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While chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed / refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, nine of whom successfully received CAR19-22 followed by NKTR-255. There were no dose limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with eight out of nine patients (89%) achieving measurable residual disease negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood and ten-fold increases in CSF CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible and associated with high rates of durable responses (NCT03233854).
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Transition metal oxide (TMO) clusters are being studied for their ability to absorb acid gases generated by energy production processes. The interaction of SO3, a byproduct of common industrial processes, with group 4 metal (Ti, Zr, and Hf) oxide nanoclusters, has been predicted using electronic structure methods. The calculations were done at the density functional theory (DFT) and correlated molecular orbital coupled cluster singles and doubles CCSD(T) theory levels. There is a reasonable agreement between the DFT/ωB97x-D energies with the CCSD(T) results. SO3 is predicted to strongly chemisorb to these clusters, as do NO2 and CO2. For SO3, these chemisorption processes favor binding to TMO clusters as SO42- sulfate in both the terminal and bridging configurations. It is predicted that SO3 fully extracts the bridging oxygen from the TMO lattice to form bridging SO42-. This is favorable because of the lower S-O bond dissociation energy of SO3, whereas other acid gases add across the bridging oxygen because of their higher A-O bond dissociation energy. SO3 is capable of physisorption as long as an exposed metal center is present in the lattice. If a metal center has a terminal oxo-group, then SO3 will prefer the SO42- configuration. An approximately linear relationship exists between the physisorption energy and proton affinity for rows 2 and 3 elements.
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Dinuclear perchlorate complexes of uranium, neptunium, and plutonium were characterized by reactivity and DFT, with results revealing structures containing pentavalent, hexavalent, and heptavalent actinyls, and actinyl-actinyl interactions (AAIs). Electrospray ionization produced native complexes [(AnO2)2(ClO4)3]- for An:An = U:U, Np:Np, Pu:Pu, and Np:Pu, which are intuitively formulated as actinyl(V) perchlorates. However, DFT identified lower-energy structures [(AnO2)(AnO3)(ClO4)2(ClO3)]- comprising a perchlorate fragmented to ClO3, actinyl(VI) cation AnVIO22+, and neutral AnO3. For U:U and Np:Np, and Np in Np:Pu, the coordinated AnO3 is calculated as actinyl(VI) with an equatorial oxo, [OylâAnVIâOyl][âOeq], whereas for Pu:Pu, it is plutonyl(V) oxyl, [OylâPuVâOyl][-Oeqâ¢]. The implied lower stability of PuVI versus NpVI indicates weaker PuâOeq versus NpâOeq bonding. Adsorption of O2 by the U:U complex suggests oxidation of UV to UVI, corroborating the assignment of perchlorate [(AnVO2)2(ClO4)3]-. DFT predicts the O2 adducts are [(AnVIO2)(O2)(AnVIO2)(ClO4)3]- with actinyls oxidized from +V to +VI by bridging peroxide, O22-. In accordance with reactivity, O2- addition is computed as substantially exothermic for U:U and least favorable for Pu:Pu. Collision-induced dissociation of native complexes eliminated ClO2 to yield [(AnO2)(O)2(AnO2)(ClO4)2]-, in which fragmented O atoms bridge as oxyl O-⢠and oxo O2- to yield uranyl(VI) and plutonyl(VI), or as oxos O2- to yield neptunyl(VII), [OylâNpVIIâOyl]3+.
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NKTR-255 is an investigational polyethylene glycol-modified recombinant human IL-15 (rhIL-15) receptor agonist, designed to improve the immunotherapeutic and anti-cancer benefit observed with rhIL-15 while circumventing the toxicities associated with this therapy. In preclinical studies, NKTR-255 has demonstrated enhanced proliferation and function of CD8+ T cells and natural killer cells, as well as enhanced anti-tumor activity and survival both as monotherapy and in combination with monoclonal antibodies in multiple cancer models. Here, we describe the rationale and design of the first-in-human Phase I, dose-escalation and dose-expansion study of NKTR-255 alone and in combination with daratumumab or rituximab in adults with relapsed/refractory multiple myeloma or non-Hodgkin's lymphoma that will determine the maximum tolerated dose and recommended Phase II dose for NKTR-255.
Lay abstract Interleukin-15 (IL-15) is a protein that helps the body's natural immune system to defend itself against infections and diseases like cancer. This article discusses a clinical trial in patients with multiple myeloma or non-Hodgkin's lymphoma that evaluates a new investigational medicine, NKTR-255, a polymer-modified form of IL-15 that has been engineered to improve its ability to provide a sustained anti-tumor immune response. The trial will explore different doses of NKTR-255 to determine patient side effects and to find the highest acceptable dose that patients can tolerate. Based on this, a dose will be chosen that offers an optimal balance between having a positive anti-cancer effect and minimizing side effects. This dose will be tested further in patients who have had different treatments in the past. If the side effects are acceptable, this dose will be tested in a new trial in a large number of patients. Clinical Trial Registration: NCT04136756 (ClinicalTrials.gov).
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Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Interleucina-15/uso terapêutico , Rituximab/uso terapêutico , Quimioterapia Combinada , Humanos , Interleucina-15/química , Polietilenoglicóis/químicaRESUMO
An extensive correlated molecular orbital theory study of the reactions of CO2 with a range of substituted amines and H2O in the gas phase and aqueous solution was performed at the G3(MP2) level with a self-consistent reaction field approach. The G3(MP2) calculations were benchmarked at the CCSD(T)/CBS level for NH3 reactions. A catalytic NH3 reduces the energy barrier more than a catalytic H2O for the formation of H2NCOOH and H2CO3. In aqueous solution, the barriers to form both H2NCOOH and H2CO3 are reduced, with HCO3- formation possible with one amine present and H2NCOO- formation possible only with two amines. Further reactions of H2NCOOH to form HNCO and urea via the Bazarov reaction have high barriers and are unlikely in both the gas phase and aqueous solution. Reaction coordinates for CH3NH2, CH3CH2NH2, (CH3)2NH, CH3CH2CH2NH2, (CH3)3N, and DMAP were also calculated. The barrier for proton transfer correlates with amine basicity for alkylammonium carbamate (ΔGaq < 15 kcal/mol) and alkylammonium bicarbonate (ΔGaq < 30 kcal/mol) formation. In aqueous solution, carbamic acids, carbamates, and bicarbonates can all form in small amounts with ammonium carbamates dominating for primary and secondary alkylamines. These results have implications for CO2 capture by amines in both the gas phase and aqueous solution as well as in the solid state, if enough water is present.
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PURPOSE: To validate healthcare claim-based algorithms for neurodevelopmental disorders (NDD) in children using medical records as the reference. METHODS: Using a clinical data warehouse of patients receiving outpatient or inpatient care at two hospitals in Boston, we identified children (≤14 years between 2010 and 2014) with at least one of the following NDDs according to claims-based algorithms: autism spectrum disorder/pervasive developmental disorder (ASD), attention deficit disorder/other hyperkinetic syndromes of childhood (ADHD), learning disability, speech/language disorder, developmental coordination disorder (DCD), intellectual disability, and behavioral disorder. Fifty cases per outcome were randomly sampled and their medical records were independently reviewed by two physicians to adjudicate the outcome presence. Positive predictive values (PPVs) and 95% confidence intervals (CIs) were calculated. RESULTS: PPVs were 94% (95% CI, 83%-99%) for ASD, 88% (76%-95%) for ADHD, 98% (89%-100%) for learning disability, 98% (89%-100%) for speech/language disorder, 82% (69%-91%) for intellectual disability, and 92% (81%-98%) for behavioral disorder. A total of 19 of the 50 algorithm-based cases of DCD were confirmed as severe coordination disorders with functional impairment, with a PPV of 38% (25%-53%). Among the 31 false-positive cases of DCD were 7 children with coordination deficits that did not persist throughout childhood, 7 with visual-motor integration deficits, 12 with coordination issues due to an underlying medical condition and 5 with ADHD and at least one other severe NDD. CONCLUSIONS: PPVs were generally high (range: 82%-98%), suggesting that claims-based algorithms can be used to study NDDs. For DCD, additional criteria are needed to improve the classification of true cases.
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Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Algoritmos , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/epidemiologia , Criança , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/epidemiologia , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/epidemiologiaRESUMO
The addition of NO2 to Group IV (MO2)n and Group VI (MO3)n (n = 1-3) nanoclusters was studied using both density functional theory (DFT) and coupled cluster theory (CCSD(T)). The structures and overall binding energetics were predicted for Lewis acid-base addition without transfer of spin (a physisorption-type process) and the formation of either cluster-ONO (HONO-like or bidentate bonding) or NO3- formation where for both the spin is transferred to the metal oxide clusters (a chemisorption-type process). Only chemisorption of NO2 is predicted to be thermodynamically allowed at temperatures ≥298 K for Group IV (MO2)n clusters with the formation of surface chemisorbed NO2 being by far the most energetically favorable. The ligand binding energies (LBEs) for physisorption and chemisorption on the TiO2 nanoclusters are consistent with computational studies of the bulk solids. Chemisorption is only predicted to occur for (CrO3)n clusters in the form of a terminal nitrate containing species whereas the larger chemisorbed nitrate structures for (MoO3)n and (WO3)n were found to be metastable and unlikely to form in any appreciable amount at temperatures of 298 K and higher. NO2 is predicted to only be capable of physisorbing to (MoO3)n and (WO3)n at lower temperatures and therefore unlikely to bind NO2 at temperatures ≥298 K. Correlations between the (MO3)nNO2 ligand bond energies and the chemical properties of the parent (MO3)n clusters (Lewis acidity, ionization potentials, excitation energies, and M = O/M-O bond strengths) are described.
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Chitin is a natural N-acetylglucosamine polymer and a major structural component of fungal cell walls. Dietary chitin is mucoadhesive; anti-inflammatory effects of chitin microparticles (CMPs; 1- to 10-µm diameters) have been demonstrated in models of inflammatory bowel disease (IBD). The goals of this study were to assess (i) whether CMPs among various chitin preparations are the most effective against colitis in male and female mice and (ii) whether host chitin-binding Toll-like receptor 2 (TLR2) and CD14 are required for the anti-inflammatory effect of chitin. We found that colitis in male mice was ameliorated by CMPs and large chitin beads (LCBs; 40 to 70 µm) but not by chitosan (deacetylated chitin) microparticles, oligosaccharide chitin, or glucosamine. In fact, LCBs were more effective than CMPs. In female colitis, on the other hand, CMPs and LCBs were equally and highly effective. Neither sex of TLR2-deficient mice showed anti-inflammatory effects when treated with LCBs. No anti-inflammatory effect of LCBs was seen in either CD14-deficient males or females. Furthermore, an in vitro study indicated that when LCBs and CMPs were digested with stomach acidic mammalian chitinase (AMC), their size-dependent macrophage activations were modified, at least in part, suggesting reduced particle sizes of dietary chitin in the stomach. Interestingly, stomach AMC activity was greater in males than females. Our results indicated that dietary LCBs were the most effective preparation for treating colitis in both sexes; these anti-inflammatory effects of LCBs were dependent on host TLR2 and CD14.
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Candida albicans/química , Quitina/uso terapêutico , Colite/dietoterapia , Colite/fisiopatologia , Disbiose/fisiopatologia , Ativação de Macrófagos/efeitos dos fármacos , Receptor 2 Toll-Like/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
We have performed an extensive computational investigation of the potential energy surfaces for the reactions of SOx (x = 2 or 3) with H2S and H2O in the gas phase and in aqueous solution at the CCSD(T)/CBS level of theory plus a self-consistent reaction field approach. Formation of a gas-phase H2SO4 from the hydrolysis of SO3 at lower temperatures requires the presence of additional water molecules. When additional waters are introduced, the barrier for H2SO4 formation is significantly reduced, and a barrierless transition occurs with only three excess waters as well as in aqueous solution. In a mixture of H2O, H2S, and SO3, formation of H2S2O3 has a lower barrier in the gas phase than does the formation of H2SO4. In aqueous solution, no barrier is predicted, and both are likely to be formed. Introduction of an additional water to the SO3 + H2S reaction results in a decrease in barrier height, nearly identical to the â¼18 kcal/mol catalytic effect of the first additional water in SO3 hydrolysis, with the barrier for H2S2O3 formation disappearing altogether in aqueous solution. Formation of H2SO3 by the way of SO2 hydrolysis is unlikely. Excess waters reduce the barrier for SO2 hydrolysis; however, the overall endothermicity is increased as waters are added. The formation of H2S2O2 from SO2 and H2S via an isostructural pathway to SO2 hydrolysis is unlikely, with additional water molecules resulting in a small increase in the overall endothermicity and a catalytic effect smaller than that observed for the SO3 reactions. The results of this work have implications pertaining to the formation of H2SO4, H2S2O3, H2SO3, and H2S2O2 in the atmospheres of Earth and Venus. These results also question the existence of H2S2O2 as an intermediate in the Claus process.
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An iodine-mediated hydration reaction of alkynes serves as a green alternative to metal-catalyzed procedures. Previous work has shown that this method works well with terminal alkynes on keto-functionalized scaffolds, including 1,3-dicarbonyls and their heteroatom analogues. It was hypothesized that the reaction proceeds through a 5-exo-dig neighboring group participation (NGP) cyclization and an α-iodo intermediate. The work described herein probes the existence of the intermediate through NMR investigations and explores the scope of the hydration process with internal alkynes. The NMR experiments confirm the existence of the α-iodo intermediate, and methodology studies demonstrate that alkyl-capped, asymmetric, internal alkynes undergo a regiospecific hydration, also via the 5-exo-dig NGP pathway.
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The NF-κB family of transcription factors is pivotal in controlling cellular responses to environmental stresses; abnormal nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling features in many autoimmune diseases and cancers. Several components of the NF-κB signaling pathway have been reported to interact with the protein TNIP2 (also known as ABIN2), and TNIP2 can both positively and negatively regulate NF-κB- dependent transcription of target genes. However, the function of TNIP2 remains elusive and the cellular machinery associating with TNIP2 has not been systematically defined. Here we first used a broad MudPIT/Halo Affinity Purification Mass Spectrometry (AP-MS) approach to map the network of proteins associated with the NF-κB transcription factors, and establish TNIP2 as an NF-κB network hub protein. We then combined AP-MS with biochemical approaches in a more focused study of truncated and mutated forms of TNIP2 to map protein associations with distinct regions of TNIP2. NF-κB interacted with the N-terminal region of TNIP2. A central region of TNIP2 interacted with the endosomal sorting complex ESCRT-I via its TSG101 subunit, a protein essential for HIV-1 budding, and a single point mutant in TNIP2 disrupted this interaction. The major gene ontology category for TNIP2 associated proteins was mRNA metabolism, and several of these associations, like KHDRBS1, were lost upon depletion of RNA. Given the major association of TNIP2 with mRNA metabolism proteins, we analyzed the RNA content of affinity purified TNIP2 using RNA-Seq. Surprisingly, a specific limited number of mRNAs was associated with TNIP2. These RNAs were enriched for transcription factor binding, transcription factor cofactor activity, and transcription regulator activity. They included mRNAs of genes in the Sin3A complex, the Mediator complex, JUN, HOXC6, and GATA2. Taken together, our findings suggest an expanded role for TNIP2, establishing a link between TNIP2, cellular transport machinery, and RNA transcript processing.
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Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , NF-kappa B/metabolismo , Mapeamento de Interação de Proteínas/métodos , Análise de Sequência de RNA/métodos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Células HEK293 , Células HeLa , Humanos , Espectrometria de Massas/métodos , Mutação , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição GênicaRESUMO
Nanoparticle (NP) chemotherapeutics can improve the therapeutic index of chemoradiotherapy (CRT). However, the effect of NP physical properties, such particle size, on CRT is unknown. To address this, we examined the effects of NP size on biodistribution, efficacy and toxicity in CRT. PEG-PLGA NPs (50, 100, 150 nm mean diameters) encapsulating wotrmannin (wtmn) or KU50019 were formulated. These NP formulations were potent radiosensitizers in vitro in HT29, SW480, and lovo rectal cancer lines. In vivo, the smallest particles avoided hepatic and splenic accumulation while more homogeneously penetrating tumor xenografts than larger particles. However, smaller particles were no more effective in vivo. Instead, there was a trend toward enhanced efficacy with medium sized NPs. The smallest KU60019 particles caused more small bowel toxicity than larger particles. Our results showed that particle size significantly affects nanotherapeutics' biodistrubtion and toxicity but does not support the conclusion that smaller particles are better for this clinical application.
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Quimiorradioterapia , Nanopartículas , Androstadienos/farmacocinética , Animais , Xenoenxertos , Humanos , Camundongos , Tamanho da Partícula , Polímeros , Neoplasias Retais , Distribuição Tecidual , WortmaninaRESUMO
Only the neutral tetrafluorides of Ce, Pr, and Tb as well as the [LnF7 ](3-) anions of Dy and Nd, with the metal in the +IV oxidation state, have been previously reported. We report our attempts to extend the row of neutral lanthanide tetrafluorides through the reaction of laser-ablated metal atoms with fluorine and their stabilization and characterization by matrix-isolation IR spectroscopy. In addition to the above three tetrafluorides, we found two new tetrafluorides, (3) NdF4 and (7) DyF4 , both of which are in the +IV oxidation state, which extends this lanthanide oxidation state to two new metals. Our experimental results are supported by quantum-chemical calculations and the role of the lanthanide oxidation state is discussed for both the LnF4 and [LnF4 ](-) species. Most of the LnF4 species are predicted to be in the +IV oxidation state and all of the [LnF4 ](-) anions are predicted to be in the +III oxidation state. The LnF4 species are predicted to be strong oxidizing agents and the LnF3 species are predicted to be moderate to strong Lewis acids.
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The development of affinity purification technologies combined with mass spectrometric analysis of purified protein mixtures has been used both to identify new protein-protein interactions and to define the subunit composition of protein complexes. Transcription factor protein interactions, however, have not been systematically analyzed using these approaches. Here, we investigated whether ectopic expression of an affinity tagged transcription factor as bait in affinity purification mass spectrometry experiments perturbs gene expression in cells, resulting in the false positive identification of bait-associated proteins when typical experimental controls are used. Using quantitative proteomics and RNA sequencing, we determined that the increase in the abundance of a set of proteins caused by overexpression of the transcription factor RelA is not sufficient for these proteins to then co-purify non-specifically and be misidentified as bait-associated proteins. Therefore, typical controls should be sufficient, and a number of different baits can be compared with a common set of controls. This is of practical interest when identifying bait interactors from a large number of different baits. As expected, we found several known RelA interactors enriched in our RelA purifications (NFκB1, NFκB2, Rel, RelB, IκBα, IκBß, and IκBε). We also found several proteins not previously described in association with RelA, including the small mitochondrial chaperone Tim13. Using a variety of biochemical approaches, we further investigated the nature of the association between Tim13 and NFκB family transcription factors. This work therefore provides a conceptual and experimental framework for analyzing transcription factor protein interactions.
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Mapas de Interação de Proteínas/genética , Proteômica , Fator de Transcrição RelA/biossíntese , Fatores de Transcrição/biossíntese , Citoplasma/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Humanos , Espectrometria de Massas , Complexos Multiproteicos/isolamento & purificação , Complexos Multiproteicos/metabolismo , Fator de Transcrição RelA/metabolismo , Fatores de Transcrição/genéticaRESUMO
Domestication can lead to significant changes in the growth and behavior of organisms. While the threat of predation is a strong selective force in the wild, the relaxation or removal of this threat in captive-rearing environments selects for reduced sensitivity to biotic stressors. Previous work has documented such changes in other taxa, but no work has been done on domestication-related losses of predation risk sensitivity in insects. We exposed both wild and domesticated (>50 generations in captivity) Lymantria dispar dispar (Lepidoptera: Erebidae) larvae to recordings of predators (wasp buzzing), nonpredators (mosquito buzzing), or no sound to compare the effects of predation risk on the two stocks. Wasp buzzing, but not mosquito buzzing, decreased survival of wild caterpillars relative to the control; domesticated caterpillars showed no such response. Domesticated L. dispar larvae appear to have reduced sensitivity to predation risk cues, suggesting that captive-reared insects may not always be analogs to their wild counterparts for risk-related behavioral studies.
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The resting zone of the postnatal growth plate is organized by slow-cycling chondrocytes expressing parathyroid hormone-related protein (PTHrP), which include a subgroup of skeletal stem cells that contribute to the formation of columnar chondrocytes. The PTHrP-Indian hedgehog feedback regulation is essential for sustaining growth plate activities; however, molecular mechanisms regulating cell fates of PTHrP+ resting chondrocytes and their eventual transformation into osteoblasts remain largely undefined. Here, in a mouse model, we specifically activated Hedgehog signaling in PTHrP+ resting chondrocytes and traced the fate of their descendants using a tamoxifen-inducible Pthrp-creER line with patched-1-floxed and tdTomato reporter alleles. Hedgehog-activated PTHrP+ chondrocytes formed large, concentric, clonally expanded cell populations within the resting zone ("patched roses") and generated significantly wider columns of chondrocytes, resulting in hyperplasia of the growth plate. Interestingly, Hedgehog-activated PTHrP+ cell descendants migrated away from the growth plate and transformed into trabecular osteoblasts in the diaphyseal marrow space in the long term. Therefore, Hedgehog activation drives resting zone chondrocytes into transit-amplifying states as proliferating chondrocytes and eventually converts these cells into osteoblasts, unraveling a potentially novel Hedgehog-mediated mechanism that facilitates osteogenic cell fates of PTHrP+ skeletal stem cells.
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Condrócitos , Proteína Relacionada ao Hormônio Paratireóideo , Proteína Vermelha Fluorescente , Camundongos , Animais , Condrócitos/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Lâmina de Crescimento , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Proteínas Hedgehog/metabolismoRESUMO
Cardiovascular disease remains the leading cause of death worldwide, with mortality rates increasing annually. This underscores the urgent need for accurate diagnostic and monitoring tools. Electrochemical detection has emerged as a promising method for swiftly and precisely measuring specific biomarkers in bodily fluids. This approach is not only cost-effective and efficient compared to traditional clinical methods, but it can also be tailored to detect individual biomarkers, which makes it particularly well-suited for point-of-care (POC) applications. The ability to conduct testing at the point of care is crucial for timely interventions and personalized disease management, empowering healthcare providers to tailor treatment plans based on real-time biomarker data. Thanks to recent advancements in nanomaterials, we've seen significant progress in electrochemical detection, leading to the development of specialized rapid immunoassay systems. These systems utilize specific antibodies to target molecules, expanding the range of detectable biomarkers. This innovation has the potential to revolutionize the diagnosis and treatment of cardiovascular diseases by enhancing detection sensitivity and specificity. Ultimately, these advancements aim to improve patient outcomes by enabling earlier diagnosis, more precise monitoring, and personalized therapeutic interventions, which will contribute to more effective management of cardiovascular health globally.
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The prevalence of autism spectrum disorder (ASD) has increased over the last decade. In this regard, many emerging therapies have been described as ASD therapies. Although ASD does not have a cure, there are several management options available that can help reduce symptom severity. ASD is highly variable and, therefore, standard treatment protocols and studies are challenging to perform. Many of these therapies also address comorbidities for which patients with ASD have an increased risk. These concurrent diagnoses can include psychiatric and neurological disorders, including attention deficit and hyperactivity disorder, anxiety disorders, and epilepsy, as well as gastrointestinal symptoms such as chronic constipation and diarrhea. Both the extensive list of ASD-associated disorders and adverse effects from commonly prescribed medications for patients with ASD can impact presenting symptomatology. It is important to keep these potential interactions in mind when considering additional drug treatments or complementary therapies. This review addresses current literature involving novel pharmacological treatments such as oxytocin, bumetanide, acetylcholinesterase inhibitors, and memantine. It also discusses additional therapies such as diet intervention, acupuncture, music therapy, melatonin, and the use of technology to aid education. Notably, several of these therapies require more long-term research to determine efficacy in specific ASD groups within this patient population.
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We present the case of a 76-year-old male who presented to our hospital with a rare infection of Lactobacillus rhamnosus. The patient had a suspected urinary tract infection (UTI) secondary to a chronic indwelling catheter; however, when symptoms did not improve on standard therapy, blood cultures revealed the growth of L. rhamnosus. The patient was found via imaging to have a concurrent infectious splenic hematoma, and aspiration confirmed the presence of L. rhamnosus. The patient resided in an area nursing home and was a poor historian; however, it is conceivable that this infection was acquired via diet or from normal gut flora as the patient did not present on probiotic supplementation. In this case report, we present both pharmaceutical and interventional treatment strategies as well as a timeline of treatment for this rarely-seen infection.
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Here we present a sensitive method for the detection and quantification of two (IL -10 and CRP) immuno-responsive biomarkers in various biofluids. The significance of these immune response biomarkers lies in them displaying elevated levels in critically ill COVID -19 patients. The developed electrochemical sensor contains a gold film electrode with ZnO nanoparticles deposited on its surface to increase the surface area of the working electrode while integrating antibody-antigen interactions into the detection system. This multiplex biosensor has a wide linear range from 0.01 µg/mL to 100 µg/mL and 0.1 pg/mL to 1000 pg/mL for CRP and IL10, respectively. The cross-reactivity of this multiplex sensor platform was evaluated between these two proteins and was <20%. Recovery studies were performed by spiking known concentrations in serum and urine samples. The recovery was calculated and ranged from 80% to 100%, confirming clinical applicability. This electrochemical sensing platform can aid in the early screening of COVID -19 patients to monitor for the development of more serious and potentially lethal symptoms.