Tuning Shortwave-Infrared J-aggregates of Aromatic Ring-Fused Aza-BODIPYs by Peripheral Substituents for Combined Photothermal and Photodynamic Therapies at Ultralow Laser Power.

Achieving photothermal therapy (PTT) at ultralow laser power density is crucial for minimizing photo-damage and allowing for higher maximum permissible skin exposure. However, this requires photothermal agents to possess not just superior photothermal conversion efficiency (PCE), but also exceptional near-infrared (NIR) absorptivity. J-aggregates, exhibit a significant redshift and narrower absorption peak with a higher extinction coefficient. Nevertheless, achieving predictable J-aggregates through molecular design remains a challenge. In this study, we successfully induced desirable J-aggregation (λabs max : 968 nm, ϵ: 2.96×105  M-1 cm-1 , λem max : 972 nm, ΦFL : 6.2 %) by tuning electrostatic interactions between π-conjugated molecular planes through manipulating molecular surface electrostatic potential of aromatic ring-fused aza-BODIPY dyes. Notably, by controlling the preparation method for encapsulating dyes into F-127 polymer, we were able to selectively generate H-/J-aggregates, respectively. Furthermore, the J-aggregates exhibited two controllable morphologies: nanospheres and nanowires. Importantly, the shortwave-infrared J-aggregated nanoparticles with impressive PCE of 72.9 % effectively destroyed cancer cells and mice-tumors at an ultralow power density of 0.27 W cm-2 (915 nm). This phototherapeutic nano-platform, which generates predictable J-aggregation behavior, and can controllably form J-/H-aggregates and selectable J-aggregate morphology, is a valuable paradigm for developing photothermal agents for tumor-treatment at ultralow laser power density.

Revolutionary Pyrazole-based Aza-BODIPY: Harnessing Photothermal Power Against Cancer Cells and Bacteria.

In the realm of cancer therapy and treatment of bacterial infection, photothermal therapy (PTT) stands out as a potential strategy. The challenge, however, is to create photothermal agents that can perform both imaging and PTT, a so-called theranostic agent. Photothermal agents that absorb and emit in the near-infrared region (750-900 nm) have recently received a lot of attention due to the extensive penetration of NIR light in biological tissues. In this study, we combined pyrazole with aza-BODIPY (PY-AZB) to develop a novel photothermal agent. PY-AZB demonstrated great photostability with a photothermal conversion efficiency (PCE) of up to 33 %. Additionally, PY-AZB can permeate cancer cells at a fast accumulation rate in less than 6 hours, according to the confocal images. Furthermore, in vitro photothermal therapy results showed that PY-AZB effectively eliminated cancer cells by up to 70 %. Interestingly, PY-AZB exhibited antibacterial activities against both gram-negative bacteria, Escherichia coli 780, and gram-positive bacteria, Staphylococcus aureus 1466. The results exhibit a satisfactory bactericidal effect against bacteria, with a killing efficiency of up to 100 % upon laser irradiation. As a result, PY-AZB may provide a viable option for photothermal treatment.

Boron-Containing Compounds for Prevention, Diagnosis, and Treatment of Human Metabolic Disorders.

The application of natural and synthetic boron-containing compounds (BCC) in biomedical field is expanding. BCC have effects in the metabolism of living organisms. Some boron-enriched supplements are marketed as they exert effects in the bone and skeletal muscle; but also, BCC are being reported as acting on the enzymes and transporters of membrane suggesting they could modify the carbohydrate metabolism linked to some pathologies of high global burden, as an example is diabetes mellitus. Also, some recent findings are showing effects of BCC on lipid metabolism. In this review, information regarding the effects and interaction of these compounds was compiled, as well as the potential application for treating human metabolic disorders is suggested.

Evaluation of the Key Advantages between Two Modalities of Boronophenylalanine Administration for Clinical Boron Neutron Capture Therapy Using an Animal Model.

In clinical boron neutron capture therapy (BNCT), boronophenylalanine (BPA) administrations through one-step infusion (OSI) and two-step infusion (TSI) are the most widely used. This study compared the advantages of OSI and TSI using a human oral squamous cell carcinoma-bearing animal model. OSI was administered at a high-dose rate of 20 mg/kg/min for 20 min (total dose: 400 mg/kg) as the first step infusion. TSI was a prolonged infusion at a low-dose rate of 1.67 mg/kg/min for 15, 30, 45, and 60 min (total dose: 25, 50, 75, and 100 mg/kg) following the first step infusion. The sigmoid Emax model was used to evaluate the boron accumulation effect in the tumor. The advantages of TSI were observed to be greater than those of OSI. The observed advantages of TSI were as follows: a stable level of boron concentration in blood; tumor to blood boron ratio (T/B); tumor to muscle boron ratio (T/M); and skin to blood boron ratio (S/B). The boron accumulation effect in tumors increased to 68.98%. Thus, effective boron concentration in these tumor cells was achieved to enhance the lethal damage in BNCT treatment. Boron concentration in the blood was equal to that in the skin. Therefore, the equivalent dose was accurately estimated for the skin.

Homocystamide Conjugates of Human Serum Albumin as a Platform to Prepare Bimodal Multidrug Delivery Systems for Boron Neutron Capture Therapy.

Boron neutron capture therapy is a unique form of adjuvant cancer therapy for various malignancies including malignant gliomas. The conjugation of boron compounds and human serum albumin (HSA)-a carrier protein with a long plasma half-life-is expected to extend systemic circulation of the boron compounds and increase their accumulation in human glioma cells. We report on the synthesis of fluorophore-labeled homocystamide conjugates of human serum albumin and their use in thiol-'click' chemistry to prepare novel multimodal boronated albumin-based theranostic agents, which could be accumulated in tumor cells. The novelty of this work involves the development of the synthesis methodology of albumin conjugates for the imaging-guided boron neutron capture therapy combination. Herein, we suggest using thenoyltrifluoroacetone as a part of an anticancer theranostic construct: approximately 5.4 molecules of thenoyltrifluoroacetone were bound to each albumin. Along with its beneficial properties as a chemotherapeutic agent, thenoyltrifluoroacetone is a promising magnetic resonance imaging agent. The conjugation of bimodal HSA with undecahydro-closo-dodecaborate only slightly reduced human glioma cell line viability in the absence of irradiation (~30 µM of boronated albumin) but allowed for neutron capture and decreased tumor cell survival under epithermal neutron flux. The simultaneous presence of undecahydro-closo-dodecaborate and labeled amino acid residues (fluorophore dye and fluorine atoms) in the obtained HSA conjugate makes it a promising candidate for the combination imaging-guided boron neutron capture therapy.

2-Aminoethyl diphenylborinate inhibits bleomycin-induced skin and pulmonary fibrosis via interrupting intracellular Ca2+ regulation.

BACKGROUND: Systemic sclerosis (SSc) causes progressive fibrosis of multiple organs with the low efficacy of immunosuppressive therapies. Our previous study indicated the SSc pathological pathways are closely correlated with Ca2+ signals, and blockage of the intracellular Ca2+ elevation facilitates inhibition of SSc pathogenesis. OBJECTIVE: Transforming growth factor ß (TGF-ß)-modulated SMAD signaling is crucial in regulating SSc pathogenesis. Whether Ca2+ signals are involved in TGF-ß1/SMAD signaling-induced fibrotic process has been further investigated. METHODS: We utilized TGF-ß1-induced myofibroblasts as a model to detect how Ca2+ signals affected SSc pathogenesis, and investigated the combination of treatment with store-operated Ca2+ entry (SOCE) associated inhibitors, 2-aminoethyl diphenylborinate (2-APB) and SKF96365 to restrain the increased Ca2+ signaling in myofibroblasts. In addition, the SSc bleomycin mouse model was used to detect the effect of 2-APB on SSc pathogenesis in vivo. RESULTS: Our findings revealed increased levels of TGF-ß1 production in SSc was associated with intracellular Ca2+ activity, and inhibition of intracellular Ca2+ regulation by 2-APB resulted in the dedifferentiation of TGF-ß1-induced myofibroblasts. This was due to the fact that 2-APB restrained the expression fibrotic markers, α-SMA, fibronectin and vimentin through inhibiting TGF-ß1/SMAD3 signaling. Thus, subcutaneous injection of 2-APB improved bleomycin-induced skin and pulmonary fibrosis. CONCLUSION: 2-APB is a potential candidate for treating fibrosis, by disrupting intracellular Ca2+ regulation in SSc to induce the dedifferentiation of myofibroblasts and meliorates fibrosis pathogenesis via inhibiting TGF-ß1/SMAD3 signaling.

Diagnosis and Management of Dermatitis, Including Atopic, Contact, and Hand Eczemas.

This is a comprehensive and current guide for the diagnosis, differential diagnosis, treatment, and management of eczematous dermatitis, with a focus on atopic dermatitis, irritant and allergic contact dermatitis, hand dermatitis including recurrent vesicular and hyperkeratotic types, asteatotic dermatitis, and nummular or discoid dermatitis. Diagnostic options highlighted are clinical history, physical examination, and patch testing. Therapeutic options highlighted are moisturizers, topical corticosteroids, topical calcineurin inhibitors, crisaborole, phototherapy, and systemic medications including biologics.

Synthesis of enriched boron nitride nanocrystals: A potential element for biomedical applications.

The shortcomings in Boron neutron capture therapy (BNCT) and Hyperthermia for killing the tumor cell desired for the synthesis of a new kind of material suitable to be first used in BNCT and later on enable the conditions for Hyperthermia to destroy the tumor cell. The desire led to the synthesis of large band gap semiconductor nano-size Boron-10 enriched crystals of hexagonal boron nitride (10BNNCs). The contents of 10BNNCs are analyzed with the help of x-ray photoelectron spectroscopy (XPS) and counter checked with Raman and XRD. The 10B-contents in 10BNNCs produce 7Li and 4He nuclei. A Part of the 7Li and 4He particles released in the cell is allowed to kill the tumor (via BNCT) whereas the rest produce electron-hole pairs in the semiconductor layer of 10BNNCs suggested to work in Hyperthermia with an externally applied field.

[Systemic varicella-zoster infection during ixazomib-containing multiagent chemotherapy for multiple myeloma].

A 58-year-old man received high-dose melphalan with autologous peripheral blood stem cell transplantation for multiple myeloma in stringent complete response (sCR). Relapse occurred 4 years after the transplantation, and he was placed on ixazomib, lenalidomide, and dexamethasone (IRd) and achieved sCR. On the 10th day of the 10th course of IRd, he developed fever followed by generalized skin eruption with vesicles, headache, and dizziness. Varicella-zoster virus (VZV) antigen from the vesicle and VZV-DNA from the cerebrospinal fluid were detected, and he was diagnosed with systemic VZV infection. He was placed on intravenous acyclovir (ACV), and the infection resolved completely. VZV infection has been recognized as an important complication associated with the use of proteasome inhibitors; however, to our knowledge, there have been no reported cases of serious systemic VZV infection associated with ixazomib. The clinical course of this case strongly suggests the importance of prophylaxis for VZV infection during treatment with ixazomib.

pH stimulus-disaggregated BODIPY: an activated photodynamic/photothermal sensitizer applicable to tumor ablation.

Herein, we report a pH stimulus-disaggregated BODIPY sensitizer (PTS) with low background-toxicity for achieving activated photodynamic/photothermal tumor therapy. Both the photodynamic and photothermal properties of PTS can be activated under acidic conditions, and PTS exhibits excellent antitumor properties, which is revealed by both in vitro and in vivo tests.

Real-world experience of dupilumab treatment for atopic dermatitis in adults: a retrospective analysis of patients' records.

BACKGROUND: Clinical trial data for dupilumab, a monoclonal antibody against the interleukin-4 receptor (IL-4Rα), have shown that it is safe and effective for the treatment of moderate to severe atopic dermatitis in patients whose disease is resistant to other therapies. However, little real-world experience with dupilumab use has been reported thus far. The aim of this retrospective study was to assess overall outcomes in adult patients with atopic dermatitis (AD) treated with dupilumab. METHODS: A retrospective review of electronic medical records was conducted for patients treated with dupilumab in the Department of Dermatology at the University of California, Irvine. RESULTS: We analyzed the medical records of 77 AD patients who received dupilumab according to standard dosing and had at least one documented follow-up visit. In 66 patients (86%), dupilumab improved clinical disease severity, with 23 patients (30%) experiencing complete clearance on dupilumab. Dupilumab was generally well-tolerated and caused no serious adverse events. The most common side effects included dry eyes, conjunctivitis, and keratitis. The most common reason for discontinuation of treatment was lack of substantial clinical improvement or progression of disease severity, followed by ophthalmologic side effects. CONCLUSIONS: Overall, dupilumab was well-tolerated and resulted in clinical improvement in our patient population. These results provide additional important information on the safety and utility of dupilumab treatment for moderate to severe atopic dermatitis in the real-world clinical setting.

Self-destructive PEG-BODIPY nanomaterials for photodynamic and photothermal therapy.

Photoactive nanoparticles are an important platform for multimodal imaging and phototherapy of tumors. Herein, amphiphilic photosensitizers were made from boron dipyrromethene (BODIPY) and poly(ethylene glycol) (PEG2k) by using a thioketal linker, which is reactive oxygen species-responsive. The photosensitizers could form stable nanoparticles in aqueous solution. The resulting nanoparticles could simultaneously produce heat and reactive oxygen species upon irradiation to achieve combined photothermal and photodynamic therapy. The produced singlet oxygen could destroy the thioketal linker, and accelerate the destruction of nanoparticles. In addition, the near-infrared fluorescence and photoacoustic imaging ability of nanoparticles can reflect the biodistribution and destiny of nanoparticles. This work highlights the application of integrated diagnostic and therapeutic photosensitizers in carriers.

Radiation-induced synthetic lethality: combination of poly(ADP-ribose) polymerase and RAD51 inhibitors to sensitize cells to proton irradiation.

Although improvements in radiation therapy were made over the years, radioresistance is still a major challenge. Cancer cells are often deficient for DNA repair response, a feature that is currently exploited as a new anti-cancer strategy. In this context, combination of inhibitors targeting complementary pathways is of interest to sensitize cells to radiation. In this work, we used PARP (Olaparib) and RAD51 (B02) inhibitors to radiosensitize cancer cells to proton and X-ray radiation. More particularly, Olaparib and B02 were used at concentration leading to limited cytotoxic (alone or in combination) but increasing cell death when the cells were irradiated. We showed that, although at limited concentration, Olaparib and B02 were able to radiosensitize different cancer cell lines, i.e. lung and pancreatic cancer cells. Antagonistic, additive or synergistic effects were observed and correlated to cell proliferation rate. The inhibitors enhanced persistent DNA damage, delayed apoptosis, prolonged cell cycle arrest and senescence upon irradiation. These results demonstrated that radiation-induced synthetic lethality might widen the therapeutic window, hence extending the use of PARP inhibitors to patients without BRCAness.

Ixazomib maintenance therapy in newly diagnosed multiple myeloma: An integrated analysis of four phase I/II studies.

OBJECTIVES: To evaluate the safety and efficacy of maintenance therapy with the oral proteasome inhibitor ixazomib in patients with newly diagnosed multiple myeloma (NDMM) not undergoing transplantation. METHODS: Data were pooled from four NDMM phase I/II studies; patients received induction therapy with once- or twice-weekly ixazomib plus lenalidomide-dexamethasone (IRd), melphalan-prednisone (IMP), or cyclophosphamide-dexamethasone (ICd), followed by single-agent ixazomib maintenance, given at the last tolerated dose during induction, until disease progression, death, or unacceptable toxicity. RESULTS: A total of 121 patients achieved stable disease or better after induction (weekly IRd, n = 25; twice-weekly IRd, n = 18; weekly or twice-weekly IMP, n = 35; weekly ICd, n = 43) and received ≥ 1 dose of ixazomib maintenance. Grade ≥ 3 drug-related adverse events occurred in 24% of patients during maintenance; each event was reported in ≤2% of patients. Rates of complete response were 22% after induction and 35% after maintenance. A total of 28 patients (23%) improved their response during maintenance. CONCLUSIONS: Ixazomib maintenance following ixazomib-based induction is associated with deepening of responses and a positive safety profile with no cumulative toxicity in patients with NDMM not undergoing transplantation, suggesting that ixazomib is feasible for long-term administration. Phase III investigation of ixazomib maintenance is ongoing.

2-Pyridone-functionalized Aza-BODIPY photosensitizer for imaging-guided sustainable phototherapy.

To overcome irradiation-dependence of cancer phototherapy, a near infrared aza-BODIPY-based photothermogenic photosensitizer BDY with 2-Pyridone group has been synthesized for imaging-guided photothermal synergistic sustainable photodynamic therapy. Multifunctional water-soluble BDY nanoparticles (NPs), with high photothermal conversion efficiency of 35.7% and excellent singlet oxygen (1O2) generation ability, are prepared by self-assembling. The reversible transformation between 2-pyridone moiety and its endoperoxide form endows BDY with continuous 1O2 generation ability under illumination and non-illumination conditions. Simultaneously, BDY NPs exhibit excellent tumor targeting properties by enhanced permeability and retention (EPR) effect and photoacoustic imaging (PAI) ability. Furthermore, the photothermal assisted sustainable photodynamic therapy can significantly inhibit tumor growth (93.4% inhibition) with almost no side effects by intermittent laser illumination. The finding highlights that this photothermal synergistic sustainable phototherapy presents great potential for clinical applications.

Atopic dermatitis.

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease, with a lifetime prevalence of up to 20% and substantial effects on quality of life. AD is characterized by intense itch, recurrent eczematous lesions and a fluctuating course. AD has a strong heritability component and is closely related to and commonly co-occurs with other atopic diseases (such as asthma and allergic rhinitis). Several pathophysiological mechanisms contribute to AD aetiology and clinical manifestations. Impairment of epidermal barrier function, for example, owing to deficiency in the structural protein filaggrin, can promote inflammation and T cell infiltration. The immune response in AD is skewed towards T helper 2 cell-mediated pathways and can in turn favour epidermal barrier disruption. Other contributing factors to AD onset include dysbiosis of the skin microbiota (in particular overgrowth of Staphylococcus aureus), systemic immune responses (including immunoglobulin E (IgE)-mediated sensitization) and neuroinflammation, which is involved in itch. Current treatments for AD include topical moisturizers and anti-inflammatory agents (such as corticosteroids, calcineurin inhibitors and cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4) inhibitors), phototherapy and systemic immunosuppressants. Translational research has fostered the development of targeted small molecules and biologic therapies, especially for moderate-to-severe disease.

BNNT/Fe3O4 System as an Efficient Tool for Magnetohyperthermia Therapy.

Nanostructured materials have been widely studied aiming to biomedical applications, primarily for the purpose of carrying drugs or molecules of interest in a selected tissue or organ. In this context, boron nitride nanotubes (BNNTs), when functionalized with specific moieties, could be useful as nanovectors for delivery of proteins, drugs, and also RNAi molecules, due to their capacity to be uptaked by cells. The introduction of magnetic nanoparticles allows the use of such system as a hyperthermia agent. Thus, once it has been targeted to tumor areas, it could kill cancer cells by magnetohyperthermia therapy. In order to study this effect, magnetite nanoparticles were incorporated into hydroxilated BNNT. The system was characterized by transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD) and vibrating sample magnetometry (VSM). The results obtained show that magnetite nanoparticles are linked to the nanotubes. Magnetic measurements show that coercivity and magnetization were not disturbed after incorporation to the BNNT. Based on this, a new methodology for in vitro magnetohyperthermia experiments was developed, aiming to treat each cell group individually preserving its sterility. The biological assays of the system demonstrate its good cell viability and the great potential of this nanomaterial as a magnetohyperthermia agent for cancer treatment.

Topical treatment utilization for patients with atopic dermatitis in the United States, and budget impact analysis of crisaborole ointment, 2.

BACKGROUND: Atopic dermatitis (AD), a chronic inflammatory skin disease, is often treated with topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI). Crisaborole ointment is a non-steroidal, phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate AD. In December 2016, crisaborole was approved in the US for mild-to-moderate AD in patients ≥2 years of age. AIMS: To evaluate real-world utilization and cost of TCS and TCI in the US and estimate the budget impact of crisaborole over 2 years from a third-party payer perspective. METHODS: TCS and TCI prescriptions in 2015 for patients ≥2 years of age with ≥1 AD diagnosis in the Truven Health Analytics MarketScan Commercial and Medicare Supplemental Research Databases were analyzed for patients receiving TCI or TCS alone or in combination (TCS/TCI population) and patients receiving TCI alone or in combination with TCS (TCI population). A budget impact model used TCS and TCI market shares, annual use, and cost per prescription. Crisaborole uptake rates of 4.7% (TCS) and 20.2% (TCI), with an annual increase of 1% in year 2, were assumed. Budget impact was calculated as total and per-member-per-month (PMPM) cost over 2 years for a health plan of 1 million members. RESULTS: Annual prescriptions/patient ranged from 1.36-6.41; annual cost/patient was $53-$1,465. The budget impact of crisaborole over 2 years in the TCS/TCI population was $350,946 (PMPM, $0.015), with increases of $162,106 in year 1 (PMPM, $0.014) and $188,841 in year 2 (PMPM, $0.016). The budget impact in the TCI population was -$22,871, with decreases of $11,160 in year 1 and $11,712 in year 2 (each PMPM, -$0.001). For both populations, one-way sensitivity analyses showed that budget impact was most sensitive to changes in crisaborole cost and annual use. CONCLUSIONS: From US payer perspectives, adoption of crisaborole results in modest pharmacy budget impact/savings.

Phosphodiesterase 4 inhibitors.

Historically, drugs available for treating atopic dermatitis (AD) have been limited to topical corticosteroids and topical calcineurin inhibitors, with systemic immunosuppressants and phototherapy reserved for severe AD. Despite their efficacy and infrequent adverse events, phobia about the use of topical steroids and calcineurin inhibitors has limited their use. More targeted options with fewer systemic and cutaneous side effects are needed for treating AD. Phosphodiesterase 4 (PDE4) is involved in the regulation of proinflammatory cytokines via the degradation of cyclic adenosine monophosphate. PDE4 activity is increased in the inflammatory cells of patients with AD, leading to increased production of proinflammatory cytokines and chemokines. Targeting PDE4 reduces the production of these proinflammatory mediators in AD. Both topical and oral PDE4 inhibitors have a favorable safety profile. Crisaborole 2% ointment, a topical PDE4, is now US Food and Drug Administration-approved for children older than 2 years and adults in the treatment of AD. Crisaborole 2% ointment shows early and sustained improvement in disease severity and pruritus and other AD symptoms, with burning and/or stinging upon application as the only related adverse event. Other PDE4 inhibitors are currently in trials with promising efficacy and safety.

Atopic dermatitis yardstick: Practical recommendations for an evolving therapeutic landscape.

The implementation of treatment guidelines for atopic dermatitis is challenging, in part because of different guidance documents being used by different groups of specialists and in part because the language of guidelines often reflects the evidence base rather than the practical "how to." The Atopic Dermatitis Yardstick is part of a series developed in response to the need to proactively address the loss of disease control for atopic illnesses at all levels of severity. It presents a comprehensive update on how to conduct a sustained step-up in therapy for the patient with inadequately controlled or poorly controlled atopic dermatitis. Patient profiles, based on current guidelines and the authors' combined clinical experience, provide a practical and clinically meaningful guide to aid physicians in helping their patients achieve the goal of clear to almost clear. The intent is not to replace guidelines but to complement their recommendations incorporating the latest research and therapies.