Citations

Matrix metalloproteinases (MMPs) have long been recognized as key mediators of tumor invasion and metastasis due to their capacity to degrade extracellular matrix components. However, clinical failure of broad-spectrum MMP inhibitors has revealed a more complex and context-dependent role for these proteases in cancer. Among them, macrophage metalloelastase, MMP-12, has emerged as a particularly intriguing enzyme with both tumor-promoting and tumor-suppressive functions. Predominantly expressed by tumor-associated macrophages, MMP-12 occupies a unique position at the interface of proteolysis, inflammation, and immune regulation within the tumor microenvironment. Accumulating evidence from experimental models and clinical studies demonstrates that MMP-12 can exert potent anti-tumorigenic effects, primarily through inhibition of angiogenesis. Mechanistically, MMP-12 generates angiostatin and other anti-angiogenic fragments, suppresses vascular endothelial growth factor signaling, and reduces tumor vascularization, thereby limiting tumor growth and metastatic expansion. In several cancer types, including lung, colorectal, and hepatocellular carcinoma, elevated MMP-12 expression has been associated with reduced tumor progression and improved patient outcomes. Conversely, MMP-12 can also promote tumor progression through extracellular matrix remodeling, facilitation of invasion, and modulation of inflammatory pathways, particularly in environments characterized by chronic inflammation or immunosuppressive macrophage phenotypes. These seemingly contradictory roles are governed by multiple context-dependent factors, including macrophage polarization, tumor type, disease stage, and microenvironmental cues such as hypoxia and cytokine signaling. In this review, we comprehensively examine the molecular regulation, functional mechanisms, and clinical relevance of MMP-12 in cancer. We highlight the dualistic nature of MMP-12 activity and discuss its implications for therapeutic strategies, emphasizing the need for selective and context-aware targeting approaches rather than broad inhibition of MMP activity.

ABSTRACT Purpose Layer fMRI is an increasingly utilized technique that provides insights into the laminar organization of brain activity. However, both blood‐oxygen‐level‐dependent (BOLD) fMRI and vascular space occupancy data (VASO) have certain limitations, such as bias towards larger cortical veins in BOLD fMRI and high specific absorption rate in VASO. This study aims to explore the feasibility of whole‐brain laminar functional quantitative susceptibility mapping (fQSM) compared to laminar BOLD fMRI and VASO at ultra‐high field. Methods Data were acquired using 3D EPI techniques. Complex data were denoised with NORDIC and susceptibility maps were computed using 3D path‐based unwrapping, the variable‐kernel sophisticated harmonic artifact reduction, as well as the streaking artifact reduction for QSM algorithms. To assess layer‐specific activation, 20 layers were segmented in the somatosensory and motor cortices, obtained from a finger tapping paradigm, and further averaged into six anatomical cortical layers. The magnitude of signal change and z ‐scores were compared across layers for each technique. Results fQSM showed the largest activation‐dependent mean susceptibility decrease in Layers II/III in M1 and Layers I/II in S1 with up to −1.3 ppb while BOLD showed the strongest mean signal increase in Layer I. Our data suggest that fQSM demonstrates less bias towards activation in superficial layers compared to BOLD. Moreover, activation‐based susceptibility change was comparable to VASO data. Conclusion Studying whole‐brain, layer‐dependent activation with submillimeter fQSM is feasible and reduces bias towards venous drainage effects on the cortical surface compared to BOLD, thereby enabling better localization of laminar activation.

Assessing balance is crucial in neurological rehabilitation, yet while wearable sensors enable real-world monitoring, identifying reliable digital biomarkers remains challenging. This study utilized a high-fidelity instrumented walkway to determine which gait parameters best predict balance impairment, providing robust targets for future wearable applications. We analyzed 49 steady-state gait metrics from 140 individuals with diverse neurological conditions. Using statistical analysis and machine learning, we evaluated these parameters against objective force plate sway scores and clinical fall-history labels. Group analysis identified 16 parameters significantly distinguishing fallers from non-fallers, and a neural network classified fallers with an area under the curve of 0.75. Across all analytical approaches, overall gait variability, e.g., Stride Width S.D. and the Gait Variability Index, emerged as a universal predictor of balance impairment and fall risk. Furthermore, while traditional linear models emphasized spatial postural control, machine learning classification uniquely identified inter-limb asymmetry as a premier driver of fall prediction. These findings indicate that instrumented gait analysis effectively identifies digital biomarkers for balance deficits. Isolating these specific metrics provides a clear blueprint for meaningful metrics required for continuous objective monitoring and future development of personalized, adaptive rehabilitation strategies.

Abstract To characterize invasive neuromodulation for insular drug‐resistant epilepsy, we retrospectively evaluated 22 patients treated with responsive neurostimulation (RNS; n = 14) or chronic subthreshold stimulation (CSS; n = 8). Stereoelectroencephalography was performed in 20 cases (91%). Median baseline seizure frequency was 10.5/month. Forty‐one percent had prior epilepsy surgery. At year 3, median seizure reduction (MSR) was 83% ( p = .01, Wilcoxon signed‐rank test), with a responder rate (RR) of 77%; MSR was 92% for CSS and 75% for RNS. There were no significant differences in MSR ( p ≥ .4) or RR ( p > .9) when comparing RNS versus CSS. Three patients achieved seizure freedom by year 3. Patients undergoing combined insular–thalamic stimulation ( n = 5) demonstrated an MSR of 84%, 86%, and 88% at 1, 2, and 3 years; seizure reduction in thalamocortical versus cortical‐only stimulation was not different ( p ≥ .1). Parasagittal lead trajectories achieved closer insular proximity than transopercular trajectories ( p < .0001, Mann–Whitney U ‐test). Median charge density at last follow‐up was 1.3 μC/cm 2 . There were no acute surgical complications and all stimulation‐related side effects resolved with programming adjustments. This study expands the limited literature on insular neuromodulation by demonstrating effectiveness of RNS and CSS, suggesting potential benefit from combined thalamocortical targeting, and defining parasagittal trajectories as a surgical approach for optimal lead proximity.

Abstract Alternaria spp. are dematiaceous ascomycetes that can cause opportunistic infections in immunocompromised hosts. They are challenging to identify and treat. However, optimal antifungal therapy remains undefined. We retrospectively reviewed antifungal susceptibilities (AST) of all Alternaria spp. isolates from adults at a tertiary care center between 2011 and 2025. We evaluated culture sources, minimum inhibitory concentration (MIC) and minimal effective concentration (MEC) distributions, and MIC₅₀/MIC₉₀ and MEC50/MEC90 values. Clinical characteristics, treatment measures, and outcomes of patients with clinically significant Alternaria spp. infections were described. Forty-one patients had Alternaria spp. isolated, most commonly from skin (n = 13), bone/joint (n = 5), nail (n = 3), or cornea (n = 3). Posaconazole and itraconazole demonstrated low MICs (MIC₅₀/MIC₉₀: 0.06/0.5 and 0.25/0.5 µg/mL, respectively). Voriconazole and isavuconazole showed higher MIC₅₀/MIC₉₀ (1/2 and 2/4 µg/mL). Caspofungin (0.125/0.5 µg/mL) and amphotericin B (0.25/1 µg/mL) had low MICs and MECs.s. Alternaria spp. represented clinically significant infection in 27 cases (66%); 26% were solid organ transplant recipients and 15% had hematologic malignancies. Other risk factors included preceding trauma (22%) and autoimmune disease (15%). Posaconazole was the most frequently used empiric agent (6, 32%). Following AST results, 14 patients (52%) received oral antifungal therapy; posaconazole was used in all 14. In addition, 7 patients (26%) received combination therapy with IV amphotericin B. Adjunctive surgery occurred in 14 cases (52%). Five patients (19%) died before completing therapy; Alternaria infections occurred predominantly in immunocompromised hosts and were frequently managed with posaconazole and surgery. Interpretive criteria for Alternaria spp. are needed to guide empiric and definitive therapy.

Abstract Medial meniscus posterior root repair improves symptoms and function, but repair alone does not normalize gait. In the referenced study, patients who underwent repair achieved an acceptable symptom state more often than those with an unrepaired tear (71.4%‐81.0% vs 10.5%‐26.3%). Gait mechanics moved toward normal but did not reach it: compared with controls, the tear group differed significantly in midstance knee extension and terminal‐stance knee adduction moment, with the repair group falling at an intermediate level. Varus thrust and reduced internal rotation persisted in both groups despite only modest differences in static mechanical alignment. This underscores that dynamic gait assessment, not a static radiograph, is beneficial to fully assess the effect of root repair. Restoration of full extension and objectively confirmed quadriceps recovery may be essential to closing this gap and to long‐term chondroprotection. This raises a rehabilitation paradox: prolonged protection safeguards healing but may potentiate quadriceps inhibition and persistent gait dysfunction. Earlier controlled weightbearing, potentially supported by meniscal centralization with multiple fixation points, warrants a prospective study. Root preservation should extend beyond fixation alone to include gait restoration, extrusion control, and long‐term joint protection.

Abstract Objective The goal of this study was to synthesize the evidence on how “status migrainosus” is defined in research studies in comparison to established International Classification of Headache Disorders (ICHD) criteria. Background Current ICHD‐3 criteria define status migrainosus as a headache attack occurring in a patient with a history of migraine with or without aura that is typical of previous attacks except for its duration (>72 h) and severity (debilitating). Despite the ICHD criteria, there are varying inclusion criteria noted in studies enrolling patients with status migrainosus. With this diagnostic uncertainty, there remains difficulty in studying this patient population. Methods This systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta‐Analysis guidelines. Ovid MEDLINE, Ovid EMBASE, All Evidence‐Based Medicine Reviews, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov , and the World Health Organization International Clinical Trials Registry Platform were searched with the end search date of August 29, 2025. We included studies that were original research focused on status migrainosus, published in English after January 1, 1988, and also included diagnostic criteria to define this condition. The abstracts and full texts were screened by independent reviewers, with a third independent reviewer remaining available to settle disputes. There were 45 studies that underwent full text review, with 19 of these studies included. Data extraction was conducted recording the criteria used to define status migrainosus, headache characteristics, and goals of each study. Results We identified four common domains among studies of status migrainosus, including use of ICHD criteria, headache duration, symptom severity, and treatment response. Reference to ICHD criteria was variable, with only 68% (13/19) of studies specifying an edition of ICHD criteria applied in recruiting or studying patients with status migrainosus. The majority of studies (16/19; 84%) used a headache duration greater than 72 h to define status migrainosus. The use of symptom severity with “debilitating” or “severe” was present in 63% (12/19) of studies and depended on the edition of ICHD criteria that was referenced. Treatment response was rarely used as a condition in defining status migrainosus, with only 15% (3/19) of studies utilizing this stipulation in diagnostic criteria. Conclusion The results of this systematic review show inconsistent application of ICHD criteria in research studies focusing on status migrainosus. These inconsistencies lead to ambiguity in how status migrainosus is defined in the research setting and limit the ability to replicate or compare studies. Guidelines outlining best practices for research of status migrainosus are necessary. For prospective studies, consistent utilization of ICHD criteria is necessary, with potential need to revise these criteria to better reflect the clinical realities of this entity. For retrospective studies, implementation of a standardized International Classification of Diseases code for status migrainosus would be of benefit to improve diagnostic clarity because the current codes are lengthy, cumbersome, and unclear.