Citations

ABSTRACT Background The sterol regulatory element‐binding protein (SREBP) pathway is essential for maintaining sterol homeostasis during B cell activation and germinal center B cell proliferation. However, its potential as a therapeutic target to treat B‐cell lymphoma remains unclear. Methods We examined SREBP protein expression in human B‐cell lymphoma samples using immunohistochemistry. Additionally, we conducted in vitro studies using SREBP signaling inhibitors in combination with rapamycin to assess their effects on cell proliferation and lipid metabolism in B‐cell lymphoma cells. Results Our analysis revealed high levels of SREBP2 protein expression in human B‐cell lymphoma samples. Inhibiting SREBP signaling or its downstream target HMG‐CoA reductase (HMGCR) with Fatostatin or Simvastatin effectively suppressed B‐cell lymphoma cell proliferation. However, B‐cell lymphoma cells responded to statin treatment by activating the mTORC1‐pS6 pathway, suggesting a compensatory mechanism to overcome statin‐induced cell cycle arrest. Combining low‐dose statin treatment with the mTOR inhibitor rapamycin produced a synergistic effect, significantly inhibiting B‐cell lymphoma proliferation, cell cycle progression, and lipid raft formation. Conclusions These results highlight the potential of a combined therapeutic approach targeting both SREBP and mTORC1 as a novel strategy for treating B‐cell lymphoma.

Waldenström macroglobulinaemia (WM) is a unique, cluster of differentiation (CD) 20+ B‐cell malignancy, with a characteristic immunoglobulin M‐secreting lymphoplasmacytic bone marrow infiltrate that is bolstered by a highly supportive microenvironment, including upregulated programmed death 1 expression. However, the impact of checkpoint inhibition in WM is unclear. Commentary on: Kothari et al. PembroWM: A phase II trial to investigate the safety and efficacy of rituximab and pembrolizumab in relapsed/refractory Waldenström's macroglobulinaemia. Br J Haematol 2024; 205: 2273‐2281 .

ABSTRACT The mechanisms leading to aneurysm occlusion after treatment with flow‐diverting devices are not fully understood. Flow modification induces thrombus formation within the aneurysm cavity, but fibrin can simultaneously accumulate and cover the device scaffold, leading to further flow modification. However, the interplay and relative importance of these processes are not clearly understood. A computational model of fibrin accumulation and flow modification after flow diversion treatment of cerebral aneurysms has been developed under the guidance of in vitro experiments and observations. The model is based on the loose coupling of flow and transport‐reaction equations that are solved separately by independent codes. Interaction or reactive terms account for thrombin production from prothrombin stimulated by thrombogenic metallic wires and inhibition by antithrombin as well as fibrin production from fibrinogen stimulated by thrombin and flow shear stress, and fibrin adhesion to device wires and already attached fibrin. The computational model was demonstrated and tested on idealized vessel and aneurysm geometries. The model was able to reproduce the salient features of fibrin accumulation after the deployment of flow‐diverting devices in idealized in vitro models of cerebral aneurysms. Namely, fibrin production in regions of high shear stress, initial accumulation at the inflow zone, and progressive occlusion of the device and corresponding flow attenuation. The computational model linking flow dynamics to fibrin production, transport, and adhesion can be used to investigate and better understand the effects that lead to fibrin accumulation and the resulting aneurysm inflow reduction and intra‐aneurysmal flow modulation.

Purpose To characterize the relationship between testosterone replacement therapy (TRT) and anterior cruciate ligament (ACL) injuries. Methods A retrospective cohort study using a large insurance database was conducted. Patients who were prescribed TRT for at least 3 months were matched with controls who were not prescribed TRT. Rates of ACL tears were compared between the cohorts. Multiple subgroups were created based on age (<25, 25‐35, 36‐45, 46‐55, 56‐65, and 65+ years). Multivariable logistic regressions were performed to determine the association of TRT with ACL tears while accounting for demographic variables and comorbidities. Results After matching, there were 160,839 patients in both the TRT cohort and the control cohort. The incidence of ACL injuries was 17.8 per 10,000 person‐years (95% confidence interval [CI]: 16.4‐19.2) for patients who were prescribed TRT and 4.9 per 10,000 person‐years (95% CI: 4.1‐5.7) for controls ( P < .001). Within 2 years of filling a testosterone prescription for at least 3 months, 572 (0.35%) patients experienced an ACL injury compared to only 157 (0.10%) controls during the same follow‐up period (odds ratio: 2.77; 95% CI: 2.26‐3.42, P < .001). When stratified by age, all groups except the <25 years of age group demonstrated a significantly higher rate of ACL tears (odds ratio 3.91‐12.3, P < .001‐.009). When separated by sex, males on TRT were 3.13 (95% CI: 2.50‐3.93, P < .001) times more likely while females on TRT were 1.94 (95% CI: 1.13‐3.41, P = .018) times more likely to experience an ACL injury compared to controls. Conclusions This study found that patients prescribed at least 3 months of TRT had a significantly higher incidence of ACL injuries compared to controls within a 2‐year follow‐up period. Level of Evidence Level III, retrospective comparative study.

Background: Maculopapular cutaneous mastocytosis (MPCM) is a rare disorder characterized by a pathologic accumulation of mast cells in the skin, which may or may not be accompanied by systemic mastocytosis. Diagnosis of MPCM on skin biopsy can be challenging because the findings may be subtle. Although mast cell density in MPCM has been reported, data informing a proposed cutoff for diagnosis and diagnostic criteria are limited. Methods: We identified adult patients diagnosed with MPCM and urticarial tissue reaction/chronic urticaria on skin biopsy and compared the mast cell and eosinophil counts per 1 mm2 in 10 cases each of MPCM, chronic urticaria, and normal skin from routine biopsies. All slides were stained with CD117, and CD117-positive mast cells were counted per 1 mm2 using digital microscopy. Eosinophils were counted on hematoxylin and eosin-stained slides per 1 mm2 using digital microscopy. Results: The median number of mast cells per 1 mm2 was significantly higher in MPCM than in cases of urticaria and normal skin/control tissue (177.3 vs. 26.8 vs. 47.8 mast cell per mm2, respectively; P ≤ 0.001). The calculated “cut point” for mastocytosis versus chronic urticaria and normal skin was 66 mast cells per 1 mm2, whereas the value for controls versus urticaria was 37 mast cells per 1 mm2. Eosinophils had similar density in MPCM and urticaria, and their presence was significant in the differentiation of MPCM and urticaria from normal tissue. Conclusions: This study adds to the literature by providing objective mast cell density data to distinguish challenging cases of cutaneous mastocytosis from urticarial reactions and normal skin. Future studies could explore the development of computer-aided estimations of cellular density with more extensive comparison with other inflammatory conditions to translate our findings more readily into clinical practice.

Abstract Endometriosis is a chronic painful condition affecting 10% of reproductive-aged women with a high prevalence of overlapping gastrointestinal symptoms. There is a significant diagnostic delay for endometriosis and current screening practices for endometriosis in gastroenterology clinic populations have not been evaluated. 112 gastroenterology providers (57.5% females, 64.3% physicians) completed an anonymized exploratory survey (40.1% response rate). Most respondents (59.4%) currently do not screen for endometriosis, but the majority (72.1%) reported they would be “extremely likely” or “somewhat likely” to screen for endometriosis after being presented with data on the high prevalence of chronic GI symptoms in patients with endometriosis.

Abstract The Midwest Aging Consortium (MAC) has emerged as a critical collaborative initiative aimed at advancing our understanding of aging and developing strategies to combat the rising prevalence of age-related diseases. Founded in 2019, MAC brings together researchers from various disciplines and institutions across the Midwestern United States to foster interdisciplinary geroscience research. This report summarizes the highlights of the Fourth Annual Symposium of MAC, which was held at Iowa State University in May 2023. The symposium featured presentations on a wide array of topics, including studies on slow-aging animals, cellular senescence and senotherapeutics, the role of the immune system in aging, metabolic changes in aging, neuronal health in aging, and biomarkers for measuring the aging process. Speakers shared findings from studies involving a variety of animals, ranging from commonly used species such as mice, rats, worms, yeast, and fruit flies, to less-common ones like naked mole-rats, painted turtles, and rotifers. MAC continues to emphasize the importance of supporting emerging researchers and fostering a collaborative environment, positioning itself as a leader in aging research. This symposium not only showcased the current state of aging biology research but also highlighted the consortium’s role in training the next generation of scientists dedicated to improving the healthspan and well-being of the aging population.