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BACKGROUND: Matings between male Aedes aegypti mosquitoes infected with wAlbB strain of Wolbachia and wildtype females yield non-viable eggs. We evaluated the efficacy of releasing wAlbB-infected Ae. aegypti male mosquitoes to suppress dengue. METHODS: We specified the protocol of a two-arm cluster-randomized test-negative controlled trial (cRCT) and emulated it using a nationally representative test-negative/positive database of individuals reporting for febrile illness to any public hospital, general practitioner or polyclinic. We retrospectively built a cohort of individuals who reside in Wolbachia locations versus a comparator control group who do not reside in Wolbachia locations, using a nationally representative database of all individuals whom report for febrile illness and were tested for dengue at the Environmental Health Institute/hospital laboratories/commercial diagnostic laboratories, through general practitioner clinic, polyclinic or public/private hospital from EW1 2019-EW 262022. We emulated a constrained randomization protocol used in cRCTs to balance dengue risk between intervention and control arms in the pre-intervention period. We used the inverse-probability weighting approach to further balance the intervention and control groups using a battery of algorithmically selected sociodemographic, environmental and anthropogenic variables. Intention-to-treat analyses was conducted to estimate the risk reduction of dengue given Wolbachia exposure. RESULTS: Intention-to-treat analyses revealed that, compared with controls, Wolbachia releases for 3, 6, 12 or more months was associated to 47%(95%CI:25-69%), 44%(33-77%) and 61%(38-78%) protective efficacy against dengue, respectively. When exposed to 12 or more months of Wolbachia releases, protective efficacies ranged from 49%(13-72%) to 77%(60-94%) across years. The proportion of virologically confirmed dengue cases was lower overall in the intervention arm. Protective efficacies were found across all years, age and sex subgroups, with higher durations of Wolbachia exposure associated to greater risk reductions of dengue. CONCLUSION: Results demonstrated that Wolbachia-mediated sterility can strengthen dengue control in tropical cities, where dengue burden is the greatest.
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BACKGROUND: This trial is a parallel, two-arm, non-blinded cluster randomised controlled trial that is under way in Singapore, with the aim of measuring the efficacy of male Wolbachia-infected Aedes aegypti deployments in reducing dengue incidence in an endemic setting with all four dengue serotypes in circulation. The trial commenced in July 2022 and is expected to conclude in September 2024. The original study protocol was published in December 2022. Here, we describe amendments that have been made to the study protocol since commencement of the trial. METHODS: The key protocol amendments are (1) addition of an explicit definition of Wolbachia exposure for residents residing in intervention sites based on the duration of Wolbachia exposure at point of testing, (2) incorporation of a high-dimensional set of anthropogenic and environmental characteristics in the analysis plan to adjust for baseline risk factors of dengue transmission, and (3) addition of alternative statistical analyses for endpoints to control for post hoc imbalance in cluster-based environmental and anthropogenic characteristics. DISCUSSION: The findings from this study will provide the first experimental evidence for the efficacy of releasing male-Wolbachia infected mosquitoes to reduce dengue incidence in a cluster-randomised controlled trial. The trial will conclude in 2024 and results will be reported shortly thereafter. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT05505682. Registered on 16 August 2022. Retrospectively registered. Last updated 11 November 2023.
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Aedes , Dengue , Mosquitos Vetores , Ensaios Clínicos Controlados Aleatórios como Assunto , Wolbachia , Dengue/prevenção & controle , Dengue/epidemiologia , Dengue/transmissão , Animais , Singapura/epidemiologia , Masculino , Aedes/microbiologia , Aedes/virologia , Humanos , Incidência , Mosquitos Vetores/microbiologia , Mosquitos Vetores/virologia , Controle de Mosquitos/métodos , Feminino , Controle Biológico de Vetores/métodosRESUMO
Water quality testing is crucial for protecting public health, especially considering the number of boil water advisories annually issued across Canada that impact daily life for residents in affected areas. To overcome these challenges, the development of drinking water safety plans and accessibility to regular testing using simple, rapid, and accurate materials are necessary. However, the significance of monitoring the accuracy of environmental microbiology testing laboratories cannot be overlooked. Participation in external quality assessment programs, such as those that include proficiency testing (PT), is a necessary risk management resource that ensures the effectiveness of these testing processes. Proficiency Testing Canada (PTC), in collaboration with the Canadian Microbiological Proficiency Testing (CMPT) program based at the University of British Columbia, have implemented a drinking-water microbiology PT program since 1996. Both PTC and CMPT are ISO/IEC 17043:2010-accredited EQA providers. The drinking water program provided PT challenges to subscribing testing laboratories twice per year. Each challenge consisted of four samples containing unknown concentrations of Escherichia coli (E. coli) and Enterobacter spp. Results from participants were assessed for accuracy based on the method of testing. This cross-sectional study evaluated 150 rural and metropolitan testing sites across Canada between 2016 and 2022. Multivariable logistic regression analysis was conducted to examine the impact of different testing methods and laboratory accreditation status on the proficiency scores. This approach enabled us to assess the association between multiple independent variables and the likelihood of achieving specific proficiency scores, providing insights into how testing methods and accreditation status affect overall performance. After adjusting for rural residence, testing time, and survey year, the membrane filtration method was positively associated with the likelihood of scoring satisfactory results compared to the enzyme-substrate method (OR: 1.75; CI: 1.37-2.24), as well as accreditation status (OR: 1.47; CI: 1.16-1.85). The potential for improvement in environmental laboratory testing performance through the implementation of regulated PT in drinking water safety plans is proposed, along with the need for reliable testing methods applicable to rapid drinking water microbiology testing.
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Vascular malformation, a key clinical phenotype of Proteus syndrome, lacks effective models for pathophysiological study and drug development due to limited patient sample access. To bridge this gap, we built a human vascular organoid model replicating Proteus syndrome's vasculature. Using CRISPR/Cas9 genome editing and gene overexpression, we created induced pluripotent stem cells (iPSCs) embodying the Proteus syndrome-specific AKTE17K point mutation for organoid generation. Our findings revealed that AKT overactivation in these organoids resulted in smaller sizes yet increased vascular connectivity, although with less stable connections. This could be due to the significant vasculogenesis induced by AKT overactivation. This phenomenon likely stems from boosted vasculogenesis triggered by AKT overactivation, leading to increased vascular sprouting. Additionally, a notable increase in dysfunctional PDGFRß+ mural cells, impaired in matrix secretion, was observed in these AKT-overactivated organoids. The application of AKT inhibitors (ARQ092, AZD5363, or GDC0068) reversed the vascular malformations; the inhibitors' effectiveness was directly linked to reduced connectivity in the organoids. In summary, our study introduces an innovative in vitro model combining organoid technology and gene editing to explore vascular pathophysiology in Proteus syndrome. This model not only simulates Proteus syndrome vasculature but also holds potential for mimicking vasculatures of other genetically driven diseases. It represents an advance in drug development for rare diseases, historically plagued by slow progress.
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BACKGROUND: Due to the absence of available therapeutics and good vaccines, vector control solutions are needed to mitigate the spread of dengue. Matings between male Aedes aegypti mosquitoes infected with the wAlbB strain of Wolbachia and wildtype females yield non-viable eggs. We evaluated the efficacy of releasing wAlbB-infected A aegypti male mosquitoes to suppress dengue incidence. METHODS: In this synthetic control study, we conducted large-scale field trials in Singapore involving release of wAlbB-infected A aegypti male mosquitoes for dengue control via vector population suppression, from epidemiological week (EW) 27, 2018, to EW 26, 2022. We selected two large towns (Yishun and Tampines) to adopt an expanding release strategy and two smaller towns (Bukit Batok and Choa Chu Kang) to adopt a targeted-release approach. Releases were conducted two times a week in high-rise public housing estates. All intervention and control locations practised the same baseline dengue control protocol. The main outcome was weekly dengue incidence rate caused by any dengue virus serotype. We used incidence data collected by the Singapore Ministry of Health to assess the efficacy of the interventions. To compare interventions, we used the synthetic control method to generate appropriate counterfactuals for the intervention towns using a weighted combination of 30 control towns between EW 1, 2014 and EW 26, 2022. FINDINGS: Our study comprised an at-risk population of 607 872 individuals living in intervention sites and 3 894 544 individuals living in control sites. Interventions demonstrated up to 77·28% (121/156, 95% CI 75·81-78·58) intervention efficacy despite incomplete coverage across all towns until EW 26, 2022. Intervention efficacies increased as release coverage increased across all intervention sites. Releases led to 2242 (95% CI 2092-2391) fewer cases per 100 000 people in intervention sites during the study period. Secondary analysis showed that these intervention effects were replicated across all age groups and both sexes for intervention sites. INTERPRETATION: Our results demonstrated the potential of Wolbachia-mediated incompatible insect technique for strengthening dengue control in tropical cities, where dengue burden is the greatest. FUNDING: Singapore Ministry of Finance, Ministry of Sustainability, and the National Environment Agency, and the Singapore National Robotics Program.
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Aedes , Dengue , Controle de Mosquitos , Mosquitos Vetores , Wolbachia , Wolbachia/fisiologia , Dengue/prevenção & controle , Dengue/epidemiologia , Dengue/transmissão , Singapura/epidemiologia , Animais , Aedes/microbiologia , Aedes/virologia , Incidência , Feminino , Masculino , Controle de Mosquitos/métodos , Mosquitos Vetores/microbiologia , Mosquitos Vetores/virologia , Humanos , Vírus da Dengue , Controle Biológico de Vetores/métodosRESUMO
BACKGROUND: HER2-expressing salivary gland carcinoma (SGC) is associated with poor prognosis. Trastuzumab deruxtecan (T-DXd, DS-8201) has shown evidence of antitumor activity for several HER2-expressing solid tumors in multiple studies. This study aimed to present the efficacy and safety of T-DXd in patients with HER2-expressing SGC from a pooled analysis. METHODS: Patients with HER2-expressing SGC were pooled from two phase I, open-label studies of T-DXd: a two-phase, multiple-dose, first-in-human study (NCT02564900) and a single-sequence crossover drug-drug interaction study (NCT03383692). Endpoints included efficacy (objective response rate [ORR], duration of response [DoR] and progression-free survival [PFS]) and safety. RESULTS: This pooled analysis included 17 patients with SGC (median age: 57 years; male: 88.2%); median (range) follow-up duration was 12.0 (2.3-|34.8) months. Among these patients, 14 had received prior HER2-targeted agents and 13 had undergone prior radiotherapy. The investigator-assessed confirmed ORR was 58.8% (95% confidence interval [CI], 32.9-|81.6). The median (95% CI) DoR and PFS were 17.6 months (4.0 to not evaluable [NE]) and 20.5 months (11.1-NE), respectively. All 17 patients reported treatment-emergent adverse events (TEAEs); 76.5% reported TEAEs of grade ≥3. The most common TEAEs were decreased appetite (94.1%), nausea (88.2%) and neutrophil count decreased (76.5%). Of the 17 patients, five (29.4%) reported adjudicated drug-related interstitial lung disease (grade 1, n = 3; grade 2, n =1; grade 3, n = 1). CONCLUSION: The results of this pooled analysis provide evidence that clinical benefit is achievable with T-DXd in patients with HER2-expressing SGC. CLINICAL TRIAL INFORMATION: FIH study, NCT02564900; DDI study, NCT03383692.
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Camptotecina , Carcinoma , Imunoconjugados , Trastuzumab , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Camptotecina/uso terapêutico , Camptotecina/análogos & derivados , Carcinoma/tratamento farmacológico , Imunoconjugados/efeitos adversos , Imunoconjugados/uso terapêutico , Receptor ErbB-2/metabolismo , Glândulas Salivares/metabolismo , Trastuzumab/efeitos adversos , Trastuzumab/uso terapêutico , FemininoRESUMO
Atherosclerosis is a primary precursor of cardiovascular disease (CVD), the leading cause of death worldwide. While proprotein convertase subtilisin/kexin 9 (PCSK9) contributes to CVD by degrading low-density lipoprotein receptors (LDLR) and altering lipid metabolism, PCSK9 also influences vascular inflammation, further promoting atherosclerosis. Here, we utilized a vascular microphysiological system to test the effect of PCSK9 activation or repression on the initiation of atherosclerosis and to screen the efficacy of a small molecule PCSK9 inhibitor. We have generated PCSK9 over-expressed (P+) or repressed (P-) human induced pluripotent stem cells (iPSCs) and further differentiated them to smooth muscle cells (viSMCs) or endothelial cells (viECs). Tissue-engineered blood vessels (TEBVs) made from P+ viSMCs and viECs resulted in increased monocyte adhesion compared to the wild type (WT) or P- equivalents when treated with enzyme-modified LDL (eLDL) and TNF-α. We also found significant viEC dysfunction, such as increased secretion of VCAM-1, TNF-α, and IL-6, in P+ viECs treated with eLDL and TNF-α. A small molecule compound, NYX-1492, that was originally designed to block PCSK9 binding with the LDLR was tested in TEBVs to determine its effect on lowering PCSK9-induced inflammation. The compound reduced monocyte adhesion in P+ TEBVs with evidence of lowering secretion of VCAM-1 and TNF-α. These results suggest that PCSK9 inhibition may decrease vascular inflammation in addition to lowering plasma LDL levels, enhancing its anti-atherosclerotic effects, particularly in patients with elevated chronic inflammation.
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DESTINY-Breast01 (NCT03248492) evaluated trastuzumab deruxtecan (T-DXd; DS-8201) in patients with heavily pretreated HER2-positive metastatic breast cancer (mBC). We present a subgroup of 24 patients with a history of treated brain metastases (BM), a population with limited treatment options. In patients with BMs, the confirmed objective response rate (cORR) was 58.3% [95% confidence interval (CI), 36.6%-77.9%], and the median progression-free survival (mPFS) was 18.1 months (95% CI, 6.7-18.1 months). In patients without BMs (n = 160), cORR was 61.3% and mPFS was 16.4 months. Eight patients (47.1%) experienced a best overall intracranial response of partial response or complete response. Seven patients (41.2%) had a best percentage change in brain lesion diameter from baseline consistent with stable disease. Two patients (8.3%) with BMs and two (1.3%) without BMs experienced progression in the brain. The safety profile of T-DXd was consistent with previous studies. The durable clinical activity of T-DXd in this population warrants further investigation. SIGNIFICANCE: Advances in treating HER2-positive metastatic breast cancer have greatly improved patient outcomes, but intracranial progression remains an important risk for which few therapeutic options are currently available. T-DXd demonstrated durable efficacy in patients with stable, treated BMs. This article is highlighted in the In This Issue feature, p. 2711.
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Neoplasias Encefálicas , Neoplasias da Mama , Imunoconjugados , Humanos , Feminino , Neoplasias da Mama/patologia , Receptor ErbB-2 , Trastuzumab/uso terapêutico , Imunoconjugados/uso terapêutico , Camptotecina/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundárioRESUMO
PURPOSE: Human epidermal growth factor receptor 2 (HER2)-targeted therapies improve survival for patients with HER2-positive breast cancer but carry risks of hematologic, cardiopulmonary, gastro-hepatobiliary, and other adverse events (AEs). In this review, we describe published AE incidences for HER2-targeted therapies for metastatic breast cancer (mBC). METHODS: We searched PubMed and Embase to identify studies on HER2-targeted therapies in HER2-positive mBC, reporting on AEs of special interest, and published between January 1, 2009, and February 6, 2020. Treatment regimens were categorized into mutually exclusive therapy-based categories, with primary therapy determined by worldwide approval date. RESULTS: One hundred and fifty-three included articles assessed a combined 29,238 patients treated with the following therapy-based regimens: trastuzumab or biosimilars (78 studies), lapatinib (40), T-DM1 (ado-trastuzumab emtansine) (20), pertuzumab (14), neratinib (8), MM-302 (1), T-DXd (2), tucatinib (3), and pyrotinib (3). While direct comparisons of AE incidence are not warranted owing to study heterogeneity, proportions of patients experiencing any Grade 3 + AE ranged across therapy-based regimens from 39.4% (lapatinib) to 66.3% (neratinib). The most common hematologic AE of special interest, of any grade and regardless of causality, was leukopenia/white blood cells decreased [21.4% (T-DXd)-46.2% (pyrotinib)]. Cardiopulmonary AEs of special interest included interstitial lung disease [2.7% (trastuzumab)-5.2% (T-DXd)], pneumonitis [0.2% (lapatinib)-7.4% (trastuzumab)], and decreased ejection fraction [1% (T-DXd)-13.6% (trastuzumab)]. Gastro-hepatobiliary AEs of special interest included nausea [33.9% (trastuzumab)-78.3% (T-DXd)], vomiting [19.2% (T-DM1)-48.2% (T-DXd)], diarrhea [19.6% (T-DM1)-96.9% (pyrotinib)], and hepatotoxicity [5.9% (lapatinib)-53.6% (T-DM1)]. CONCLUSION: Differing AE profiles for anti-HER2 therapies should be considered when assessing benefit-risk profile for treatment options.
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Medicamentos Biossimilares , Neoplasias da Mama , Maitansina , Segunda Neoplasia Primária , Ado-Trastuzumab Emtansina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Medicamentos Biossimilares/uso terapêutico , Neoplasias da Mama/patologia , Feminino , Humanos , Incidência , Lapatinib/efeitos adversos , Segunda Neoplasia Primária/etiologia , Receptor ErbB-2/metabolismo , TrastuzumabRESUMO
BACKGROUND: Trastuzumab emtansine is the current standard treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer whose disease progresses after treatment with a combination of anti-HER2 antibodies and a taxane. METHODS: We conducted a phase 3, multicenter, open-label, randomized trial to compare the efficacy and safety of trastuzumab deruxtecan (a HER2 antibody-drug conjugate) with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. The primary end point was progression-free survival (as determined by blinded independent central review); secondary end points included overall survival, objective response, and safety. RESULTS: Among 524 randomly assigned patients, the percentage of those who were alive without disease progression at 12 months was 75.8% (95% confidence interval [CI], 69.8 to 80.7) with trastuzumab deruxtecan and 34.1% (95% CI, 27.7 to 40.5) with trastuzumab emtansine (hazard ratio for progression or death from any cause, 0.28; 95% CI, 0.22 to 0.37; P<0.001). The percentage of patients who were alive at 12 months was 94.1% (95% CI, 90.3 to 96.4) with trastuzumab deruxtecan and 85.9% (95% CI, 80.9 to 89.7) with trastuzumab emtansine (hazard ratio for death, 0.55; 95% CI, 0.36 to 0.86; prespecified significance boundary not reached). An overall response (a complete or partial response) occurred in 79.7% (95% CI, 74.3 to 84.4) of the patients who received trastuzumab deruxtecan and in 34.2% (95% CI, 28.5 to 40.3) of those who received trastuzumab emtansine. The incidence of drug-related adverse events of any grade was 98.1% with trastuzumab deruxtecan and 86.6% with trastuzumab emtansine, and the incidence of drug-related adverse events of grade 3 or 4 was 45.1% and 39.8%, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; none of these events were of grade 4 or 5. CONCLUSIONS: Among patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane, the risk of disease progression or death was lower among those who received trastuzumab deruxtecan than among those who received trastuzumab emtansine. Treatment with trastuzumab deruxtecan was associated with interstitial lung disease and pneumonitis. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast03 ClinicalTrials.gov number, NCT03529110.).
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Ado-Trastuzumab Emtansina/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Camptotecina/análogos & derivados , Imunoconjugados/uso terapêutico , Trastuzumab/uso terapêutico , Ado-Trastuzumab Emtansina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Feminino , Humanos , Imunoconjugados/efeitos adversos , Estimativa de Kaplan-Meier , Doenças Pulmonares Intersticiais/induzido quimicamente , Pessoa de Meia-Idade , Pneumonia/induzido quimicamente , Intervalo Livre de Progressão , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Trastuzumab/efeitos adversosRESUMO
Pain is one of the most common medical conditions and affects more Americans than diabetes, heart disease, and cancer combined. Current pain treatments mainly rely on opioid analgesics and remain unsatisfactory. The life-threatening side effects and addictive properties of opioids demand new therapeutic approaches. Nanomedicine may be able to address these challenges as it allows for sensitive and targeted treatments without some of the burdens associated with current clinical pain therapies. This review discusses the physiology of pain, the current landscape of pain treatment, novel targets for pain treatment, and recent and ongoing efforts to effectively treat pain using nanotechnology-based approaches. We highl ight advances in nanoparticle-based drug delivery to reduce side effects, gene therapy to tackle the source of pain, and nanomaterials-based scavenging to proactively mediate pain signaling.
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PURPOSE: To evaluate drug-drug interactions between the human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd; DS-8201a) and the OATP1B/CYP3A inhibitor ritonavir or the strong CYP3A inhibitor itraconazole. PATIENTS AND METHODS: Patients with HER2-expressing advanced solid tumors were enrolled in this phase I, open-label, single-sequence crossover study (NCT03383692) and received i.v. T-DXd 5.4 mg/kg every 3 weeks. Patients received ritonavir (cohort 1) or itraconazole (cohort 2) from day 17 of cycle 2 through the end of cycle 3. Primary endpoints were maximum serum concentration (C max) and partial area under the concentration-time curve from beginning of cycle through day 17 (AUC17d) for T-DXd and deruxtecan (DXd) with (cycle 3) and without (cycle 2) ritonavir or itraconazole treatment. RESULTS: Forty patients were enrolled (cohort 1, n = 17; cohort 2, n = 23). T-DXd C max was similar whether combined with ritonavir [cohort 1, cycle 3/cycle 2; 90% confidence interval (CI): 1.05 (0.98-1.13)] or itraconazole [cohort 2, 1.03 (0.96-1.09)]. T-DXd AUC17d increased from cycle 2 to 3; however, the cycle 3/cycle 2 ratio upper CI bound remained at ≤1.25 for both cohorts. For DXd (cycle 3/cycle 2), C max ratio was 0.99 (90% CI, 0.85-1.14) for cohort 1 and 1.04 (0.92-1.18) for cohort 2; AUC17d ratio was 1.22 (1.08-1.37) and 1.18 (1.11-1.25), respectively. The safety profile of T-DXd plus ritonavir or itraconazole was consistent with previous studies of T-DXd monotherapy. T-DXd demonstrated promising antitumor activity across HER2-expressing solid-tumor types. CONCLUSIONS: T-DXd was safely combined with ritonavir or itraconazole without clinically meaningful impact on T-DXd or DXd pharmacokinetics.
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Camptotecina/análogos & derivados , Imunoconjugados/farmacocinética , Imunoconjugados/uso terapêutico , Itraconazol/farmacocinética , Itraconazol/uso terapêutico , Neoplasias/tratamento farmacológico , Ritonavir/farmacocinética , Ritonavir/uso terapêutico , Trastuzumab/farmacocinética , Trastuzumab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Estudos Cross-Over , Combinação de Medicamentos , Feminino , Humanos , Imunoconjugados/efeitos adversos , Itraconazol/efeitos adversos , Masculino , Pessoa de Meia-Idade , Neoplasias/química , Neoplasias/patologia , Receptor ErbB-2/análise , Ritonavir/efeitos adversos , Trastuzumab/efeitos adversos , Resultado do TratamentoRESUMO
Three-dimensional (3D) microphysiological systems (MPSs) mimicking human organ function in vitro are an emerging alternative to conventional monolayer cell culture and animal models for drug development. Human induced pluripotent stem cells (hiPSCs) have the potential to capture the diversity of human genetics and provide an unlimited supply of cells. Combining hiPSCs with microfluidics technology in MPSs offers new perspectives for drug development. Here, the integration of a newly developed liver MPS with a cardiac MPS-both created with the same hiPSC line-to study drug-drug interaction (DDI) is reported. As a prominent example of clinically relevant DDI, the interaction of the arrhythmogenic gastroprokinetic cisapride with the fungicide ketoconazole was investigated. As seen in patients, metabolic conversion of cisapride to non-arrhythmogenic norcisapride in the liver MPS by the cytochrome P450 enzyme CYP3A4 was inhibited by ketoconazole, leading to arrhythmia in the cardiac MPS. These results establish integration of hiPSC-based liver and cardiac MPSs to facilitate screening for DDI, and thus drug efficacy and toxicity, isogenic in the same genetic background.
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Trastuzumab deruxtecan (T-DXd) is a HER2-targeting antibody-drug conjugate composed of a novel enzyme-cleavable linker and membrane-permeable topoisomerase I inhibitor payload. T-DXd has been approved for HER2-positive metastatic breast cancer and for HER2-positive metastatic gastric cancer. The approval in breast cancer was based on results from the DESTINY-Breast01 (U201; NCT03248492) and J101 (NCT02564900) trials. Here, we present dose justification for the approved 5.4 mg/kg every-3-weeks (Q3W) dose based on exposure-efficacy evaluated in patients with HER2-positive breast cancer (N = 337) from these 2 trials. Exposure-safety was assessed in patients with all tumor types (N = 639, n = 512 with breast cancer) across 5 trials, including J101 and DESTINY-Breast01. T-DXd doses ranged from 0.8-8.0 mg/kg Q3W; most patients received 5.4 (n = 312) or 6.4 mg/kg (n = 291). For each end point, multivariate logistic or Cox regression analysis was performed using various exposure metrics of T-DXd and released drug. A statistically significant association was observed between intact T-DXd area under the concentration-time curve (AUC) and confirmed objective response rate (ORR; P = 0.028). No significant exposure-response relationships were observed between intact T-DXd or released drug and duration of response or progression-free survival; however, follow-up was limited. All evaluated safety end points demonstrated a significant (P < 0.05) relationship with either intact T-DXd or released drug, with higher adverse event (AE) rates projected at higher exposures. Dose-response projections suggested an increase in ORR (67.5% vs. 62.9%) and toxicity (e.g., grade ≥ 3 all-cause treatment-emergent AEs: 61% vs. 54%) with T-DXd 6.4 vs. 5.4 mg/kg. Results demonstrate the benefit-risk profile at different doses and guide clinicians in the use of the 5.4-mg/kg Q3W dose in patients with HER2-positive metastatic breast cancer.
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Adenocarcinoma/tratamento farmacológico , Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Camptotecina/análogos & derivados , Imunoconjugados/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Trastuzumab/administração & dosagem , Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Área Sob a Curva , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Imunoconjugados/farmacocinética , Imunoconjugados/uso terapêutico , Estimativa de Kaplan-Meier , Modelos Logísticos , Análise Multivariada , Modelos de Riscos Proporcionais , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Trastuzumab/farmacocinética , Trastuzumab/uso terapêuticoRESUMO
BACKGROUND: Hundreds of millions of people get a mosquito-borne disease every year and nearly one million die. Transmission of these infections is primarily tackled through the control of mosquito vectors. The accurate quantification of mosquito dispersal is critical for the design and optimization of vector control programs, yet the measurement of dispersal using traditional mark-release-recapture (MRR) methods is logistically challenging and often unrepresentative of an insect's true behavior. Using Aedes aegypti (a major arboviral vector) as a model and two study sites in Singapore, we show how mosquito dispersal can be characterized by the spatial analyses of genetic relatedness among individuals sampled over a short time span without interruption of their natural behaviors. RESULTS: Using simple oviposition traps, we captured adult female Ae. aegypti across high-rise apartment blocks and genotyped them using genome-wide SNP markers. We developed a methodology that produces a dispersal kernel for distance which results from one generation of successful breeding (effective dispersal), using the distance separating full siblings and 2nd- and 3rd-degree relatives (close kin). The estimated dispersal distance kernel was exponential (Laplacian), with a mean dispersal distance (and dispersal kernel spread σ) of 45.2 m (95% CI 39.7-51.3 m), and 10% probability of a dispersal > 100 m (95% CI 92-117 m). Our genetically derived estimates matched the parametrized dispersal kernels from previous MRR experiments. If few close kin are captured, a conventional genetic isolation-by-distance analysis can be used, as it can produce σ estimates congruent with the close-kin method if effective population density is accurately estimated. Genetic patch size, estimated by spatial autocorrelation analysis, reflects the spatial extent of the dispersal kernel "tail" that influences, for example, the critical radii of release zones and the speed of Wolbachia spread in mosquito replacement programs. CONCLUSIONS: We demonstrate that spatial genetics can provide a robust characterization of mosquito dispersal. With the decreasing cost of next-generation sequencing, the production of spatial genetic data is increasingly accessible. Given the challenges of conventional MRR methods, and the importance of quantified dispersal in operational vector control decisions, we recommend genetic-based dispersal characterization as the more desirable means of parameterization.
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Aedes/fisiologia , Distribuição Animal , Controle de Mosquitos , Mosquitos Vetores/fisiologia , Aedes/genética , Animais , Variação Genética , Mosquitos Vetores/genética , Singapura , Análise Espacial , Fatores de TempoRESUMO
House Index, Container Index, and Breteau Index are the most commonly used indices for dengue vector surveillance. However, these larval indices are a poor proxy for measuring the adult population-which is responsible for disease transmission. Information on the adult distribution and density are important for assessing transmission risk as well as for developing effective control strategies. This study introduces a new entomological index, Gravitrap aegypti index (GAI), which estimates the adult female Aedes aegypti population in the community and presents its association with dengue cases. Gravitraps were deployed across 34 treatment sites in Singapore from September 2013 to September 2016. The GAI, derived from the Gravitrap surveillance data, was analysed to investigate the spatio-temporal patterns of the Ae. aegypti population in Singapore. The index was further categorised into low, moderate, and high-risk groups and its association with dengue cases were examined. A Before-After Control Impact analysis was performed to evaluate the epidemiology impact of Gravitrap system on dengue transmission. The Ae. aegypti population exhibits a seasonal pattern, and spatial heterogeneity in Ae. aegypti abundance was observed among treatment sites. The Ae. aegypti population was also found to be unevenly distributed among floors of an apartment block, with low floors (floors 1-4) having a higher abundance of mosquitoes trapped than mid (floors 5-8) and high (floors ≥9) floors. Areas with high GAI were shown to have higher dengue case count. Gravitrap has also demonstrated to be a good dengue control tool. The contribution of cases by treatment sites to the national numbers was lower after Gravitraps deployment. The GAI, which is of better relevance to dengue transmission risk, could be recommended as an indicator for decision making in vector control efforts, and to monitor the spatio-temporal variability of the adult Aedes population in the country. In addition, findings from this study indicate that Gravitraps can be used as a dengue control tool to reduce dengue transmission.
Assuntos
Aedes/fisiologia , Surtos de Doenças/prevenção & controle , Controle de Mosquitos/instrumentação , Controle de Mosquitos/métodos , Aedes/virologia , Animais , Dengue/epidemiologia , Vírus da Dengue , Meio Ambiente , Feminino , Insetos Vetores , Densidade Demográfica , SingapuraRESUMO
Though the blood-brain barrier (BBB) is vital for the maintenance of brain homeostasis, it also accounts for a high attrition rate of therapies targeting the central nervous system (CNS). The challenge of delivery across the BBB is attributed to a combination of low permeability through an endothelium closely knit by tight and adherens junctions, extremely low rates of endothelial transcytosis, and efflux transporters. In the past decade, enormous research efforts have been spent to develop BBB penetration strategies using biochemical or physical stimuli, aided by BBB-on-chips or microphysiological BBB models to facilitate in vitro studies. Here, we discuss recent advances in BBB-chip technology that have enabled effective preclinical screenings of brain targeting therapeutics and external stimulation, such as sonoporation and electroporation, for improved BBB penetration.
Assuntos
Barreira Hematoencefálica , Preparações Farmacêuticas , Transporte Biológico , Encéfalo , Sistemas de Liberação de MedicamentosRESUMO
Liquid biopsy holds promise towards practical implementation of personalized theranostics of cancer. In particular, circulating tumour cells (CTCs) can provide clinically actionable information that can be directly linked to prognosis or therapy decisions. In this study, gene expression patterns and genetic mutations in single CTCs are simultaneously analysed by strategically combining microfluidic technology and in situ molecular profiling technique. Towards this, the development and demonstration of the OPENchip (On-chip Post-processing ENabling chip) platform for single CTC analysis by epithelial CTC enrichment and subsequent in situ molecular profiling is reported. For in situ molecular profiling, padlock probes that identify specific desired targets to examine biomarkers of clinical relevance in cancer diagnostics were designed and used to create libraries of rolling circle amplification products. We characterize the OPENchip in terms of its capture efficiency and capture purity, and validate the probe design using different cell lines. By integrating the obtained results, molecular analyses of CTCs from metastatic breast cancer (HER2 (ERBB2) gene expression and PIK3CA mutations) and metastatic pancreatic cancer (KRAS gene mutations) patients were demonstrated without any off-chip processes. The results substantiate the potential implementation of early molecular detection of cancer through sequencing-free liquid biopsy.
Assuntos
Neoplasias da Mama , Células Neoplásicas Circulantes , Neoplasias da Mama/genética , Feminino , Expressão Gênica , Humanos , Biópsia Líquida , Mutação , Análise de Sequência com Séries de OligonucleotídeosRESUMO
PURPOSE: Trastuzumab deruxtecan (T-DXd, formerly DS-8201a) is a novel human epidermal growth factor receptor 2 (HER2)-targeted antibody drug conjugate (ADC) with a topoisomerase I inhibitor payload. A dose escalation and expansion phase I study evaluated the safety and activity of T-DXd in patients with advanced HER2-expressing/mutated solid tumors. Here, results for T-DXd at the recommended doses for expansion (RDE) in patients with HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization-) breast cancer (ClinicalTrials.gov identifier: NCT02564900) are reported. PATIENTS AND METHODS: Eligible patients had advanced/metastatic HER2-low-expressing breast cancer refractory to standard therapies. The RDE of 5.4 or 6.4 mg/kg T-DXd were administered intravenously once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. Antitumor activity and safety were assessed. RESULTS: Between August 2016 and August 2018, 54 patients were enrolled and received ≥ 1 dose of T-DXd at the RDE. Patients were extensively pretreated (median, 7.5 prior therapies). The confirmed objective response rate by independent central review was 20/54 (37.0%; 95% CI, 24.3% to 51.3%) with median duration of response of 10.4 months (95% CI, 8.8 month to not evaluable). Most patients (53/54; 98.1%) experienced ≥ 1 treatment-emergent adverse event (TEAE; grade ≥ 3; 34/54; 63.0%). Common (≥ 5%) grade ≥ 3 TEAEs included decreases in neutrophil, platelet, and WBC counts; anemia; hypokalemia; AST increase; decreased appetite; and diarrhea. Three patients treated at 6.4 mg/kg suffered fatal events associated with T-DXd-induced interstitial lung disease (ILD)/pneumonitis as determined by an independent adjudication committee. CONCLUSION: The novel HER2-targeted ADC, T-DXd, demonstrated promising preliminary antitumor activity in patients with HER2-low breast cancer. Most toxicities were GI or hematologic in nature. ILD is an important identified risk and should be monitored closely and proactively managed.