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Salimicrobium sp. PL1-032A was isolated from Pearse Lakes, Western Australia. The sequenced genome consists of a single chromosome (2,705,688 bp) with a GC content of 47.2%. The isolation of Salimicrobium sp. PL1-032A contributes to the collection of culturable extremophiles and offers potential insight into the Pearse Lakes biome.
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Health-related quality of life (HRQoL) measures individual well-being across physical, psychological, and social domains. Patients with predominantly antibody deficiency (PAD) are at risk for morbidity and mortality, however, the effect of these complications on HRQoL requires additional study. Patients with PAD were asked to voluntarily complete the Centers for Disease Control (CDC) HRQoL-14 Healthy Days Measure questionnaire. These results were compared to data from the CDC-initiated Behavioral Risk Factor Surveillance System (BRFSS), a cross-sectional questionnaire including questions from CDC-HRQOL-14. Statistical analyses included two-proportion Z-test, t-tests, and analysis of variance. 83 patients with PAD completed the survey. Patients were sub-stratified into mild (23.7%), moderate (35.5%), severe (40.8%), and secondary (8.4%) PAD. "Fair or poor" health status was reported in 52.6% of PAD patients. Mental health challenges ≥ 14 days/month occurred in 25% of patients. Physical health issues ≥ 14 days/month was reported in 44.7% of patients. Activity limitations were noted by 80.3% of patients. There were no statistically significant differences by PAD severity. Patients with autoimmune and inflammatory disease co-morbidities reported more mental health challenges compared to those without (78% vs. 54.3%, p = 0.02). Compared to the CDC-BRFSS data, significantly more patients with PAD reported "fair or poor" health status (53% vs 12.0%; p < 0.0001), mental health challenges (24.1% vs 14.7%; p = 0.02), and poor physical health (44.6% vs 8.0%; p < 0.0001). Patients with PAD had significantly reduced HRQoL compared to CDC-BRFSS respondents from a similar geographical region. Decreased HRQoL was prevalent across all PAD severity levels. Additional research is needed to improve HRQoL for patients with PAD.
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Qualidade de Vida , Humanos , Estudos Transversais , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Inquéritos e Questionários , Nível de Saúde , Idoso , Adulto Jovem , Síndromes de Imunodeficiência/epidemiologia , Estados Unidos/epidemiologia , AdolescenteRESUMO
BACKGROUND: Malnutrition is a major consequence of head and neck cancer (HNC), often leading to decreased skeletal muscle mass and impacting survival. The goal of this study is to determine the effect of sarcopenia, as defined by skeletal muscle index (SMI), on survival in patients with HNC. METHODS: This is a retrospective review of patients with HNC treated with surgery and/or radiation at a single tertiary care institute. All had pre-treatment imaging available for skeletal muscle index (SMI) measurements, and SMI was calculated at the level of the 3rd cervical vertebra. Sarcopenia was defined as an SMI < 41 cm2/m2 in females and as <43 cm2/m2 in underweight or healthy weight males. Sarcopenia was defined as <53 cm2/m2 in overweight or obese males. Chi-square analysis was performed to compare recurrence and survival rates, and survival analysis was performed via Kaplan-Meir curve. RESULTS: Hundred and twelve patients with HNC were evaluated, 84 men and 28 women with an average age of 60.9 years. Tumors were primarily located in the oral cavity (24.1%) and oropharynx (42%). The majority (69.6%) underwent surgery. Mean body mass index prior to treatment was 28. Sixty-nine patients (61.6%) in our cohort had low SMI. Mean follow-up was 3.9 ± 2.2 years. Recurrence rate was 26% in those with low SMI versus 2% in those without. Patients with low SMI were more likely to have a recurrence (p = 0.02). Overall survival was 72.5% in those with low SMI and 81% in those with normal SMI (p = 0.09). CONCLUSIONS: Defining sarcopenia as a low skeletal muscle index at the third cervical vertebra is clinically relevant. This study demonstrates that low SMI at this level, and thus sarcopenia, was strongly associated with higher rates of recurrence.
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The development of active, stable, and more affordable electrocatalysts for acidic oxygen evolution reaction (OER) is of great importance for the practical application of electrolyzers and the advancement of renewable energy conversion technologies. Currently, IrO2 is the only catalyst with high stability and activity, but a high cost. Further optimization of the catalyst is limited by the lack of understanding of catalytic behaviors at the acid-IrO2 interface. Here, in strong interaction with the experiment, we develop an explicit model based on grand-canonical density function theory (GC-DFT) calculations to describe acidic OER over IrO2. Compared to the explicit models reported previously, hydronium cations (H3O+) are introduced at the electrochemical interface in the current model. As a result, a variation in stable IrO2 surface configuration under the OER operating condition from previously proposed complete *O-coverage to a mixture coverage of *OH and *O is revealed, which is well supported by in situ Raman measurements. In addition, the accuracy of predicted overpotential is increased in comparison with the experimentally measured. More importantly, an alteration of the potential limiting step from previously identified *O â *OOH to *OH â *O is observed, which opens new opportunities to advance the IrO2-based catalysts for acidic OER.
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We report an electrochemical method for doping two-dimensional (2D) superatomic semiconductor Re6Se8Cl2 that significantly improves the material's electrical transport while retaining the in-plane and stacking structures. The electrochemical reduction induces the complete dissociation of chloride anions from the surface of each superatomic nanosheet. After the material is dehalogenated, we observe the electrical conductivity (σ) increases by two orders of magnitude while the 3D electron carrier density (n3D) increases by three orders of magnitude. In addition, the thermal activation energy (Ea) and electron mobility (µe) decrease. We conclude that we have achieved effective electron-doping in 2D superatomic Re6Se8Cl2, which significantly improves the electrical transport properties. Our work sets the foundation for electrochemically doping and tuning the transport properties of other 2D superatomic materials.
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BACKGROUND: Cystic Fibrosis causing mutations in the gene CFTR, reduce the activity of the CFTR channel protein, and leads to mucus aggregation, airway obstruction and poor lung function. A role for CFTR in the pathogenesis of other muco-obstructive airway diseases such as Chronic Obstructive Pulmonary Disease (COPD) has been well established. The CFTR modulatory compound, Ivacaftor (VX-770), potentiates channel activity of CFTR and certain CF-causing mutations and has been shown to ameliorate mucus obstruction and improve lung function in people harbouring these CF-causing mutations. A pilot trial of Ivacaftor supported its potential efficacy for the treatment of mucus obstruction in COPD. These findings prompted the search for CFTR potentiators that are more effective in ameliorating cigarette-smoke (CS) induced mucostasis. METHODS: Small molecule potentiators, previously identified in CFTR binding studies, were tested for activity in augmenting CFTR channel activity using patch clamp electrophysiology in HEK-293 cells, a fluorescence-based assay of membrane potential in Calu-3 cells and in Ussing chamber studies of primary bronchial epithelial cultures. Addition of cigarette smoke extract (CSE) to the solutions bathing the apical surface of Calu-3 cells and primary bronchial airway cultures was used to model COPD. Confocal studies of the velocity of fluorescent microsphere movement on the apical surface of CSE exposed airway epithelial cultures, were used to assess the effect of potentiators on CFTR-mediated mucociliary movement. RESULTS: We showed that SK-POT1, like VX-770, was effective in augmenting the cyclic AMP-dependent channel activity of CFTR. SK-POT-1 enhanced CFTR channel activity in airway epithelial cells previously exposed to CSE and ameliorated mucostasis on the surface of primary airway cultures. CONCLUSION: Together, this evidence supports the further development of SK-POT1 as an intervention in the treatment of COPD.
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Aminofenóis , Brônquios , Regulador de Condutância Transmembrana em Fibrose Cística , Células Epiteliais , Quinolonas , Humanos , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Quinolonas/farmacologia , Aminofenóis/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Fumaça/efeitos adversos , Células Cultivadas , Células HEK293 , Agonistas dos Canais de Cloreto/farmacologia , Agonistas dos Canais de Cloreto/uso terapêutico , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismoRESUMO
Introduction: Kidney supportive care (KSC) integrates kidney and palliative care to improve quality of life for people with chronic kidney disease (CKD). Despite increasing interest and global advocacy to integrate KSC into kidney care, evidence to guide optimal care delivery is limited. Methods: This observational cross-sectional study used an online survey to describe current KSC models in Australia, Aotearoa-New Zealand, and the UK. Results: Between April and December 2022, 114 nephrology units responded (response rate 67%), with 66% having a dedicated KSC service (UK, 74%; Australia, 58%; and New Zealand, 67%). Many different health care professionals worked in KSC services with diversity in clinical resources and activities between units and across countries. Overall, funding for KSC services was low, with a median full time equivalent (FTE) per unit (standardized per 100 people receiving hemodialysis [HD]) of 0.51 (interquartile range [IQR], 0.17-1.05) and 4 units provided a service without allocated funding. The scope of KSC service was wide-ranging and prioritized activities included symptom management, psychological support, complex future treatment planning and discussion, and care coordination. There were no significant differences between countries in terms of location of care provision, frequency of review, referral patterns or discharge rates; however, there was variation described within countries. Conclusion: Models of KSC vary markedly across kidney units and between countries. Despite this variation, there was consistency in terms of clinical priorities which were person-centered and focused on physical and psychosocial well-being. Further research is required to evaluate the effectiveness of KSC provision, alongside improved funding methods to ensure sustainable and equitable KSC delivery.
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Ocular syphilis is a re-emerging inflammatory eye disease with a clear gender imbalance, disproportionately affecting men. We investigated the impact of gender on the presentation, management practices and clinical outcomes of this condition. Data generated from a study of patients consecutively diagnosed with ocular syphilis who attended a subspecialist uveitis service at one of four hospitals in Brazil over a 30-month period were disaggregated for analysis by gender. Two-hundred and fourteen eyes (161 men and 53 women) of 127 patients (96 men and 31 women) were included. Posterior uveitis was the most common presentation in both men and women (80.1% vs. 66.7%, p > 0.05), but men were significantly more likely to have vitritis as a feature of their disease (49.4% versus 28.8%, p = 0.019). Three eyes of women had nodular anterior scleritis (p = 0.015). Men were more likely to undergo a lumbar puncture to assess for neurosyphilis (71.9% vs. 51.6%, p = 0.048), but men and women undergoing a lumbar puncture were equally likely to have a cerebrospinal fluid abnormality (36.2% vs. 25.0%, p = 0.393). All patients were treated with aqueous penicillin G or ceftriaxone, and there was a trend towards more men receiving adjunctive systemic corticosteroid treatment as part of their management (65.2% vs. 46.7%, p = 0.071). There were no significant differences in the age of presentation, bilaterality of disease, anatomical classification of uveitis, initial or final visual acuity, and rates of ocular complications between men and women. Our findings indicate that ocular syphilis has comparable outcomes in men and women, but that there are differences in the type of ocular inflammation and management practices between the genders.
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Sífilis , Humanos , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Sífilis/tratamento farmacológico , Sífilis/diagnóstico , Fatores Sexuais , Infecções Oculares Bacterianas/tratamento farmacológico , Infecções Oculares Bacterianas/microbiologia , Infecções Oculares Bacterianas/diagnóstico , Brasil/epidemiologia , Antibacterianos/uso terapêutico , Uveíte/tratamento farmacológico , Uveíte/diagnóstico , Idoso , Resultado do TratamentoRESUMO
Marinococcus sp. PL1-022 was isolated from Pearse Lakes, Western Australia. The sequenced genome consists of a chromosome (3,140,198 bp; 48.2% GC) and two plasmids (58,083 bp and 19,399 bp; 41.4 and 50.7% GC-content, respectively). Isolation of Marinococcus sp. PL1-022 adds to the increasing repertoire of culturable extremophiles.
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Idiomarina sp. PL1-037 was isolated from Pearse Lakes, Rottnest Island, Western Australia. The sequenced completed genome for PL1-037 is composed of a single chromosome (2,804,934 bp) with a GC content of 47.1%. Isolation of Idiomarina sp. PL1-037 provides insights about culturable extremophiles from the Pearse lakes microbiome.
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Health-related quality of life (HRQoL) measures individual well-being across physical, psychological, and social domains. Patients with predominantly antibody deficiency (PAD) are at risk for morbidity and mortality, however, the effect of these complications on HRQoL requires additional study. Patients with PAD were asked to voluntarily complete the Centers for Disease Control (CDC) HRQoL-14 Healthy Days Measure questionnaire. These results were compared to data from the CDC-initiated Behavioral Risk Factor Surveillance System (BRFSS), a cross-sectional questionnaire including questions from CDC-HRQOL-14. Statistical analyses included two-proportion Z-test, t-tests, and analysis of variance. 83 patients with PAD completed the survey. Patients were sub-stratified into mild (23.7%), moderate (35.5%), severe (40.8%), and secondary (8.4%) PAD. "Fair or poor" health status was reported in 52.6% of PAD patients. Mental health challenges ≥ 14 days/month occurred in 25% of patients. Physical health issues ≥ 14 days/month was reported in 44.7% of patients. Activity limitations were noted by 80.3% of patients. There were no statistically significant differences by PAD severity. Patients with autoinflammatory disease co-morbidities reported more mental health challenges compared to those without (78% vs. 54.3%, p = 0.02). Compared to the CDC-BRFSS data, significantly more patients with PAD reported "fair or poor" health status (53% vs 12.0%; p < 0.0001), mental health challenges (24.1% vs 14.7%; p = 0.02), and poor physical health (44.6% vs 8.0%; p < 0.0001). Patients with PAD had significantly reduced HRQoL compared to CDC-BRFSS respondents from a similar geographical region. Decreased HRQoL was prevalent across all PAD severity levels. Additional research is needed to improve HRQoL for patients with PAD.
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Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) continues to be a global threat due to its ability to evolve and generate new subvariants, leading to new waves of infection. Additionally, other coronaviruses like Middle East respiratory syndrome coronavirus (MERS-CoV, formerly known as hCoV-EMC), which first emerged in 2012, persist and continue to present a threat of severe illness to humans. The continued identification of novel coronaviruses, coupled with the potential for genetic recombination between different strains, raises the possibility of new coronavirus clades of global concern emerging. As a result, there is a pressing need for pan-CoV therapeutic drugs and vaccines. After the extensive optimization of an HCV protease inhibitor screening hit, a novel 3CLPro inhibitor (MK-7845) was discovered and subsequently profiled. MK-7845 exhibited nanomolar in vitro potency with broad spectrum activity against a panel of clinical SARS-CoV-2 subvariants and MERS-CoV. Furthermore, when administered orally, MK-7845 demonstrated a notable reduction in viral burdens by >6 log orders in the lungs of transgenic mice infected with SARS-CoV-2 (K18-hACE2 mice) and MERS-CoV (K18-hDDP4 mice).
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Antivirais , SARS-CoV-2 , Animais , Camundongos , SARS-CoV-2/efeitos dos fármacos , Humanos , Antivirais/farmacologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Tratamento Farmacológico da COVID-19 , Inibidores de Proteases/farmacologia , COVID-19/virologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologiaRESUMO
AIMS: To assess adherence and persistence to sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1-RA), and dipeptidyl peptidase-4 inhibitors (DPP4i) in routine care. METHODS: Using retrospective healthcare data from the Stockholm region, Sweden, we evaluated new-users of these agents during 2015-2020. We investigated adherence (≥80 % of days covered by an active supply), persistence (no treatment gap ≥ 60 days), and predictors for non-adherence and non-persistence. RESULTS: We identified 24,470 new-users of SGLT2i (10,743), GLP1-RA (10,315), and/or DPP4i (9,488). Over 2.8 years median follow-up, the proportion demonstrating adherence was higher for SGLT2i (57 %) than DPP4i (53 %, comparison p < 0.001), and for GLP1-RA than DPP4i (54 % vs 53 %, p < 0.001). Similarly, persistence was higher for both SGLT2i and GLP-RA than DPP4i (respectively, 50 % vs 44 %, p < 0.001; 49 % vs 44 %, p < 0.001). Overall adherence was better among users who were older, had a history of high blood pressure, used more non-diabetic medications, had lower Hba1c, had better kidney function, and had completed secondary schooling or university. Women had worse adherence to SGLT2i and GLP1-RA than DPP4i. CONCLUSIONS: We report adherence and persistence to SGLT2i, GLP1-RA and DPP4i in routine care, and identify prognostic factors that could inform implementation interventions to improve uptake of these important therapies.
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Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Hipoglicemiantes , Adesão à Medicação , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adesão à Medicação/estatística & dados numéricos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Suécia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glicemia/efeitos dos fármacos , Glicemia/análise , Glicemia/metabolismo , AdultoRESUMO
INTRODUCTION: Palbociclib is a widely used treatment for advanced breast cancer in older adults. However, the existing evidence regarding its safety and tolerability in this age group is inconsistent and limited to retrospective subgroup or pooled analyses. MATERIALS AND METHODS: We conducted a prospective single-arm multicenter phase 2 study to evaluate the safety and tolerability of palbociclib in participants aged 70 years or older with advanced hormone receptor-positive breast cancer. Participants were given palbociclib in combination with their physician's choice of endocrine therapy (letrozole or fulvestrant). The primary endpoint was the incidence of grade 3+ adverse events (AEs) by six months. Secondary endpoints included AE-related dose delays, dose reductions, early discontinuations, and hospitalizations. Additionally, we compared these endpoints by age groups (70-74 and ≥ 75 years). RESULTS: Of the 90 participants (median age 74 years [70-87]) enrolled, 75.6% (95% confidence interval [CI], 65.4-84.0) had grade 3+ AEs by six months. The most frequent grade 3+ AEs were neutropenia (61%), fatigue (4%), and nausea (3%). Febrile neutropenia was uncommon (1.1%). Due to AEs, 36% had dose delays, 34% had dose reductions, 10% had early discontinuations, and 10% had hospitalizations. Compared to those aged 70-74 years, participants aged ≥75 years had higher rates of early discontinuations (5.9% vs 15.9%, a difference of 9.5% [95% CI 3.5%-22.5%]). DISCUSSION: Palbociclib has an overall favorable safety profile in adults aged ≥70 with advanced breast cancer. However, adults ≥75 years had a trend toward higher rates of AE-related early discontinuations compared to those 70-74 years. Further research is needed to evaluate tolerability and improve the delivery of palbociclib in older adults. CLINICALTRIALS: gov:NCT03633331.
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Neoplasias da Mama , Piperazinas , Piridinas , Humanos , Piridinas/efeitos adversos , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Idoso , Feminino , Neoplasias da Mama/tratamento farmacológico , Piperazinas/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Idoso de 80 Anos ou mais , Estudos Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Fulvestranto/administração & dosagem , Fulvestranto/uso terapêutico , Letrozol/administração & dosagem , Letrozol/uso terapêutico , Fatores EtáriosRESUMO
Intratumoral (IT) therapy is a powerful method of controlling tumor growth, but a major unsolved problem is the rapidity that injected drugs exit tumors, limiting on-target exposure and efficacy. We have developed a generic long acting IT delivery system in which a drug is covalently tethered to hydrogel microspheres (MS) by a cleavable linker; upon injection the conjugate forms a depot that slowly releases the drug and "bathes" the tumor for long periods. We established technology to measure tissue pharmacokinetics and studied MSs attached to SN-38, a topoisomerase 1 inhibitor. When MS ~ SN-38 was injected locally, tissues showed high levels of SN-38 with a long half-life of ~ 1 week. IT MS ~ SN-38 was ~ tenfold more efficacious as an anti-tumor agent than systemic SN-38. We also propose and provide an example that long-acting IT therapy might enable safe use of two drugs with overlapping toxicities. Here, long-acting IT MS ~ SN-38 is delivered with concurrent systemic PARP inhibitor. The tumor is exposed to both drugs whereas other tissues are exposed only to the systemic drug; synergistic anti-tumor activity supported the validity of this approach. We propose use of this approach to increase efficacy and reduce toxicities of combinations of immune checkpoint inhibitors such as αCTLA-4 and αPD-1.
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Irinotecano , Animais , Camundongos , Humanos , Irinotecano/administração & dosagem , Irinotecano/farmacocinética , Microesferas , Hidrogéis/química , Linhagem Celular Tumoral , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/farmacocinética , Inibidores da Topoisomerase I/uso terapêutico , Sistemas de Liberação de Medicamentos , Feminino , Neoplasias/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , Injeções Intralesionais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologiaRESUMO
Central nervous system tumors have resisted effective chemotherapy because most therapeutics do not penetrate the blood-tumor-brain-barrier. Nanomedicines between ~ 10 and 100 nm accumulate in many solid tumors by the enhanced permeability and retention effect, but it is controversial whether the effect can be exploited for treatment of brain tumors. PLX038A is a long-acting prodrug of the topoisomerase 1 inhibitor SN-38. It is composed of a 15 nm 4-arm 40 kDa PEG tethered to four SN-38 moieties by linkers that slowly cleave to release the SN-38. The prodrug was remarkably effective at suppressing growth of intracranial breast cancer and glioblastoma (GBM), significantly increasing the life span of mice harboring them. We addressed the important issue of whether the prodrug releases SN-38 systemically and then penetrates the brain to exert anti-tumor effects, or whether it directly penetrates the blood-tumor-brain-barrier and releases the SN-38 cargo within the tumor. We argue that the amount of SN-38 formed systemically is insufficient to inhibit the tumors, and show by PET imaging that a close surrogate of the 40 kDa PEG carrier in PLX038A accumulates and is retained in the GBM. We conclude that the prodrug penetrates the blood-tumor-brain-barrier, accumulates in the tumor microenvironment and releases its SN-38 cargo from within. Based on our results, we pose the provocative question as to whether the 40 kDa nanomolecule PEG carrier might serve as a "Trojan horse" to carry other drugs past the blood-tumor-brain-barrier and release them into brain tumors.
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Barreira Hematoencefálica , Neoplasias Encefálicas , Irinotecano , Pró-Fármacos , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Irinotecano/farmacocinética , Barreira Hematoencefálica/metabolismo , Camundongos , Pró-Fármacos/farmacocinética , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Humanos , Linhagem Celular Tumoral , Feminino , Ensaios Antitumorais Modelo de Xenoenxerto , Glioblastoma/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Camptotecina/uso terapêuticoRESUMO
Improved understanding of proton transfer in nanopores is critical for a wide range of emerging applications, yet experimentally probing mechanisms and energetics of this process remains a significant challenge. To help reveal details of this process, we developed and applied a machine learning potential derived from first-principles calculations to examine water reactivity and proton transfer in TiO2 slit-pores. We find that confinement of water within pores smaller than 0.5 nm imposes strong and complex effects on water reactivity and proton transfer. Although the proton transfer mechanism is similar to that at a TiO2 interface with bulk water, confinement reduces the activation energy of this process, leading to more frequent proton transfer events. This enhanced proton transfer stems from the contraction of oxygen-oxygen distances dictated by the interplay between confinement and hydrophilic interactions. Our simulations also highlight the importance of the surface topology, where faster proton transport is found in the direction where a unique arrangement of surface oxygens enables the formation of an ordered water chain. In a broader context, our study demonstrates that proton transfer in hydrophilic nanopores can be enhanced by controlling pore size, surface chemistry, and topology.
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Malignant rhabdoid tumors (MRTs) are among the most aggressive and treatment-resistant malignancies affecting infants, originating in the kidney, brain, liver, and soft tissues. The 5-year event-free survival rate for these cancers is a mere 20%. In nearly all cases of MRT, the SMARCB1 gene (occasionally SMARCA4)-a pivotal component of the SWI/SNF chromatin remodeling complex-is homozygously deleted, although the precise etiology of these tumors remains unknown. While young patients with localized MRT generally show improved outcomes, especially those who are older and have early-stage disease, the overall prognosis remains poor despite optimal standard treatments. This highlights the urgent need for more effective treatment strategies. We investigated the antitumor activity of a PARP1 inhibitor (talazoparib, TLZ) combined with a DNA alkylating agent (temozolomide, TMZ) in MRT xenograft models. PARP1 is a widely targeted molecule in cancer treatment and, beyond its role in DNA repair, it participates in transcriptional regulation by recruiting chromatin remodeling complexes to modulate DNA accessibility for RNA polymerases. To widen the therapeutic window of the drug combination, we employed PEGylated TLZ (PEG~TLZ), which has been reported to reduce systemic toxicity through slow drug release. Remarkably, our findings indicate that five out of six MRT xenografts exhibited an objective response to PEG~TLZ+TMZ therapy. Significantly, the loss of SMARCB1 was found to confer a protective effect, correlating with higher expression levels of DNA damage and repair proteins in SMARCB1-deficient MRT cells. Additionally, we identified MGMT as a potential biomarker indicative of in vivo MRT response to PEG~TLZ+TMZ therapy. Moreover, our analysis revealed alterations in signaling pathways associated with the observed antitumor efficacy. This study presents a novel and efficacious therapeutic approach for MRT, along with a promising candidate biomarker for predicting tumor response.
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Unprecedented plastic production has resulted in over six billion tons of harmful waste. Certain insect taxa emerge as potential agents of plastic biodegradation. Through a comprehensive manual and bibliometric literature analysis, this review analyses and consolidates the growing literature related to insect-mediated plastic breakdown. Over 23 insect species, representing Coleoptera, Lepidoptera, and 4 other orders, have been identified for their capacity to consume plastic polymers. Natural and synthetic polymers exhibit high-level similarities in molecular structure and properties. Thus, in conjunction with comparative genomics studies, we link plastic-degrading enzymatic capabilities observed in certain insects to the exaptation of endogenous enzymes originally evolved for digesting lignin, cellulose, beeswax, keratin and chitin from their native dietary substrates. Further clarification is necessary to distinguish mineralisation from physicochemical fragmentation and to differentiate microbiome-mediated degradation from direct enzymatic reactions by insects. A bibliometric analysis of the exponentially growing body of literature showed that leading research is emerging from China and the USA. Analogies between natural and synthetic polymer's degradation pathways will inform engineering robust enzymes for practical plastic bioremediation applications. By aggregating, analysing, and interpreting published insights, this review consolidates our mechanistic understanding of insects as a potential natural solution to the escalating plastic waste crisis.