Electrochemical-Shock Synthesis of Nanoparticles from Sub-femtoliter Nanodroplets.

ConspectusNanoparticles have witnessed immense development in the past several decades due to their intriguing physicochemical properties. The modern chemist is interested not only in methods of synthesizing nanoparticles with tunable properties but also in the chemistry that nanoparticles can drive. While several methods exist to synthesize nanoparticles, it is often advantageous to put nanoparticles on a variety of conductive substrates for multiple applications (such as energy storage and conversion). Despite enjoying over 200 years of development, electrodeposition of nanoparticles suffers from a lack of control over nanoparticle size and morphology. There have been heroic efforts to address these issues over time. With an understanding that structure-function studies are imperative to understand the chemistry of nanoparticles, new methods are necessary to electrodeposit a variety of nanoparticles with control over macromorphology and also microstructure.This Account details our group's efforts in overcoming challenges of classical nanoparticle electrodeposition by electrodepositing nanoparticles from water nanodroplets. When a nanodroplet full of metal salt precursor is incident on the electrode biased sufficiently negative to drive electroplating, nanoparticles form at a fast rate (on the order of microseconds to milliseconds). We start with the general nuts-and-bolts of the experiment (nanodroplet formation and methods for electrodeposition). The deposition of new nanomaterials often requires one to develop new methods of measurement, and we detail new measurement tools for quantifying nanoparticle porosity and nanopore tortuosity within single nanoparticles. We achieve nanopore characterization by using Focused Ion Beam milling and Scanning Electron Microscopy. Owing to the small size of the nanodroplets and fast mass transfer (the contents of a femtoliter droplet can be electrolyzed in only a few milliseconds), the use of nanodroplets also allows the electrodeposition of high entropy alloy nanoparticles at room temperature.We detail how a deep understanding of ion transfer mechanisms can be used to expand the library of possible metals that can be deposited. Furthermore, simple ion changes in the dispersed droplet phase can decrease the cost per experiment by orders of magnitude. Finally, electrodeposition in aqueous nanodroplets can also be combined with stochastic electrochemistry for a variety of interesting studies. We detail the quantification of the growth kinetics of single nanoparticles in single aqueous nanodroplets. Nanodroplets can also be used as tiny reactors to trap only a few molecules of a metal salt precursor. Upon reduction to the zerovalent metal, electrocatalysis at very small metal clusters can be probed and evaluated with time using steady-state electrochemical measurements. Overall, this burgeoning synthetic tool is providing unexpected avenues of tunability of metal nanoparticles on conductive substrates.

Measurement of Neuropeptide Y Using Aptamer-Modified Microelectrodes by Electrochemical Impedance Spectroscopy.

Aptamer-modified microelectrodes for Neuropeptide Y measurement by electrochemical impedance spectroscopy was described here. The advantages of using carbon fiber or platinum microelectrodes are because they are promising materials with high electrical conductivity, chemical stability, and high surface area that can be easily modified on their surface. The immobilization and biofouling were studied and compared using EIS. Moreover, the adsorption of NPY to the aptamer-modified microelectrodes was also demonstrated by EIS. Changes of -ω*Zimag, an impedance factor that gives information of the capacitance, is directly correlated with concentrations. A widely linear range was obtained from 10 to 1000 ng/mL of NPY. This method was able to detect NPY without performing a redox reaction by adsorption at the surface of the microelectrodes, with the specificity provided by aptamer functionalization of the microelectrode surface.

Checkpoint Inhibitors for Non-Small Cell Lung Cancer Among Older Adults.

Non-small cell lung cancer (NSCLC) is mostly a disease of older adults, with its incidence and mortality rates increasing exponentially after the age of 65 years. Immune checkpoint inhibitors (ICIs) have changed the scene of NSCLC treatment after a long and relatively stagnant period of standard treatment regimens. However, little is known about the specific impact of these agents in older adults for whom care is often complicated by a variety of syndromes. This underlines the importance of understanding the dynamics of new cancer treatments in an older patient population. In this paper, we will review ICIs' mechanism of action and data from published clinical trials relevant to older adults. In addition, we will discuss immune aging and treatment-related toxicity as potential challenges facing the use of checkpoint inhibitors in older adults with NSCLC.

Immune Checkpoint Inhibitors in Older Adults.

Cancer is primarily a disease of older adults. The treatment of advanced stage tumors usually involves the use of systemic agents that may be associated with significant risk of toxicity, especially in older patients. Immune checkpoint inhibitors are newcomers to the oncology world with improved efficacy and better safety profiles when compared to traditional cytotoxic drugs. This makes them an attractive treatment option. While there are no elderly specific trials, this review attempts to look at the current available data from a geriatric oncology perspective. We reviewed data from phase III studies that led to newly approved indications of checkpoint inhibitors in non-small cell lung cancer, melanoma, and renal cell cancer. Data were reviewed with respect to response, survival, and toxicity according to three groups: <65 years, 65-75 years, and >75 years. Current literature does not allow one to draw definitive conclusions regarding the role of immune checkpoint inhibitors in older adults. However, they may offer a potentially less toxic but equally efficacious treatment option for the senior adult oncology patient.

Anodic Electrodeposition of IrO x Nanoparticles from Aqueous Nanodroplets.

Electrodeposition has been used for centuries to create new materials. However, synthetic platforms are still necessary to enrich a variety of nanomaterials that can be electrodeposited. For instance, IrO x is a popular material for the water oxidation reaction, but electrodeposition strategies for the controlled growth of IrO x nanoparticles are lacking. Here, we demonstrate the anodic electrodeposition of IrO x nanoparticles from aqueous nanodroplets. Field emission scanning electron microscopy (FESEM) and scanning transmission electron microscopy (STEM) images confirm the macro- and microstructure of the resulting nanoparticles. IrO x nanoparticles of 43 ± 10 nm in diameter were achieved. X-ray photoelectron spectroscopy (XPS) showed the presence of Ir(III) and Ir(IV) hydrated oxyhydroxide species. The synthesis of IrO x nanoparticles under anodic conditions using water nanodroplets expands the capabilities of our technique and provides a tunable platform for IrO x nanoparticle electrodeposition.

Case Report of Seronegative Cancer-Associated Retinopathy in a Patient with Small Cell Lung Carcinoma.

Cancer-associated retinopathy (CAR) is a rare paraneoplastic syndrome characterized by autoimmune destruction of photoreceptor cells. It is associated with several tumor types, including small cell lung carcinoma (SCLC). Corticosteroids have been the mainstay treatment for CAR, although no therapeutic standard has truly been established. A 66-year-old female with significant smoking history and age-related macular degeneration (ARMD) presented with rapidly declining bilateral visual acuity. Ophthalmologic examination findings appeared consistent with the known diagnosis of ARMD but did not otherwise present a clear alternative etiology. Imaging with a computed tomography (CT) scan revealed a right hilar mass which was confirmed to be limited stage SCLC based on a subsequent biopsy and further imaging with a positron emission tomography/computed tomography (PET/CT) scan. Antibody testing was negative for anti-recoverin antibodies. The patient experienced a complete response to chemoradiation with cisplatin and etoposide; however, her ocular symptoms did not respond to a combined treatment approach with corticosteroids, plasmapheresis, and intravenous immunoglobulin (IVIG). While CAR represents a rare condition in SCLC, cases that are seronegative for anti-recoverin are even less common. Further, the diagnosis of CAR by ophthalmologic examination may be more challenging in patients with pre-existing ocular diseases, such as macular degeneration. Clinicians should have suspicion for paraneoplastic blindness in patients with known risk factors for malignancy, whose ocular symptoms are inconsistent with exam findings.

Friend or Foe: Factor XII Deficiency Discovered Incidentally during Management of NSTEMI.

Factor XII (FXII) deficiency is a rare coagulopathy that typically goes undiagnosed due to the lack of abnormal bleeding or thrombosis. However, the accompanying prolonged activated partial thromboplastin time (aPTT) can create difficulties with maintaining therapeutic anticoagulation in the setting of acute coronary syndrome (ACS). Here, we present the case of a 52-year-old man presenting with chest pain and diagnosed with an NSTEMI but also found with a prolonged baseline aPTT ultimately secondary to FXII deficiency. Here, we discuss the diagnostic work-up of an isolated prolonged aPTT to identify possible etiologies, such as FXII deficiency, and ultimately inform ACS management.

A Review of Hodgkin Lymphoma in the Era of Checkpoint Inhibitors.

Hodgkin lymphoma (HL) is a hematopoietic malignancy of B-cells that has a bimodal distribution with respect to age and incidence. With the introduction of doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) and radiation combined, the prognosis of HL has significantly improved, with five-year survival rates approaching 95%. While HL has become highly curable, the side effect profiles of ABVD are dire and warrant continuous review. Because HL is often diagnosed in populations in their 20s-30s, patients are forced to undergo fertility preservation procedures as well as deal with other long-term side effects of chemotherapy (including doxorubicin dose-dependent cardiotoxicity and bleomycin-induced lung toxicity). The opportunity cost of the treatment in the short term and vulnerability to treatment-induced malignancies decades later dramatically affect the quality of life of HL patients. New therapies have developed over the past several decades with respect to immunotherapies, particularly programmed death protein 1 inhibitors (e.g., nivolumab and pembrolizumab). Studies have shown checkpoint inhibitors to be effective in treating HL with an objective response rate of 69% for relapsed/refractory classical HL for nivolumab use. Checkpoint inhibitors will continue to help maintain the high five-year survival rate for HL and hopefully have a more favorable side effect profile in the short term, as well as later in the patient's life. This article seeks to summarize treatment options for HL while comparing outcomes and side effect profiles with the addition of checkpoint inhibitors.

IL-4 and TGF-beta 1 counterbalance one another while regulating mast cell homeostasis.

Mast cell responses can be altered by cytokines, including those secreted by Th2 and regulatory T cells (Treg). Given the important role of mast cells in Th2-mediated inflammation and recent demonstrations of Treg-mast cell interactions, we examined the ability of IL-4 and TGF-beta1 to regulate mast cell homeostasis. Using in vitro and in vivo studies of mouse and human mast cells, we demonstrate that IL-4 suppresses TGF-beta1 receptor expression and signaling, and vice versa. In vitro studies demonstrated that IL-4 and TGF-beta1 had balancing effects on mast cell survival, migration, and FcepsilonRI expression, with each cytokine cancelling the effects of the other. However, in vivo analysis of peritoneal inflammation during Nippostrongylus brasiliensis infection in mice revealed a dominant suppressive function for TGF-beta1. These data support the existence of a cytokine network involving the Th2 cytokine IL-4 and the Treg cytokine TGF-beta1 that can regulate mast cell homeostasis. Dysregulation of this balance may impact allergic disease and be amenable to targeted therapy.

Enabling practical nanoparticle electrodeposition from aqueous nanodroplets.

The rapid rise of technology in the modern world has led to an increased demand for energy. Consequently, it is essential to increase the efficiency of current energy-producing systems due to the poor activity of their catalysts. Nanoparticles play a significant role in energy storage and conversion; however, electrodeposition of nanoparticles is difficult to achieve due to surface heterogeneities, nanoparticle diffusion layer overlap, and the inability to electrodeposit multi-metallic nanoparticles with stoichiometric control. These problems can be solved through nanodroplet-mediated electrodeposition, a technique where water nanodroplets are filled with metal salt precursors that form stable nanoparticles when they collide with a negatively-biased electrode. Further, this method has demonstrated control over nanoparticle size and morphology, displaying a wide variety of applications for the generation of materials with excellent catalytic properties. Historically, the cost of nanodroplet-mediated electrodeposition experimentation is prohibitive because practitioners use 0.1 M to 0.5 M tetrabutylammonium perchlorate (TBAP) dissolved in the oil phase (∼10 mL). Such high concentrations of electrolytes have been used to lower ohmic drop and provide ions to maintain charge balance during electrodeposition. Here, we show that supporting electrolyte is not necessary for the oil phase. In fact, one can use a suitable salt (such as lithium perchlorate) in the aqueous phase to achieve nanoparticle electrodeposition. This simple change, grounded in an understanding of ion transfer, drives down the cost per experiment by nearly three orders of magnitude, representing a necessary step forward in enabling practical nanoparticle electrodeposition from water nanodroplets. This approach is a promising procedure for future cost-effective energy conversion systems relying on electrocatalytic nanoparticles.

The electrodeposition of gold nanoparticles from aqueous nanodroplets.

Nanodroplet-mediated electrodeposition is a reliable method for electrodepositing nanoparticles by confining a small amount of metal-salt precursor in water nanodroplets (radius ∼400 nm) suspended in an oil continuous phase. This technique provides a great advantage in terms of nanoparticle size, morphology, and porosity. For an electrochemical reaction to proceed in the aqueous nanodroplet, the electroneutrality condition must be maintained. Classically, [NB4][ClO4] or a comparable salt is added to the oil continuous phase to maintain charge balance. Unfortunately, the presence of this salt in the oil phase causes some metal salts, such as HAuCl4, to phase transfer, disallowing the formation of gold nanoparticles. Here, we demonstrate the partitioning of HAuCl4 is orders of magnitude lower using Inductively Coupled Plasma Mass Spectrometry (ICP-MS) when LiClO4 is added to the nanodroplet phase and [NBu4][ClO4] is not added to the continuous phase. This simple change allows for the electrodeposition of gold nanoparticles. Scanning electron microscopy shows the morphology and size distribution of gold nanoparticles obtained at different concentrations of LiClO4. Transmission electron microscopy in selected diffraction mode was used and it determined the gold nanoparticles obtained are polycrystalline with miller indices of (222) and (200). This work widens the variety of nanoparticles that can be electrodeposited from nanodroplets for applications in energy storage and conversion, photoelectrochemistry, and biosensing.

Danger signals and nonself entity of tumor antigen are both required for eliciting effective immune responses against HER-2/neu positive mammary carcinoma: implications for vaccine design.

Using parental FVB mice and their neu transgenic counterparts, FVBN202, we showed for the first time that dangerous hyperplasia of mammary epithelial cells coincided with breaking immunological tolerance to the neu "self" tumor antigen, though such immune responses failed to prevent formation of spontaneous neu-overexpressing mammary carcinoma (MMC) or reject transplanted MMC in FVBN202 mice. On the other hand, neu-specific immune responses appeared to be effective against MMC in parental FVB mice because of the fact that rat neu protein was seen as "nonself" antigen in these animals and the protein was dangerously overexpressed in MMC. Interestingly, low/intermediate expression of the neu "nonself" protein in tumors induced immune responses but such immune responses failed to reject the tumor in FVB mice. Our results showed that self-nonself (SNS) entity of a tumor antigen or danger signal alone, while may equally induce an antigen-specific immune response, will not warrant the efficacy of immune responses against tumors. On the other hand, entity of antigen in the context of dangerous conditions, i.e. abnormal/dangerous overexpression of the neu nonself protein, will warrant effective anti-tumor immune responses in FVB mice. This unified "danger-SNS" model suggests focusing on identification of naturally processed cryptic or mutated epitopes, which are considered semi-nonself by the host immune system, along with novel dangerous adjuvant in vaccine design.