expam-high-resolution analysis of metagenomes using distance trees.

SUMMARY: Shotgun metagenomic sequencing provides the capacity to understand microbial community structure and function at unprecedented resolution; however, the current analytical methods are constrained by a focus on taxonomic classifications that may obfuscate functional relationships. Here, we present expam, a tree-based, taxonomy agnostic tool for the identification of biologically relevant clades from shotgun metagenomic sequencing. AVAILABILITY AND IMPLEMENTATION: expam is an open-source Python application released under the GNU General Public Licence v3.0. expam installation instructions, source code and tutorials can be found at https://github.com/seansolari/expam. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Everolimus Concentration in Saliva to Predict Stomatitis: A Feasibility Study in Patients with Cancer.

BACKGROUND: Most patients with cancer treated with everolimus experience stomatitis, which seriously affects the quality of life. The salivary concentrations of everolimus may predict the incidence and severity of stomatitis. The authors aimed to examine whether it was feasible to quantify the everolimus concentration in saliva and subsequently use it to predict stomatitis. METHODS: Saliva and whole blood samples were taken from patients with cancer, who were treated with everolimus in the dosage of either 10 mg once a day or 5 mg twice a day. Everolimus concentrations in saliva samples were measured by liquid chromatography-tandem mass spectrometry. A published population pharmacokinetic model was extended with the everolimus concentration in saliva to assess any association between everolimus in the blood and saliva. Subsequently, the association between the occurrence of stomatitis and the everolimus concentration in saliva was studied. RESULTS: Eleven patients were included in this study; saliva samples were available from 10 patients, including 3 patients with low-grade stomatitis. Everolimus concentrations were more than 100-fold lower in saliva than in whole blood (accumulation ratio 0.00801 and relative standard error 32.5%). Interindividual variability (67.7%) and residual unexplained variability (84.0%) were high. The salivary concentration of everolimus tended to be higher in patients with stomatitis, 1 hour postdose ( P = 0.14). CONCLUSIONS: Quantification of the everolimus concentration in saliva was feasible and revealed a nonsignificant correlation between everolimus concentration in the saliva and the occurrence of stomatitis. If future research proves this relationship to be significant, the everolimus concentration in the saliva may be used as an early predictor of stomatitis without invasive sampling. Thereby, in patients with high salivary everolimus concentrations, precautions can be taken to decrease the incidence and severity of stomatitis.

A phase Ib study of the highly selective MET-TKI savolitinib plus gefitinib in patients with EGFR-mutated, MET-amplified advanced non-small-cell lung cancer.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are recommended first-line treatments in EGFR-mutated (EGFRm) non-small-cell lung cancer (NSCLC). However, acquired resistance (e.g. MET amplification) is frequently observed. Savolitinib (volitinib, HMPL-504, AZD6094) is an oral, potent, and highly selective MET-TKI. In this phase Ib, open-label, multicenter study, we enrolled Chinese patients with EGFRm advanced NSCLC, whose disease progressed following prior EGFR-TKI treatment. In the safety run-in, patients received savolitinib 600 or 800 mg plus gefitinib 250 mg orally once daily, and dose-limiting toxicities were recorded. In the expansion phase, patients with MET amplification received savolitinib plus gefitinib. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity. Thirteen patients were enrolled in the safety phase (median age 52 years, 46% female) and 51 enrolled in the expansion phase (median age 61 years, 67% female). No dose-limiting toxicities were reported in either dose group during the safety run-in. Adverse events of grade ≥ 3 in the safety run-in and expansion phases (n = 57) were reported in 21 (37%) patients. The most frequently reported adverse events (all grades) were: vomiting (n = 26, 46%), nausea (n = 23, 40%), increased aspartate aminotransferase (n = 22, 39%). Of four deaths, none were treatment-related. The objective response rates in EGFR T790M-negative, -positive, and -unknown patients were 52% (12/23), 9% (2/23), and 40% (2/5), respectively. Savolitinib 600 mg plus gefitinib 250 mg once daily had an acceptable safety profile and demonstrated promising antitumor activity in EGFRm, MET-amplified advanced NSCLC patients who had disease progression on EGFR-TKIs. NCT02374645, Date of registration: March 2nd 2015.

Analogs of the carotane antibiotic fulvoferruginin from submerged cultures of a Thai Marasmius sp.

A recent find of a Marasmius species in Northern Thailand led to the isolation of five unprecedented derivatives of the carotane antibiotic fulvoferruginin (1), fulvoferruginins B-F (2-6). The structures of these sesquiterpenoids were elucidated using HRESIMS, 1D and 2D NMR, as well as CD spectroscopy. Assessing the bioactivity, fulvoferruginin emerged as a potent cytotoxic agent of potential pharmaceutical interest.

Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study.

BACKGROUND: Preclinical data suggest that EGFR tyrosine kinase inhibitors (TKIs) plus MET TKIs are a possible treatment for EGFR mutation-positive lung cancers with MET-driven acquired resistance. Phase 1 safety data of savolitinib (also known as AZD6094, HMPL-504, volitinib), a potent, selective MET TKI, plus osimertinib, a third-generation EGFR TKI, have provided recommended doses for study. Here, we report the assessment of osimertinib plus savolitinib in two global expansion cohorts of the TATTON study. METHODS: In this multi-arm, multicentre, open-label, phase 1b study, we enrolled adult patients (aged ≥18 years) with locally advanced or metastatic, MET-amplified, EGFR mutation-positive non-small-cell lung cancer, who had progressed on EGFR TKIs. We considered two expansion cohorts: parts B and D. Part B consisted of three cohorts of patients: those who had been previously treated with a third-generation EGFR TKI (B1) and those who had not been previously treated with a third-generation EGFR TKI who were either Thr790Met negative (B2) or Thr790Met positive (B3). In part B, patients received oral osimertinib 80 mg and savolitinib 600 mg daily; after a protocol amendment (March 12, 2018), patients who weighed no more than 55 kg received a 300 mg dose of savolitinib. Part D enrolled patients who had not previously received a third-generation EGFR TKI and were Thr790Met negative; these patients received osimertinib 80 mg plus savolitinib 300 mg. Primary endpoints were safety and tolerability, which were assessed in all dosed patients. Secondary endpoints included the proportion of patients who had an objective response per RECIST 1.1 and was assessed in all dosed patients and all patients with centrally confirmed MET amplification. Here, we present an interim analysis with data cutoff on March 29, 2019. This study is registered with ClinicalTrials.gov, NCT02143466. FINDINGS: Between May 26, 2015, and Feb 14, 2019, we enrolled 144 patients into part B and 42 patients into part D. In part B, 138 patients received osimertinib plus savolitinib 600 mg (n=130) or 300 mg (n=8). In part D, 42 patients received osimertinib plus savolitinib 300 mg. 79 (57%) of 138 patients in part B and 16 (38%) of 42 patients in part D had adverse events of grade 3 or worse. 115 (83%) patients in part B and 25 (60%) patients in part D had adverse events possibly related to savolitinib and serious adverse events were reported in 62 (45%) patients in part B and 11 (26%) patients in part D; two adverse events leading to death (acute renal failure and death, cause unknown) were possibly related to treatment in part B. Objective partial responses were observed in 66 (48%; 95% CI 39-56) patients in part B and 23 (64%; 46-79) in part D. INTERPRETATION: The combination of osimertinib and savolitinib has acceptable risk-benefit profile and encouraging antitumour activity in patients with MET-amplified, EGFR mutation-positive, advanced NSCLC, who had disease progression on a previous EGFR TKI. This combination might be a potential treatment option for patients with MET-driven resistance to EGFR TKIs. FUNDING: AstraZeneca.

Therapeutic Drug Monitoring of Oral Anticancer Drugs: The Dutch Pharmacology Oncology Group-Therapeutic Drug Monitoring Protocol for a Prospective Study.

BACKGROUND: Oral anticancer drugs show a high interpatient variability in pharmacokinetics (PK), leading to large differences in drug exposure. For many of these drugs, exposure has been linked to efficacy and toxicity. Despite this knowledge, these drugs are still administered in a one-size-fits-all approach. Consequently, individual patients have a high probability to be either underdosed, which can lead to decreased antitumor efficacy, or overdosed, which could potentially result in increased toxicity. Therapeutic drug monitoring (TDM), personalized dosing based on measured drug levels, could be used to circumvent underdosing and overdosing and thereby optimize treatment outcomes. METHODS: In this prospective clinical study (www.trialregister.nl; NL6695), the feasibility, tolerability, and efficacy of TDM of oral anticancer drugs will be evaluated. In total, at least 600 patients will be included for (at least) 23 different compounds. Patients starting regular treatment with one of these compounds at the approved standard dose can be included. PK sampling will be performed at 4, 8, and 12 weeks after the start of treatment and every 12 weeks thereafter. Drug concentrations will be measured, and trough concentrations (Cmin) will be calculated. In cases where Cmin falls below the predefined target and acceptable toxicity, a PK-guided intervention will be recommended. This could include emphasizing compliance, adapting concomitant medication (due to drug-drug interactions), instructing to take the drug concomitant with food, splitting intake moments, or recommending a dose increase. DISCUSSION: Despite a strong rationale for the use of TDM for oral anticancer drugs, this is currently not yet widely adopted in routine patient care. This prospective study will be a valuable contribution to demonstrate the additional value of dose optimization on treatment outcome for these drugs.

Fast and Straightforward Method for the Quantification of Pazopanib in Human Plasma Using LC-MS/MS.

BACKGROUND: Pazopanib is an angiogenesis inhibitor approved for renal cell carcinoma and soft-tissue sarcoma. Studies indicate that treatment with pazopanib could be optimized by adapting the dose based on measured pazopanib plasma concentrations. METHODS: We describe the validation and clinical application of a fast and straightforward method for the quantification of pazopanib in human plasma for the purpose of therapeutic drug monitoring and bioanalytical support of clinical trials. Stable isotopically labeled C,H3-pazopanib was used as internal standard. Plasma samples were prepared for analysis by protein precipitation using methanol and diluted with 10 mmol/L ammonium hydroxide buffer. Chromatographic separation was performed on a C18 column using isocratic elution with ammonium hydroxide in water and methanol. For detection, a tandem mass spectrometer, equipped with a turbo ion spray interface was used in positive ion mode at m/z 438 → m/z 357 for pazopanib and m/z 442 → m/z 361 for the internal standard. RESULTS: Final runtime was 2.5 minutes. All validated parameters were within pre-established limits and fulfilled the FDA and EMA requirements for bioanalytical method validation. After completion of the validation, the routine application of the method was tested by analyzing clinical study samples that were collected for the purpose of therapeutic drug monitoring. CONCLUSIONS: In conclusion, the described method was successfully validated and was found to be robust for routine application to analyze samples from cancer patients treated with pazopanib.

Nematicidal Cyclic Lipodepsipeptides and a Xanthocillin Derivative from a Phaeosphariaceous Fungus Parasitizing Eggs of the Plant Parasitic Nematode Heterodera filipjevi.

The new cyclic lipodepsipeptide ophiotine (1), two new arthrichitin derivatives named arthrichitins B (4) and C (5), a new xanthocillin-like alkaloid, xanthomide Z (2), and the previously described arthrichitin (3) were isolated from the liquid culture broth of a nematode-associated fungus with affinities to the genus Ophiosphaerella. The structural elucidation and determination of the absolute configuration of the new molecules were accomplished using a combination of spectroscopic and chemical techniques, including 1D and 2D NMR, HRMS, and Marfey's analysis. Opiotine (1) displayed moderate nematicidal activity against the host nematode ( Heterodera filipjevi), while xanthomide Z (2) exhibited very weak activity. Arthrichitin C (5) showed very weak cytotoxic effects on several cancer cell lines, with IC50 values in the range of 24-33 µM. Xanthomide Z is among few xanthocillin derivatives that comprise formamide functions instead of the cyano functions that are usually observed in this class of fungal alkaloids.

[Prevent bacteria from communicating: Divide to cure]. / Empêcher les bactéries de communiquer : diviser pour mieux soigner.

Quorum Sensing (QS) is a communication system used by numerous bacteria to synchronize their behavior according to the cell density. In this way, bacteria secrete and sense small mediating molecules, called autoinducers (AI), which concentration increases in the environment proportionally to bacterial cell number. QS induces major physiological and phenotypic changes such as virulence induction and biofilm formation. Biofilm represents a physical barrier which shelters bacteria poorly sensitive to antimicrobial treatments and favors the apparition of resistance mechanisms. Disturbing QS is referred to as quorum quenching (QQ). This strategy is used by microorganisms themselves to prevent the development of specific group behaviors. Two strategies are mainly employed: the use of quorum sensing inhibitors (QSI) and of quorum quenching enzymes (QQE) that degrades AI. Many studies have been dedicated to identifying QSI (natural or synthetic) as well as QQE and demonstrating their anti-virulence and anti-biofilm effects on numerous bacterial species. Synergistic effects between QQ and traditional treatments such as antibiotherapy or with reemerging phage therapy have been put forward. The efficiency of numerous QSI and QQE was thereby demonstrated either with in vitro or in vivo animal models leading to the development of medical devices containing QSI and QQE to improve already existing treatments.

1.15 PW-850 J compressed beam demonstration using the PETAL facility.

The Petawatt Aquitaine Laser (PETAL) facility was designed and constructed by the French Commissariat à l'énergie atomique et aux énergies alternatives (CEA) as an additional PW beamline to the Laser MegaJoule (LMJ) facility. PETAL energy is limited to 1 kJ at the beginning due to the damage threshold of the final optics. In this paper, we present the commissioning of the PW PETAL beamline. The first kJ shots in the amplifier section with a large spectrum front end, the alignment of the synthetic aperture compression stage and the initial demonstration of the 1.15 PW @ 850 J operations in the compression stage are detailed. Issues encountered relating to damage to optics are also addressed.

A dihydrochalcone derivative and further steroidal saponins from Sansevieria trifasciata Prain.

Phytochemical investigation of the aerial parts of Sansevieria trifasciata, one of the most common Dracaenaceae plants, has resulted in the isolation of a new dihydrochalcone derivative named trifasciatine C (1), four previously unreported steroidal saponins as two pairs of inseparable regioisomers: trifasciatosides K/L (2/3), M/N (4/5), together with the known 1,2-(dipalmitoyl)-3-O-ß-D-galactopyranosylglycerol (6), aconitic acid (7), and 1-methyl aconitic acid (8). Their structures were elucidated mainly by extensive spectroscopic analysis (1D and 2D nuclear magnetic resonance) and high-resolution electronspray ionization-mass spectrometry, as well as chemical methods and comparison of their spectral data with those of related compounds. Compounds 2/3 and 4/5 were evaluated for their antiproliferative activity on Hela cells, and no significant effect was observed.

Furanones and Anthranilic Acid Derivatives from the Endophytic Fungus Dendrothyrium variisporum.

Extracts from an endophytic fungus isolated from the roots of the Algerian plant Globularia alypum showed prominent antimicrobial activity in a screening for novel antibiotics. The producer organism was identified as Dendrothyrium variisporum by means of morphological studies and molecular phylogenetic methods. Studies on the secondary metabolite production of this strain in various culture media revealed that the major components from shake flasks were massarilactones D (1) and H (2) as well as two new furanone derivatives for which we propose the trivial names (5S)-cis-gregatin B (3) and graminin D (4). Scale-up of the fermentation in a 10 L bioreactor yielded massarilactone D and several further metabolites. Among those were three new anthranilic acid derivatives (5-7), two known anthranilic acid analogues (8 and 9) and three cyclopeptides (10-12). Their structures were elucidated on the basis of extensive spectroscopic analysis (1D- and 2D-NMR), high-resolution mass spectrometry (HRESIMS), and the application of the modified Mosher's method. The isolated metabolites were tested for antimicrobial and cytotoxic activities against various bacteria, fungi, and two mammalian cell lines. The new Metabolite 5 and Compound 9 exhibited antimicrobial activity while Compound 9 showed cytotoxicity activity against KB3.1 cells.

[Enzymes for disrupting bacterial communication, an alternative to antibiotics?] / Des enzymes pour bloquer la communication bactérienne, une alternative aux antibiotiques ?

Quorum sensing (QS) is used by bacteria to communicate and synchronize their actions according to the cell density. In this way, they produce and secrete in the surrounding environment small molecules dubbed autoinducers (AIs) that regulate the expression of certain genes. The phenotypic traits regulated by QS are diverse and include pathogenicity, biofilm formation or resistance to anti-microbial treatments. The strategy, aiming at disrupting QS, known as quorum quenching (QQ), has emerged to counteract bacterial virulence and involves QS-inhibitors (QSI) or QQ-enzymes degrading AIs. Differently from antibiotics, QQ aims at blocking cell signaling and does not alter bacterial survival. This considerably decreases the selection pressure as compared to bactericide treatments and may reduce the occurrence of resistance mechanisms. QQ-enzymes are particularly appealing as they may disrupt molecular QS-signal without entering the cell and in a catalytic way. This review covers several aspects of QQ-based medical applications and the potential subsequent emergence of resistance is discussed.

[The specificities of orthopedic trauma in the geriatric patient]. / Les particularités de la traumatologie de l'appareil locomoteur chez le sujet gériatrique.

Aging of the population represents an ubiquitous and ever-growing phenomenon in the developed countries. Geriatric traumatology is a constant-developping sub-speciality of orthopedics and traumatology; it deals with the specific medical problems developed by older patients when affected by muskuloskeletal trauma. The optimal treatment of this pathology as well as the age threshold used to define the "geriatric" patient are still subjects of debate. Chronological age cannot be used as the sole inclusion criteria; physiological age as defined by comorbidities seems to be more appropriate. The aim of this article is to provide a general overview of the problems that the orthopedic surgeons faces when dealing with geriatric trauma: timing of surgery and anesthesia, technical aspects of surgery and fractures, complications and problems with the postoperative management of geriatric patients. Geriatric trauma is already today an important problem; it will certainly become a great challenge in coming years. The solution must reside in a multidisciplinary approach backed up by a solid infra-structure and good management decisions.

Subcutaneous Versus Intravenous Amivantamab, Both in Combination With Lazertinib, in Refractory Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer: Primary Results From the Phase III PALOMA-3 Study.

PURPOSE: Phase III studies of intravenous amivantamab demonstrated efficacy across epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). A subcutaneous formulation could improve tolerability and reduce administration time while maintaining efficacy. PATIENTS AND METHODS: Patients with EGFR-mutated advanced NSCLC who progressed after osimertinib and platinum-based chemotherapy were randomly assigned 1:1 to receive subcutaneous or intravenous amivantamab, both combined with lazertinib. Coprimary pharmacokinetic noninferiority end points were trough concentrations (Ctrough; on cycle-2-day-1 or cycle-4-day-1) and cycle-2 area under the curve (AUCD1-D15). Key secondary end points were objective response rate (ORR) and progression-free survival (PFS). Overall survival (OS) was a predefined exploratory end point. RESULTS: Overall, 418 patients underwent random assignment (subcutaneous group, n = 206; intravenous group, n = 212). Geometric mean ratios of Ctrough for subcutaneous to intravenous amivantamab were 1.15 (90% CI, 1.04 to 1.26) at cycle-2-day-1 and 1.42 (90% CI, 1.27 to 1.61) at cycle-4-day-1; the cycle-2 AUCD1-D15 was 1.03 (90% CI, 0.98 to 1.09). ORR was 30% in the subcutaneous and 33% in the intravenous group; median PFS was 6.1 and 4.3 months, respectively. OS was significantly longer in the subcutaneous versus intravenous group (hazard ratio for death, 0.62; 95% CI, 0.42 to 0.92; nominal P = .02). Fewer patients in the subcutaneous group experienced infusion-related reactions (IRRs; 13% v 66%) and venous thromboembolism (9% v 14%) versus the intravenous group. Median administration time for the first infusion was reduced to 4.8 minutes (range, 0-18) for subcutaneous amivantamab and to 5 hours (range, 0.2-9.9) for intravenous amivantamab. During cycle-1-day-1, 85% and 52% of patients in the subcutaneous and intravenous groups, respectively, considered treatment convenient; the end-of-treatment rates were 85% and 35%, respectively. CONCLUSION: Subcutaneous amivantamab-lazertinib demonstrated noninferiority to intravenous amivantamab-lazertinib, offering a consistent safety profile with reduced IRRs, increased convenience, and prolonged survival.

Lower intracellular concentration of cryoprotectants after vitrification than after slow freezing despite exposure to higher concentration of cryoprotectant solutions.

STUDY QUESTION: What is the intracellular concentration of cryoprotectant (ICCP) in mouse zygotes during vitrification (VIT) and slow-freezing (SLF) cryopreservation procedures? SUMMARY ANSWER: Contrary to common beliefs, it was observed that the ICCP in vitrified zygotes is lower than after SLF, although the solutions used in VIT contain higher concentrations of cryoprotectants (CPs). WHAT IS KNOWN ALREADY: To reduce the likelihood of intracellular ice crystal formation, which has detrimental effects on cell organelles and membranes, VIT was introduced as an alternative to SLF to cryopreserve embryos and gametes. Combined with high cooling and warming rates, the use of high concentrations of CPs favours an intracellular environment that supports and maintains the transition from a liquid to a solid glass-like state devoid of crystals. Although the up-to-date publications are reassuring in terms of obstetric and perinatal outcomes after VIT, a fear about exposing gametes and embryos to high amounts of CPs that exceed 3-4-fold those found in SLF was central to a debate initiated by advocates of SLF procedures. STUDY DESIGN, SIZE, DURATION: Two experimental set-ups were applied. The objective of a first study was to determine the ICCP at the end of the exposure steps to the CP solutions with our VIT protocol (n = 31). The goal of the second investigation was to compare the ICCP between VIT (n = 30) and SLF (n = 30). All experiments were performed in triplicates using mouse zygotes. The study took place at the GIGA-Research Institute of the University of Liège. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cell volume is modified by changes in extracellular osmolarity. Hence, we estimated the final ICCP after the incubation steps in the VIT solutions by exposing the cells to sucrose (SUC) solutions with defined molarities. The ICCP was calculated from the SUC concentration that produced no change in cell volume, i.e. when intra- and extracellular osmolarities were equivalent. Cell volume was monitored by microscopic cinematography. ICCP was compared between SLF and VIT based on the principle that a high ICCP lowers the probability of (re)crystallization during warming but increases the probability of over-swelling of the cell due to fast inflow of water. The survival rates of mouse zygotes after SLF or VIT were compared using either (i) various warming rates or (ii) various concentrations of SUC in the warming dilution medium. MAIN RESULTS AND THE ROLE OF CHANCE: The ICCP in mouse zygotes during the VIT procedure prior to plunging them in liquid nitrogen was ∼2.14 M, i.e. one-third of the concentration in the VIT solution. After SLF, the warming rate did not affect the zygote survival rate. In contrast, only 3/30 vitrified zygotes survived when warmed slowly but as many as 30/30 zygotes survived when warming was fast (>20 000°C/min). Vitrified zygotes showed significantly higher survival rates than slow-frozen zygotes when they were placed directly in the culture medium or in solutions containing low concentrations of SUC (P < 0.01). These two experiments demonstrate a lower ICCP after VIT than after SLF. LIMITATIONS, REASONS FOR CAUTION: The results should not be directly extrapolated to other stages of development or to other species due to possible differences in membrane permeability to water and CPs. WIDER IMPLICATIONS OF THE FINDINGS: The low ICCP we observed after VIT removes the concern about high ICCP after VIT, at least in murine zygotes and helps to explain the observed efficiency and lack of toxicity of VIT. STUDY FUNDING / COMPETING INTEREST(S): The study was funded by the FNRS (National Funds for Scientific Research). The authors declare that they have no competing interests.

Short-term whole body vibration exercise in adult healthy horses.

The purpose of this study was to analyze the acute effect of whole body vibration exercise (WBVE) on clinical parameters and blood values in horses. Seven horses were exposed to a 10 min WBVE at a frequency of 15-21 Hz. Clinical parameters and venous blood samples were taken before and directly after WBVE. Acute short-term WBVE produced a decrease in serum cortisol (p = 0.02) and creatine-kinase (p = 0.02) values. Clinical parameters, hematology, fibrinogen, lactate, IGF-I, GGT, creatinine, myeloperoxidase activity and bone marker values were not significantly changed by WBVE. In adult sound horses WBVE was well tolerated and did not cause any sign of measured discomfort.

Disease-specific loss of microbial cross-feeding interactions in the human gut.

Many gut microorganisms critical to human health rely on nutrients produced by each other for survival; however, these cross-feeding interactions are still challenging to quantify and remain poorly characterized. Here, we introduce a Metabolite Exchange Score (MES) to quantify those interactions. Using metabolic models of prokaryotic metagenome-assembled genomes from over 1600 individuals, MES allows us to identify and rank metabolic interactions that are significantly affected by a loss of cross-feeding partners in 10 out of 11 diseases. When applied to a Crohn's disease case-control study, our approach identifies a lack of species with the ability to consume hydrogen sulfide as the main distinguishing microbiome feature of disease. We propose that our conceptual framework will help prioritize in-depth analyses, experiments and clinical targets, and that targeting the restoration of microbial cross-feeding interactions is a promising mechanism-informed strategy to reconstruct a healthy gut ecosystem.

New 21-nordammarane saponins with anti-inflammatory and cytotoxic activities from Lavigeria macrocarpa Oliv.

Chemical investigation of the ethanol extract from the stems and roots of the medicinal plant Lavigeria macrocarpa led to the isolation and structure elucidation of three previously unreported 21-nordammarane-type saponins namely 6α,27-dihydroxy-3,20-dioxo-21-nordammar-24-(Z)-ene 27-O-[α-L-rhamnopyranosyl-(1→2)-ß-D-glucopyranoside] (1), 6α,27-dihydroxy-3-oxo-21-nordammar-24-(Z)-ene 27-O-ß-D-glucopyranoside (2), and 2α,3ß,6α,27-tetrahydroxy-21-nordammar-24-(Z)-ene 27-O-ß-D-glucopyranoside (3) trivially named lavigemacrocarposide A-C, along with eight known secondary metabolites. Acid hydrolysis of lavigemacrocarposide A yielded a new prosapogenin namely 6α,27-dihydroxy-3,20-dioxo-21-nordammar-24-(Z)-ene 27-O-ß-D-glucopyranoside (1a) and the previously unreported artefactual aglycones 1b and 1c. Their structures were elucidated by spectroscopic analyses including mass spectrometry, 1D and 2D NMR as well as chemical evidence. The EtOH extract, some isolated compounds as well as the prosapogenin (1a) and compounds 1b and 1c were evaluated for anti-inflammatory and cytotoxic activity. Icacine (5) exhibited a significant cytotoxicity against both HeLa and MCF-7 cell lines with an IC50 value of 0.78 µg/mL. All the tested compounds showed more that 50% inhibition of NO production, except for 1 and 2.

The Genus Dacryodes Vahl.: Ethnobotany, Phytochemistry and Biological Activities.

Dacryodes Vahl. species, belonging to the Burseraceae family, are widely used in traditional medicine in tropical regions to treat a range of ailments including malaria, wounds, tonsillitis, and ringworms. This review discusses the distribution, ethnobotanical uses, phytochemistry, and bioactivities of Dacryodes species. The intent is to spur future research into isolating and identifying key active principles, secondary metabolites, and crude extracts, and evaluating their pharmacological and toxicological effects, as well as the mechanism of actions to understand their medicinal benefits. A systematic review of scientific electronic databases from 1963 to 2022 including Scifinder, Scopus, Pubmed, Springer Link, ResearchGate, Ethnobotany Research and Applications, Google Scholar, and ScienceDirect was conducted with a focus on Dacryodes edulis (G.Don) H.J. Lam and Dacryodes rostrata (Blume) H.J. Lam. Pharmacological data revealed that D. edulis isolates contain secondary metabolites and other phytochemical groups belonging to the terpenoids class with anti-microbial, anticancer, antidiabetic, antiinflammatory and hepatoprotective activities, highlighting its pharmacological potential in the therapy or management of diverse cancers, cardiovascular, and neurological diseases. Thus, phytochemicals and standardized extracts from D. edulis could offer safer and cost-effective chemopreventive and chemotherapeutic health benefits/regimen, or as alternative therapeutic remedy for several human diseases. Nevertheless, the therapeutic potential of most of the plants in the genus have not been exhaustively explored with regard to phytochemistry and pharmacology, but mostly complementary approaches lacking rigorous, scientific research-based knowledge. Therefore, the therapeutic potentials of the Dacryodes genus remain largely untapped, and comprehensive research is necessary to fully harness their medicinal properties.