Obesity induces PD-1 on macrophages to suppress anti-tumour immunity.

Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can in some cases enhance survival3-5 and responses to immune checkpoint blockade therapies, including anti-PD-1, which targets PD-1 (encoded by PDCD1), an inhibitory receptor expressed on immune cells6-8. Although obesity promotes chronic inflammation, the role of the immune system in the obesity-cancer connection and immunotherapy remains unclear. It has been shown that in addition to T cells, macrophages can express PD-19-12. Here we found that obesity selectively induced PD-1 expression on tumour-associated macrophages (TAMs). Type I inflammatory cytokines and molecules linked to obesity, including interferon-γ, tumour necrosis factor, leptin, insulin and palmitate, induced macrophage PD-1 expression in an mTORC1- and glycolysis-dependent manner. PD-1 then provided negative feedback to TAMs that suppressed glycolysis, phagocytosis and T cell stimulatory potential. Conversely, PD-1 blockade increased the level of macrophage glycolysis, which was essential for PD-1 inhibition to augment TAM expression of CD86 and major histocompatibility complex I and II molecules and ability to activate T cells. Myeloid-specific PD-1 deficiency slowed tumour growth, enhanced TAM glycolysis and antigen-presentation capability, and led to increased CD8+ T cell activity with a reduced level of markers of exhaustion. These findings show that obesity-associated metabolic signalling and inflammatory cues cause TAMs to induce PD-1 expression, which then drives a TAM-specific feedback mechanism that impairs tumour immune surveillance. This may contribute to increased cancer risk yet improved response to PD-1 immunotherapy in obesity.

Armed actor interventions in humanitarian and public health crises: examining perspectives of crisis-affected community members.

BACKGROUND: Despite frequently providing non-military services in times of crisis, little systematic research has examined the perspectives of crisis-affected community members on the role of armed actors responding to humanitarian crises and public health emergencies. METHODS: To address this research gap, 175 interviews were conducted (2020-2021) amongst humanitarian and public health practitioners; armed actors; and crisis-affected community members across three country and four crisis contexts. Specifically, this effort included an Ebola outbreak in the Democratic Republic of the Congo; a refugee crisis on the Jordanian-Syrian border; and a volcanic eruption and COVID-19 outbreak in the Philippines. Data was analysed using grounded theory principles. RESULTS: Crisis-affected community members held diverse views. Non-state armed groups (NSAGs) and government armed actors were characterised as antagonists by some but supportive by others; gender issues were central to perceptions of armed actors, in ways that were both prejudicing and favourable. Overall perception was most closely linked to armed actor roles rather than the relative amount of conflict in a given area. CONCLUSIONS: Findings nuance the relevant literature characterizing NSAGs as disruptive agents, and also the relevant literature that does not fully consider the nuances of gender and armed actor roles as deeply relevant to crisis-affected community perspectives on armed actors. These findings have important implications for both policy and academic discourse on militarization and localization.

Health care utilisation in Cox's Bazar district, Bangladesh, during the first year of the COVID-19 pandemic: A mixed-methods study among host communities.

To respond to the COVID-19 pandemic, countries introduced public health and social measures that had indirect societal, economic consequences. Concerns during epidemics include continuity of routine health services. We investigate how healthcare utilisation and healthcare seeking behaviour changed during the first year of the COVID-19 pandemic among host communities in Cox's Bazar, Bangladesh. This mixed-methods study combines quantitative analyses of routine health data and population-based findings about healthcare seeking behaviours. Trends in consultations changed according to facility level (higher-level facilities included Upazila Health Complexes and District Hospitals; lower-level facilities included Community Clinics and Union Health and Family Welfare Centers). At the pandemic's beginning, drops were seen at higher-level health facilities for outpatient department (OPD) consultations, respiratory infections, and antenatal care. Minor reductions or increases were seen at lower-level facilities for the same services. Half of the subdistricts reported a cumulative increase in OPD and respiratory tract infection consultations. Most subdistricts reported a cumulative decrease in antenatal care. Child vaccinations dropped in all subdistricts, half of which did not catch-up, resulting in a cumulative decrease of delivered doses. Fear of contracting COVID-19 and financial constraints were the main reasons for decreased access. Drivers of healthcare seeking behaviours should be better understood to guide preparedness and service delivery modalities at primary and secondary levels.

Hand-worn devices for assessment and rehabilitation of motor function and their potential use in BCI protocols: a review.

Introduction: Various neurological conditions can impair hand function. Affected individuals cannot fully participate in activities of daily living due to the lack of fine motor control. Neurorehabilitation emphasizes repetitive movement and subjective clinical assessments that require clinical experience to administer. Methods: Here, we perform a review of literature focused on the use of hand-worn devices for rehabilitation and assessment of hand function. We paid particular attention to protocols that involve brain-computer interfaces (BCIs) since BCIs are gaining ground as a means for detecting volitional signals as the basis for interactive motor training protocols to augment recovery. All devices reviewed either monitor, assist, stimulate, or support hand and finger movement. Results: A majority of studies reviewed here test or validate devices through clinical trials, especially for stroke. Even though sensor gloves are the most commonly employed type of device in this domain, they have certain limitations. Many such gloves use bend or inertial sensors to monitor the movement of individual digits, but few monitor both movement and applied pressure. The use of such devices in BCI protocols is also uncommon. Discussion: We conclude that hand-worn devices that monitor both flexion and grip will benefit both clinical diagnostic assessment of function during treatment and closed-loop BCI protocols aimed at rehabilitation.

Moving humanitarian-military relations forward: a new typology.

This article presents a new typology for humanitarian-military relations (HMR). This typology can serve as an analytical framework for assessing, during humanitarian emergencies, how civilian responders can and should engage with armed actors. The typology considers two factors: (1) the nature of crisis-affected population's perceptions of an armed actor, and (2) the extent of alignment of civilian responders' and armed actors' interests and objectives. This typology is empirically rooted in an in-depth analysis of HMR across four humanitarian response contexts: (1) the Kivu Ebola Epidemic in the Democratic Republic of the Congo, (2) the Rukban forced displacement crisis along the Jordan-Syria border, (3) the Taal volcano eruption in the Philippines, and (4) the COVID-19 pandemic in the Philippines. The analysis presented in this article is based on 175 qualitative interviews conducted with civilian responders, armed actors, and crisis-affected individuals across these contexts.

Forces exerted and transduced by cancer-associated fibroblasts during cancer progression.

Although it is well-known that cancer-associated fibroblasts (CAFs) play a key role in regulating tumor progression, the effects of mechanical tissue changes on CAFs are understudied. Myofibroblastic CAFs (myCAFs), in particular, are known to alter tumor matrix architecture and composition, heavily influencing the mechanical forces in the tumor microenvironment (TME), but much less is known about how these mechanical changes initiate and maintain the myCAF phenotype. Additionally, recent studies have pointed to the existence of CAFs in circulating tumor cell clusters, indicating that CAFs may be subject to mechanical forces beyond the primary TME. Due to their pivotal role in cancer progression, targeting CAF mechanical regulation may provide therapeutic benefit. Here, we will discuss current knowledge and summarize existing gaps in how CAFs regulate and are regulated by matrix mechanics, including through stiffness, solid and fluid stresses, and fluid shear stress.

Temporal application of lysyl oxidase during hierarchical collagen fiber formation differentially effects tissue mechanics.

The primary source of strength in menisci, tendons, and ligaments are hierarchical collagen fibers; however, these fibers are not regenerated after injury nor in engineered replacements, resulting in limited repair options. Collagen strength is reliant on fiber alignment, density, diameter, and crosslinking. Recently, we developed a culture system which guides cells in high-density collagen gels to develop native-like hierarchically organized collagen fibers, which match native fiber alignment and diameters by 6 weeks. However, tensile moduli plateau at 1MPa, suggesting crosslinking may be lacking. Collagen crosslinking is regulated by lysyl oxidase (LOX) which forms immature crosslinks that condense into mature trivalent crosslinks. Trivalent crosslinks are thought to be the primarily source of strength in fibers, but it's not well understood how they form. The objective of this study was to evaluate the effect of exogenous LOX in our culture system at different stages of hierarchical fiber formation to produce stronger replacements and to better understand factors affecting crosslink maturation. We found treatment with LOX isoform LOXL2 did not restrict hierarchical fiber formation, with constructs still forming aligned collagen fibrils by 2 weeks, larger fibers by 4 weeks, and early fascicles by 6 weeks. However, LOXL2 treatment did significantly increase mature pyridinium (PYD) crosslink accumulation and tissue mechanics, with timing of LOXL2 supplementation during fiber formation having a significant effect. Overall, we found one week of LOXL2 supplementation at 4 weeks produced constructs with native-like fiber organization, increased PYD accumulation, and increased mechanics, ultimately matching the tensile modulus of immature bovine menisci. STATEMENT OF SIGNIFICANCE: Collagen fibers are the primary source of strength and function in connective tissues throughout the body, however it remains a challenge to develop these fibers in engineered replacements, greatly reducing treatment options. Here we demonstrate lysyl oxidase like 2 (LOXL2) can be used to significantly improve the mechanics of tissue engineered constructs, but timing of application is important and will most likely depend on degree of collagen organization or maturation. Currently there is limited understanding of how collagen crosslinking is regulated, and this system is a promising platform to further investigate cellular regulation of LOX crosslinking. Understanding the mechanism that regulates LOX production and activity is needed to ultimately regenerate functional repair or replacements for connective tissues throughout the body.

Weakly migratory metastatic breast cancer cells activate fibroblasts via microvesicle-Tg2 to facilitate dissemination and metastasis.

Cancer cell migration is highly heterogeneous, and the migratory capability of cancer cells is thought to be an indicator of metastatic potential. It is becoming clear that a cancer cell does not have to be inherently migratory to metastasize, with weakly migratory cancer cells often found to be highly metastatic. However, the mechanism through which weakly migratory cells escape from the primary tumor remains unclear. Here, utilizing phenotypically sorted highly and weakly migratory human breast cancer cells, we demonstrate that weakly migratory metastatic cells disseminate from the primary tumor via communication with stromal cells. While highly migratory cells are capable of single cell migration, weakly migratory cells rely on cell-cell signaling with fibroblasts to escape the primary tumor. Weakly migratory cells release microvesicles rich in tissue transglutaminase 2 (Tg2) which activate murine fibroblasts and lead weakly migratory cancer cell migration in vitro. These microvesicles also induce tumor stiffening and fibroblast activation in vivo and enhance the metastasis of weakly migratory cells. Our results identify microvesicles and Tg2 as potential therapeutic targets for metastasis and reveal a novel aspect of the metastatic cascade in which weakly migratory cells release microvesicles which activate fibroblasts to enhance cancer cell dissemination.

Diabetic hyperglycemia promotes primary tumor progression through glycation-induced tumor extracellular matrix stiffening.

Diabetes mellitus is a complex metabolic disorder that is associated with an increased risk of breast cancer. Despite this correlation, the interplay between tumor progression and diabetes, particularly with regard to stiffening of the extracellular matrix, is still mechanistically unclear. Here, we established a murine model where hyperglycemia was induced before breast tumor development. Using the murine model, in vitro systems, and patient samples, we show that hyperglycemia increases tumor growth, extracellular matrix stiffness, glycation, and epithelial-mesenchymal transition of tumor cells. Upon inhibition of glycation or mechanotransduction in diabetic mice, these same metrics are reduced to levels comparable with nondiabetic tumors. Together, our study describes a novel biomechanical mechanism by which diabetic hyperglycemia promotes breast tumor progression via glycating the extracellular matrix. In addition, our work provides evidence that glycation inhibition is a potential adjuvant therapy for diabetic cancer patients due to the key role of matrix stiffening in both diseases.