0.6 to 1.9 nm). Molecular electrostatic potential and Hirshfeld population analysis revealed both nucleophilic and electrophilic sites in the interior and exterior cage surfaces. HOMO-LUMO gaps range from 3.98 to 4.89 eV and 5.10-5.18 eV for the boroxine- and borazine-cages, respectively. Our findings provide insights into the design and properties of highly porous boroxine and borazine cages for nanoscience.

Discontinuation versus continuation of imatinib in patients with advanced gastrointestinal stromal tumours (BFR14): exploratory long-term follow-up of an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: The long-term impact of tyrosine kinase inhibitor (TKI) discontinuation on resistance and survival in patients with advanced gastrointestinal stromal tumours (GIST) is unclear. We report the exploratory long-term outcomes of patients with advanced GIST stopping imatinib in the BFR14 trial. METHODS: BFR14, an open-label, randomised, phase 3 trial, was done in 17 comprehensive cancer centres or hospitals across France. Patients with advanced GIST aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-3, no previous treatment with imatinib, and no previous malignancy were eligible. Patients were treated with oral imatinib 400 mg daily. Patients with a complete or partial response, or stable disease, according to Response Evaluation Criteria in Solid Tumours (1.0) at 1 year, 3 years, and 5 years from the start of treatment were randomly assigned (1:1) to treatment discontinuation until progression (interruption group) or treatment continuation until progression (continuation group). Randomisation was done centrally with computer-generated permuted blocks of two and six patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. Secondary endpoints included time to imatinib resistance and overall survival. Analyses were conducted on an intention-to-treat basis in all randomly assigned patients who were not lost to follow-up. This trial is registered with ClinicalTrial.gov, NCT00367861. FINDINGS: Between May 12, 2003, and March 16, 2004, after 1 year of imatinib, 32 patients were randomly assigned to the interruption group and 26 to the continuation group. Between June 13, 2005, and May 30, 2007, after 3 years of imatinib, 25 patients were randomly assigned to the interruption group and 25 to the continuation group. Between Nov 9, 2007, and July 12, 2010, after 5 years of imatinib, 14 patients were randomly assigned to the interruption group and 13 to the continuation group. Median follow-up was 235·2 months (IQR 128·8-236·6) after the 1-year randomisation, 200·9 months (190·2-208·4) after the 3-year randomisation, and 164·5 months (134·4-176·4) after the 5-year randomisation. Median progression-free survival in the interruption group versus the continuation group after 1 year of imatinib was 6·1 months (95% CI 2·5-10·1) versus 27·8 months (19·5-37·9; hazard ratio [HR] 0·36 [95% CI 0·20-0·64], log-rank p=0·0003), after 3 years of imatinib was 7·0 months (3·5-11·7) versus 67·0 months (48·8-85·6; 0·15 [0·07-0·32], log-rank p<0·0001), and after 5 years of imatinib was 12·0 months (9·0-16·6) versus not reached (NR; NR-NR; 0·13 [0·03-0·58], log-rank p=0·0016). The median time to imatinib resistance after 1 year of imatinib was 28·7 months (95% CI 18·1-39·1) versus 90·6 months (25·3-156·1; HR 0·93 [95% CI 0·51-1·71], log-rank p=0·82), after 3 years was 66·2 months (43·0-89·6) versus 127·3 months (15·0-239·7; 0·35 [0·17-0·72, log-rank p=0·0028), and after 5 years was 58·6 months (0·0-167·4) versus NR (NR-NR; 0·24 [0·05-1·12], log-rank p=0·049). Median overall survival after 1 year of imatinib was 56·0 months (95% CI 30·3-82·9) versus 105·0 months (20·6-189·6; HR 0·84 [95% CI 0·46-1·54], log-rank p=0·57), after 3 years was 104·0 months (90·7-118·7) versus 134·0 months (89·7-178·3; 0·40 [0·20-0·82], log-rank p=0·0096), and after 5 years was NR (NR-NR) versus 110·4 months (82·7-154·1; 1·28 [0·41-3·99]; log-rank p=0·67), INTERPRETATION: Imatinib interruption in patients with GIST without progressive disease is not recommended. Imatinib interruption in non-progressing patients with GIST was associated with rapid progression, faster resistance to imatinib, and shorter overall survival in the long-term follow-up when compared with imatinib continuation in patients after 3 years and 5 years of imatinib. FUNDING: Centre Léon Bérard, INCa, CONTICANET, Ligue Contre le Cancer, and Novartis.

Role of 18F-FDG-PET/CT in the initial staging of very high-risk Ewing Sarcoma in a prospective multicentric Phase II Study: Is there still a place for bone marrow sampling?

BACKGROUND: The Ewing Sarcoma Family of Tumors (ESFT) constitutes a group of rare malignancies, wherein approximately one-third of cases exhibit metastatic spread, particularly impacting prognosis when bone and/or bone marrow (BM) are involved. Primary extra-pulmonary metastatic ESFT often necessitates intensified therapeutic approaches. Accurate staging plays a pivotal role in clinical decision-making, with fluorine-18-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) currently serving as a non-invasive modality for assessing ESFT's BM extent. METHODS: In the French phase II COMBINAIR3 (NCT03011528) study, a comprehensive approach for patients with extra-pulmonary ESFT metastasis was evaluated. We prospectively compared the efficacy of PET/CT to BM aspiration and biopsy (BMAB) analysis in patients undergoing initial staging. RESULTS: Among the 42 patients analyzed (median age 14 y, 2:1 male/female ratio), 45% presented with pelvic primary tumors and 83% had bone/BM involvement at diagnosis. Our findings showed PET/CT had 100% specificity and 83.3% sensitivity in detecting initial BM involvement. Overall, PET/CT correctly classified 92.8% of patients, reaching 100% accuracy in patients identified with bone involvement, thus surpassing the standard BMAB. DISCUSSION: These results suggest that the conventional use of BMAB in the initial staging of high-risk ESFT patients can be omitted, promoting PET/CT as a non-invasive alternative, thus improving staging accuracy and treatment decisions in ESFT management.

Improved cognition after rifaximin treatment is associated with changes in intra- and inter-brain network functional connectivity.

BACKGROUND: Rifaximin is a non-reabsorbable antibiotic which acts at gut level, and improves cognition and inflammatory parameters in minimal hepatic encephalopathy (MHE) patients, but not all patients show the same level of response. This study aims to assess brain activity, both within and between brain networks, following rifaximin treatment, considering the differences between response groups as well. METHODS: Twenty-two healthy controls and 53 patients with cirrhosis (22 without and 31 with MHE, diagnosed by Psychometric Hepatic Encephalopathy Score, PHES) performed psychometric, attention and coordination tests, and blood inflammatory parameters were measured. Resting-state functional magnetic resonance imaging (fMRI) acquisitions were performed on controls and MHE patients. Eighteen MHE patients underwent a rifaximin treatment for 6 months, after which all measures were repeated. fMRI images were analysed and changes after treatment were assessed. RESULTS: After rifaximin treatment, 13 patients improved their PHES score (Responder patients) while 5 did not (Non-responder patients). No significant decrease in blood ammonia was observed after rifaximin treatment, but there was a decrease in plasma inflammatory cytokines in responder patients. A global effect of rifaximin was detected on the sensorimotor and fronto-parietal networks. Responder patients showed a relative increase of thalamic network connectivity in comparison to non-responder patients. Before treatment, responder and non-responder patients showed connectivity differences in basal ganglia network. The connection of the sensorimotor and thalamic networks between them and with other networks suffered changes after treatment. These connections between networks mostly decreased after treatment. All changes and differences showed a significant level of correlation with the performance of psychometric tests and the blood levels of inflammatory biomarkers. CONCLUSIONS: There was an improvement of the communication between executive, motor and attention-related brain areas, and their functional independence following rifaximin treatment. Patients who respond also show a less deteriorated connection involved in these functions before treatment. Results suggest that the improved inflammatory state of MHE patients, following rifaximin treatment would favour the observed changes in brain function and enhanced cognitive performance.

CD59 gene: 143 haplotypes of 22,718 nucleotides length by computational phasing in 113 individuals from different ethnicities.

BACKGROUND: CD59 deficiency due to rare germline variants in the CD59 gene causes disabilities, ischemic strokes, neuropathy, and hemolysis. CD59 deficiency due to common somatic variants in the PIG-A gene in hematopoietic stem cells causes paroxysmal nocturnal hemoglobinuria. The ISBT database lists one nonsense and three missense germline variants that are associated with the CD59-null phenotype. To analyze the genetic diversity of the CD59 gene, we determined long-range CD59 haplotypes among individuals from different ethnicities. METHODS: We determined a 22.7 kb genomic fragment of the CD59 gene in 113 individuals using next-generation sequencing (NGS), which covered the whole NM_203330.2 mRNA transcript of 7796 base pairs. Samples came from an FDA reference repository and our Ethiopia study cohorts. The raw genotype data were computationally phased into individual haplotype sequences. RESULTS: Nucleotide sequencing of the CD59 gene of 226 chromosomes identified 216 positions with single nucleotide variants. Only three haplotypes were observed in homozygous form, which allowed us to assign them unambiguously as experimentally verified CD59 haplotypes. They were also the most frequent haplotypes among both cohorts. An additional 140 haplotypes were imputed computationally. DISCUSSION: We provided a large set of haplotypes and proposed three verified long-range CD59 reference sequences, based on a population approach, using a generalizable rationale for our choice. Correct long-range haplotypes are useful as template sequences for allele calling in high-throughput NGS and precision medicine approaches, thus enhancing the reliability of clinical diagnostics. Long-range haplotypes can also be used to evaluate the influence of genetic variation on the risk of transfusion reactions or diseases.

Effect of COVID-19 on infections associated with medical devices in critical care.

OBJECTIVES: This study explores the hypothesis that COVID-19 patients are at a heightened risk of healthcare-associated infections (HAIs) associated with medical device usage compared to non-COVID-19 patients. Our primary objective was to investigate the correlation between COVID-19 infection in ICU patients and subsequent HAIs following invasive medical device insertion. Additionally, we aim to assess the impact of SARS-CoV-2 infection on onset times concerning specific microorganisms and the type of medical device, providing valuable insights into this intricate relationship in intensive care settings. METHODOLOGY: A retrospective cohort study was conducted using ICU patient records at our hospital from 2020 to 2022. This investigation entailed evaluating the timing of HAIs while distinguishing between patients with and without SARS-CoV-2 infection. We identified and analyzed the type of isolation and infection attributed to the medical device while controlling for ICU duration and ventilator days using Cox regression. RESULTS: Our study included 127 patients without SARS-CoV-2 infection and 140 patients with SARS-CoV-2 infection. The findings indicated a higher incidence of HAI caused by various microorganisms associated with any medical device in patients with SARS-CoV-2 (HR = 6.86; 95% CI-95%: 3.26-14.43; p < 0.01). After adjusting for ICU duration and ventilator days, a heightened frequency of HAIs persisted in SARS-CoV-2-infected individuals. However, a detailed examination of HAIs revealed that only ventilation-associated pneumonia (VAP) displayed a significant association (HR = 6.69; 95% CI: 2.59-17.31; p < 0.01). A statistically significant correlation between SARS-CoV-2 infection and the isolation of S. aureus was also observed (p = 0.034). The prevalence of S. aureus infection was notably higher in patients with SARS-CoV-2 (RR = 8.080; 95% CI: 1.052-62.068; p < 0.01). CONCLUSIONS: The frequency of pathogen isolates in invasive medical devices exhibited an association with SARS-CoV-2 infection. Critically ill patients with SARS-CoV-2 are more prone to developing early-onset VAP than those without SARS-CoV-2 infection.

Chemical Constituents from Agave applanata and Its Antihyperglycemic, Anti-inflammatory, and Antimicrobial Activities Associated with Its Tissue Repair Capability.

Agave applanata is a Mexican agave whose fresh leaves are employed to prepare an ethanol tonic used to relieve diabetes. It is also applied to skin to relieve varicose and diabetic foot ulcers, including wounds, inflammation, and infections. In this study, the chemical composition of this ethanol tonic is established and its association with antihyperglycemic, anti-inflammatory, antimicrobial, and wound healing activities is discussed. The fresh leaves of A. applanata were extracted with ethanol : H2O (85 : 15). A fraction of this extract was lyophilized, and the remainder was partitioned into CH2Cl2, n-BuOH, and water. CH2Cl2 and n-BuOH fractions were subjected to a successive open column chromatography process. The structure of the isolated compounds was established using nuclear magnetic resonance and mass spectrometry spectra. The antihyperglycemic activity was evaluated through in vivo sucrose and glucose tolerance experiments, as well as ex vivo intestinal absorption and hepatic production of glucose. Wound healing and edema inhibition were assayed in mice. The minimum inhibitory concentrations (MICs) of the hydroalcoholic extract, its fractions, and pure compounds were determined through agar microdilution against the most isolated pathogens from diabetic foot ulcers. Fatty acids, ß-sitosterol, stigmasterol, hecogenin (1: ), N-oleyl-D-glucosamine, ß-daucosterol, sucrose, myo-inositol, and hecogenin-3-O-α-L-rhamnopyranosyl-(1 → 3)-ß-D-xylopyranosyl-(1 → 2)-[ß-D-xylopyranosyl-(1 → 3)-ß-D-glucopyranosyl-(1 → 3)]-ß-D-glucopyranosyl-(1 → 4)-ß-D-galactopyranoside (2: ) were characterized. This research provides evidence for the pharmacological importance of A. applanata in maintaining normoglycemia, showing anti-inflammatory activity and antimicrobial effects against the microorganisms frequently found in diabetic foot ulcers. This plant plays an important role in wound healing and accelerated tissue reparation.

Three double-dose reinforced hepatitis B revaccination scheme for patients with cirrhosis unresponsive to the standard regimen: an open-label randomised clinical trial.

OBJECTIVE: We aimed to compare the response rates between two different hepatitis B virus vaccination schedules for cirrhotic subjects who were non-responders to the first three 40 µg doses (month 0-1-2), and identify factors associated with the final response. DESIGN: A total of 120 cirrhotic patients (72.5% decompensated) were randomised at a 1:1 ratio to receive a single 40 µg booster vaccination at month 6 (classical arm) versus an additional round of three new 40 µg doses administered at monthly intervals (experimental arm). The main outcome was the rate of postvaccinal anti-hepatitis B surface antibodies levels ≥10 mIU/mL. RESULTS: Efficacy by ITT analysis was higher in the experimental arm (46.7%) than in the classical one (25%); OR 2.63, p=0.013. The experimental arm increased response rates compared with the classical one from 31% to 68% (OR 4.72; p=0.007), from 24.4% to 50% (OR 3.09; p=0.012) and from 24.4% to 53.8% (OR 3.62; p=0.007), in Child A, Model for End-Stage Liver Disease (MELD) <15 and MELD-Na<15 patients, respectively. Patients with more advanced liver disease did not benefit from the reinforced scheme. Both regimens showed similar safety profiles. Multivariable analysis showed that the experimental treatment was independently response associated when adjusted across three logistic regression models indicating equivalent cirrhosis severity. CONCLUSION: For cirrhotic patients, the revaccination of non-responders to the first three dose cycle, with three additional 40 µg doses, achieved significantly better response rates to those obtained with an isolated 40 µg booster dose. TRIAL REGISTRATION NUMBER: NCT01884415.

Serotype-associated immune response and network immunoclusters in children and adults during acute Dengue virus infection.

The present study was designed as an exploratory investigation to characterize the overall profile of chemokines, growth factors, and pro-inflammatory/regulatory cytokines during acute DENV infection according to DENV-1, DENV-2, DENV-4 serotypes and age: children: <1-10-year-old (yo); adolescents:11-20 yo; adults 21-40 yo; and older adults: 41-75 yo. The levels of soluble immunemediators were measured in serum by high-throughput microbeads array in 636 subjects including 317 DENV-infected and 319 age-matching non-infected control (NI). Overall, most soluble mediators were increased in DENV-infected patients as compared to NI group regardless of age and DENV serotype, with high magnitude order of increase for CCL2, CXCL10, IL-1ß, IFN-γ, IL1-Ra (fold change >3x), except PDGF in which no fold change was observed. Moreover, despite the age ranges, DENV-1 and DENV-4 presented increased levels of VEGF, IL-6, and TNF-α in serum but decreased levels of PDGF, while DENV-2 exhibited increased levels of CXCL8, CCL4, and IL-12. Noteworthy was that DENV-2 showed increased levels of IL-12, IL-15, IL-17, IL-4, IL-9, and IL-13, and maintained an unaltered levels of PDGF at younger ages (<1-10 yo and 11-20 yo), whereas in older ages (21-40 yo and 41-75 yo), the results showed increased levels of CCL2, IL-6, and TNF-α, but lower levels of PDGF. In general, DENV infection at younger age groups exhibited more complex network immunoclusters as compared to older age groups. Multivariate analysis revealed a clustering of DENV cases according to age for a set of soluble mediators especially in subjects infected with DENV-2 serotype. Altogether, our findings demonstrate that the profile of circulating soluble mediators differs substantially in acute DENV according to age and DENV serotypes suggesting the participation of serotype-associated immune response, which may represent a potential target for development of therapeutics and could be used to assist medical directive for precise clinical management of severe cases.

Management and outcomes of adolescent and young adult sarcoma patients: results from the French nationwide database NETSARC.

BACKGROUND: The initial management of patients with sarcoma is a critical issue. We used the nationwide French National Cancer Institute-funded prospective sarcoma database NETSARC to report the management and oncologic outcomes in adolescents and young adults (AYAs) patients with sarcoma at the national level. PATIENTS AND METHODS: NETSARC database gathers regularly monitored and updated data from patients with sarcoma. NETSARC was queried for patients (15-30 years) with sarcoma diagnosed from 2010 to 2017 for whom tumor resection had been performed. We reported management, locoregional recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS) in AYA treated in French reference sarcoma centers (RSC) and outside RSC (non-RSC) and conducted multivariable survival analyses adjusted for classical prognostic factors. RESULTS: Among 3,227 patients aged 15-30 years with sarcoma diagnosed between 2010 and 2017, the study included 2,227 patients with surgery data available, among whom 1,290 AYAs had been operated in RSC, and 937 AYAs in non-RSC. Significant differences in compliance to guidelines were observed including pre-treatment biopsy (RSC: 85.9%; non-RSC 48.1%), pre-treatment imaging (RSC: 86.8%; non-RSC: 56.5%) and R0 margins (RSC 57.6%; non-RSC: 20.2%) (p < 0.001). 3y-OS rates were 81.1% (95%CI 78.3-83.6) in AYA in RSC and 82.7% (95%CI 79.4-85.5) in AYA in non-RSC, respectively. Whereas no significant differences in OS was observed in AYAs treated in RSC and in non-RSC, LRFS and PFS were improved in AYAs treated in RSC compared to AYAs treated in non-RSC (Hazard Ratios (HR): 0.58 and 0.83, respectively). CONCLUSIONS: This study highlights the importance for AYA patients with sarcoma to be managed in national sarcoma reference centers involving multidisciplinary medical teams with paediatric and adult oncologists.

Calcitonin Gene-Related Peptide, Vascular Endothelial Growth Factor, and Clinical Manifestations in Women With Fibromyalgia.

BACKGROUND: Fibromyalgia is a complex illness to diagnose and treat, which significantly impairs patients' quality of life. OBJECTIVES: The study aims were to compare levels of calcitonin gene-related peptide and vascular endothelial growth factor between patients with fibromyalgia and healthy controls and to examine their relationship with the main clinical manifestations of fibromyalgia. METHODS: This case-control study included 42 women diagnosed with fibromyalgia and 22 healthy women. Serum calcitonin gene-related peptide and vascular endothelial growth factor levels were spectrophotometrically analyzed by enzyme-linked immunosorbent assay. Clinical manifestations were assessed by means of self-administered questionnaires, including functional capacity in daily living activities, musculoskeletal pain, fatigue, anxiety, and sleep quality. The predictive value of these parameters in fibromyalgia was determined by receiver operating characteristic curve analysis. RESULTS: Serum calcitonin gene-related peptide levels significantly increased in the fibromyalgia group in comparison to the control group. However, there were no significant differences in vascular endothelial growth factor levels between patients and controls. No significant correlations were found between calcitonin gene-related peptide and vascular endothelial growth factor and the symptoms analyzed. DISCUSSION: Serum calcitonin gene-related peptide levels were dysregulated in women with fibromyalgia and may be a reliable parameter to help diagnose this complex syndrome.

Protocols for studying the crayfish plague pathogen, Aphanomyces astaci, and its host-pathogen interactions.

The crayfish plague caused by the pathogen Aphanomyces astaci has decimated the European and Asian populations of freshwater crayfish and represents an important threat to the other highly susceptible crayfish species in the world, such as the Australian, Madagascar, and South American species. The development and application of molecular methods addressed to the identification of A. astaci has increased exponentially during the last decades in contrast to a slow trend of the pathogen biology and host interaction. There is still a need for a better comprehension of the A. astaci-crayfish interactions, specifically the resistance and tolerance immune mechanism. These types of studies required a robust basic knowledge on the developmental biology of the pathogen in order to reproduce life stages and to perform infection experiments. A great piece of work in this area was carried out during the 1960 s to 80 s in University of Uppsala. Thus, the purpose of this work was to update previous protocols as well as to generate new guidelines to reproduce key developmental biology stages of A. astaci, to eventually identify crayfish populations with higher resistance and tolerance to this pathogen. This work also refers to other methodologies and guidelines for the diagnosis of crayfish plague, the pathogen isolation, and the in vitro production of zoospores.

Peptide probes for proteases - innovations and applications for monitoring proteolytic activity.

Proteases are excellent biomarkers for a variety of diseases, offer multiple opportunities for diagnostic applications and are valuable targets for therapy. From a chemistry-based perspective this review discusses and critiques the most recent advances in the field of substrate-based probes for the detection and analysis of proteolytic activity both in vitro and in vivo.

Associations among serum VEGF and CGRP levels with the peripheral vascular blood flow of the skin of the hands in women with Fibromyalgia.

BACKGROUND: Fibromyalgia (FM) is a long-term condition of unknown physiopathology, whose hallmark symptoms are diffuse musculoskeletal chronic pain and fatigue. OBJECTIVES: We aimed to analyze the associations among serum vascular endothelial growth factor (VEGF) and calcitonin gene-related peptide (CGRP) levels with the peripheral temperature of the skin of both hands and the core body temperature in patients with FM and healthy controls. METHODS: We conducted a case-control observational study with fifty-three women diagnosed with FM and twenty-four healthy women. VEGF and CGRP levels were spectrophotometrically analyzed in serum by enzyme-linked immunosorbent assay. We used an infrared thermography camera to assess the peripheral temperature of the skin of the dorsal thumb, index, middle, ring, and pinkie fingertips and dorsal centre as well as the palm thumb, index, middle, ring, and pinkie fingertips, palm centre and thenar and hypothenar eminences of both hands and an infrared thermographic scanner to record the tympanic membrane and axillary temperature. RESULTS: Linear regression analysis adjusting for age, menopause status, and body mass index showed that serum VEGF levels were positively associated with the maximum (ß = 65.942, 95% CI [4.100,127.784], p = 0.037), minimum (ß = 59.216, 95% CI [1.455,116.976], p = 0.045), and mean (ß = 66.923, 95% CI [3.142,130.705], p = 0.040) temperature of the thenar eminence of the non-dominant hand, as well as with the maximum temperature of the hypothenar eminence of the non-dominant hand (ß = 63.607, 95% CI [3.468,123.747], p = 0.039) in women diagnosed with FM. CONCLUSIONS: Mild associations were observed between serum VEGF levels and the peripheral temperature of the skin in hand areas in patients with FM; therefore, it is not possible to establish a clear relationship between this vasoactive molecule and vasodilation of the hands in these patients.

Neurofilament Light Chain Protein in Plasma and Extracellular Vesicles Is Associated with Minimal Hepatic Encephalopathy and Responses to Rifaximin Treatment in Cirrhotic Patients.

Neurofilament light chain protein (NfL) levels reflect neuronal damage in several neurological diseases and have been proposed as a possible biomarker. Plasma extracellular vesicles (EVs) could play an important role as mediators of the inflammatory changes associated with inducing minimal hepatic encephalopathy (MHE) in cirrhotic patients. This study investigated the association of NfL levels in plasma and EVs with the presence of MHE in cirrhotic patients, and with responses to rifaximin treatment. The NfL levels in plasma and EVs were assessed in 71 patients with liver cirrhosis (40 with MHE and 31 without MHE) and 26 controls. A total of 31 patients with MHE received rifaximin treatment. We examined changes in NfL levels in plasma and EVs before and after 6 months of rifaximin treatment. The NfL measures were correlated with cognitive alterations and plasma inflammatory cytokines. MHE patients showed increased plasma levels of NfL, which were reverted after rifaximin treatment in patients who responded to treatment. The NfL content in EVs also showed a reversal pattern in MHE patients treated with rifaximin. In multivariable analyses, NfL levels were independently associated with the presence of MHE. We also showed that patients with high levels of both ammonia and fractalkine had significantly higher NfL levels than patients with low levels of least one of these parameters. Rifaximin treatment in MHE patients showed promising results in improving axonal damage, suggesting that rifaximin may have therapeutic benefits against disease progression in MHE.

Mild Cognitive Impairment Is Associated with Enhanced Activation of Th17 Lymphocytes in Non-Alcoholic Fatty Liver Disease.

Patients with nonalcoholic fatty liver disease (NAFLD) may show mild cognitive impairment (MCI). The mechanisms involved remain unclear. The plasma concentrations of several cytokines and chemokines were measured in 71 NAFLD patients (20 with and 51 without MCI) and 61 controls. Characterization and activation of leukocyte populations and CD4+ sub-populations were carried out and analyzed by flow cytometry. We analyzed the cytokines released from CD4+ cell cultures and the mRNA expression of transcription factors and receptors in peripheral blood mononuclear cells. The appearance of MCI in NAFLD patients was associated with increased activation of CD4+ T lymphocytes, mainly of the Th17 subtype, increased plasma levels of pro-inflammatory and anti-inflammatory cytokines such as IL-17A, IL-23, IL-21, IL-22, IL-6, INF-γ, and IL-13, and higher expression of the CCR2 receptor. Constitutive expression of IL-17 was found in cultures of CD4+ cells from MCI patients, reflecting Th17 activation. High IL-13 plasma levels were predictive of MCI and could reflect a compensatory anti-inflammatory response to the increased expression of pro-inflammatory cytokines. This study identified some specific alterations of the immune system associated with the appearance of neurological alterations in MCI patients with NAFLD that could be the basis to improve and restore cognitive functions and quality of life in these patients.

Mechanochemical Mediated Coexistence of B←N Coordination and Hydrogen Bonding.

Mechanochemistry afforded a photoactive cocrystal via coexisting (B)O-H⋅⋅⋅N hydrogen bonds and B←N coordination. Specifically, solvent-free mechanochemical ball mill grinding and liquid-assisted grinding of a boronic acid and an alkene resulted in mixtures of hydrogen-bonded and coordinated complexes akin to mixtures of noncovalent complexes that can be obtained in solution in equilibria processes. The alkenes of the hydrogen-bonded assembly undergo an intermolecular [2+2] photodimerization in quantitative conversion, effectively reporting the outcome of the self-assembly processes. Our results suggest that interplay involving noncovalent bonds subjected to mechanochemical conditions can lead to functional solids where, in the current case, the structure composed of the weaker hydrogen bonding interactions predominates.

Doxorubicin alone versus doxorubicin with trabectedin followed by trabectedin alone as first-line therapy for metastatic or unresectable leiomyosarcoma (LMS-04): a randomised, multicentre, open-label phase 3 trial.

BACKGROUND: Metastatic leiomyosarcomas have a poor prognosis, and currently doxorubicin alone is used as the standard first-line treatment. Doxorubicin combined with trabectedin has shown promising results in phase 1 and 2 studies. We aimed to identify and compare the progression-free survival of patients with metastatic or unresectable uterine or soft tissue leiomyosarcoma treated with doxorubicin and trabectedin combined as first-line therapy versus doxorubicin alone in a phase 3 trial. METHODS: LMS-04 was a randomised, multicentre, open-label, superiority phase 3 trial, which included patients from 20 centres of the French Sarcoma Group (anticancer centers or hospitals with an oncological unit) in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-1, and had metastatic or relapsed unresectable leiomyosarcomas that had not previously been treated with chemotherapy. Patients were randomly assigned (1:1), by means of an interactive web response system (permuted blocks of different sizes from two to six), to receive either intravenous doxorubicin alone (75 mg/m2) once every 3 weeks for up to six cycles or of intravenous doxorubicin (60 mg/m2) plus intravenous trabectedin (1·1 mg/m2) once every 3 weeks up to six cycles followed by maintenance with trabectedin alone. Surgery for residual disease was allowed in both groups after six cycles of treatment. Randomisation was stratified by tumour location (uterine vs soft tissue) and disease (locally advanced vs metastatic). The primary endpoint was progression-free survival assessed by blinded independent central review and according to Response Evaluation Criteria in Solid Tumours 1.1 criteria. Efficacy analyses were performed on all randomly assigned patients, based on the intention-to-treat principle. The safety population included all randomly assigned patients who received at least one cycle of treatment. This trial is registered with ClinicalTrials.gov, NCT02997358, and is closed to enrolment. FINDINGS: Between Jan 18, 2017, and March 21, 2019, 150 patients were enrolled (67 with uterine leiomyosarcomas and 83 with soft tissue leiomyosarcomas) and included in the intention-to-treat population: 76 in the doxorubicin alone group and 74 in the doxorubicin plus trabectedin group. The median duration of follow-up was 36·9 months (IQR 30·0-43·2) in the doxorubicine group and 38·8 months (32·7-44·2) in the doxorubicin plus trabectedin group. Median progression-free survival was significantly longer with doxorubicin plus trabectedin versus doxorubicin alone (12·2 months [95% CI 10·1-15·6] vs 6·2 months [4·1-7·1]; adjusted hazard ratio 0·41 [95% CI 0·29-0·58]; p<0·0001). The most common grade 3-4 adverse events were neutropenia (ten [13%] of 75 patients in the doxorubicin alone group vs 59 [80%] in the doxorubicin plus trabectedin group), anaemia (four [5%] vs 23 [31%]), thrombocytopenia (0 vs 35 [47%]), and febrile neutropenia (seven [9%] vs 21 [28%]). Nine (12%) patients in the doxorubicin alone group and 15 (201%) patients in the doxorubicin plus trabectedin group has serious adverse events. There was only one treatment-related death, reported in the doxorubicin alone group (cardiac failure). INTERPRETATION: Doxorubicin plus trabectedin in first-line therapy was found to significantly increase progression-free survival in patients with metastatic or unresectable leiomyosarcomas compared with doxorubicin alone, despite a higher but manageable toxicity, and could be considered an option for the first-line treatment of metastatic leiomyosarcomas. FUNDING: PharmaMar.

Survival of Patient With Hemorrhagic Meningitis Associated With Inhalation Anthrax.

This report describes a 49-year-old male construction worker who acquired a Bacillus anthracis infection after working on a sheep farm. He experienced a severe respiratory infection, septic shock, and hemorrhagic meningoencephalitis with severe intracranial hypertension. After several weeks with multiple organ dysfunction syndrome, he responded favorably to antibiotic treatment. Three weeks into his hospitalization, an intracranial hemorrhage and cerebral edema led to an abrupt deterioration in his neurological status. A single dose of raxibacumab was added to his antimicrobial regimen on hospital day 27. His overall status, both clinical and radiographic, improved within a few days. He was discharged 2 months after admission and appears to have fully recovered.