Macrophage HIF-1α Is an Independent Prognostic Indicator in Kidney Cancer.

PURPOSE: Clear cell renal cell carcinoma (ccRCC) is frequently associated with inactivation of the von Hippel-Lindau tumor suppressor, resulting in activation of HIF-1α and HIF-2α. The current paradigm, established using mechanistic cell-based studies, supports a tumor promoting role for HIF-2α, and a tumor suppressor role for HIF-1α. However, few studies have comprehensively examined the clinical relevance of this paradigm. Furthermore, the hypoxia-associated factor (HAF), which regulates the HIFs, has not been comprehensively evaluated in ccRCC. EXPERIMENTAL DESIGN: To assess the involvement of HAF/HIFs in ccRCC, we analyzed their relationship to tumor grade/stage/outcome using tissue from 380 patients, and validated these associations using tissue from 72 additional patients and a further 57 patients treated with antiangiogenic therapy for associations with response. Further characterization was performed using single-cell mRNA sequencing (scRNA-seq), RNA-in situ hybridization (RNA-ISH), and IHC. RESULTS: HIF-1α was primarily expressed in tumor-associated macrophages (TAMs), whereas HIF-2α and HAF were expressed primarily in tumor cells. TAM-associated HIF-1α was significantly associated with high tumor grade and increased metastasis and was independently associated with decreased overall survival. Furthermore, elevated TAM HIF-1α was significantly associated with resistance to antiangiogenic therapy. In contrast, high HAF or HIF-2α were associated with low grade, decreased metastasis, and increased overall survival. scRNA-seq, RNA-ISH, and Western blotting confirmed the expression of HIF-1α in M2-polarized CD163-expressing TAMs. CONCLUSIONS: These findings highlight a potential role of TAM HIF-1α in ccRCC progression and support the reevaluation of HIF-1α as a therapeutic target and marker of disease progression.

Volumetric and shear processes in crystalline rock approaching faulting.

Understanding the approach to faulting in continental rocks is critical for identifying processes leading to fracturing in geomaterials and the preparation process of large earthquakes. In situ dynamic X-ray imaging and digital volume correlation analysis of a crystalline rock core, under a constant confining pressure of 25 MPa, are used to elucidate the initiation, growth, and coalescence of microfractures leading to macroscopic failure as the axial compressive stress is increased. Following an initial elastic deformation, microfractures develop in the solid, and with increasing differential stress, the damage pervades the rock volume. The creation of new microfractures is accompanied by propagation, opening, and closing of existing microfractures, leading to the emergence of damage indices that increase as powers of the differential stress when approaching failure. A strong spatial correlation is observed between microscale zones with large positive and negative volumetric strains, microscale zones with shears of opposite senses, and microscale zones with high volumetric and shear strains. These correlations are attributed to microfracture interactions mediated by the heterogeneous stress field. The rock fails macroscopically as the microfractures coalesce and form a geometrically complex 3D volume that spans the rock sample. At the onset of failure, more than 70% of the damage volume is connected in a large fracture cluster that evolves into a fault zone. In the context of crustal faulting dynamics, these results suggest that evolving rock damage around existing locked or future main faults influences the localization process that culminates in large brittle rupture events.

Strength of Mechanical Memories is Maximal at the Yield Point of a Soft Glass.

We show experimentally that both single and multiple mechanical memories can be encoded in an amorphous bubble raft, a prototypical soft glass, subject to an oscillatory strain. In line with recent numerical results, we find that multiple memories can be formed sans external noise. By systematically investigating memory formation for a range of training strain amplitudes spanning yield, we find clear signatures of memory even beyond yielding. Most strikingly, the extent to which the system recollects memory is largest for training amplitudes near the yield strain and is a direct consequence of the spatial extent over which the system reorganizes during the encoding process. Our study further suggests that the evolution of force networks on training plays a decisive role in memory formation in jammed packings.