Tissue Stiffness Research Articles

The Intermittent Pneumatic Compression Influences Edema Fluid Movement and Promotes the Compensatory Drainage Pathways in Patients with Breast Cancer Related Lymphedema.

Introduction: Upper limb lymphedema is the most common complication after breast cancer therapy. Suddenly disturbed lymphatic transport in the affected arm causes tissue fluid accumulation in tissue spaces, limb enlargement, and secondary changes in tissue. Early compression therapy is necessary. We aim to evaluate the effectiveness of intermittent pneumatic compression (IPC) in fluid movement along the limb and the possibility of creating compensatory drainage pathways. Methods and Results: We investigated 25 patients with Breast Cancer Related Lymphedema (BCRL) stages II and III. Indocyanine green observation and measurement of skin water concentration and skin and subcutaneous tissue stiffness were done before and after a single 45-minute session of IPC. After IPC, we observed the movement of edema fluid upper in the arm (92%) and in three main directions not seen before IPC: to the ipsilateral supraclavicular lymph node (30%), to the ipsilateral axilla (22%), and to the axilla, chest, and scapula (26%). We noticed two changes in fluorescent intensity along the entire limb: a decrease in the hand and forearm, an increase in the arm (64%), and a decrease along some parts or the entire limb (36%). Skin and subcutaneous tissue stiffness decreased at all limb levels. The highest, statistically significant reduction of subcutaneous tissue stiffness was noticed in the middle forearm and elbow (36.4% and 33.4%, respectively). Conclusions: IPC can effectively move edema fluid from the distal to the proximal part of the limb, promote compensatory drainage pathways, and decrease tissue stiffness. This compression type should be applied even in the early stages to prevent limb enlargement and secondary tissue changes.

Transient shear wave elastometry using a portable magnetic resonance sensor.

Magnetic resonance elastography (MRE) provides detailed maps of tissue stiffness, helping to diagnose various health conditions, but requires the use of expensive clinical MRI scanners. Our approach utilizes compact, cost-effective portable MR sensors that offer bulk characterization of material properties in a region of interest close to the surface (within 1-2cm). This accessible instrument could enable routine monitoring and prevention of diseases not readily evaluated with conventional tools. The method was tested on tissue-mimicking phantoms with varying stiffness. The gels were excited with acoustic pulses (one cycle of a sinusoidal waveform) at a fixed distance from the MR sensor. A series of delays between acoustic excitation and MR signal detection allowed time for the pulse to travel to the sensitive region. The "arrival time" of the shear wave, determined by the time-dependent MR signal response, was used to calculate the shear wave speed. MR measurements of shear wave speed were compared with optical sensor measurements and manufacturer-tabulated values, aligning with expected relative differences between samples. A portable MR-based transient elastometry technique for measuring tissue elasticity was developed and demonstrated on tissue-mimicking phantoms. Future improvements include using a new portable magnet to investigate depth-dependent changes in elasticity in stratified samples and integrating MR relaxation and diffusion measurements for comprehensive tissue analysis. This approach can complement conventional MRE in applications where a portable, affordable, and localized assessment of tissue stiffness is required.

Shear Wave Elastography Evaluation of Testicular Stiffness in Dogs Affected by Testicular Pathology

Shear wave elastography (SWE) is an advanced ultrasound technique that assesses tissue stiffness by measuring shear wave speed (SWS) produced after an acoustic impulse. It includes bidimensional (2D-SWE) and focal point (pSWE) methods, allowing qualitative and quantitative analysis of tissue stiffness. This study aimed to describe the elastographic features of testicular abnormalities in dogs, supported by histological findings. Eighteen dogs with testicular abnormalities underwent B-mode ultrasound, power and color Doppler ultrasound, 2D-SWE, and pSWE before orchiectomy. Five cryptorchid testes were excluded and thirty-one testes (12 normal, 7 with leydigomas, 6 with seminomas, 1 with a round cell tumor, and 5 with orchitis) were examined. Normal testes, lesions, and adjacent healthy tissues (no evident ultrasound changes, NEUC) were sampled. Testicular abnormalities presented SWS values of 1.05–4.89 m/s (2D-SWE) and 1.35–5.31 m/s (pSWE). Significant differences were observed among normal testes, NEUC areas, and those with orchitis, leydigomas, and seminomas by both 2D-SWE and pSWE. Normal testes were significantly softer than ones with leydigomas, seminomas, and orchitis, and NEUC areas also had different SWS values compared to those with tumors and orchitis (p < 0.05). However, SWE techniques lacked specificity in differentiating between orchitis and tumors. Diagnostic accuracy of SWE techniques for testicular lesions remains challenging and requires further investigation to fully address its clinical potential.

A multifunctional sensor for cell traction force, matrix remodeling and biomechanical assays in self-assembled 3D tissues in vitro.

Cell-matrix interactions, mediated by cellular force and matrix remodeling, result in dynamic reciprocity that drives numerous biological processes and disease progression. Currently, there is no available method for directly quantifying cell traction force and matrix remodeling in three-dimensional matrices as a function of time. To address this long-standing need, we developed a high-resolution microfabricated device that enables longitudinal measurement of cell force, matrix stiffness and the application of mechanical stimulation (tension or compression) to cells. Here a specimen comprising of cells and matrix self-assembles and self-integrates with the sensor. With primary fibroblasts, cancer cells and neurons we have demonstrated the feasibility of the sensor by measuring single or multiple cell force with a resolution of 1 nN and changes in tissue stiffness due to matrix remodeling by the cells. The sensor can also potentially be translated into a high-throughput system for clinical assays such as patient-specific drug and phenotypic screening. We present the detailed protocol for manufacturing the sensors, preparing experimental setup, developing assays with different tissues and for imaging and analyzing the data. Apart from microfabrication of the molds in a cleanroom (one time operation), this protocol does not require any specialized skillset and can be completed within 4-5 h.

Data-Driven Depiction of Aging Related Physiological Volume Shrinkage in Brain White Matter: An Image Processing Based Three-Dimensional Micromechanical Model

Abstract Aging in the human brain, both in healthy and pathological conditions, leads to significant microstructural alterations, resulting in cognitive decline, with cerebral atrophy being a major contributing factor. This atrophy, characterized by the loss of neurons and glial cells, plays a crucial role in the reduction of brain function. While magnetic resonance imaging (MRI) and magnetic resonance elastography (MRE) provide noninvasive tools to measure brain morphology (volume changes) and regional mechanical properties (tissue stiffness) at the millimeter scale, they are unable to capture cellular-level or micron-scale changes in brain tissue. The challenge is in correlating the mechanical property changes observed at the millimeter scale with the underlying cellular-level micro-architectural alterations. To address this limitation, an ensemble of three-dimensional micromechanical finite element (FE) models was developed, utilizing MRI/MRE data to compute the mechanics of the aging brain with a higher level of detail. Using image processing techniques in Python's NIBABEL library, a mathematical model was constructed to quantify volume fraction (VF) shrinkage in brain white matter (BWM). These models incorporate uniaxial tensile loading and simulate the interactions between axons, myelin, and the glial matrix. Among the three finite element models compared, model type III, which includes both volume fraction changes and shear modulus degeneration, showed a high-order age-related atrophy and brain softening. This approach emphasizes the significant role of computational mechanics in linking macroscopic MRI measurements to cellular-scale changes, enhancing our understanding of brain tissue degeneration.

The Multifactorial Relationship Between Bone Tissue Water and Stiffness at the Proximal Femur

Bone mechanical function is determined by multiple factors, some of which are still being elucidated. Here, we present a multivariate analysis of the role of bone tissue composition in the proximal femur stiffness of cadaver bones (n = 12, age 44–93). Stiffness was assessed by testing under loading conditions simulating a sideways fall onto the hip. Compositional properties of cortical and trabecular tissues were quantified in femoral neck cross sections by Fourier transform infrared (FTIR) spectroscopy and near infrared (NIR) spectroscopy. In addition, cross-sectional areas and cortical thickness and tissue mineral density (TMD) were measured at the femoral neck. Pearson correlation analysis showed a significant (p < 0.05) negative relationship between bone stiffness and cortical and trabecular water content, both total (r = -0.63) and tightly bound to matrix and mineral (r = -55). Additionally, significant (p < 0.05) positive correlations were found between stiffness and bone area, both total (r = 0.67) and trabecular (r = 0.58). However, linear regression using each of these properties to predict bone stiffness resulted in weak models (R2 = 0.36–0.48). Interestingly, we found markedly stronger models (cross-validated R2 = 0.80–0.92) by using partial least squares (PLS) regression to predict stiffness based on combinations of bone properties. The models with highest R2 values were found when including bone water parameters as explanatory variables, both total and tightly bound, in cortical and trabecular. This study provides new insights by revealing a multifactorial relationship in which higher bone water content across different tissue compartments contributes to lower bone stiffness, highlighting bone water as a potential biomarker of bone quality and proximal femur mechanical function.

Fast-Relaxing Hydrogels Promote Pancreatic Adenocarcinoma Cell Aggressiveness through Integrin β1 Signaling.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense extracellular matrix (ECM) exhibiting high stiffness and fast stress relaxation. In this work, gelatin-based viscoelastic hydrogels were developed to mimic the compositions, stiffness, and fast stress relaxation of PDAC tissues. The hydrogels were cross-linked by gelatin-norbornene-boronic acid (GelNB-BA), thiolated macromers, and a 1,2-diol-containing linear synthetic polymer PHD. Controlling the thiol-norbornene cross-linking afforded tunable stiffness, whereas increasing PHD content led to hydrogels with PDAC-mimicking fast stress relaxation. In vitro studies, including proliferation, morphology, and mRNA-sequencing, showed that fast-relaxing hydrogels supported PDAC cell proliferation, epithelial-mesenchymal transition (EMT), and integrin β1 activation. Blocking integrin β1 in vitro led to upregulating EMT markers in both slow and fast-relaxing hydrogels. However, this strategy profoundly impacted tumor growth rate and reduced tumor size but did not alter metastasis patterns in an orthotopic mouse model. This suggests a need to further evaluate the antitumor effect of integrin β1 blockade.

DOP075 Tissue fibrosis modulates interleukin (IL)-13 signaling in intestinal epithelial cells

Abstract Background Inflammatory Bowel Diseases (IBDs) are characterized by chronic inflammation of the intestinal tissue and persistent disruption of the intestinal epithelial barrier. A common and dangerous complication of chronic inflammation during IBD is fibrosis, a mechanical stiffening of the intestinal tissue [1,2]. Previous work suggests that immune cell activity, for example Interleukin (IL)-13-mediated macrophage activation, can be mechanosensitive [3,4]. However, it is not currently well understood how fibrosis affects the inflammatory response in intestinal epithelial cells. Methods To address how tissue stiffness impacts intestinal inflammation, we studied the effects of inflammatory cytokine signaling in intestinal epithelial cells using a recently developed intestinal organoid monolayer model. We cultured intestinal organoid monolayers on soft (0.5kPa), intermediate (5kPa) or stiff (15kPa) hydrogels to mimic physiological or fibrotic conditions and studied the cellular response to IL-13, an inflammatory cytokine implicated in IBD and loss of barrier integrity. To investigate the impacts of substrate stiffness and IL-13 signaling on epithelial cell function, we combined high-resolution live microscopy, quantitative image analysis using AI-based models and biophysical measurements. Results We found that substrate mechanosensing and IL-13 signaling interact synergistically to modulate intestinal epithelial stem cell differentiation, leading to a dramatic increase in the frequency of secretory cells. Furthermore, organoids cultured on stiff substrates no longer respond to IL-13 treatment, suggesting that fibrotic conditions may promote an inflamed-like state even in the absence of inflammatory cytokines. To further investigate cross-talk between substrate mechanics and IL-13 signalling, we inhibited downstream IL-13 signalling and cell contractility. We found that both the stiffness- and IL-13-induced phenotypes could be rescued by either inhibiting myosin-2 activity or blocking downstream IL-13 signalling, further indicating a co-dependence and synergy of substrate stiffness and IL-13. Further experiments implicate the relocalization of myosin-2 to the cell cortex and increased nuclear accumulation of the mechanosensitive protein YAP in mediating this response. Experiments using mouse models of colitis further support a role for YAP in this process. Conclusion Taken together, this work reveals how tissue mechanics modulate the inflammatory response in the intestinal epithelium. Future translational work based on these findings will inspire new approaches to mitigate the effects of fibrosis during IBD.

Magnetic Resonance Acoustic Radiation Force Imaging (MR-ARFI).

This review covers the theoretical background, pulse sequence considerations, practical implementations, and multitudes of applications of magnetic resonance acoustic radiation force imaging (MR-ARFI) described to date. MR-ARFI is an approach to encode tissue displacement caused by the acoustic radiation force of a focused ultrasound field into the phase of a MR image. The displacement encoding is done with motion encoding gradients (MEG) which have traditionally been added to spin echo-type and gradient recalled echo-type pulse sequences. Many different types of MEG (monopolar, bipolar, tripolar etc.) have been described and pros and cons are discussed. We further review studies investigating the safety of MR-ARFI, as well as approaches to simulate the MR-ARFI displacement. Lastly, MR-ARFI applications such as for focal spot localization, tissue stiffness interrogation following thermal ablation, trans-skull aberration correction, and simultaneous MR-ARFI and MR thermometry are discussed. EVIDENCE LEVEL: N/A TECHNICAL EFFICACY: Stage 1.

Elastographic evaluation for fatty liver disease in north Indian children and adolescents with type 1 diabetes.

The prevalence and predisposing factors to metabolic dysfunction-associated fatty liver disease (MAFLD) in children with type 1 Diabetes (T1D) living in developing countries are unknown. A cross-sectional study was conducted in children with T1D. The presence of liver fat and tissue stiffness were assessed by ultrasonography and shear-wave elastography (SWE), respectively. The SWE values were correlated to body mass index (BMI), glycemic control, disease duration, and gamma-glutamyl transferase (GGT). Healthy non-obese children (n=36) were recruited as controls. One hundred children with T1D were grouped (Group A-C) according to the disease duration (<5, 5-10, and >10 years, respectively). The mean diabetes duration and glycated hemoglobin were 5.9±4.0 years and 8.2±0.55 %, respectively. The mean SWE values were significantly higher in the patient groups compared to controls (5.07±0.67, 5.27±0.65, 5.16±0.50, vs. 4.80±0.82 kPa, p-value 0.006). The liver stiffness based on SWE showed a positive but weak relationship with BMI, diabetes duration, glycemic control, and GGT levels. A significantly higher number of children with T1D had MAFLD [9(20 %), 7(24.1 %), 7(26.9 %), vs. 1(3 %), p-value <0.001] based on ultrasonography. Children with T1D showed higher liver stiffness values than controls. A weakly positive relationship of liver stiffness was observed with BMI, duration of diabetes, glycemic control, and serum GGT. Approximately one-fourth of children with diabetes showed sonographic evidence of hepatic steatosis. Larger studies are needed to ascertain the effects of obesity, diabetes duration, and metabolic control on the prevalence and progression of MAFLD in children with T1D.

Identifying and targeting key driver genes for collagen production within the 11q13/14 breast cancer amplicon.

Breast cancers of the IntClust-2 type, characterized by amplification of a small portion of chromosome 11, have a median survival of only five years. Several cancer-relevant genes occupy this portion of chromosome 11, and it is thought that overexpression of a combination of driver genes in this region is responsible for the poor outcome of women in this group. In this study we used a gene editing method to knock out, one by one, each of 198 genes that are located within the amplified region of chromosome 11 and determined how much each of these genes contributed to the survival of breast cancer cells. In addition to well-known drivers such as CCND1 and PAK1, we identified two different genes (SERPINH1 and P4HA3), that encode proteins involved in collagen synthesis and organization. Using both in vitro and in vivo functional analyses, we determined that P4HA3 and/or SERPINH1 provide a critical driver function on IntClust-2 basic processes, such as viability, proliferation, and migration. Inhibiting these enzymes via genetic or pharmacologic means reduced collagen synthesis and impeded oncogenic signaling transduction in cell culture models, and a small-molecule inhibitor of P4HA3 was effective in treating 11q13 tumor growth in an animal model. As collagen has a well-known association with tissue stiffness and aggressive forms of breast cancer, we believe that the two genes we identified provide an opportunity for a new therapeutic strategy in IntClust-2 breast cancers. Implications: Breast cancers with 11q13/14 chromosomal amplifications may be vulnerable to inhibitors of collagen synthesis.

Fourier energy spectrum centroid: a robust and efficient approach for shear wave speed estimation in ω–k space

Objective.The propagation speed of a shear wave, whether externally or internally induced, in biological tissues is directly linked to the tissue's stiffness. The group shear wave speed (SWS) can be estimated using a class of time-of-flight (TOF) methods in the time-domain or phase speed-based methods in the frequency domain. However, these methods suffer from biased estimations or time-consuming computations, and they are especially prone to wave distortions inin vivocases. In this work, we present a parameter-free, robust, and efficient group SWS estimation method coined as Fourier energy spectrum centroid (FESC).Approach.The proposed FESC method is based on the center of mass inω-kspace. It was evaluated on data from computer simulations with additive Gaussian noise, a commercial elasticity phantom, anex vivopig liver, andin vivobiceps brachii muscles of three young healthy male subjects. The FESC method was compared with two 2D frequency-domain methods: Max-fre, which considers phase SWS at the peak ofk-space, and Fre-regre, which applies linear regression of phase SWS within a fixed bandwidth. Two additional benchmarks included time-domain methods based on cross-correlation (X-Corr) and radon sum transformation (RD).Main results.Statistical results showed that our FESC method and the RD method had comparable accuracy and robustness, outperforming the other benchmark methods. In the simulation and phantom studies, when the signal-to-noise ratio was higher than 25 dB, our FESC showed higher accuracy than RD. In thein vivostudy, our FESC method had better repeatability than RD. Furthermore, the proposed FESC method was 100 times faster than the runner-up method, X-Corr, and 3,000 times faster than the least efficient method, RD.Significance.All results indicated that our proposed Fourier-based method shows promise in reliably and efficiently providing reference values for group SWS in homogeneous bulk media.

Shear wave elastography for thyroid nodule evaluation in patients with chronic autoimmune thyroiditis.

Shear wave elastography (SWE) is a valuable tool in discerning the malignancy risk of thyroid nodules. This study investigates whether 2D-SWE can reliably differentiate malignant thyroid nodules in patients with chronic autoimmune thyroiditis (CAT), despite the challenges posed by fibrosis, which can increase tissue stiffness and complicate diagnosis. This retrospective observational study evaluated 130 thyroid nodules (91 benign, 39 malignant) in patients with underlying CAT using conventional ultrasound (B-mode) and 2D-SWE with SuperSonic Mach30 equipment (Supersonic Imagine, Aix-en-Provence, France). Pathology reports served as the reference standard. Out of the 130 nodules, 30% were malignant, and 70% were benign. 2D-SWE proved to be an excellent distinguisher between benign and malignant nodules. Malignant nodules had significantly higher elasticity indices compared to benign nodules (mean elasticity index: 47.2 kPa vs. 18.1 kPa, p < 0.0001; maximum elasticity index: 75 kPa vs. 26.2 kPa, p < 0.0001). The mean elasticity index was the most reliable elastographic parameter (AUC 0.907, sensitivity 87.2% [95% CI: 77.3-94.0%], specificity 84.6% [95% CI: 75.4-91.5%], and NPV 93.9% for a cut-off value of 30.5 kPa). Our results confirm that 2D-SWE can accurately diagnose malignant thyroid nodules in cases with CAT (p < 0.0001), supporting its use as a complementary tool to conventional ultrasound.

Substrate stiffness dictates unique doxorubicin-induced senescence-associated secretory phenotypes and transcriptomic signatures in human pulmonary fibroblasts.

Cells are subjected to dynamic mechanical environments which impart forces and induce cellular responses. In age-related conditions like pulmonary fibrosis, there is both an increase in tissue stiffness and an accumulation of senescent cells. While senescent cells produce a senescence-associated secretory phenotype (SASP), the impact of physical stimuli on both cellular senescence and the SASP is not well understood. Here, we show that mechanical tension, modeled using cell culture substrate rigidity, influences senescent cell markers like SA-β-gal and secretory phenotypes. Comparing human primary pulmonary fibroblasts (IMR-90) cultured on physiological (2kPa), fibrotic (50kPa), and plastic (approximately 3 GPa) substrates, followed by senescence induction using doxorubicin, we identified unique high-stiffness-driven secretory protein profiles using mass spectrometry and transcriptomic signatures, both showing an enrichment in collagen proteins. Consistently, clusters of p21 + cells are seen in fibrotic regions of bleomycin induced pulmonary fibrosis in mice. Computational meta-analysis of single-cell RNA sequencing datasets from human interstitial lung disease confirmed these stiffness SASP genes are highly expressed in disease fibroblasts and strongly correlate with mechanotransduction and senescence-related pathways. Thus, mechanical forces shape cell senescence and their secretory phenotypes.

The (un)known crosstalk between metabolism and mechanotransduction: Implications for metabolic syndrome (MetS)-associated neurological complications.

Metabolic syndrome (MetS) has been associated with disruptions in tissue mechanical homeostasis and inflammatory and metabolic derangements. However, the direct correlation between metabolic alterations and changes in tissue stiffness, and whether they could play a role as upstream initiators of disease pathology remains to be investigated. This emerging concept has yet to be put into clinical practice as many questions concerning the interplay between extracellular matrix mechanical properties and regulation of metabolic pathways remain unsolved. This review will highlight key foundational studies examining mutual regulation of cell metabolism and mechanotransduction, and opening questions lying ahead for better understanding MetS pathophysiology.

Nondestructive Mechanical Characterization of Bioengineered Tissues by Digital Holography.

Mechanical properties of engineered connective tissues are critical for their success, yet modern sensors that measure physical qualities of tissues for quality control are invasive and destructive. The goal of this work was to develop a noncontact, nondestructive method to measure mechanical attributes of engineered skin substitutes during production without disturbing the sterile culture packaging. We optimized a digital holographic vibrometry (DHV) system to measure the mechanical behavior of Apligraf living cellular skin substitute through the clear packaging in multiple conditions: resting on solid agar as when the tissue is shipped, on liquid media in which it is grown, and freely suspended in air as occurs when the media is removed for feeding. We utilized full-field measurement to assess the complete surface deformation pattern to compare with vibration theory and found the patterns observed in air showed the closest behavior to theory. To simulate the effects of the actual culture dish geometry and the trilayer composition of the tissue on the porous membrane support, we employed finite element (FE) analysis. To simulate changes in thickness and stiffness that may occur with manufacturing process variations, we dried samples over time and observed measurable increases in the fundamental mode frequency which could be predicted by altering the thickness of the tissue layers in the FE model. However, quantitative estimates of the engineered tissue stiffness based on vibration theory are unrealistically high due to the signal being dominated by the stiff underlying membrane on which the tissue is cultured. Thus, although DHV is not able to specifically quantify the thickness or modulus or identify small spot defects, it has the potential to be used assess the overall properties of a tissue in-line and noninvasively for quality control.

Probing the physical hallmarks of cancer.

The physical microenvironment plays a crucial role in tumor development, progression, metastasis and treatment. Recently, we proposed four physical hallmarks of cancer, with distinct origins and consequences, to characterize abnormalities in the physical tumor microenvironment: (1) elevated compressive-tensile solid stresses, (2) elevated interstitial fluid pressure and the resulting interstitial fluid flow, (3) altered material properties (for example, increased tissue stiffness) and (4) altered physical micro-architecture. As this emerging field of physical oncology is being advanced by tumor biologists, cell and developmental biologists, engineers, physicists and oncologists, there is a critical need for model systems and measurement tools to mechanistically probe these physical hallmarks. Here, after briefly defining these physical hallmarks, we discuss the tools and model systems available for probing each hallmark in vitro, ex vivo, in vivo and in clinical settings. We finally review the unmet needs for mechanistic probing of the physical hallmarks of tumors and discuss the challenges and unanswered questions associated with each hallmark.

Penile shear-wave elastography predicts the outcome of botulinum neurotoxin (Botox) in the management of non-responders to phosphodiesterase-5-inhibitors: A pilot study

ABSTRACT Objective Botulinum neurotoxin (BoNT) was introduced as a minimally invasive treatment option for erectile dysfunction (ED). However, there is no proven method that predicts improvement after BoNT injection. Shear wave elastography is an emerging imaging modality that evaluates tissue stiffness. This study aims to assess the reliability of SWE in predicting BoNT response in patients with ED and phosphodiesterase 5 inhibitors (PDE-5i) non-responders. Methods This study comprised 20 men presenting with ED and PDE-5i non-responders. Mean tissue stiffness values (TSVs) were measured by SWE, international index of erectile function (IIEF-5), erection hardness score (EHS), sexual encounter profile questions 2 and 3 (SEP-2 and SEP-3), and global assessment questionnaire (GAQ) were evaluated before and after 100 IU of BoNT injection by 6 and 12 weeks. Results In comparison with baseline, there was a significant improvement in IIEF-5 and EHS scores after BoNT injection at 6- and 12 weeks (p < 0.001). Similar improvements were observed in SEP-2&3 (p < 0001 & p = 0.001, respectively) and GAQ-1&2 (p = 0.008 & p = 0.006, respectively). We found that mean SWE in a penile flaccid state can predict failure of clinically significant improvement after BoNT injection using a cutoff point of 12.7 kPa (sensitivity = 100%, specificity = 54%, AUC = 0.86, p = 0.014). Conclusion This finding could be applied to avoid unnecessary BoNT injections in men with ED and PDE-5i non-responders.

Triple-action cancer therapy using laser-activated NO-releasing metallomicellar nanophotosensitizer for pyroptosis-driven immune reprogramming.

Cancer photoimmunotherapy represents an intelligent and highly efficient therapeutic approach that harnesses the photothermal effect to precisely target and ablate tumor tissues, while simultaneously modulating the immune system to achieve tumor elimination. The integration of multifunctional therapeutic modalities for combined photoimmunotherapy requires advanced drug delivery systems. However, the design of a single nanoagent capable of serving as a multifunctional nanophotosensitizer remains a significant challenge. In this study, we developed a metallomicellar nanophotosensitizer named TAGNO, which offers a synergistic tri-modal cancer treatment strategy by combining photothermal therapy (PTT), gas therapy (GT), and immunotherapy. The TAGNO nanophotosensitizer consists of a gold nanorod core, responsible for inducing the photothermal effect, coated with an amphiphilic polymer functionalized with tumor cell penetrating peptide to accommodate lipophilic small molecule BNN6, a nitric oxide (NO) donor for GT. We demonstrated that TAGNO exhibited high tumor accumulation, excellent stability, and biocompatibility, ensuring the safe delivery of NO to the tumor site. Upon near-infrared (NIR) laser irradiation, TAGNO effectively raised the temperature within tumor tissues while sparing the surrounding healthy tissues and enabled controlled NO release. Once released, the NO interacts with hydrogen peroxide in the hypoxic tumor microenvironment, forming peroxynitrite (ONOO-), which induces mitochondrial dysfunction and triggers pyroptotic cell death. Pyroptosis induced immunogenic cell death and the subsequent release of tumor antigens, activating cytotoxic T cells and promoting M1 macrophage polarization, effectively controlling both primary and secondary tumor growth. Furthermore, laser-induced NO release facilitated the relaxation of stiff tumor tissues, enhancing blood vessel dilation and oxygenation. This improvement promoted immune cell infiltration while suppressing immunosuppressive cells. Overall, this innovative combination of PTT, GT, and immunotherapy presents a potent and synergistic strategy for the treatment of malignant colon tumors, achieving complete tumor eradication.

Evaluation of renal elasticity by shear wave elastography in children with Familial Mediterranean Fever.

Familial Mediterranean Fever (FMF) is a genetic disorder that can cause kidney damage. Shear wave elastography (SWE), a non-invasive method, was used to evaluate the decrease in renal tissue elasticity as a predictive parameter for amyloidosis. This study aimed to examine the changes in renal elasticity in patients with FMF using the renal SWE measurement method. The present study included 50 pediatric patients diagnosed with FMF. The median SWE values of both kidneys were compared between the groups. Acute phase reactants were also evaluated. The SWE measurements (for the left kidney p = 0.007, for the right kidney p = 0.06) and proteinuria levels (p < 0.001) of the patient group were found to be higher than those of the control group. No correlation was observed between the disease activity score and the SWE measurements. Erythrocyte sedimentation rate (p < 0.001), C-reactive protein (p < 0.001) and urine protein/creatinine ratio (p < 0.001) were significantly higher in the remission period compared to the control group, whereas estimated glomerular filtration rate was found to be low in the patient group (p < 0.001), which was considered as an indicator that subclinical inflammation continued in the course of the disease. The acute phase reactants were elevated in patients with FMF even in the remission period which indicates that the disease is constantly active and have the potential to cause damage in all organs and tissues. It is thought that this subclinical inflammation may also contribute to increased tissue stiffness, which may serve as a predictor for the development of amyloidosis.