A glucose-responsive âclosed-loopâ insulin delivery system mimicking the function of pancreatic cells has tremendous potential to improve quality of life and health in diabetics. Here, we report ...a novel glucose-responsive insulin delivery device using a painless microneedle-array patch (âsmart insulin patchâ) containing glucose-responsive vesicles (GRVs; with an average diameter of 118 nm), which are loaded with insulin and glucose oxidase (GO â) enzyme. The GRVs are self-assembled from hypoxia-sensitive hyaluronic acid (HS-HA) conjugated with 2-nitroimidazole (NI), a hydrophobic component that can be converted to hydrophilic 2-aminoimidazoles through bioreduction under hypoxic conditions. The local hypoxic microenvironment caused by the enzymatic oxidation of glucose in the hyperglycemic state promotes the reduction of HS-HA, which rapidly triggers the dissociation of vesicles and subsequent release of insulin. The smart insulin patch effectively regulated the blood glucose in a mouse model of chemically induced type 1 diabetes. The described work is the first demonstration, to our knowledge, of a synthetic glucose-responsive device using a hypoxia trigger for regulation of insulin release. The faster responsiveness of this approach holds promise in avoiding hyperglycemia and hypoglycemia if translated for human therapy.
Drug delivery systems inspired by natural particulates hold great promise for targeted cancer therapy. An endosome formed by internalization of plasma membrane has a massive amount of membrane ...proteins and receptors on the surface, which is able to specifically target the homotypic cells. Herein, we describe a simple method to fabricate an internalized compartments encapsulated nanogel with endosome membrane components (EM-NG) from source cancer cells. Following intracellular uptake of methacrylated hyaluronic acid (m-HA) adsorbed SiO2/Fe3O4 nanoparticles encapsulating a crosslinker and a photoinitiator, EM-NG was readily prepared through in situ crosslinking initiated under UV irradiation after internalization. The resulting nanogels loaded with doxorubicin (DOX) displayed enhanced internalization efficiency to the source cells through a specific homotypic affinity in vitro. However, when treated with the non-source cells, the EM-NGs exhibited insignificant difference in therapeutic efficiency compared to a bare HA nanogel with DOX. This study illustrates the potential of utilizing an internalized compartments encapsulated formulation for targeted cancer therapy, and offers guidelines for developing a natural particulate-inspired drug delivery system.
Drug delivery systems inspired by natural particulates hold great promise for targeted cancer therapy. An endosome formed by internalization of plasma membrane has a massive amount of membrane ...proteins and receptors on the surface, which is able to specifically target the homotypic cells. Herein, we describe a simple method to fabricate an internalized compartments encapsulated nanogel with endosome membrane components (EM-NG) from source cancer cells. Following intracellular uptake of methacrylated hyaluronic acid (m-HA) adsorbed SiO
2
/Fe
3
O
4
nanoparticles encapsulating a crosslinker and a photoinitiator, EM-NG was readily prepared through
in situ
crosslinking initiated under UV irradiation after internalization. The resulting nanogels loaded with doxorubicin (DOX) displayed enhanced internalization efficiency to the source cells through a specific homotypic affinity
in vitro
. However, when treated with the non-source cells, the EM-NGs exhibited insignificant difference in therapeutic efficiency compared to a bare HA nanogel with DOX. This study illustrates the potential of utilizing an internalized compartments encapsulated formulation for targeted cancer therapy, and offers guidelines for developing a natural particulate-inspired drug delivery system.
Drug delivery systems inspired by natural particulates hold great promise for targeted cancer therapy.
Drug delivery systems inspired by natural particulates hold great promise for targeted cancer therapy. Endosome formed by internalization of plasma membrane has massive of membrane proteins and ...receptors on the surface, which is able to specifically target to the homotypic cells. Herein, we describe a simple method to fabricate an endosome membrane-coated nanogel (EM-NG) from source cancer cells. Following intracellular uptake of methacrylated hyaluronic acid (
m
-HA) adsorbed SiO
2
/Fe
3
O
4
nanoparticles encapsulating crosslinker and photoiniator, EM-NG was readily prepared through
in situ
crosslinking initiated under UV irradiation inside endosome. The resulting endosome mimetic nanogels loaded with Doxorubicin (DOX) displayed enhanced internalization efficiency to the source cells through a specific homotypic affinity
in vitro
. However, when treated the non-source cells, the EM-NGs exhibited insignificant difference in therapeutic efficiency compared to bare HA nanogel with DOX. This study illustrates the potential of utilizing endosome membrane-mimicking formulation for targeted cancer therapy, and offers guideline for developing natural particulates-inspired drug delivery system.
Diabetes is a major public health problem currently affecting 382 million people across the world. A synthetic insulin delivery system that mimics the function of insulin-secreting cells and ...continuously releases insulin in response to blood glucose level changes holds great promise in improving the quality of life for diabetics. Here we report a new glucose-responsive formulation for self-regulated delivery of insulin using injectable hyaluronic acid (HA) microgels (µHA, average diameter: 5.9 ± 2.3
µ
m) integrated with acid-degradable ketal-modified dextran-based glucose responsive nanoparticles (GRN, average diameter: 226.9 ± 20.6 nm). Packed with insulin and a glucose-specific enzyme (glucose oxidase, GOx) by a double-emulsion method, the dextran nanoparticles can be dissolved and subsequently release insulin in a hyperglycemic state, triggered by the enzymatic conversion of glucose into gluconic acid. To further avoid the burst release, reduce loss of enzymes, and facilitate administration, we integrated nanoparticles into HA microgels, crosslinked through an emulsion procedure.
In vitro
studies demonstrated that the insulin release rate associated with HA microgels was effectively regulated by changes in the glucose concentration.
In vivo
studies, in which chemically-induced type 1 diabetic mice were subcutaneously injected with the microgels, validated that a single injection of the developed formulation stabilized the blood glucose levels in the normoglycemic state (<200 mg/dL) for over 1 week.
Justification for the Proposed Workshop:As more medical practices adopt the use of interconnected Electronic Health Records (EHR’s), the issue of overdiagnosis may become increasingly impactful as a ...single EHR may be accessed by multiple care providers in distinct clinical settings, each with variable pre-existing relationships to the patient. In such contexts, overdiagnosed conditions applied to a patient’s problem list may result in unintended downstream consequences in excess of those that might be expected from the use of more traditional, site-specific paper charts. As such, the widespread use of interconnected EHR’s may exacerbate long-term patient labelling associated with an overdiagnosed condition. Evidencing the need for caution regarding overdiagnosis and the use of EHR’s are studies which have previously shown that patients who have had a misdiagnosed and/or overdiagnosed antibiotic hypersensitivity applied to their EHR are less likely to receive optimal therapy in the future and are therefore exposed to potentially worse clinical outcomes.Following the recent inclusion of the term ‘overdiagnosis’ to the list of searchable medical subject headings (MeSH) of the US National Library of Medicine, researchers are now able to research the topic of overdiagnosis more efficiently. We propose that a workshop be conducted to draw upon the collective knowledge Preventing Overdiagnosis 2022 Conference attendees with the goal of formalizing a proposed research agenda for topics related to how the use of EHR’s may be contributing to the overdiagnosis problem. As a team of facilitators, the authors of this proposal would plan to lead the attendees of this workshop into separate breakout group discussions each aimed at exploring suggested research topics and their associated ethical considerations.Suggested Topics for Discussion:What might patient preferences be regarding the duration that a diagnosis remains on the patient’s problem list? Might these preferences change depending on the diagnosis?Should approaches be adopted to limit the lifespan of a diagnostic label within an EHR?What are the potential benefits of a diagnostic label persisting indefinitely within a patient’s EHR? What are the potential harms of a diagnostic label persisting indefinitely within a patient’s EHR?Projected Outcomes of the Proposed Workshop:Attendees will gather an increased understanding of this topic through direct discussion with colleagues and subject-matter-experts.The authors of this proposal would collect the deliberations and conclusions accumulated through this interactive workshop to develop a commentary for publication outlining the specific agenda-items suggested for future research.
Mobile phone mental health applications (apps) are widely used, and usage has only been accelerated by the global COVID-19 pandemic. These apps often offer a suggested diagnosis as well as treatment ...guidance. Despite the extensive use of these apps, there is no evidence on the effect they may have on overdiagnosis of mental health conditions, specifically depression. Given the nature of mental health, overdiagnosis can be particularly difficult to quantify and attempts to study overdiagnosis in mental health have often focused on misdiagnosis. Overdiagnosis is separate from misdiagnosis and occurs when overdetection or overdefinition occur. Overdefinition is of relevance in mental health as the DSM-V criteria have been critiqued as being overinclusive such that normal aspects of life are medicalized. Overdiagnosis of depression can have significant effects on the user in the forms of treatment side effects, stigma and labelling harms as well as direct and indirect costs. From a systems level, overdiagnosis results in inefficient use of resources and potential diversion of resources away from those most in need.ObjectivesTo understand if mobile phone mental health apps have the potential to contribute to the overdiagnosis of depression in users with milder and self-limited depressive symptoms or grief reactions.MethodsA review of the relevant literature was conducted using PubMed. The top 25 apps using the search term ‘depression’ on the Apple App Store and Google Play App Store were reviewed.ResultsNumerous apps (8/25 on each app store) inappropriately used a general screening and treatment response tracking tool, the PHQ-9 questionnaire, as a diagnostic tool. These apps and others provided users with a suggested diagnosis of depression in the context of short term mild depressive symptoms that do not meet DSM-V criteria for Major Depressive Disorder (MDD). This may reflect misdiagnosis, however beyond this phenomenon, these apps appear to be susceptible to overdiagnosis as well. Users may meet diagnostic criteria for MDD however symptoms may be sufficiently transient or mild that clinicians using their clinical judgement would not make a diagnosis of depression. Mental health apps lack this fine-tuned clinical judgment and have the potential to indiscriminately make the diagnosis in those experiencing non-pathologic aspects of everyday experiences. The top 12 apps in each store represent greater than 90% of the monthly active users of all depression apps. Among the top 12 apps, 4/12 after making a suggested diagnosis of depression then offered links to for profit web-based therapy services that in some cases have funded the app itself or reimbursed the app for successful referrals.ConclusionPhysicians need to be aware of this potential for overdiagnosis of depression and should clarify how a patient’s previous history of depression was diagnosed. Additionally, patients presenting with depressive symptoms may have already used these apps to reach a premature diagnostic conclusion and expect a certain level of treatment based on the recommendations of these apps. This can strain the therapeutic relationship and care must be taken to explain the nuances of diagnosis and treatment that these apps often overlook.
To evaluate tumor response, pharmacodynamic effects, and safety of a combination of lomeguatrib (LM), an O6-methylguanine DNA-methyltransferase (MGMT) inactivator, and temozolomide (TMZ), TMZ alone, ...and LM/TMZ after disease progression on TMZ alone in patients with advanced melanoma.
Patients with unresectable stage III or IV cutaneous melanoma who had no prior systemic chemotherapy were randomly assigned to receive either 40 to 80 mg LM and 125 mg/m2 TMZ or 200 mg/m2 TMZ on days 1 through 5 of each 28-day treatment cycle. Drugs were administered orally for up to six cycles of treatment. Patients on TMZ alone were offered LM/TMZ at progression, if fit enough to receive treatment.
One hundred four patients were enrolled, with 52 in each trial arm. Twenty-seven TMZ-treated patients received LM/TMZ after progression on TMZ. Unexpectedly, analysis of tumor biopsies showed rapid recovery of MGMT after LM/TMZ with 40 mg/d LM. Therefore, doses of LM were escalated to 60 then 80 mg/d. Tumor response rates were 13.5% with LM/TMZ and 17.3% with TMZ alone. No patient responded to LM/TMZ having progressed through TMZ. Median time to disease progression was 65.5 days for LM/TMZ and 68 days for TMZ. All treatments were well tolerated, although hematologic and gastrointestinal adverse events were common. A higher incidence of hematological adverse events was observed in the LM/TMZ combination arm.
The efficacy of LM and TMZ in the current dosing schedule is similar to that of TMZ alone. To maintain MGMT depletion in tumor dosing of LM needs to be continued beyond that of TMZ.
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