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During every significant conflict in U.S. history, the military has employed advisors in some capacity. Advisors have played a critical role for the U.S. Army in conflicts from Baron Friedrich [...]

In October 2017, the U.S. Army released the new Field Manual (FM) 3-0, Operations, and other related doctrine for future conflicts. (1) Military doctrine is an important component of any [...]

Canine malignant melanoma provides a clinically relevant, large animal parallel patient population to study the GD2-reactive hu14.18-IL-2 immunocytokine as it is similar to human melanoma and expresses GD2. The objectives of this study were to evaluate safety, radiation fractionation, and identify informative biomarkers of an in-situ tumor vaccine involving local radiation therapy plus intratumoral–immunocytokine in melanoma tumor-bearing dogs. Twelve dogs (six dogs/arm) with locally advanced or metastatic melanoma were randomized to receive a single 8 Gy fraction (arm A) or three 8 Gy fractions over 1 week (arm B) to the primary site and regional lymph nodes (when clinically involved) with the single or last fraction 5 days before intratumoral–immunocytokine at 12 mg/m2on 3 consecutive days. Serial tumor biopsies were obtained. All 12 dogs completed protocol treatment, and none experienced significant or unexpected adverse events. Evidence of antitumor activity includes one dog with a complete response at day 60, one dog with a partial response at day 60, and four dogs with mixed responses. Histology of serial biopsies shows a variably timed increase in intratumoral lymphocytic inflammation in some dogs. Canine NanoString analyses of serial biopsies identified changes in gene signatures of innate and adaptive cell types versus baseline. There were no significant differences in NanoString results between arm A and arm B. We conclude that intratumoral–immunocytokine in combination with local radiation therapy in canine melanoma is well tolerated and has antitumor activity with the potential to inform clinical development in melanoma patients.

In October 2017, the U.S. Army released the new Field Manual (FM) 3-0, Operations, and other related doctrine for future conflicts. (1) Military doctrine is an important component of any [...]

Substantial changes are altering the future operating environment. Lethal autonomous weapon systems (LAWS) are likely in a developmental phase similar to combat aviation before World War I. Within a decade, [...]

The Department of Defense (DOD) has used drones in almost every military operation since the 1950s to provide reconnaissance, surveillance, and intelligence on enemy forces. (1) They have been called [...]

The in situvaccine effect of radiation therapy (RT) has been shown to be limited in both preclinical and clinical settings, possibly due to the inadequacy of RT alone to stimulate in situvaccination in immunologically “cold” tumor microenvironments (TMEs) and the mixed effects of RT in promoting tumor infiltration of both effector and suppressor immune cells. To address these limitations, we combined intratumoral injection of the radiated site with IL2 and a multifunctional nanoparticle (PIC). The local injection of these agents produced a cooperative effect that favorably immunomodulated the irradiated TME, enhancing the activation of tumor-infiltrating T cells and improving systemic anti-tumor T cell immunity. In syngeneic murine tumor models, the PIC+IL2+RT combination significantly improved the tumor response, surpassing the single or dual combinations of these treatments. Furthermore, this treatment led to the activation of tumor-specific immune memory and improved abscopal effects. Our findings suggest that this strategy can be used to augment the in situvaccine effect of RT in clinical settings.

People with disabilities encounter many financial expenses that those without disabilities do not incur. In this article, we provide estimates of the extra costs associated with living with a disability in the United States. Drawing on four nationally representative surveys, we estimate that a household containing an adult with a work disability requires, on average, 29% more income (or an additional $18,322 a year for a household at the median income level) to obtain the same standard of living as a comparable household without a member with a disability. Single adults with disabilities are estimated to have higher costs than those with disabilities who are married, and adults with cognitive impairments are estimated to have higher costs compared to those with other kinds of impairments. We further calculate the federal poverty rate for households that include adults with disabilities adjusted for the direct additional costs of disability. The rate rises from 24% to 35% after adjusting for the extra costs of disability, which would result in an estimated 2.2 million more people with disabilities counted as poor. This suggests that the official poverty measure in the United States substantially underestimates the degree of deprivation experienced by people with disabilities.

ABSTRACTFocal radiation therapy (RT) has attracted considerable attention as a combinatorial partner for immunotherapy (IT), largely reflecting a well-defined, predictable safety profile and at least some potential for immunostimulation. However, only a few RT-IT combinations have been tested successfully in patients with cancer, highlighting the urgent need for an improved understanding of the interaction between RT and IT in both preclinical and clinical scenarios. Every year since 2016, ImmunoRad gathers experts working at the interface between RT and IT to provide a forum for education and discussion, with the ultimate goal of fostering progress in the field at both preclinical and clinical levels. Here, we summarize the key concepts and findings presented at the Sixth Annual ImmunoRad conference.

Fission yeast TRP channel Pkd2p is the homologue of human polycystins. The pkd2mutant exhibits defects in the contractile ring closure and cell separation during cytokinesis. This essential protein localizes to the cleavage furrow, where it likely regulates osmotic homeostasis during cytokinesis.

In this study, Chiasson-MacKenzie et al. show that merlin deficiency primes the membrane:cytoskeleton interface for EGF-induced macropinocytosis via a mechanism involving increased cortical ezrin, altered actomyosin, and stabilized cholesterol-rich membranes. Their study provides new insight into fundamental mechanisms of macropinocytotic uptake and processing and suggests new ways to interfere with or exploit macropinocytosis in NF2 mutant and other tumors.

We report an in situ vaccination, adaptable to nearly any type of cancer, combining radiotherapy targeting one tumor and intratumoral injection of this site with tumor-specific antibody and IL2 (3xTx). In a Phase I clinical trial, administration of 3xTx (with an immunocytokine fusion of tumor-specific antibody and IL2, hu14.18-IL2) to subjects with metastatic melanoma increases peripheral CD8+T cell effector polyfunctionality. This suggests the potential for 3xTx to promote antitumor immunity against metastatic tumors. In poorly immunogenic syngeneic murine melanoma or head and neck carcinoma models, 3xTx stimulates CD8+T-cell-mediated antitumor responses at targeted and non-targeted tumors. During 3xTx, NK cells promote CTLA4+regulatory-T-cell (Treg) apoptosis in non-targeted tumors. This is dependent on NK cell expression of CD86, which is upregulated downstream of KLRK1. NK cell depletion increases Treginfiltration, diminishing CD8+T-cell-dependent antitumor response. These findings demonstrate that NK cells sustain and propagate CD8+T cell immunity following 3xTx.

INTRODUCTION: Breast cancer is common in women and often treated with radiation therapy to the chest wall, which is known to cause injury to the underlying ribs. It is also [...]

INTRODUCTION: Leprosy is a chronic granulomatous infection of the skin and peripheral nerves with Mycobacterium leprae. It can be difficult to distinguish from other granulomatous diseases, including sarcoidosis. This case [...]

INTRODUCTION: Unlike systemic amyloidosis, when amyloidosis is localized to the lungs, this uncommon condition usually involves the lungs in one of two ways. In can be confined to the tracheobronchial [...]

The FEV3/FVC ratio is not discussed in the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines for lung function interpretation in spite of narrow confidence limits of normal and its association with smoking. We sought to determine whether a reduction in only the FEV3/FVC ratio was associated with physiologic changes compared with subjects with normal FEV1/FVC and FEV3/FVC ratios.

Low-dose targeted radionuclide therapy combined with immune checkpoint inhibition enhances complete response rates in preclinical tumor models.