Local Flare Research Articles

Correlation of previous local vaccination site “flares” during immunotherapy for metastatic melanoma with complete responses to therapy.

e21534 Background: mRNA vaccines have been shown to stimulate T-cells targeting patient-specific tumor neoantigens. When combined with immune checkpoint inhibitors (ICI) in a randomized Phase II trial, mRNA vaccines demonstrated improvement in recurrence free survival and distant metastasis free survival compared to ICI alone. We retrospectively examined patients (pts) with advanced melanoma treated more than 5 years ago on clinical trials with adjuvant NYESO1 or mRNA vaccine therapies (VT) then ICI upon recurrence and analyzed biomarkers correlating with treatment response. Methods: This retrospective study examined 22 pts with advanced melanoma treated between 2004-2017 with adjuvant vaccine therapies (VT). 10 of the 22 pts subsequently developed recurrent disease and were treated with ICI. We evaluated disease free interval following ICI, sex, age, BRAF status, HLA type, site of primary and metastatic disease, initial vaccine treatment, vaccine toxicities, stage and sites of melanoma recurrence, ICI treatment, response and toxicities, vaccine site flares or cutaneous immune related adverse events (irAEs) following ICI. Results: Of the 22 patients (11 male, 11 female) treated with adjuvant VT, median age at first vaccine was 53 years old. HLA type was known for 11 pts. Stage at initial VT was IIB to IIIC. 14 pts recurred following adjuvant VT. Median time from vaccine initiation to melanoma recurrence was 3.2 years (range 6.5 months to 11 years). 10 pts received ICI for recurrent melanoma, 3 pts received ipilimumab, 2 anti-PD1 monotherapy, 4 ipilimumab and nivolumab, and 1 nivolumab/relatlimab. Stage at first ICI was IIIB to IV M1d. 9 pts experienced cutaneous irAEs. 7 pts experienced local vaccine site flare reactions following ICI treatment. Additionally, 2 pts experienced vitiligo, 2 with dermatologic flares (bullous pemphigoid and psoriatic rash), 2 with generalized rash that resolved with steroid cream. 1 pt did not experience rash, vaccine site flare, nor irAE dermatologic flare. Of the pts who recurred, 2 pts had BRAF V600E mutations, and 1 of these pts experienced vaccine flare, the other did not. 1 pt with a BRAF Q16L mutation did not have vaccine flare. 6 out of 7 BRAF wild type pts who recurred and received ICI experienced a localized vaccine site flare. Median disease-free interval following ICI treatment was 1.5 years (range 3 months to 9 years). All 10 pts are disease-free and off ICI being closely monitored. Conclusions: Evidence of prior localized vaccination “flare” may be a biomarker for a complete immunologic response in pts with metastatic disease treated with immunotherapy. ICI targeting CTLA-4 and/or PD-1 both triggered this localized vaccination site response, suggesting that T cell memory and immunologic activation against melanoma antigens translate into clinical responses.

Combined Immunotherapy Improves Outcome for Replication-Repair-Deficient (RRD) High-Grade Glioma Failing Anti-PD-1 Monotherapy: A Report from the International RRD Consortium.

Hypermutant RRD-HGG are susceptible to checkpoint inhibitors beyond initial progression, leading to improved survival when reirradiation and synergistic immune/targeted agents are added. This is driven by their unique biological and immune properties, which evolve over time. Future research should focus on combinatorial regimens that increase patient survival while limiting immune toxicity. This article is featured in Selected Articles from This Issue, p. 201.

Clinical characteristics of flares in patients with rheumatoid arthritis after total hip and total knee arthroplasty.

Clinical characteristics of flares in patients with rheumatoid arthritis after total hip and total knee arthroplasty.

Human pain ratings to electrical sinusoids increase with cooling through a cold-induced increase in C-fibre excitability.

Low-frequency sinusoidal current applied to human skin evokes local axon reflex flare and burning pain, indicative of C-fibre activation. Because topical cooling works well as a local analgesic, we examined the effect of cooling on human pain ratings to sinusoidal and rectangular profiles of constant current stimulation. Unexpectedly, pain ratings increased upon cooling the skin from 32 to 18°C. To explore this paradoxical observation, the effects of cooling on C-fibre responses to stimulation with sinusoidal and rectangular current profiles were determined in ex vivo segments of mouse sural and pig saphenous nerve. As expected by thermodynamics, the absolute value of electrical charge required to activate C-fibre axons increased with cooling from 32°C to 20°C, irrespective of the stimulus profile used. However, for sinusoidal stimulus profiles, cooling enabled a more effective integration of low-intensity currents over tens of milliseconds resulting in a delayed initiation of action potentials. Our findings indicate that the paradoxical cooling-induced enhancement of electrically evoked pain in people can be explained by an enhancement of C-fibre responsiveness to slow depolarization at lower temperatures. This property may contribute to symptoms of enhanced cold sensitivity, especially cold allodynia, associated with many forms of neuropathic pain.

A Global Sharing Mechanism of Resources: Modeling a Crucial Step in the Fight against Pandemics.

To face crises like the COVID-19 pandemic, resources such as personal protection equipment (PPE) are needed to reduce the infection rate and protect those in close contact with patients. The increasing demand for those products can, together with pandemic-related disruptions in the global supply chain, induce major local resource scarcities. During the first phase of the COVID-19 pandemic, we witnessed a reflex of ‘our people first’ in many regions. In this paper, however, we show that a cooperative sharing mechanism can substantially improve the ability to face epidemics. We present a stylized model in which communities share their resources such that each can receive them whenever a local epidemic flares up. Our main finding is that cooperative sharing can prevent local resource exhaustion and reduce the total number of infected cases. Crucially, beneficial effects of sharing are found for a large range of possible community sizes and cooperation combinations, not only for small communities being helped by large communities. Furthermore, we show that the success of sharing resources heavily depends on having a sufficiently long delay between the onsets of epidemics in different communities. These results thus urge for the pairing of a global sharing mechanism with measures to slow down the spread of infections from one community to the other. Our work uses a stylized model to convey an important and clear message to a broad public, advocating that cooperative sharing strategies in international resource crises are the most beneficial strategy for all. It stresses essential underlying principles of and contributes to designing a resilient global supply chain mechanism able to deal with future pandemics by design, rather than being subjected to the coincidental and unequal distribution of opportunities per community that we see at present.

300 mm Large Area Wire Grid Polarizers with 50 nm Half-Pitch by ArF Immersion Lithography

The large area wire grid polarizers (LA-WGPs) with 50 nm half-pitch were fabricated using ArF immersion lithography overcoming the limit of the shot field size. To realize the 50 nm line and space patterns on a 300 mm wafer, a zero-distance stitching process that connects the shot fields is suggested. To compensate for mutual interference between the shot fields which is called the local flare effect (LFE), the shot field arrangement is changed with optical proximity correction (OPC). Using a master wafer produced by the suggested method, 300 mm large-area WGPs were fabricated by the nano-imprint process. The WGPs have more than 80% transmittance in the visible light region, and the possibility of performance improvement can be confirmed depending on the number and method of the etch process.

Toxic flare phenomenon in osteoblastoma: A case report with literature review

Osteoblastomas are benign neoplasm of the bone that is characterized by clinical and histological similarity to osteoid osteomas. They are larger (>1.5–2 cm) and tend to affect the axial skeleton. Patients typically present commonly in the second or third decades of life with a male predilection. The flare phenomenon in osteoblastoma is a rare but known entity showing florid multifocal periostitis. Few cases have been reported in the literature. Focally aggressive osteoblastomas also present with flare phenomenon mediated by prostaglandin-induced inflammation. We report a strikingly unusual case of an osteoblastoma of the spine in a 23-year-old male patient who presented in our outpatient department with complaints of low backache, weight loss, intermittent stiffness, and fever for the past year. The patient was HLA-B27 positive, diagnosed as ankylosing spondylitis, and clinical symptoms were attributed to sacroiliitis. However, his fever and weight loss, while on treatment, were unexplained. Roentgenogram, computed tomography, and magnetic resonance imaging of the patient depicted a large bone tumor centered at the junction of the right pedicle and transverse process of L5 vertebra, associated with severe reactive marrow edema, periosteal reaction, periostitis, and sclerosis in the posterior vertebral elements also extending into the L4 vertebra. The lesion was suspected to be osteoblastoma with close imaging differential as osteosarcoma. CT-guided biopsy proved osteoblastoma with acute local toxic flare.

Rosacea with persistent facial erythema and high Demodex density effectively treated with topical ivermectin alone or combined with oral carvedilol.

Topical ivermectin is effective in treating papulopustular rosacea, but its effect on persistent facial erythema of rosacea with high Demodex densities has not been well documented. We retrospectively reviewed 39 rosacea patients with persistent facial erythema and high Demodex densities. Clinician's erythema assessment (CEA) and Demodex density were evaluated before and after topical ivermectin alone or combined with oral carvedilol. Three patients (all with papulopustular rosacea, in ivermectin group) dropped out due to early ivermectin-induced local flare of rosacea. In the remaining patients (ivermectin group n = 14; ivermectin-carvedilol group n = 22), the CEA grade and Demodex density were significantly reduced, both P < .01. There was no statistically significant difference between the two groups in CEA before and after treatment (P = .07 and P = .23, respectively), and in Demodex density (P = .82 and .10, respectively). Both regimens markedly improved the persistent facial erythema with response being excellent in 26 of 36 patients (72%), good in 2, fair in 4 and none in 4. There was a correlation between the reduction of CEA and Demodex density after treatment (rho = 0.50, P = .002). The results showed that topical ivermectin was effective in reducing persistent facial erythema of rosacea with Demodex overgrowth.

Hylan G-F20 and galactomannan joint flares are associated to acute synovitis and release of inflammatory cytokines

BackgroundInjection of Hylan G-F20 (HY) into joints may provoke local flares, which mechanisms may involve reaction to protein contaminants. We have previously developed a protein-free saline-soluble galactomannan derived from guar gum (GM) that displays both analgesia and chondroprotection in experimental osteoarthritis (OA). We now demonstrate that both GM and Hylan G-F20 (HY) promote mild synovitis with cytokine release after intra-articular injection.MethodsMice received 100 μg/25 μL GM or HY or saline into the knees. Joint pain was evaluated using von Frey test; cell influx, interleukin (IL)-1, IL-6, and CXCL-1 (pg/mL) levels were assessed in joint lavage at 6 h. Synovia were excised for histopathology.ResultsNeither GM nor HY after being given into mice knee joints induced pain albeit promoting mild cell influx into joint washings as well as mild synovitis at histology, with no damage to the underlying cartilage. HY but not GM promoted IL-1 release into mice joints. Both compounds induced IL-6 and CXCL-1 release.ConclusionIntra-articular injection of HY or GM promote acute transient synovitis whilst not provoking detectable significant joint damage. Local administration of these polysaccharides induces acute intra-articular release of inflammatory cytokines, which may account for joint flares following viscosupplementation.

A single reaction-diffusion equation for the multifarious eruptions of urticaria.

Urticaria is a common skin disorder characterized by the rapid appearance and disappearance of local skin edema and flares with itching. It is characterized by various macroscopic skin eruptions unique to patients and/or subtypes of urticaria with respect to shape, size, color, and/or duration of eruptions. Nevertheless, the mechanism underlying multifarious eruptions in urticaria is largely unknown. The eruptions are believed to be evoked by histamine release from mast cells in the skin. However, the majority of visible characteristics of urticaria cannot be explained by a simple injection of histamine to the skin. To explain the multifarious eruptions of urticaria, we developed a single reaction-diffusion model suggesting the self-activation and self-inhibition regulation of histamine release from mast cells. Using the model, we found that various geometrical shapes of eruptions typically observed in patients can be explained by the model parameters and randomness or strength of the initial stimuli to mast cells. Furthermore, we verified that the wheal-expanding speed of urticaria, which is shown to be much smaller than that of the intradermal injection experimental system may be explained by our model and a simple diffusion equation. Our study suggests that the simple reaction-diffusion dynamics, including the independent self-activating and -inhibitory regulation of histamine release, may account for the essential mechanism underlying the formation of multifarious eruptions in urticaria.

53 - Local Tumor Flare Following Radiosurgery and Ipilimumab (Ipi) for Melanoma Brain Metastases: Increased Immune Response?

53 - Local Tumor Flare Following Radiosurgery and Ipilimumab (Ipi) for Melanoma Brain Metastases: Increased Immune Response?

Characterization of a short-pulse high-power diode operated with anode effects

AbstractUsually, the high-power microwave (HPM) devices suffer from impedance collapse and cathode material degradation or even failure. When the intense electron beam bombards the anode (or named as collector in HPM device), an anode plasma could appear under certain conditions. In this case, the impedance collapse is caused by the expansions of the cathode and anode plasmas and diode current overshot caused by the bipolar flow. In this paper, characterization of a short-pulse high-power diode operated with anode effects with a dielectric fiber (velvet) cathode is discussed. The bipolar flow (or anode plasma) is indeed evident at beam power densities ~11 MW/cm2and the pulse durations of ~50 ns. The analysis results of the deposit dose and thermal regime of the anode show that the electron stimulated desorption played an important role in the generation of anode plasma in this case. With the effect of anode plasma, the appearance of local cathode plasma flares (or nonuniform electron emission) is particularly detrimental for the diode closure. Micro-structure and elemental surface compositions of cathode are changed by the anode splashing, which is very harmful to the performance of cathode.

Identification of a Neuronal Receptor Controlling Anaphylaxis.

Allergic reactions can in severe cases induce a state of circulatory shock referred to as anaphylaxis. Histamine, the primary mediator of this condition, is released from immune cells, and, therefore, anaphylaxis has so far been considered an immune system disorder. However, we here show that the glutamatergic receptor mGluR7, expressed on a subpopulation of both peripheral and spinal cord neurons, controls histamine-induced communication through calcium-dependent autoinhibition with implications for anaphylaxis. Genetic ablation of mGluR7, and thus altered regulation of histamine-sensing neurons, caused an anaphylaxis-like state in mGluR7(-/-) mice, which could be reversed by antagonizing signaling between neurons and mast cells but not by antagonizing a central itch pathway. Our findings demonstrate the vital role of nervous system control by mGluR7 in anaphylaxis and open up possibilities for preventive strategies for this life-threatening condition.

Mask Effects on Resist Variability in Extreme Ultraviolet Lithography

Resist variability is one of the challenges that must to be solved in extreme UV lithography. One of the root causes of the resist roughness are the mask contributions. Three different effects may plays a non-negligible role: mask pattern roughness transfer – or mask line edge roughness, speckle effects caused by mask surface roughness, and mask layout which causes local flare amplification at wafer level. In this paper, mask contributions to the pattern variability are individually assessed experimentally and via stochastic simulations for both lines/spaces and contact holes. It was found that the predominant effect is the mask layout, while the speckle contribution is barely detectable.

光学表面中频误差对光刻物镜短程杂散光影响分析

光学表面中频误差对光刻物镜短程杂散光影响分析

Efficiency, error and yield in light-directed maskless synthesis of DNA microarrays

BackgroundLight-directed in situ synthesis of DNA microarrays using computer-controlled projection from a digital micromirror device--maskless array synthesis (MAS)--has proved to be successful at both commercial and laboratory scales. The chemical synthetic cycle in MAS is quite similar to that of conventional solid-phase synthesis of oligonucleotides, but the complexity of microarrays and unique synthesis kinetics on the glass substrate require a careful tuning of parameters and unique modifications to the synthesis cycle to obtain optimal deprotection and phosphoramidite coupling. In addition, unintended deprotection due to scattering and diffraction introduce insertion errors that contribute significantly to the overall error rate.ResultsStepwise phosphoramidite coupling yields have been greatly improved and are now comparable to those obtained in solid phase synthesis of oligonucleotides. Extended chemical exposure in the synthesis of complex, long oligonucleotide arrays result in lower--but still high--final average yields which approach 99%. The new synthesis chemistry includes elimination of the standard oxidation until the final step, and improved coupling and light deprotection. Coupling Insertions due to stray light are the limiting factor in sequence quality for oligonucleotide synthesis for gene assembly. Diffraction and local flare are by far the largest contributors to loss of optical contrast.ConclusionsMaskless array synthesis is an efficient and versatile method for synthesizing high density arrays of long oligonucleotides for hybridization- and other molecular binding-based experiments. For applications requiring high sequence purity, such as gene assembly, diffraction and flare remain significant obstacles, but can be significantly reduced with straightforward experimental strategies.

Petits tours: representações do circuito turístico em Lawrence Durrel, David Lodge e Didier van Cauwelaert

O grand tour cedeu, progressivamente, lugar a pequenos circuitos. As grandes paisagens inexploradas quase desapareceram. Ao grande aristocrata sucedeu o turista. O contacto com os autóctones não passa de um simulacro, amiúde encenado para conferir cor local. O exotismo desapareceu e a aventura acantona-se em actividades radicais – ou, até, na esfera virtual. À semelhança da rainha Charlotte, para quem a contemplação do quadro expressamente encomendado a Johann Zoffany, The Tribuna of the Uffizi, substituía a visita in loco à galeria florentina, os turistas a que faremos referência, a partir de três narrativas de Lawrence Durrell, David Lodge e Didier Van Cauwelaert, contentam-se em consumir os roteiros, as paisagens e a gastronomia de locais-bilhete postal. Em contrapartida, este tipo de férias propicia o estudo atento dos companheiros de viagem, pelo que a análise antropológica e sociológica se centra no homo turisticus (Lipovetsky) e constitui uma heterotopia (Foucault).

A novel model of inflammatory pain in human skin involving topical application of sodium lauryl sulfate

Sodium lauryl sulfate (SLS) is a known irritant. It releases pro-inflammatory mediators considered pivotal in inflammatory pain. The sensory effects of SLS in the skin remain largely unexplored. In this study, SLS was evaluated for its effect on skin sensory functions. Eight healthy subjects were recruited for this study. Skin sites were randomized to topical SLS 0.25, 0.5, 1, 2% and vehicle for 24 h. Topical capsaicin 1% was applied for 30 min at 24 h after SLS application. Assessments included laser Doppler imaging of local vasodilation and flare reactions, rating of spontaneous pain, assessment of primary thermal and tactile hyperalgesia, and determination of secondary dynamic and static hyperalgesia. SLS induced significant and dose-dependent local inflammation and primary hyperalgesia to tactile and thermal stimulation at 24 h after application, with SLS 2% treatment eliciting results comparable to those observed following treatment with capsaicin 1%. SLS induced no spontaneous pain, small areas of flare, and minimal secondary hyperalgesia. The primary hyperalgesia vanished within 2-3 days, whereas the skin inflammation persisted and was only partly normalized by Day 6. SLS induces profound perturbations of skin sensory functions lasting 2-3 days. SLS-induced inflammation may be a useful model for studying the mechanisms of inflammatory pain.

ON THE PROSPECT OF CONSTRAINING BLACK HOLE SPIN THROUGH X-RAY SPECTROSCOPY OF HOTSPOTS

Future X-ray instrumentation is expected to allow us to significantly improve the constraints derived from the Fe K lines in active galactic nuclei, such as the black hole angular momentum (spin) and the inclination angle of the putative accretion disk. We consider the possibility that measurements of the persistent, time-averaged Fe K line emission from the disk could be supplemented by the observation of a localized flare, or "hotspot," orbiting close to the black hole. Although observationally challenging, such measurements would recover some of the information loss that is inherent to the radially integrated line profiles. We present calculations for this scenario to assess the extent to which, in principle, black hole spin may be measured. We quantify the feasibility of this approach using realistic assumptions about likely measurement uncertainties.

The Analgesic Effect of a Metered-Dose 8% Lidocaine Pump Spray In Posttraumatic Peripheral Neuropathy: A Pilot Study

A topical lidocaine patch is effective in the treatment of posttraumatic peripheral neuropathy (PTPN), but it is not suited for breakthrough pain because of difficulty with an additional application. Here, we examined the effect of 8% lidocaine pump spray (Xylocaine pump spray, XPS) on peripheral neuropathic pain caused by surgery or injury. Thirty-one patients with PTPN were randomized to receive either XPS or saline placebo pump spray applied to painful skin areas. The optimal dose of up to 30 sprays (0.1 mL/single spray, 30 times) was individually determined as the dose which completely covered the painful site. After a 7-day period, the patients were crossed over to receive the optimal dose of the alternative spray. Pain was assessed with a visual analog scale. XPS, but not placebo pump spray, significantly decreased the visual analog scale for continuing pain and tactile allodynia. The effect persisted for a median of 5 h (range, 2-60 h) after application. Mild side effects were reported in three patients with XPS consisting of local irritation (n = 3) and local flare (n = 1). All adverse events disappeared without medication within a few hours. The present study suggests that XPS provides a significant improvement in PTPN due to its prompt analgesia, lack of systemic side effects and convenience.