The immune system influences the fate of developing cancers by not only functioning as a tumour promoter that facilitates cellular transformation, promotes tumour growth and sculpts tumour cell ...immunogenicity, but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion. Yet, clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer-induced immunosuppression. In many individuals, immunosuppression is mediated by cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), two immunomodulatory receptors expressed on T cells. Monoclonal-antibody-based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits-including durable responses--to patients with different malignancies. However, little is known about the identity of the tumour antigens that function as the targets of T cells activated by checkpoint blockade immunotherapy and whether these antigens can be used to generate vaccines that are highly tumour-specific. Here we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T-cell rejection antigens following anti-PD-1 and/or anti-CTLA-4 therapy of mice bearing progressively growing sarcomas, and we show that therapeutic synthetic long-peptide vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Although mutant tumour-antigen-specific T cells are present in progressively growing tumours, they are reactivated following treatment with anti-PD-1 and/or anti-CTLA-4 and display some overlapping but mostly treatment-specific transcriptional profiles, rendering them capable of mediating tumour rejection. These results reveal that tumour-specific mutant antigens are not only important targets of checkpoint blockade therapy, but they can also be used to develop personalized cancer-specific vaccines and to probe the mechanistic underpinnings of different checkpoint blockade treatments.
The AP1 transcription factor Batf3 is required for homeostatic development of CD8α(+) classical dendritic cells that prime CD8 T-cell responses against intracellular pathogens. Here we identify an ...alternative, Batf3-independent pathway in mice for CD8α(+) dendritic cell development operating during infection with intracellular pathogens and mediated by the cytokines interleukin (IL)-12 and interferon-γ. This alternative pathway results from molecular compensation for Batf3 provided by the related AP1 factors Batf, which also functions in T and B cells, and Batf2 induced by cytokines in response to infection. Reciprocally, physiological compensation between Batf and Batf3 also occurs in T cells for expression of IL-10 and CTLA4. Compensation among BATF factors is based on the shared capacity of their leucine zipper domains to interact with non-AP1 factors such as IRF4 and IRF8 to mediate cooperative gene activation. Conceivably, manipulating this alternative pathway of dendritic cell development could be of value in augmenting immune responses to vaccines.
Highlights • Laser immunotherapy (LIT) is a novel cancer treatment strategy that uses local photothermal irradiation and a local immunological stimulation. • A novel immunoadjuvant, glycated chitosan ...(GC), was developed to work with laser interaction to creates an in situ autologous cancer vaccine (inCVAX). • Furthermore, inCVAX has been administered in initial clinical trials for the treatment of patients with metastatic breast cancer with promising outcomes.
Follicular unit excision (FUE) has risen to the forefront as the world's most popular hair transplant procedure. However, most writing on this subject has catered to the advanced practitioner. The ...goal of this article will be to focus on safe planning and decision making along with key technical steps that will guide the beginner surgeon to harvest a graft safely and to harvest the donor area in a uniform way to avoid overharvesting. Topics covered in this article also include instrumentation and decision making between FUE versus linear strip excision.
Yeast activity during wine fermentation directly contributes to wine quality, but the source and movement of yeasts in vineyards and winery environments have not been resolved. Here, we investigate ...the yeast species associated with the Drosophila insect vector to help understand yeast dispersal and persistence. Drosophila are commonly found in vineyards and are known to have a mutualistic relationship with yeasts in other ecosystems. Drosophilids were collected from vineyards, grape waste (marc) piles and wineries during grape harvest. Captured flies were identified morphologically, and their associated yeasts were identified. Drosophila melanogaster/D. simulans, D. hydei and Scaptodrosophila lativittata were identified in 296 captured Drosophila flies. These flies were associated with Metschnikowia pulcherrima, Hanseniaspora uvarum, Torulaspora delbrueckii and H. valbyensis yeasts. Yeast and Drosophila species diversity differed between collection locations (vineyard and marc: R = 0.588 for Drosophila and R = 0.644 for yeasts). Surprisingly, the primary wine fermentation yeast, Saccharomyces cerevisiae, was not isolated. Drosophila flies are preferentially associated with different yeast species in the vineyard and winery environments, and this association may help the movement and dispersal of yeast species in the vineyard and winery ecosystem.
Yeasts may be transmitted by Drosophila in the vineyard and winery.
It is becoming apparent that to obtain robust and prolonged antitumor responses in cancer immunotherapy, appropriate adjunct agents promoting both tumor antigen delivery and immune rejection ...enhancement are critically required. The semisynthetic biopolymer N-dihydrogalactochitosan (GC) is emerging as a promising such candidate. In the present study, the effects of GC were investigated when combined with cancer vaccines generated by photodynamic therapy (PDT) using mouse tumor model SCCVII (squamous cell carcinoma). The adjunct GC treatment was found to enhance therapeutic benefit obtained with PDT vaccine, while reducing the numbers of myeloid-derived suppressor cells. Another important property of GC is promoting directly the death of SCCVII cells sustaining injury from PDT mediated by various photosensitizers. This effect is extended to cells treated by cryoablation therapy (CAT) performed by exposure to −80 °C. A capacity of GC for preferential binding to PDT treated cells was demonstrated using fluorescence microscopy. In vitro testing with specific caspase-1 inhibitor revealed a pro-survival role of this enzyme in membrane lipid repair mechanisms following combined PDT plus GC treatment. In conclusion, GC represents a uniquely promising adjunct for various PDT protocols, photothermal and similar rapid tumor-ablating therapies.
•N-dihydrogalactochitosan (GC) acts as adjunct to tumor photodynamic therapy (PDT).•GC enhances the efficacy of therapeutic cancer vaccines generated by PDT.•GC preferentially binds to PDT-damaged cells and directly enhances their killing.•GC amplifies tumor cell killing mediated by cryoablation therapy.
Photothermal therapy (PTT) is recently clinically established cancer therapy that uses near-infrared light for thermal ablation of solid tumors. The biopolymer N-dihydrogalactochitosan (GC) was shown ...in multiple reports to act as a very effective adjunct to tumor PTT. In the present study, mouse tumor model SCCVII (squamous cell carcinoma) was used with two protocols, in situ tumor PTT and therapeutic PTT vaccine for tumors, for investigating the effects of GC. The results reveal that GC can potentiate tumoricidal action of PTT through both direct and indirect mechanisms. In addition to previously known capacity of GC for activating immune effector cells, the indirect means is shown to include reducing the populations of immunoregulatory T cells (Tregs) in PTT-treated tumors. Testing the effects of GC on PTT-treated SCCVII tumor cells in vitro uncovered the existence of a direct mechanism evident by reduced colony survival of these cells. Fluorescence microscopy demonstrated increased binding of fluorescein-labeled GC to PTT-treated compared to untreated SCCVII cells that can be blocked by pre-exposure to annexin V. The results of additional in vitro testing with specific inhibitors demonstrate that these direct mechanisms do not involve the engagement of death surface receptors that trigger extrinsic apoptosis pathway signaling but may be linked to pro-survival activity of caspase-1. Based on the latter, it can be suggested that GC-promoted killing of PTT-treated cells stems from interference of GC bound to damaged membrane components with the repair of these structures that consequently hinders cell survival.
•N-dihydrogalactochitosan (GC) acts as adjunct to tumor photothermal therapy (PTT).•GC enhances the efficacy of therapeutic cancer vaccines generated by PTT.•GC preferentially binds to PTT-damaged cells and directly enhances their killing.
INTRODUCTION The aim of SRS is to obliterate the AVM hence reducing the annual hemorrhage rate. Traditionally, patient's head was fixed intraoperatively to a metal head frame with pins secured into ...the skull bone (frame-based SRS). Nowadays, the head frame and pins have been superseded by a thermal moulding face mask (frameless SRS). Although frameless SRS reduces the risks that frame-based SRS carries, whether it achieves the same efficacy and outcomes as frame-based SRS remained an unsolved question. METHODS A retrospective study was conducted in Tuen Mun Hospital recruiting patients with AVM treated by SRS from the years 1998 to 2016. Data was collected from CDARS which is a large comprehensive database system in Hospital Authority in Hong Kong.Variables studied included patient factors, disease factors and treatment factors. Primary outcome was defined as the complete obliteration rate whereas secondary outcomes include rate of post-SRS hemorrhage, rate of radionecrosis and functional outcome in terms of modified Rankin Scale. RESULTS 60 patients were included and complete obliteration rate was observed in 46 patients (77%). Variables identified to have a statistical significance in determining the obliteration rate were maximal diameter, volume and Spetzler-Martin grade of AVM with P-values of .001, .006 and .001 respectively. For secondary outcomes, overall post-SRS hemorrhage rate was noted to be 10%.There was no significant difference found between frame-based and frameless SRS groups in terms of obliteration, post-SRS hemorrhage or mRS. Lastly, radionecrosis was found to be 11.7%. CONCLUSION Stereotactic radiosurgery (SRS) is a useful treatment option for brain arteriovenous malformation and frameless SRS is able to achieve similar results.
Introduction: The purpose of this study was to quantify the effects of the coronavirus disease 2019 (COVID-19) pandemic on pediatric emergency departments (PED) across the United States (US), ...specifically its impact on trainee clinical education as well as patient volume, admission rates, and staffing models.
Methods: We conducted a cross-sectional study of US PEDs, targeting PED clinical leaders via a web-based questionnaire. The survey was sent via three national pediatric emergency medicine distribution lists, with several follow-up reminders.
Results: There were 46 questionnaires included, completed by PED directors from 25 states. Forty-two sites provided PED volume and admission data for the early pandemic (March-July 2020) and a pre-pandemic comparison period (March-July 2019). Mean PED volume decreased >32% for each studied month, with a maximum mean reduction of 63.6% (April 2020). Mean percentage of pediatric admissions over baseline also peaked in April 2020 at 38.5% and remained 16.4% above baseline by July 2020. During the study period, 33 (71.1%) sites had decreased clinician staffing at some point. Only three sites (6.7%) reported decreased faculty protected time. All PEDs reported staffing changes, including decreased mid-level use, increased on-call staff, movement of staff between the PED and other units, and added tele-visit shifts. Twenty-six sites (56.5%) raised their patient age cutoff; median was 25 years (interquartile ratio 25-28). Of 44 sites hosting medical trainees, 37 (84.1%) reported a decrease in number of trainees or elimination altogether. Thirty (68.2%) sites had restrictions on patient care provision by trainees: 28 (63.6%) affected medical students, 12 (27.3%) affected residents, and two (4.5%) impacted fellows. Fifteen sites (34.1%) had restrictions on procedures performed by medical students (29.5%), residents (20.5%), or fellows (4.5%).
Conclusion: This study highlights the marked impact of the COVID-19 pandemic on US PEDs, noting decreased patient volumes, increased admission rates, and alterations in staffing models. During the early pandemic, educational restrictions for trainees in the PED setting disproportionately affected medical students over residents, with fellows’ experience largely preserved. Our findings quantify the magnitude of these impacts on trainee pediatric clinical exposure during this period.
The utility of point-of-care ultrasound is well supported by the medical literature. Consequently, pediatric emergency medicine providers have embraced this technology in everyday practice. Recently, ...the American Academy of Pediatrics published a policy statement endorsing the use of point-of-care ultrasound by pediatric emergency medicine providers. To date, there is no standard guideline for the practice of point-of-care ultrasound for this specialty. This document serves as an initial step in the detailed “how to” and description of individual point-of-care ultrasound examinations. Pediatric emergency medicine providers should refer to this paper as reference for published research, objectives for learners, and standardized reporting guidelines.
PDF
