Multiphoton excited polymerized biomimetic models of collagen fiber morphology to study single cell and collective migration dynamics in pancreatic cancer.

The respective roles of aligned collagen fiber morphology found in the extracellular matrix (ECM) of pancreatic cancer patients and cellular migration dynamics have been gaining attention because of their connection with increased aggressive phenotypes and poor prognosis. To better understand how collagen fiber morphology influences cell-matrix interactions associated with metastasis, we used Second Harmonic Generation (SHG) images from patient biopsies with Pancreatic ductal adenocarcinoma (PDAC) as models to fabricate collagen scaffolds to investigate processes associated with motility. Using the PDAC BxPC-3 metastatic cell line, we investigated single and collective cell dynamics on scaffolds of varying collagen alignment. Collective or clustered cells grown on the scaffolds with the highest collagen fiber alignment had increased E-cadherin expression and larger focal adhesion sites compared to single cells, consistent with metastatic behavior. Analysis of single cell motility revealed that the dynamics were characterized by random walk on all substrates. However, examining collective motility over different time points showed that the migration was super-diffusive and enhanced on highly aligned fibers, whereas it was hindered and sub-diffusive on un-patterned substrates. This was further supported by the more elongated morphology observed in collectively migrating cells on aligned collagen fibers. Overall, this approach allows the decoupling of single and collective cell behavior as a function of collagen alignment and shows the relative importance of collective cell behavior as well as fiber morphology in PDAC metastasis. We suggest these scaffolds can be used for further investigations of PDAC cell biology. STATEMENT OF SIGNIFICANCE: Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate, where aligned collagen has been associated with poor prognosis. Biomimetic models representing this architecture are needed to understand complex cellular interactions. The SHG image-based models based on stromal collagen from human biopsies afford the measurements of cell morphology, cadherin and focal adhesion expression as well as detailed motility dynamics. Using a metastatic cell line, we decoupled the roles of single cell and collective cell behavior as well as that arising from aligned collagen. Our data suggests that metastatic characteristics are enhanced by increased collagen alignment and that collective cell behavior is more relevant to metastatic processes. These scaffolds provide new insight in this disease and can be a platform for further experiments such as testing drug efficacy.

Quantified planar collagen distribution in healthy and degenerative mitral valve: biomechanical and clinical implications.

Degenerative mitral valve disease is a common valvular disease with two arguably distinct phenotypes: fibroelastic deficiency and Barlow's disease. These phenotypes significantly alter the microstructures of the leaflets, particularly the collagen fibers, which are the main mechanical load carriers. The predominant method of investigation is histological sections. However, the sections are cut transmurally and provide a lateral view of the microstructure of the leaflet, while the mechanics and function are determined by the planar arrangement of the collagen fibers. This study, for the first time, quantitatively examined planar collagen distribution quantitatively in health and disease using second harmonic generation microscopy throughout the thickness of the mitral valve leaflets. Twenty diseased samples from eighteen patients and six control samples were included in this study. Healthy tissue had highly aligned collagen fibers. In fibroelastic deficiency they are less aligned and in Barlow's disease they are completely dispersed. In both diseases, collagen fibers have two preferred orientations, which, in contrast to the almost constant one orientation in healthy tissues, also vary across the thickness. The results indicate altered in vivo mechanical stresses and strains on the mitral valve leaflets as a result of disease-related collagen remodeling, which in turn triggers further remodeling.

A Mathematical Model for Postimplant Collagen Remodeling in an Autologous Engineered Pulmonary Arterial Conduit.

This study was undertaken to develop a mathematical model of the long-term in vivo remodeling processes in postimplanted pulmonary artery (PA) conduits. Experimental results from two extant ovine in vivo studies, wherein polyglycolic-acid (PGA)/poly-L-lactic acid tubular conduits were constructed, cell seeded, incubated for 4 weeks, and then implanted in mature sheep to obtain the remodeling data for up to two years. Explanted conduit analysis included detailed novel structural and mechanical studies. Results in both studies indicated that the in vivo conduits remained dimensionally stable up to 80 weeks, so that the conduits maintained a constant in vivo stress and deformation state. In contrast, continued remodeling of the constituent collagen fiber network as evidenced by an increase in effective tissue uniaxial tangent modulus, which then stabilized by one year postimplant. A mesostructural constitute model was then applied to extant planar biaxial mechanical data and revealed several interesting features, including an initial pronounced increase in effective collagen fiber modulus, paralleled by a simultaneous shift toward longer, more uniformly length-distributed collagen fibers. Thus, while the conduit remained dimensionally stable, its internal collagen fibrous structure and resultant mechanical behaviors underwent continued remodeling that stabilized by one year. A time-evolving structural mixture-based mathematical model specialized for this unique form of tissue remodeling was developed, with a focus on time-evolving collagen fiber stiffness as the driver for tissue-level remodeling. The remodeling model was able to fully reproduce (1) the observed tissue-level increases in stiffness by time-evolving simultaneous increases in collagen fiber modulus and lengths, (2) maintenance of the constant collagen fiber angular dispersion, and (3) stabilization of the remodeling processes at one year. Collagen fiber remodeling geometry was directly verified experimentally by histological analysis of the time-evolving collagen fiber crimp, which matches model predictions very closely. Interestingly, the remodeling model indicated that the basis for tissue homeostasis was maintenance of the collagen fiber ensemble stress for all orientations, and not individual collagen fiber stresses. Unlike other growth and remodeling models that traditionally treat changes in the external boundary conditions (e.g., changes in blood pressure) as the primary input stimuli, the driver herein is changes to the internal constituent collagen fiber themselves due to cellular mediated cross-linking.

Early Stages of Ex Vivo Collagen Glycation Disrupt the Cellular Interaction and Its Remodeling by Mesenchymal Stem Cells-Morphological and Biochemical Evidence.

Mesenchymal stem cells (MSCs), pivotal for tissue repair, utilize collagen to restore structural integrity in damaged tissue, preserving its organization through concomitant remodeling. The non-enzymatic glycation of collagen potentially compromises MSC communication, particularly upon advancing the process, underlying various pathologies such as late-stage diabetic complications and aging. However, an understanding of the impact of early-stage collagen glycation on MSC interaction is lacking. This study examines the fate of in vitro glycated rat tail collagen (RTC) upon exposure to glucose for 1 or 5 days in contact with MSCs. Utilizing human adipose tissue-derived MSCs (ADMSCs), we demonstrate their significantly altered interaction with glycated collagen, characterized morphologically by reduced cell spreading, diminished focal adhesions formation, and attenuated development of the actin cytoskeleton. The morphological findings were confirmed by ImageJ 1.54g morphometric analysis with the most significant drop in the cell spreading area (CSA), from 246.8 µm2 for the native collagen to 216.8 µm2 and 163.7 µm2 for glycated ones, for 1 day and 5 days, respectively, and a similar trend was observed for cell perimeter 112.9 µm vs. 95.1 µm and 86.2 µm, respectively. These data suggest impaired recognition of early glycated collagen by integrin receptors. Moreover, they coincide with the reduced fibril-like reorganization of adsorbed FITC-collagen (indicating impaired remodeling) and a presumed decreased sensitivity to proteases. Indeed, confirmatory assays reveal diminished FITC-collagen degradation for glycated samples at 1 day and 5 days by attached cells (22.8 and 30.4%) and reduced proteolysis upon exogenous collagenase addition (24.5 and 40.4%) in a cell-free system, respectively. The mechanisms behind these effects remain uncertain, although differential scanning calorimetry confirms subtle structural/thermodynamic changes in glycated collagen.

Mapping the unicellular transcriptome of the ascending thoracic aorta to changes in mechanosensing and mechanoadaptation during aging.

Aortic stiffening is an inevitable manifestation of chronological aging, yet the mechano-molecular programs that orchestrate region- and layer-specific adaptations along the length and through the wall of the aorta are incompletely defined. Here, we show that the decline in passive cyclic distensibility is more pronounced in the ascending thoracic aorta (ATA) compared to distal segments of the aorta and that collagen content increases in both the medial and adventitial compartments of the ATA during aging. The single-cell RNA sequencing of aged ATA tissues reveals altered cellular senescence, remodeling, and inflammatory responses accompanied by enrichment of T-lymphocytes and rarefaction of vascular smooth muscle cells, compared to young samples. T lymphocyte clusters accumulate in the adventitia, while the activation of mechanosensitive Piezo-1 enhances vasoconstriction and contributes to the overall functional decline of ATA tissues. These results portray the immuno-mechanical aging of the ATA as a process that culminates in a stiffer conduit permissive to the accrual of multi-gerogenic signals priming to disease development.

Exposure to atrazine and endosulfan alters oviductal adenogenesis in the broad-snouted caiman (Caiman latirostris).

The molecular pathways involved in oviductal adenogenesis are highly conserved among vertebrates. In this work, we study the histomorphological changes and molecular pathways involved in Caiman latirostris oviductal adenogenesis and the effects of in ovo exposure to environmentally relevant doses of endosulfan (END) and atrazine (ATZ) on these processes. To this end, the histomorphological changes at epithelial and subepithelial compartments, the protein expressions of ß-catenin and Wnt-7a, and the gene expression of metalloproteinases (MMPs) and its inhibitors (TIMPs) were evaluated as biomarkers of oviductal adenogenesis in prepubertal juvenile C. latirostris. Exposure to END altered adenogenesis-related epithelium characteristics and mRNA expression of MMP2, MMP9, and TIMP1. Exposure to ATZ increased the width of the subepithelial stroma with loosely arranged collagen fibers and increased ß-catenin expression in buds (invaginated structures that precede glands). The results demonstrate that in ovo exposure to ATZ and END alters oviductal adenogenesis at tissue, cellular, and molecular levels. An altered oviductal adenogenesis could impair fertility, raising concern on the effects of pesticide pollution in wildlife and domestic animals.

Bomb pulse 14 C evidence for consistent remodeling rates of cortical femur collagen in middle-late adulthood.

OBJECTIVES: Bomb pulse (BP) radiocarbon (14 C) dating methods are used by forensic anthropologists to estimate the year-of-death (YOD) of unidentified individuals. Method resolution and accuracy depend on establishing lag times, or the difference between a tissue's BP 14 C-derived year and the YOD, of various tissue types from known deceased persons. Bone lag times span many years and are thought to increase with age as a function of slowing remodeling rates. However, remodeling rates for various skeletal elements, bone structures and phases are not well known. MATERIALS AND METHODS: Here a simple method is used to estimate bone remodeling rates from a compilation of published cortical femur bone collagen BP 14 C measurements (n = 102). Linear regression models and nonparametric tests are used to detect changes in lag times and remodeling rates with increasing age-at-death. RESULTS: Remodeling rates and lag times of 3.5%/year and 29 years, respectively, are estimated from individuals aged 40-97 years. In contrast to previous work, the analysis yielded modest and negligible changes in remodeling rates and lag times with advancing age. Moreover, statistically significant differences in remodeling rates and lag times were not found between reported females and males. DISCUSSION: Implications for the temporal contexts within an individual's lifetime of biogeochemical data in archaeology and forensic anthropology are discussed, warranting additional BP 14 C studies of known individuals and integration with histomorphometric analysis.

Research on evolution process of full-layer incision of skin tissue under different laser incidences.

Considering difficulties of achieving vertical incidence of beam in different positions of skin, it is significant to study potential effects of incidence angles of laser on incisions. Surgical platform with a 1064 nm continuous fiber laser was established. Incident angle was adopted and real-time temperature fluctuations in laser operating area could be monitored. The rats were treated with laser at day 0 and day 3 after incision modeling, and H&E, Masson, Sirius Red, and Immuno-histochemical staining and enzyme-linked immunosorbent assay were adopted at day 3, 7, 14 to analyze the performance of healing. Laser with energy density of 67.54 J/mm2 can effectively accelerate wound healing in vivo, in which a laser with incident angle around 60° can effectively avoid scar hyperplasia. Therefore, the use of low energy laser with a small deflection angle has a good clinical application prospect in promoting wound healing.

Novel insights into the role of Discoidin domain receptor 2 (DDR2) in cancer progression: a new avenue of therapeutic intervention.

Discoidin domain receptors (DDRs), including DDR1 and DDR2, are a unique class of receptor tyrosine kinases (RTKs) activated by collagens at the cell-matrix boundary interface. The peculiar mode of activation makes DDRs as key cellular sensors of microenvironmental changes, with a critical role in all physiological and pathological processes governed by collagen remodeling. DDRs are widely expressed in fetal and adult tissues, and experimental and clinical evidence has shown that their expression is deregulated in cancer. Strong findings supporting the role of collagens in tumor progression and metastasis have led to renewed interest in DDRs.  However, despite an increasing number of studies, DDR biology remains poorly understood, particularly the less studied DDR2, whose involvement in cancer progression mechanisms is undoubted. Thus, the understanding of a wider range of DDR2 functions and related molecular mechanisms is expected. To date, several lines of evidence support DDR2 as a promising target in cancer therapy. Its involvement in key functions in the tumor microenvironment makes DDR2 inhibition particularly attractive to achieve simultaneous targeting of tumor and stromal cells, and tumor regression, which is beneficial for improving the response to different types of anti-cancer therapies, including chemo- and immunotherapy. This review summarizes current research on DDR2, focusing on its role in cancer progression through its involvement in tumor and stromal cell functions, and discusses findings that support the rationale for future development of direct clinical strategies targeting DDR2.

Picosecond lasers in cosmetic dermatology: where are we now? An overview of types and indications.

Q-switched lasers have undeniably revolutionized the field of laser dermatology since four decades ago. Just as the first-generation laser emits its photonic signal in a few nanoseconds, the picosecond laser delivers pulse widths of at least ten times shorter. These devices offer a powerful tool for treating a wide range of skin conditions with a minimal downtime for visible improvement. For the current study, a literature research was performed on the dermatological applications of picosecond laser. The literature searched on this topic between 1999 and 2023 accessible through various platforms produce a result of 62 articles. The included studies have discussed the application of picosecond laser technology in tattoo removal, treatment of epidermal and dermal pigmentation, and collagen remodeling. After sifting the data from the articles into tables, the results were discussed in detail. The study shows a lot of evidence towards the efficacy of picosecond laser, yet it draws attention to its downsides.

Extracellular matrix remodeling proteins as biomarkers for clinical assessment and treatment outcomes in eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic progressive inflammatory disease of the esophagus, characterized by extracellular matrix remodeling and fibrotic stricture formation. Disease monitoring requires multiple re-endoscopies with esophageal biopsies. Hence non-invasive methods for determining tissue fibrosis and treatment efficacy are warranted. AIMS: To investigate the ability of extracellular matrix proteins in serum as potential biomarkers of tissue remodeling and clinical, endoscopic, and histological disease outcomes in adult EoE patients. METHODS: Protein-fingerprint assays were used to measure neo-epitope specific fragments of collagen remodeling, human-neutrophil elastase degraded calprotectin, and citrullinated or non-citrullinated vimentin in the serum of an adult EoE-cohort. Biomarker analysis, symptoms, endoscopic features and histological disease activity (eosinophils(eos) per high-power-field(hpf)) were evaluated at baseline and after six weeks of dietary intervention. RESULTS: Patients with a baseline (Endoscopic Reference score) EREFS fibrosis subscore ≥ 2 presented with increased fibrolysis of cross-linked type III collagen (CTX-III) (p < 0.01), whereas low CTX-III levels were observed in patients achieving histological remission (< 15 eos/hpf) (vs. no histological remission (p < 0.05). Progression of endoscopic fibrosis after intervention was associated with increased levels of type-III (PRO-C3) and -VI collagen (PRO-C6) formation (all; p < 0.05). A baseline EREFS inflammatory subscore ≥ 2 correlated with higher neutrophilic activity (Cpa9-HNE) at week 6 (p < 0.05). Moreover, increased degradation of type-III (C3M) and -IV (C4M/PRO-C4) collagens were associated with remission of food impaction after intervention (all; p < 0.05). CONCLUSION: Serum extracellular matrix remodeling proteins demonstrated potential as surrogate biomarkers for assessing histological disease remission, endoscopic fibrosis, and remission of symptoms of food impaction after diet intervention in adult EoE patients.

HNRNPC promotes collagen fiber alignment and immune evasion in breast cancer via activation of the VIRMA-mediated TFAP2A/DDR1 axis.

BACKGROUND: Cancers aggressively reorganize collagen in their microenvironment, leading to the evasion of tumor cells from immune surveillance. However, the biological significance and molecular mechanism of collagen alignment in breast cancer (BC) have not been well established. METHODS: In this study, BC-related RNA-Seq data were obtained from the TCGA database to analyze the correlation between DDR1 and immune cells. Mouse BC cells EO771 were selected for in vitro validation, and dual-luciferase experiments were conducted to examine the effect of TFAP2A on DDR1 promoter transcription activity. ChIP experiments were performed to assess TFAP2A enrichment on the DDR1 promoter, while Me-RIP experiments were conducted to detect TFAP2A mRNA m6A modification levels, and PAR-CLIP experiments were conducted to determine VIRMA's binding to TFAP2A mRNA and RIP experiments to investigate HNRNPC's recognition of m6A modification on TFAP2A mRNA. Additionally, an in vivo mouse BC transplant model and the micro-physiological system was constructed for validation, and Masson staining was used to assess collagen fiber arrangement. Immunohistochemistry was conducted to identify the number of CD8-positive cells in mouse BC tumors and Collagen IV content in ECM, while CD8 + T cell migration experiments were performed to measure CD8 + T cell migration. RESULTS: Bioinformatics analysis showed that DDR1 was highly expressed in BC and negatively correlated with the proportion of anti-tumor immune cell infiltration. In vitro cell experiments indicated that VIRMA, HNRNPC, TFAP2A, and DDR1 were highly expressed in BC cells. In addition, HNRNPC promoted TFAP2A expression and, therefore, DDR1 transcription by recognizing the m6A modification of TFAP2A mRNA by VIRMA. In vivo animal experiments further confirmed that VIRMA and HNRNPC enhanced the TFAP2A/DDR1 axis, promoting collagen fiber alignment, reducing anti-tumor immune cell infiltration, and promoting immune escape in BC. CONCLUSION: This study demonstrated that HNRNPC promoted DDR1 transcription by recognizing VIRMA-unveiled m6A modification of TFAP2A mRNA, which enhanced collagen fiber alignment and ultimately resulted in the reduction of anti-tumor immune cell infiltration and promotion of immune escape in BC.

Vimentin-mediated myosin 10 aggregation at tips of cell extensions drives MT1-MMP-dependent collagen degradation in colorectal cancer.

Colorectal cancer (CRC) is a high prevalence adenocarcinoma with progressive increases in metastasis-related mortality, but the mechanisms governing the extracellular matrix (ECM) degradation important for metastasis in CRC are not well-defined. We investigated a functional relationship between vimentin (Vim) and myosin 10 (Myo10), and whether this relationship is associated with cancer progression. We tested the hypothesis that Vim regulates the aggregation of Myo10 at the tips of cell extensions, which increases membrane-type 1 matrix metalloproteinase (MT1-MMP)-associated local collagen proteolysis and ECM degradation. Analysis of CRC samples revealed colocalization of Vim with Myo10 and MT1-MMP in cell extensions adjacent to sites of collagen degradation, suggesting an association with local cell invasion. We analyzed cultured CRC cells and fibroblasts and found that Vim accelerates aggregation of Myo10 at cell tips, which increases the cell extension rate. Vim stabilizes the interaction of Myo10 with MT1-MMP, which in turn increases collagenolysis. Vim depletion reduced the aggregation of Myo10 at the cell extension tips and MT1-MMP-dependent collagenolysis. We propose that Vim interacts with Myo10, which in turn associates with MT1-MMP to facilitate the transport of these molecules to the termini of cell extensions and there enhance cancer invasion of soft connective tissues.

Interrelationship Between Inflammatory Biomarkers and Collagen Remodeling Proteins in Atrial Fibrillation.

INTRODUCTION: Atrial Fibrillation (AF) is the most prevalent cardiac arrhythmia worldwide. Inflammation and structural remodeling of the left atrium are thought to be involved in the pathogenesis of AF. This study explores collagen remodeling and inflammatory biomarkers in AF patients compared to healthy controls to discern their role in AF. MATERIALS AND METHODS: Plasma samples were collected from AF patients undergoing first AF ablation (n = 72) and compared with commercially available human plasma samples from healthy subjects (n = 62). The collagen remodeling biomarkers and inflammatory biomarkers in the AF patients and control population were quantified using sandwich ELISA kits. GraphPad prism was used to perform statistical analyses. RESULTS: There was a statistically significant elevation in all the collagen remodeling biomarkers and inflammatory biomarkers in the AF patients compared to healthy controls. Spearman correlation analysis demonstrated significant correlations between inflammatory and collagen remodeling biomarkers, and among the collagen biomarkers. Of note, CRP was found to be correlated with TIMP-1, ICTP and PIIINP. IL6 and TIMP-1 were also found to be intercorrelated. Furthermore, correlations were noted among the different collagen remodeling peptides, and between TNFα and IL6, two of the inflammatory markers explored in this study. CONCLUSIONS: The elevation of the inflammatory biomarkers and collagen remodeling proteins in AF patients is suggestive of inflammation and increased collagen turnover. The association between inflammatory biomarkers and collagen remodeling proteins may contribute to their regulation and role in the remodeling process.

2-kDa hyaluronan ameliorates human facial wrinkles through increased dermal collagen density related to promotion of collagen remodeling.

BACKGROUND/AIMS: Hyaluronan (HA) oligosaccharides are involved in several biological processes, primarily collagen remodeling and wound healing. Collagen remodeling is retarded in aging skin and causes wrinkles. The aim of this study was to evaluate the effect of 2-kDa HA oligosaccharides (HA2k) on wrinkles by permeation through the stratum corneum and promotion of collagen remodeling. METHODS: A 3D skin model and excised human skin were used to evaluate the permeation of fluorescein-labeled HA2k. The effect of HA2k on collagen metabolism was evaluated by measuring the protein level of type 1 pro-collagen (COL1A1) and matrix metalloproteinase-1 (MMP-1) in the 3D skin model. 0.1% HA2k solution and vehicle control was applied to the human forearm for 8 weeks to evaluate dermal collagen density. To evaluate the effect of HA2k on depth of facial wrinkles, a randomized controlled trial was conducted with 0.1% HA2k lotion and vehicle lotion for 8 weeks. RESULTS: HA2k was confirmed to permeate through the stratum corneum by fluorescent microscopy. Both COL1A1 and MMP-1 were upregulated by HA2k application in a 3D skin model culture. The collagen density was higher for the HA2k-treated forearm than for the vehicle control-treated forearm after 4 weeks. The maximum wrinkle depths in the nasolabial fold and crow's feet area were significantly shallower in the HA2k lotion group than in the control group. CONCLUSION: HA2k permeated the stratum corneum, activated collagen synthesis and degradation simultaneously, and ameliorated wrinkles.

Collagen Molecular Damage is a Hallmark of Early Atherosclerosis Development.

Remodeling of extracellular matrix proteins underlies the development of cardiovascular disease. Herein, we utilized a novel molecular probe, collagen hybridizing peptide (CHP), to target collagen molecular damage during atherogenesis. The thoracic aorta was dissected from ApoE-/- mice that had been on a high-fat diet for 0-18 weeks. Using an optimized protocol, tissues were stained with Cy3-CHP and digested to quantify CHP with a microplate assay. Results demonstrated collagen molecular damage, inferred from Cy3-CHP fluorescence, was a function of location and time on the high-fat diet. Tissue from the aortic arch showed a significant increase in collagen molecular damage after 18 weeks, while no change was observed in tissue from the descending aorta. No spatial differences in fluorescence were observed between the superior and inferior arch tissue. Our results provide insight into the early changes in collagen during atherogenesis and present a new opportunity in the subclinical diagnosis of atherosclerosis.

Collagen Remodeling along Cancer Progression Providing a Novel Opportunity for Cancer Diagnosis and Treatment.

The extracellular matrix (ECM) is a significant factor in cancer progression. Collagens, as the main component of the ECM, are greatly remodeled alongside cancer development. More and more studies have confirmed that collagens changed from a barrier to providing assistance in cancer development. In this course, collagens cause remodeling alongside cancer progression, which in turn, promotes cancer development. The interaction between collagens and tumor cells is complex with biochemical and mechanical signals intervention through activating diverse signal pathways. As the mechanism gradually clears, it becomes a new target to find opportunities to diagnose and treat cancer. In this review, we investigated the process of collagen remodeling in cancer progression and discussed the interaction between collagens and cancer cells. Several typical effects associated with collagens were highlighted in the review, such as fibrillation in precancerous lesions, enhancing ECM stiffness, promoting angiogenesis, and guiding invasion. Then, the values of cancer diagnosis and prognosis were focused on. It is worth noting that several generated fragments in serum were reported to be able to be biomarkers for cancer diagnosis and prognosis, which is beneficial for clinic detection. At a glance, a variety of reported biomarkers were summarized. Many collagen-associated targets and drugs have been reported for cancer treatment in recent years. The new targets and related drugs were discussed in the review. The mass data were collected and classified by mechanism. Overall, the interaction of collagens and tumor cells is complicated, in which the mechanisms are not completely clear. A lot of collagen-associated biomarkers are excavated for cancer diagnosis. However, new therapeutic targets and related drugs are almost in clinical trials, with merely a few in clinical applications. So, more efforts are needed in collagens-associated studies and drug development for cancer research and treatment.

Demystifying the mechanism of action of professional facial peeling: In-vivo visualization and quantification of changes in inflammation, melanin and collagen using Vivascope® and ConfoScan®.

Professional peeling using chemicals (chemical peeling) is a popular non-surgical procedure commonly used for the treatment for photoaging, pigmentary disorders, scarring, fine lines, and wrinkles. The objective of our case study was to elucidate the mechanism of action of professional peels/peeling. For proof-of-concept, we used a commercial blended peel containing trichloroacetic acid and lactic acid. The facial peeling was performed by a physician on four subjects. These subjects were followed over time in the clinic to take clinical pictures and monitor surface and anatomical changes in inflammation, melanin, and collagen at regular intervals post-peel (5 min, 48 h, and day 9). Dermoscope and Vivascope® were used to image surface and subsurface anatomical changes, respectively, and ConfoScan® was used to quantify aforementioned anatomical changes. Based on Vivascope and ConfoScan analysis, we could see clear visual clinical evidence of controlled injury-healing mechanism of peel's action: immediate but transient onset of inflammation within 5 min (indicate injury response by skin), followed by melanin redistribution evident at 48 h (indicate activation of skin's defense system), and remodeled fibrous collagen network without any inflammatory cells on day 9 (healing response). To our knowledge, this is the first ever clinical study to deconvolute the mysterious mechanism of action of peels, in-vivo.

The Science of Anastomotic Healing.

Intestinal anastomotic tissue follows a similar pattern of healing that is seen in all tissues with characteristic inflammatory, proliferative, and remodeling phases. Several aspects of intestinal healing are distinct from other tissues, however, including its time course and interaction with the environment of the gastrointestinal tract. As the anastomosis progresses through each stage, initial inflammatory cells are replaced by collagen-producing fibroblasts that generate the anastomosis' strength. A complex network of cell-to-cell signaling mediates this process through the release of cytokines and growth factors including platelet-derived growth factor (PDGF), transforming growth factor-ß (TGF-ß), and vascular endothelial growth factor (VEGF). Interventions based on these signaling pathways have been shown to improve anastomotic strength in animals, though methods for improving anastomotic healing in human patients remain unclear. Given the risks associated with anastomotic failure in patients, there is value in monitoring inflammatory markers and cytokines that can indicate the presence of a leak.

InMode Evoke radiofrequency hands-free facial remodeling for skin rejuvenation.

Demand for facial contouring procedures has increased dramatically in recent years. Common regions of concern for patients seeking a rejuvenated, more youthful appearance include the cheeks, jawline, submental area, and neck. Radiofrequency technology offers a non-invasive and effective method of improving skin laxity and subcutaneous fat in these areas. The Evoke system from InMode Aesthetics is a radiofrequency modality designed to address the lower face and neck that stimulates collagen remodeling for skin tightening and thermal lipolysis for improved facial contour. While alternate technologies for radiofrequency facial remodeling are commercially available, Evoke is the first of its kind in introducing a reliable, operator-independent hands-free device developed based on InMode's proprietary Acquire, Control, and Extend technology targeting the deep fibro-septal network to provide optimal and consistent outcomes.