Inflammation and cancer: friend or foe?

Chronic inflammation plays a crucial role in the onset and progression of pathologies like neurodegenerative and cardiovascular diseases, diabetes, and cancer, since tumor development and chronic inflammation are linked, sharing common signaling pathways. At least 20% of breast and colorectal cancers are associated with chronic inflammation triggered by infections, irritants, or autoimmune diseases. Obesity, chronic inflammation, and cancer interconnection underscore the importance of population-based interventions in maintaining healthy body weight, to disrupt this axis. Given that the dietary inflammatory index is correlated with an increased risk of cancer, adopting an anti-inflammatory diet supplemented with nutraceuticals may be useful for cancer prevention. Natural products and their derivatives offer promising antitumor activity with favorable adverse effect profiles; however, the development of natural bioactive drugs is challenging due to their variability and complexity, requiring rigorous research processes. It has been shown that combining anti-inflammatory products, such as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and statins, with plant-derived products demonstrate clinical utility as accessible adjuvants to traditional therapeutic approaches, with known safety profiles. Pharmacological approaches targeting multiple proteins involved in inflammation and cancer pathogenesis emerge as a particularly promising option. Given the systemic and multifactorial nature of inflammation, comprehensive strategies are essential for long term success in cancer therapy. To gain insights into carcinogenic phenomena and discover diagnostic or clinically relevant biomarkers, is pivotal to understand genetic variability, environmental exposure, dietary habits, and TME composition, to establish therapeutic approaches based on molecular and genetic analysis. Furthermore, the use of endocannabinoid, cannabinoid, and prostamide-type compounds as potential therapeutic targets or biomarkers requires further investigation. This review aims to elucidate the role of specific etiological agents and mediators contributing to persistent inflammatory reactions in tumor development. It explores potential therapeutic strategies for cancer treatment, emphasizing the urgent need for cost-effective approaches to address cancer-associated inflammation.

Understanding the Formation Mechanisms of Silicon Particles from the Thermal Disproportionation of Hydrogen Silsesquioxane.

Crystalline silicon particles sustaining Mie resonances are readily obtained from the thermal processing of hydrogen silsesquioxane (HSQ). Here, the mechanisms involved in silicon particle formation and growth from HSQ are investigated through real-time in situ analysis using an environmental transmission electron microscope and X-ray diffractometer. The nucleation of Si nanodomains is observed starting around 1000 °C. For the first time, a highly mobile intermediate phase is experimentally observed, thus demonstrating a previously unknown growth mechanism. At least two growth processes occur simultaneously: the coalescence of small particles into larger particles and growth mode by particle displacement through the matrix toward the HSQ grain surface. Postsynthetic characterization by scanning electron microscopy further supports the latter growth mechanism. The gaseous environment employed during synthesis impacts particle formation and growth under both in situ and ex situ conditions, impacting the particle yield and structural homogeneity. Understanding the formation mechanisms of particles provides promising pathways for reducing the energy cost of this synthetic route.

Soluble HLA-G (sHLA-G) measurement might be useful as an early diagnostic biomarker and screening test for gastric cancer.

Gastric cancer (GC) is the fifth most frequent malignancy worldwide and has a high mortality rate related to late diagnosis. Although the gold standard for the GC diagnosis is endoscopy with biopsy, nonetheless, it is not cost-effective and is invasive for the patient. The Human leukocyte antigen G (HLA-G) molecule is a checkpoint of the immune response. Its overexpression in cancer is associated with immune evasion, metastasis, poor prognosis, and lower overall survival. We evaluate the plasma levels of soluble HLA-G, (sHLA-G) in patients with GC and benign gastric pathologies using an ELISA test. A higher concentration of sHLA-G in patients with GC than in those with benign pathologies, higher levels of plasma sHLA-G in women with GC compared with men and significant differences in the sHLA-G levels between the benign gastric pathologies evaluated, was our main findings. As no significant differences were found between the GC assessed stages in our study population, we suggest that sHLA-G is not an adequate marker for staging GC, but it does have diagnostic potential. In addition to providing information on the potential of sHLA-G as a diagnostic marker for GC, our study demonstrate that HLA-G molecules can be found in the membrane of exosomes, which highlights the need to perform studies with a larger number of samples to explore the functional implications of HLA-G positive exosomes in the context of gastric cancer, and to determine the clinical significance and possible applications of these findings in the development of non-invasive diagnostic methods.

The role of immune checkpoints in antitumor response: a potential antitumor immunotherapy.

Immunotherapy aims to stimulate the immune system to inhibit tumor growth or prevent metastases. Tumor cells primarily employ altered expression of human leukocyte antigen (HLA) as a mechanism to avoid immune recognition and antitumor immune response. The antitumor immune response is primarily mediated by CD8+ cytotoxic T cells (CTLs) and natural killer (NK) cells, which plays a key role in the overall anti-tumor immune response. It is crucial to comprehend the molecular events occurring during the activation and subsequent regulation of these cell populations. The interaction between antigenic peptides presented on HLA-I molecules and the T-cell receptor (TCR) constitutes the initial signal required for T cell activation. Once activated, in physiologic circumstances, immune checkpoint expression by T cells suppress T cell effector functions when the antigen is removed, to ensures the maintenance of self-tolerance, immune homeostasis, and prevention of autoimmunity. However, in cancer, the overexpression of these molecules represents a common method through which tumor cells evade immune surveillance. Numerous therapeutic antibodies have been developed to inhibit immune checkpoints, demonstrating antitumor activity with fewer side effects compared to traditional chemotherapy. Nevertheless, it's worth noting that many immune checkpoint expressions occur after T cell activation and consequently, altered HLA expression on tumor cells could diminish the clinical efficacy of these antibodies. This review provides an in-depth exploration of immune checkpoint molecules, their corresponding blocking antibodies, and their clinical applications.

Real-World Characterization of the Portuguese Population Living with HIV who Initiated Raltegravir Based-Regimens: The REALITY Study.

INTRODUCTION: Although raltegravir has been available since 2007, data are lacking on the Portuguese population living with HIV who initiated this antiretroviral therapy. Hence, this study aimed to characterize the patients who initiated raltegravir-based regimens between January 2015 and December 2017, on sociodemographics, clinical features, and treatment satisfaction. MATERIAL AND METHODS: Observational, retrospective, multicentre study conducted at 11 reference sites. Sociodemographic and clinical data were collected retrospectively from hospital medical records. For participants continuing raltegravir at study inclusion, the HIV Treatment Satisfaction Questionnaire was administered to assess satisfaction with raltegravir-based therapy. Descriptive statistics were performed. Treatment-naïve and treatment-experienced subgroups were compared for demographic and clinical variables. RESULTS: A total of 302 patients were included; mostly men (69.5%) with a mean age of 49 years old. Approximately half of the patients had at least one non-AIDS-related comorbidity at baseline (53.3%), such as hypercholesterolemia, arterial hypertension, diabetes mellitus, and depression. Moreover, 52.3% were treatment-experienced patients with up to two treatments prior to raltegravir. Across the study time points, there was a reduction in the viral load and improvement in CD4 counts in both the treatment-naïve and treatment-experienced subgroups. Continuing users of raltegravir reported high treatment satisfaction (55.4 ± 7.2 points). CONCLUSION: Raltegravir-based regimens seem like a valid therapeutic option in heterogeneous populations of HIV-infected patients, in patients with previous ART experience and as part of first-line therapeutic options alongside with the latest generation of drugs from its class.

Introdução: Apesar de o raltegravir estar disponível desde 2007, os dados na população portuguesa com VIH que iniciou esta terapêutica antirretroviral são escassos. Deste modo, este estudo teve por objetivo caracterizar os doentes que iniciaram um regime terapêutico baseado em raltegravir entre janeiro de 2015 e dezembro de 2017, relativamente a dados sociodemográficos, características clínicas e satisfação com o tratamento. Material e Métodos: Estudo observacional, retrospetivo, multicêntrico conduzido em 11 centros de referência. Os dados sociodemográficos e clínicos foram recolhidos retrospetivamente nos processos clínicos. Os participantes que continuaram o regime com raltegravir após a inclusão no estudo preencheram o HIV Treatment Satisfaction Questionnaire para avaliar a satisfação com a terapêutica. Foram efetuadas análises de estatística descritiva e comparações para as variáveis sociodemográficas e clínicas nos subgrupos de doentes naïve de tratamento e de doentes com experiência terapêutica. Resultados: Foram incluídos 302 doentes, maioritariamente do sexo masculino (69,5%) com idade média de 49 anos. Aproximadamente metade dos doentes tinha pelo menos uma comorbilidade não relacionada com SIDA no início do estudo (53,3%), tais como hipercolesterolemia, hipertensão arterial, diabetes mellitus ou depressão. Adicionalmente, 52,3% eram doentes com experiência terapêutica com até dois tratamentos anteriores ao raltegravir. Ao longo do estudo verificou-se uma redução na carga viral e uma melhoria nas contagens de CD4 em ambos os subgrupos de doentes (doentes naïve de tratamento e doentes com experiência terapêutica). Os doentes com uso continuado de raltegravir reportaram uma elevada satisfação com o tratamento (55,4 ± 7,2 pontos). Conclusão: Os regimes terapêuticos baseados em raltegravir parecem ser uma opção terapêutica válida em populações heterogéneas de doentes infetados com VIH, em doentes com experiência em ART e como tratamento de primeira linha, em paralelo com outras terapêuticas de última geração.

Spatial organization of biochemical cues in 3D-printed scaffolds to guide osteochondral tissue engineering.

Functional repair of osteochondral (OC) tissue remains challenging because the transition from bone to cartilage presents gradients in biochemical and physical properties necessary for joint function. Osteochondral regeneration requires strategies that restore the spatial composition and organization found in the native tissue. Several biomaterial approaches have been developed to guide chondrogenic and osteogenic differentiation of human mesenchymal stem cells (hMSCs). These strategies can be combined with 3D printing, which has emerged as a useful tool to produce tunable, continuous scaffolds functionalized with bioactive cues. However, functionalization often includes one or more post-fabrication processing steps, which can lead to unwanted side effects and often produce biomaterials with homogeneously distributed chemistries. To address these challenges, surface functionalization can be achieved in a single step by solvent-cast 3D printing peptide-functionalized polymers. Peptide-poly(caprolactone) (PCL) conjugates were synthesized bearing hyaluronic acid (HA)-binding (HAbind-PCL) or mineralizing (E3-PCL) peptides, which have been shown to promote hMSC chondrogenesis or osteogenesis, respectively. This 3D printing strategy enables unprecedented control of surface peptide presentation and spatial organization within a continuous construct. Scaffolds presenting both cartilage-promoting and bone-promoting peptides had a synergistic effect that enhanced hMSC chondrogenic and osteogenic differentiation in the absence of differentiation factors compared to scaffolds without peptides or only one peptide. Furthermore, multi-peptide organization significantly influenced hMSC response. Scaffolds presenting HAbind and E3 peptides in discrete opposing zones promoted hMSC osteogenic behavior. In contrast, presenting both peptides homogeneously throughout the scaffolds drove hMSC differentiation towards a mixed population of articular and hypertrophic chondrocytes. These significant results indicated that hMSC behavior was driven by dual-peptide presentation and organization. The downstream potential of this platform is the ability to fabricate biomaterials with spatially controlled biochemical cues to guide functional tissue regeneration without the need for differentiation factors.

Impact of Synthesis Conditions in Na-Rich Prussian Blue Analogues.

Sodium-rich iron hexacyanoferrates were prepared by coprecipitation, hydrothermal route, and under reflux, with or without dehydration. They were obtained with different structures described in cubic, orthorhombic, or rhombohedral symmetry, with variable compositions in sodium, water, and cationic vacancies and with a variety of morphologies. This series of sodium-rich Prussian blue analogues allowed addressing the relationship between synthesis conditions, composition, structure, morphology, and electrochemical properties in Na-ion batteries. A new orthorhombic phase with the Na1.8Fe2(CN)6·0.7H2O composition synthesized by an hydrothermal route at 140 °C is reported for the first time, whereas a phase of Na2Fe2(CN)6·2H2O composition obtained under reflux, previously described with a monoclinic structure, shows in fact a rhombohedral structure.

Correlation between the Dynamics of Nanoconfined Water and the Local Chemical Environment in Calcium Silicate Hydrate Nanominerals.

Invited for the cover of this issue is Cyril Aymonier and co-workers at University of Bordeaux and University of the Basque Country. The image depicts the different distributions of water molecules in xonotlite and tobermorite nanominerals synthesised in supercritical water. Read the full text of the article at 10.1002/chem.202100098.

Correlation between the Dynamics of Nanoconfined Water and the Local Chemical Environment in Calcium Silicate Hydrate Nanominerals.

Calcium silicate hydrates are members of a large family of minerals with layered structures containing pendant CaOH and SiOH groups that interact with confined water molecules. To rationalize the impact of the local chemical environment on the dynamics of water, SiOH- and CaOH-rich model nanocrystals were synthesized by using the continuous supercritical hydrothermal method and then systematically studied by a combination of spectroscopic techniques. In our comprehensive analysis, the ultrafast relaxation dynamics of hanging hydroxy groups can be univocally assigned to CaOH or SiOH environments, and the local chemical environment largely affects the H-bond network of the solvation water. Interestingly, the ordered "ice-like" solvation water found in the SiOH-rich environments is converted to a disordered "liquid-like" distribution in the CaOH-rich environment. This refined picture of the dynamics of confined water and hydroxy groups in calcium silicate hydrates can also be applied to other water-containing materials, with a significant impact in many fields of materials science.

Fabricating spatially functionalized 3D-printed scaffolds for osteochondral tissue engineering.

Three-dimensional (3D) printing of biodegradable polymers has rapidly become a popular approach to create scaffolds for tissue engineering. This technique enables fabrication of complex architectures and layer-by-layer spatial control of multiple components with high resolution. The resulting scaffolds can also present distinct chemical groups or bioactive cues on the surface to guide cell behavior. However, surface functionalization often includes one or more post-fabrication processing steps, which typically produce biomaterials with homogeneously distributed chemistries that fail to mimic the biochemical organization found in native tissues. As an alternative, our laboratory developed a novel method that combines solvent-cast 3D printing with peptide-polymer conjugates to spatially present multiple biochemical cues in a single scaffold without requiring post-fabrication modification. Here, we describe a detailed, stepwise protocol to fabricate peptide-functionalized scaffolds and characterize their physical architecture and biochemical spatial organization. We used these 3D-printed scaffolds to direct human mesenchymal stem cell differentiation and osteochondral tissue formation by controlling the spatial presentation of cartilage-promoting and bone-promoting peptides. This protocol also describes how to seed scaffolds and evaluate matrix deposition driven by peptide organization.

Ionothermal Synthesis of Polyanionic Electrode Material Na3V2(PO4)2FO2 through a Topotactic Reaction.

Polyanionic Na3V2(PO4)2FO2 has been successfully prepared for the first time by ionothermal reaction in 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide (EMIM TFSI) ionic liquid. Its structure and elemental stoichiometry are confirmed by X-ray diffraction, NMR spectroscopy, and ICP-OES, respectively. Furthermore, the scanning electron microscopy reveals that the as-obtained material possesses an original platelet-like morphology. A topochemical reaction mechanism is proposed to explain the formation of the 3D framework of Na3V2(PO4)2FO2 from layered compound α-VOPO4·2H2O. Galvanostatic electrochemical tests indicate a modification of the desodiation and sodiation mechanism of the as-prepared Na3V2(PO4)2FO2 compared to those synthesized by conventional solid-state approaches. Furthermore, the electrochemical performance of Na3V2(PO4)2FO2 obtained at different cycling rates is also discussed.

Aluminum substitution for vanadium in the Na3V2(PO4)2F3 and Na3V2(PO4)2FO2 type materials.

Among the positive electrode materials for Na-ion batteries, Na3V2(PO4)2F3 is considered as one of the most promising and generates high interest. Here, we study the influence of the sol-gel synthesis parameters on the structure and on the electrochemical signature of the partially substituted Na3V2-zAlz(PO4)2(F,O)3 materials. We demonstrate that the acidity of the starting solution influences the vanadium oxidation state of the final product. For the first time we report on the possibility of controlling the double Al/V and O/F substitution that leads to the preparation of the Na3V2-zAlz(PO4)2F1+zO2-z solid solution.

Monitoring the Crystal Structure and the Electrochemical Properties of Na3(VO)2(PO4)2F through Fe3+ Substitution.

We here present the synthesis of a new material, Na3(VO)Fe(PO4)2F2, by the sol-gel method. Its atomic and electronic structural descriptions are determined by a combination of several diffraction and spectroscopy techniques such as synchrotron X-ray powder diffraction and synchrotron X-ray absorption spectroscopy at V and Fe K edges, 57Fe Mössbauer, and 31P solid-state nuclear magnetic resonance spectroscopy. The crystal structure of this newly obtained phase is similar to that of Na3(VO)2(PO4)2F, with a random distribution of Fe3+ ions over vanadium sites. Even though Fe3+ and V4+ ions situate on the same crystallographic position, their local environment can be studied separately using 57Fe Mössbauer and X-ray absorption spectroscopy at Fe and V K edges, respectively. The Fe3+ ion resides in a symmetric octahedral environment, while the octahedral site of V4+ is greatly distorted due to the presence of the vanadyl bond. No electrochemical activity of the Fe4+/Fe3+ redox couple is detected, at least up to 5 V, whereas the reduction of Fe3+ to Fe2+ has been observed at ∼1.5 V versus Na+/Na through the insertion of 0.5 Na+ into Na3(VO)Fe(PO4)2F2. Comparing to Na3(VO)2(PO4)2F, the electrochemical profile of Na3(VO)Fe(PO4)2F2 in the same cycling condition shows a smaller polarization which could be due to a slight improvement in Na+ diffusion process thanks to the presence of Fe3+ in the framework. Furthermore, the desodiation mechanism occurring upon charging is investigated by operando synchrotron X-ray diffraction and operando synchrotron X-ray absorption at V K edge.

Alkali-Glass Behavior in Honeycomb-Type Layered Li3-xNaxNi2SbO6 Solid Solution.

Layered oxide compositions Li3-xNaxNi2SbO6 have been prepared by solid-state synthesis. A complete solid solution is evidenced and characterized by X-ray and neutron diffraction as well as 7Li and 23Na solid-state nuclear magnetic resonance spectroscopy. The transition-metal layer is characterized by the classic honeycomb Ni2+/Sb5+ ordering, whereas a more uncommon randomly mixed occupancy of lithium and sodium is evidenced within the alkali interslab space. In situ X-ray diffraction and density functional theory calculations show that this alkali disordered feature is entropically driven. Fast cooling then appears as a synthesis root to confine bidimensional alkali glass within crystalline layered oxides.

3D printing with peptide-polymer conjugates for single-step fabrication of spatially functionalized scaffolds.

Biodegradable polymer-based scaffolds are widely used to provide support during early stages of regeneration and can be functionalized with various chemical groups or bioactive cues to promote desired cellular behavior. However, these scaffolds are often modified post-fabrication, which can lead to undesired changes and homogeneously distributed chemistries that fail to mimic the spatial biochemical organization found in native tissues. To address these challenges, surface functionalization can be achieved by 3D printing with pre-functionalized biodegradable polymers, such as peptide-modified polymer conjugates, to control the deposition of preferred chemistries. Peptide-PCL conjugates were synthesized with the canonical cell adhesion peptide motif RGDS or its negative control RGES and 3D printed into scaffolds displaying one or both peptides. The peptides were also modified with bioorthogonal groups, biotin and azide, to visualize peptide concentration and location by labeling with complementary fluorophores. Peptide concentration on the scaffold surface increased with increasing peptide-PCL conjugate concentration added to the ink prior to 3D printing, and scaffolds printed with the highest RGDS(biotin)-PCL concentrations showed a significant increase in NIH3T3 fibroblast adhesion. To demonstrate spatial control of peptide functionalization, multiple printer heads were used to print both peptide-PCL conjugates into the same construct in alternating patterns. Cells preferentially attached and spread on RGDS(biotin)-PCL fibers compared to RGES(azide)-PCL fibers, illustrating how spatial functionalization can be used to influence local cell behavior within a single biomaterial. This presents a versatile platform to generate multifunctional biomaterials that can mimic the biochemical organization found in native tissues to support functional regeneration.

Comparison of the mitral valve morphologies of Cavalier King Charles Spaniels and dogs of other breeds using 3D transthoracic echocardiography.

BACKGROUND: Myxomatous mitral valve disease (MMVD) is more prevalent in Cavalier King Charles Spaniels (CKCSs) compared to dogs of other breeds at a given age. Abnormal valvular stress is thought to contribute to the development and progression of MMVD, and a relationship exists between mitral valve (MV) morphology and stress acting on the valve. OBJECTIVES: To determine whether the MV morphology of healthy adult CKCSs differs from the morphology of healthy adult dogs of other breeds determined by RT-3DTTE. ANIMALS: Thirty-five healthy CKCSs and 41 healthy dogs of other breeds. METHODS: Prospective cross-sectional study. Dogs underwent physical examination, conventional echocardiography, and RT-3DTTE. RT-3DTTE datasets were analyzed using dedicated software for MV morphologic analysis. Morphologic variables were compared between CKCSs and dogs of other breeds. RESULTS: The MV of healthy CKCSs had a smaller annulus height (0.46 ± 0.11 vs. 0.56 ± 0.17; P = .0021), tenting height (0.26 ± 0.12 vs. 0.42 ± 0.18; P < .001), tenting area (0.42 ± 0.15 vs. 0.79 ± 0.34; P < .001), normalized tenting volume (0.09 [0.05-0.13] vs. 0.14 [0.10-0.20]; P < .001), and normalized area of the posterior leaflet (0.57 ± 0.15 vs. 0.66 ± 0.18; P = .016) compared to healthy dogs of other breeds; this results in CKCSs having a flatter MV with reduced tenting, compared to the MV of other breeds. CONCLUSIONS AND CLINICAL IMPORTANCE: These morphologic features could confer a mechanical disadvantage and play a role in the predisposition of CKCSs to the early development of MMVD.

Polymorphism, Weak Interactions and Phase Transitions in Chalcogen-Phosphorus Heterocycles.

A series of P-E-containing heterocycles (E=chalcogen) with aromatic backbones were synthesised and characterised by single-crystal and powder XRD, microanalysis and mass spectrometry. Solution- and solid-state 31 P and 77 Se NMR spectroscopy revealed significant differences between the NMR parameters in solution and in the solid state, related to conformational changes in the molecules. Many compounds were shown to exhibit a number of different polymorphic structures (identified by single-crystal XRD), although the bulk material studied by solid-state NMR spectroscopy often contained just one major polymorph. For the unoxidised heterocycles, the presence of weak intermolecular J couplings was also investigated by DFT calculations.

Treatment of cutaneous actinomycosis with amoxicillin/clavulanic acid.

OBJECTIVE: To evaluate the efficacy and tolerability of amoxicillin/clavulanic (AMX/CLV) acid as treatment for cutaneous actinomycosis. METHODS: We present a long-term follow-up study of cutaneous actinomycosis patients. Cervicofacial (CFA) and abdominal (AA) were recruited during 6 years. Diagnoses were based on clinical and microbiological characteristics; presence of granules, isolation and identification of etiological agents were carried out in each case. Patients received AMX-CLV 875/125 mg BID PO at a maximum period of 12 weeks. RESULTS: Twenty-two cases were enrolled; the mean age was 45.2 years old. Twenty patients (91%) presented CFA and two AA (9%). All patients with CFA had dental caries, seven (35%) with periodontal disease and 10 (50%) had type-2 diabetes mellitus (T2DM). One case of AA had history of intrauterine device and other appendicitis. Granules were observed in all the cases, the main etiological agent was Actinomyces israelii 16/22 (72.7%). Clinical and microbiological cure was achieved in 19/22 cases (86.4%), the remaining patients presented clinical improvement. The average duration of the treatment was 6.6 weeks. Side effects were recorded in 4/19 cases (18.2%), three of them presented nausea and one diarrhea. CONCLUSION: Treatment with AMX/CLV acid showed efficacy in the management of actinomycosis with cutaneous involvement.

Small mammalian animal models of heart disease.

There is an urgent clinical need to develop new therapeutic approaches for treating cardiovascular disease, but the biology of cardiovascular regeneration is complex. Model systems are required to advance our understanding of the pathogenesis, progression, and mechanisms underlying cardiovascular disease as well as to test therapeutic approaches to regenerate tissue and restore cardiac function following injury. An ideal model system should be inexpensive, easily manipulated, reproducible, physiologically representative of human disease, and ethically sound. The choice of animal model needs to be considered carefully since it affects experimental outcomes and whether findings of the study can be reasonably translated to humans. This review presents a guideline for the commonly used small animal models (mice, rats, rabbits, and cats) used in cardiac research as an effort to standardize the most relevant procedures and obtain translatable and reproducible results.

Increasing the Brønsted acidity of Ph2PO2H by the Lewis acid B(C6F5)3. Formation of an eight-membered boraphosphinate ring [Ph2POB(C6F5)2O]2.

Autoprotolysis of the metastable acid (C6F5)3BOPPh2OH, prepared in situ by the reaction of the rather weak Brønsted acid Ph2PO2H with the strong Lewis acid B(C6F5)3, gave rise to the formation of the eight-membered ring [Ph2POB(C6F5)2O]2 and C6F5H. The conjugate base was isolated as stable sodium crown ether salt [Na(15-crown-5)][Ph2PO2B(C6F5)3].