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Nack Hwan Kim,1 Youngki Hong,2 Sang-Heon Lee3 1Biomedical Research Center, Korea University Anam Hospital, Seoul, Republic of Korea; 2Department of Sports Medicine, Cheongju University, Cheongju, Republic of Korea; 3Department of Physical Medicine and Rehabilitation, Korea University Anam Hospital, Seoul, Republic of Korea Purpose: To report on the 2-year clinical outcomes of focal ablation using a navigable plasma disc decompression device in patients with lumbar herniated nucleus pulposus (HNP).Patients and methods: This was a prospective, single-cohort study conducted in a clinical center. A total of 170 patients with lumbar HNP were assessed for pain intensity using the visual analog scale (VAS), for disability level using the Oswestry Disability Questionnaire (ODI), for health-related quality of life using the short form-36 version 2 of the bodily pain scale (SF-36 BP), and for the angles of passive straight leg raise (SLR) test. The herniated portions of the target discs were ablated using a navigable catheter under a well-instructed protocol with informed consent. Outcome data were prospectively collected before the procedure: 1 week after the procedure: and then 1, 3, 6, 12, and 24 months postoperatively. For statistical analysis, repeated-measures analysis of variance was performed.Results: Two years after the procedure, the mean VAS decreased from 7.1±1.7 to 2.1±1.9, the mean ODI decreased from 50.9±17.2 to 20.3% ± 14.6%, and the mean SF-36 BP increased from 38.8±8.4 to 45.8±9.4 (P

Objective: We evaluated whether superficial lymphatic anatomy and functional lymph node drainage are symmetric between the right and left upper extremities of healthy female volunteers, and if handedness is associated with symmetry of superficial lymphatic anatomy., Background: Symmetry of lymphatic anatomy has been assumed historically. This assumption of individual anatomic symmetry is being utilized clinically and in research without validation., Methods: 36 normal female volunteers underwent bilateral indocyanine green (ICG) lymphography and lymphoscintigraphy of the upper extremities. Eight collecting vessel pathways of each upper extremity were mapped on ICG lymphography. 13 lymph node groups were visualized on lymphoscintigraphy. Symmetry of lymphatic anatomy and functional drainage were established by comparing the right and left extremities of each participant. Hand dominance was assessed by hand grip strength on a hand dynamometer., Results: Among the 36 participants, 10 (28%) showed symmetry of all eight upper extremity lymphatic pathways with ICG. However, only 1 (3%) participant demonstrated complete symmetry amongst the 13 lymph node groups. Total symmetry of lymphatic channels was observed on ICG in seven (39%) participants with hand dominance and three (17%) participants without hand dominance (X2 = 2.215, P = 0.137)., Conclusion: Lymphatic anatomy and functional drainage of the upper extremities are not consistently symmetric. Functional nodal drainage as demonstrated by lymphoscintigraphy shows less symmetry than anatomic studies of lymphatic channels using ICG. Symmetric lymphatic anatomy does not appear to correlate with hand dominance. These findings challenge the prevailing assumption of left-right lymphatic symmetry., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

An N-protected methylenedioxymethamphetamine (MDMA), N-tert-butoxycarbonyl-3,4-methylenedioxymethamphetamine (t-BOC-3,4-MDMA), contains tert-butoxycarbonyl and can remain undetected in the illicit drug market. It is a new type of precursor substance that is not a chemical intermediate and can be converted into a controlled substance, MDMA, by deprotection of the N-tert-butoxycarbonyl group. Categorization of this chemical into a precursor or psychotropic substance is an issue because it is an unprecedented precursor that could have misuse potential. Although MDMA causes rewarding and reinforcing effect through dopaminergic transmission, the misuse potential of t-BOC-3,4-MDMA has not yet been characterized. Here, we aim to evaluate the misuse potential of t-BOC-3,4-MDMA. The response to the drug at a dose of 5 mg/kg was determined by a climbing test, and its rewarding and reinforcing properties were assessed through conditioned place preference and self-administration tests. In the conditioned place preference test, intraperitoneal administration of t-BOC-3,4-MDMA (5 mg/kg) significantly altered place preference in mice. In the self-administration models, t-BOC-3,4-MDMA induced drug-taking behavior at the dose of 0.5 mg/kg/infusion (intravenous) during 2 hr sessions under fixed-ratio schedules in mice. In addition, microdialysis experiments verified that t-BOC-3,4-MDMA impacted the dopamine levels of the brain (striatum) of rats. These experimental results indicate that t-BOC-3,4-MDMA has a potential for misuse. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Reduced fibroblast activity is a critical factor in the progression of diabetic ulcers. CD248, a transmembrane glycoprotein prominently expressed in activated fibroblasts, plays a pivotal role in wound healing. However, the role of CD248 in diabetic wound healing and the CD248 regulatory pathway remains largely unexplored. Our study shows that CD248 expression is significantly reduced in skin wounds from both patients and mice with diabetes. Single-cell transcriptome data analyses reveal a marked reduction of CD248-enriched secretory-reticular fibroblasts in diabetic wounds. We identify IGF-1 as a key regulator of CD248 expression through the protein kinase B/mTOR signaling pathway and the SP1 transcription factor. Overexpression of CD248 enhances fibroblast motility, elucidating the under-representation of CD248-enriched fibroblasts in diabetic wounds. Immunohistochemical staining of diabetic wound samples further confirms low SP1 expression and fewer CD248-positive secretory-reticular fibroblasts. Further investigation reveals that elevated TNFα levels in diabetic environment promotes IGF-1 resistance, and inhibiting IGF-1 induced CD248 expression. In summary, our findings underscore the critical role of the IGF1-SP1-CD248 axis in activating reticular fibroblasts during wound-healing processes. Targeting this axis in fibroblasts could help develop a therapeutic regimen for diabetic ulcers., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There is a discrepancy in the surgical and endoscopic literature for managing duodenal perforations. Although often managed conservatively, surgical repair is the standard treatment for duodenal perforations. This contrasts with the gastroenterology literature, which now recommends endoscopic repair of duodenal perforations, which are more frequently iatrogenic from the growing field of advanced endoscopic procedures. This study aims to provide a scoping review to summarize the current literature content and quality on endoscopic repair of duodenal perforations., Methods: The protocol for performing this scoping review was outlined by the Joanna Briggs Institute. All studies that reported primary outcomes of patients who had undergone endoscopic repair of duodenal perforations before February 2022, regardless of perforation etiology or repair type were reviewed, with studies after 1999 meeting inclusion criteria. The study excluded articles that did not report clinical outcomes of endoscopic repair, articles that did not describe where in the gastrointestinal tract the endoscopic repair occurred, pediatric patients, and animal studies., Results: 7606 abstracts were screened, with 474 full articles reviewed and 152 studies met inclusion criteria. 560 patients had duodenal perforations repaired endoscopically, with a technical success rate of 90.4% and a survival rate of 86.7%. Most of these perforations (74.5%) were iatrogenic from endoscopic procedures or surgery. Only one randomized control trial (RCT) was found, and 53% of studies were case reports., Conclusion: These results suggest that endoscopic repair could emerge as a viable first-line treatment for duodenal perforation and highlight the need for more high-quality research in this topic., (© 2024. The Author(s).)

Background: Histotripsy is a novel, ultrasound-based ablative technique that was recently approved by the Food and Drug Administration for hepatic targets. It has several promising additional theoretical applications that need to be further investigated. Its basis as a nonthermal cavitational technology presents a unique advantage over existing thermal ablation techniques in maximizing local effects while minimizing adjacent tissue destruction. This review discusses the technical basis and current preclinical and clinical data surrounding histotripsy., Methods: This was a comprehensive review of the literature surrounding histotripsy and the clinical landscape of existing ablative techniques using the PubMed database. A technical summary of histotripsy's physics and cellular effect was described. Moreover, data from recent clinical trials, including Hope4Liver, and future implications regarding its application in various benign and malignant conditions were discussed., Results: Preclinical data demonstrated the efficacy of histotripsy ablation in various organ systems with minimal tissue destruction when examined at the histologic level. The first prospective clinical trial involving histotripsy in hepatocellular carcinoma and liver metastases, Hope4Liver, demonstrated a primary efficacy of 95.5% with minimal complications (6.8%). This efficacy was replicated in similar trials involving the treatment of benign prostatic hypertrophy., Discussion: In addition to the noninvasive ability to ablate lesions in the liver, histotripsy offers additional therapeutic potential. Early data suggest a potential complementary therapeutic effect when combining histotripsy with existing immunologic therapies because of the technology's theoretical ability to sensitize tumors to adaptive immunity. As with most novel therapies, the effect of histotripsy on the oncologic therapeutic landscape remains uncertain., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Autosomal recessive congenital ichthyosis (ARCI) is a genetically heterogeneous disorder with aberrant skin scaling and increased transepidermal water loss (TEWL). Current treatments for ARCI are limited and suboptimal. We present the case of a 27-year-old man with ARCI resulting from a homozygous missense variant in TGM1. RNA-sequencing of lesional skin revealed aberrant Janus kinase-signal transducer and activator of transcription signalling, providing a rationale for innovative treatment with a Janus kinase inhibitor. We prescribed oral tofacitinib (11 mg daily) for 26 weeks. Rapid improvements in erythema and fissuring occurred within the first month. Sustained reductions in 5-D itch scale and Dermatology Life Quality Index scores were also observed. TEWL decreased for the first 10 weeks but increased thereafter. Tofacitinib downregulated inflammatory genes and pathways, while enhancing skin barrier markers. Moreover, transglutaminase 1 distribution was normalized although enzymatic activity remained deficient. This study suggests that oral tofacitinib may be a useful therapy to consider for patients with ARCI., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

In response to corneal injury, an activation of corneal epithelial stem cells and their direct progeny the early transit amplifying (eTA) cells to rapidly proliferate is critical for proper re-epithelialization. Thus, it is important to understand how such stem/eTA cell activation is regulated. Angiotensin-converting enzyme 2 (ACE2) is predominantly expressed in the stem/eTA-enriched limbal epithelium but its role in the limbal epithelium was unclear. Single cell RNA sequencing (scRNA-seq) suggested that Ace2 involved the proliferation of the stem/eTA cells. Ace2 was reduced following corneal injury. Such reduction enhanced limbal epithelial proliferation and downregulated LCN2, a negative regulator of proliferation in a variety of tissues, via upregulating TGFA and consequently activating epidermal growth factor receptor (EGFR). Inhibition of EGFR or overexpression of LCN2 reversed the increased proliferation in limbal epithelial cells lacking ACE2. Our findings demonstrate that after corneal injury, ACE2 is downregulated, which activates limbal epithelial cell proliferation via a TGFA/EGFR/LCN2 pathway., Competing Interests: D Batlle and J Wysocki are coinventors of patents entitled “Active Low Molecular Weight Variants of ACE2,” and “Soluble ACE2 Variants and Uses therefor.” D Batlle is founder of Angiotensin Therapeutics Inc. D Batlle has received consulting fees from Advicenne unrelated to this work and received unrelated research support from a grant from AstraZeneca; J Wysocki reports scientific advisor capacity for Angiotensin Therapeutics Inc. All other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 The Authors.)

Background: Dominant dystrophic epidermolysis bullosa (DDEB) is characterized by trauma-induced blisters and, in some individuals, intense pruritus. Precisely what causes itch in DDEB and optimal ways to reduce it have not been fully determined., Objectives: To characterize DDEB skin transcriptomes to identify therapeutic targets to reduce pruritus in patients., Methods: Using bulk RNA sequencing, we evaluated affected and unaffected skin biopsy samples from six patients with DDEB (all with the very itchy pruriginosa subtype) and four healthy individuals. Single-cell transcriptomes of affected (n = 2) and unaffected (n = 1) DDEB skin and healthy skin (n = 2) were obtained. Dupilumab treatment was provided for three patients., Results: The skin bulk transcriptome showed significant enrichment of T helper (Th)1/2 and Th17 pathways in affected DDEB skin compared with nonlesional DDEB skin and healthy skin. Single-cell transcriptomics showed an association of glycolytically active GATA3+ Th2 cells in affected DDEB skin. Treatment with dupilumab in three people with DDEB led to significantly reduced visual analogue scale (VAS) itch scores after 12 weeks (mean VAS 3.83) compared with pretreatment (mean VAS 7.83). Bulk RNAseq and quantitative polymerase chain reaction showed that healthy skin and dupilumab-treated epidermolysis bullosa (EB) pruriginosa skin have similar transcriptomic profiles and reduced Th1/Th2 and Th17 pathway enrichment., Conclusions: Single-cell RNAseq helps define an enhanced DDEB-associated Th2 profile and rationalizes drug repurposing of anti-Th2 drugs in treating DDEB pruritus., Competing Interests: Conflicts of interest J.A.M. currently serves on the Editorial Advisory Board of BJD. The other authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Tumor endothelial marker 1 (TEM1), an activated mesenchymal cell marker, is implicated in tissue remodeling and repair. Herein, we investigated the role and therapeutic implications of TEM1 in abdominal aortic aneurysm (AAA), a potentially life-threatening aortic disease characterized by vascular inflammation and matrix turnover. Characterization of human AAA revealed increased TEM1 expression derived mainly from medial vascular smooth muscle cells (VSMCs) and adventitial fibroblasts. Bioinformatics analysis demonstrated the association between TEM1-expressing VSMCs and fibroblasts and collagen gene expression. Consistently, collagen content and TEM1 expressed by VSMCs and fibroblasts were increased during CaCl 2 -induced AAA formation in mice. TEM1 silencing in VSMCs and fibroblasts inhibited transforming growth factor-β1-induced phenotypic change, SMAD2 phosphorylation, and COL1A1 gene expression. Also, Tem1 deficiency reduced collagen synthesis and exacerbated CaCl 2 -induced AAA formation in mice without disturbing elastin destruction and inflammatory responses. In contrast, rTEM1 promoted phenotypic change and COL1A1 gene expression through SMAD2 phosphorylation in VSMCs and fibroblasts. Treatment with rTEM1 enhanced collagen synthesis, attenuated elastin fragmentation, and inhibited CaCl 2 -induced and angiotensin II-infused AAA formation. In summary, TEM1 in resident stromal cells regulates collagen synthesis to counteract aortic wall failure during AAA formation. Matrix integrity restored by rTEM1 treatment may hold therapeutic potential against AAA., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Advanced care planning (ACP) is the process of establishing goals for end-of-life care. We aimed to examine ACP's prevalence, associated factors, and impact in a cohort of patients undergoing gastrostomy tube procedures., Methods: Adult patients who underwent gastrostomy tube placement from 2016 to 2021 ​at a tertiary center were identified. Variables evaluated included age, sex, race, comorbidities, and median income of patient home zip code. Primary outcomes included the presence of ACP, length of stay (LOS), and 90-day mortality. Analysis was performed using independent T tests, Mann Whitney U-tests, and Chi Square analysis. ACP, LOS, and 90-day mortality were analyzed with multivariate analysis., Results: 877 patients underwent gastrostomy tube placement and 10.6 ​% had ACP. Black race was an isolated factor negatively associated with ACP (OR 0.423, p ​= ​0.013). There was no difference in the proportion of patients with or without ACP who died within 90 days of the procedure (17 ​% vs. 15 ​%, p ​= ​0.836). Average LOS was 6 days shorter for patients with ACP (p ​< ​0.001)., Conclusion: This study highlights the significant underutilization and racial disparity in ACP, and found that ACP does not negatively impact outcomes or perioperative mortality for patients undergoing gastrostomy tube placement., Competing Interests: Declaration of competing interest Each of the authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Acne keloidalis is a primary scarring alopecia characterized by longstanding inflammation in the scalp causing keloid-like scar formation and hair loss. Histologically, acne keloidalis is characterized by mixed leukocytic infiltrates in the acute stage followed by a granulomatous reaction and extensive fibrosis in the later stages. To further explore its pathogenesis, bulk RNA sequencing, single-cell RNA sequencing, and spatial transcriptomics were applied to occipital scalp biopsy specimens of lesional and adjacent no-lesional skin in patients with clinically active disease. Unbiased clustering revealed 19 distinct cell populations, including 2 notable populations: POSTN + fibroblasts with enriched extracellular matrix signatures and SPP1 + myeloid cells with an M2 macrophage phenotype. Cell communication analyses indicated that fibroblasts and myeloid cells communicated by SPP1 signaling networks in lesional skin. A reverse transcriptomics in silico approach identified corticosteroids as possessing the capability to reverse the gene expression signatures of SPP1 + myeloid cells and POSTN + fibroblasts. Intralesional corticosteroid injection greatly reduced SPP1 and POSTN gene expression as well as acne keloidalis disease activity. Spatial transcriptomics and immunofluorescence staining verified microanatomic specificity of SPP1 + myeloid cells and POSTN + fibroblasts with disease activity. In summary, the communication between POSTN + fibroblasts and SPP1 + myeloid cells by SPP1 axis may contribute to the pathogenesis of acne keloidalis., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Secretion and transport of intestinal chylomicrons (CMs) via lymphatics to the blood circulation is stimulated primarily by fat ingestion, whereas several other factors have also been shown to play important roles in regulating CM secretion rate. Among these factors, active regulation of lymphatic pumping has not been appreciated to date. The gut peptide and intestinal growth factor glucagon-like peptide-2 (GLP-2) has emerged as a robust enhancer of intestinal lipid mobilization and secretion. The present study aims to elucidate GLP-2's impact on lacteal contractility and assess enteric nervous system (ENS) involvement in GLP-2-induced effects on lipid mobilization., Methods: Using intravital imaging of a prospero-related homeobox 1-enhanced green fluorescent protein rat model, we assessed GLP-2's effect on lacteal contractility, in the presence and absence of the ENS inhibitor mecamylamine (MEC). Concurrently, to explore the physiological relevance, we examined GLP-2's impact on lymph flow and triglyceride (TG) output in vivo in a rat lymph fistula model., Results: GLP-2 significantly increased lacteal contractility, and this effect was inhibited by MEC. In the rat lymph fistula model, GLP-2 increased lymph flow, lymph volume, cumulative lymph volume, and TG output while reducing lymph TG concentration. MEC administration blocked these effects of GLP-2. Peak enhancement of lacteal contractility and enhancement of lymph flow in vivo occurred simultaneously with maximal effect at 15-20 minutes post GLP-2 administration, suggesting that GLP-2 enhances lipid transport by stimulating lymphatic contractility., Conclusion: For the first time, through imaging and concurrent rat lymphatic fistula studies, we demonstrated active regulation of lymphatic contractility as a key determinant of CM secretion and that intact ENS was required to observe this effect., (© 2024 The Authors.)

Piezo1 regulates multiple aspects of the vascular system by converting mechanical signals generated by fluid flow into biological processes. Here, we find that Piezo1 is necessary for the proper development and function of meningeal lymphatic vessels and that activating Piezo1 through transgenic overexpression or treatment with the chemical agonist Yoda1 is sufficient to increase cerebrospinal fluid (CSF) outflow by improving lymphatic absorption and transport. The abnormal accumulation of CSF, which often leads to hydrocephalus and ventriculomegaly, currently lacks effective treatments. We discovered that meningeal lymphatics in mouse models of Down syndrome were incompletely developed and abnormally formed. Selective overexpression of Piezo1 in lymphatics or systemic administration of Yoda1 in mice with hydrocephalus or Down syndrome resulted in a notable decrease in pathological CSF accumulation, ventricular enlargement and other associated disease symptoms. Together, our study highlights the importance of Piezo1-mediated lymphatic mechanotransduction in maintaining brain fluid drainage and identifies Piezo1 as a promising therapeutic target for treating excessive CSF accumulation and ventricular enlargement., (© 2024. The Author(s).)

Background: Socioeconomic status inequality is an important variable in the emergence of urological diseases in humans. This study set out to investigate the association between the prevalence of overactive bladder (OAB) and the poverty income ratio (PIR) that served as a more influential indicator of socioeconomic status compared to education and occupation., Method: Data from the National Health and Nutrition Examination Survey (NHANES) conducted from 2007 to 2020 were used in this cross-sectional study. The association between the PIR and OAB was examined using weighted multivariate logistic regression and weighted restricted cubic splines (RCS). Additionally, interaction analysis was used for investigation to the connections between PIR and OAB in various covariate groups in order to confirm the stability of the results., Results: We observed a noteworthy inverse association between PIR and OAB after adjusting for potential confounding variables (OR = 0.87, 95% CI, 0.84-0.90, p  < 0.0001). PIR was transformed into categorical variables, and the association held steady after that (1.0 < PIR <4.0 vs. PIR ≤ 1.0, OR = 0.70, 95% CI =0.63-0.77, p  < 0.0001; PIR ≥ 4.0 vs. PIR ≤ 1.0, OR = 0.56, 95% CI =0.48-0.65, p  < 0.0001). Additionally, RCS analysis showed that PIR and OAB had a negative nonlinear response relationship. Subgroup analyses showed that the inverse association between PIR and prevalence of OAB was stronger in obese than in nonobese individuals (P for interaction < 0.05)., Conclusion: In our study, we observed a significant negative association between the PIR and the prevalence of OAB. In the future, PIR could be used as a reference standard to develop strategies to prevent and treat OAB., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lin, Li, Xu, Chen, Zheng, Hong and Liu.)

Human adipose-derived stem cells (ASCs) have shown immense potential for regenerative medicine. Our previous work demonstrated that chitosan nano-deposited surfaces induce spheroid formation and differentiation of ASCs for treating sciatic nerve injuries. However, the underlying cell fate and differentiation mechanisms of ASC-derived spheroids remain unknown. Here, we investigate the epigenetic regulation and signaling coordination of these therapeutic spheroids. During spheroid formation, we observed significant increases in histone 3 trimethylation at lysine 4 (H3K4me3), lysine 9 (H3K9me3), and lysine 27 (H3K27me3), accompanied by increased histone deacetylase (HDAC) activities and decreased histone acetyltransferase activities. Additionally, HDAC5 translocated from the cytoplasm to the nucleus, along with increased nuclear HDAC5 activities. Utilizing single-cell RNA sequencing (scRNA-seq), we analyzed the chitosan-induced ASC spheroids and discovered distinct cluster subpopulations, cell fate trajectories, differentiation traits, and signaling networks using the 10x Genomics platform, R studio/language, and the Ingenuity Pathway Analysis (IPA) tool. Specific subpopulations were identified within the spheroids that corresponded to a transient reprogramming state (Cluster 6) and the endpoint cell state (Cluster 3). H3K4me3 and H3K9me3 were discovered as key epigenetic regulators by IPA to initiate stem cell differentiation in Cluster 6 cells, and confirmed by qPCR and their respective histone methyltransferase inhibitors: SNDX-5613 (a KMT2A inhibitor for H3K4me3) and SUVi (an SUV39H1 inhibitor for H3K9me3). Moreover, H3K9me3 and HDAC5 were involved in regulating downstream signaling and neuronal markers during differentiation in Cluster 3 cells. These findings emphasize the critical role of epigenetic regulation, particularly H3K4me3, H3K9me3, and HDAC5, in shaping stem cell fate and directing lineage-specific differentiation., (© The Author(s) 2023. Published by Oxford University Press.)

Released antibiotics from source to stream can influence bacterial communities and potentially alter the ecosystem. This research provides a comprehensive examination of the sources, distribution, and bacterial community dynamics associated with varied antibiotic release sources adjacent to the stream. The residual of antibiotics from different sources was determined, and the bacterial community structure was examined to reveal the differences in the bacteria community in the stream. The residual of antibiotics was quantified with liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the Illumina MiSeq platform was utilized to sequence bacterial 16S rRNA genes, providing comprehensive insights into the bacterial community structure in the sediment across five different sites. Results indicated that the presence and distribution of antibiotics were significantly influenced by released sources. In the case of the bacterial community, the Proteobacteria and Firmicutes were the most dominant phyla in the sediment, and especially, the Firmicutes showed higher abundance in sites mostly affected by livestock sources. Additionally, livestock gut bacteria such as Clostridium saudiense , Proteiniclasticum ruminis , and Turicibacter sanguinis were prevalent in antibiotic-contaminated sites adjacent to livestock facilities. Overall, this study provides critical insights into the effect of antibiotic contamination by verifying the relationship between the occurrence of antibiotic residuals and the alteration in the bacterial community in the stream.

Background: The Asian American, Native Hawaiian, and Pacific Islander (AANHPI) population is among the fastest-growing population in the USA. However, this is not reflected in scientific research, in which ethnic groups are often combined. We identified trends in treatment and outcomes for pancreatic cancer in a disaggregated AANHPI population. We hypothesize that patients from different AANHPI groups have differences in survival., Patients and Methods: A retrospective analysis of the National Cancer Database between 2010 and 2019 identified patients treated for pancreatic cancer. We identified demographic factors for patients of Caucasian, African American, and disaggregated Asian subpopulations. Survival curves were generated and multivariate analysis was performed to help determine which factors impacted overall survival., Results: A total of 296,448 patients met the inclusion criteria. Of those, 8568 (3%) patients were Asian. Median survival of AANHPI patients was 11.3 months, as compared with Caucasians (8.9 months) and African Americans (8.1 months) (p < 0.0001). Asian Indians had the highest median survival (14.3 months), whereas the Japanese subpopulation had the lowest (7.6 months) (p < 0.0001). There were significant differences in median survival between the different AANHPI subpopulations irrespective of stage. Multivariate analysis demonstrated that belonging to an AANHPI racial/ethnic group, excluding Japanese and Filipino, was associated with decreased risk of overall mortality., Discussion: Significant differences were identified in the overall median survival for patients with pancreatic cancer between AANHPI subpopulations. Disparities in socioeconomic factors may have played a role in overall survival. This study highlights the need to include disaggregated data in future studies to subdue disparities in cancer care for patients., (© 2023. Society of Surgical Oncology.)

Background: Pathologic scars, including keloids and hypertrophic scars, represent a common form of exaggerated cutaneous scarring that is difficult to prevent or treat effectively. Additionally, the pathobiology of pathologic scars remains poorly understood. We aim at investigating the impact of TEM1 (also known as endosialin or CD248), which is a glycosylated type I transmembrane protein, on development of pathologic scars., Methods: To investigate the expression of TEM1, we utilized immunofluorescence staining, Western blotting, and single-cell RNA-sequencing (scRNA-seq) techniques. We conducted in vitro cell culture experiments and an in vivo stretch-induced scar mouse model to study the involvement of TEM1 in TGF-β-mediated responses in pathologic scars., Results: The levels of the protein TEM1 are elevated in both hypertrophic scars and keloids in comparison to normal skin. A re-analysis of scRNA-seq datasets reveals that a major profibrotic subpopulation of keloid and hypertrophic scar fibroblasts greatly expresses TEM1, with expression increasing during fibroblast activation. TEM1 promotes activation, proliferation, and ECM production in human dermal fibroblasts by enhancing TGF-β1 signaling through binding with and stabilizing TGF-β receptors. Global deletion of Tem1 markedly reduces the amount of ECM synthesis and inflammation in a scar in a mouse model of stretch-induced pathologic scarring. The intralesional administration of ontuxizumab, a humanized IgG monoclonal antibody targeting TEM1, significantly decreased both the size and collagen density of keloids., Conclusions: Our data indicate that TEM1 plays a role in pathologic scarring, with its synergistic effect on the TGF-β signaling contributing to dermal fibroblast activation. Targeting TEM1 may represent a novel therapeutic approach in reducing the morbidity of pathologic scars., (© 2024. The Author(s).)

Pancreatic neuroendocrine tumors (PNETs) are characterized by dysregulated signaling pathways that are crucial for tumor formation and progression. The efficacy of traditional therapies is limited, particularly in the treatment of PNETs at an advanced stage. Epigenetic alterations profoundly impact the activity of signaling pathways in cancer development, offering potential opportunities for drug development. There is currently a lack of extensive research on epigenetic regulation in PNETs. To fill this gap, we first summarize major signaling events that are involved in PNET development. Then, we discuss the epigenetic regulation of these signaling pathways in the context of both PNETs and commonly occurring-and therefore more extensively studied-malignancies. Finally, we will offer a perspective on the future research direction of the PNET epigenome and its potential applications in patient care.

Background and Objectives : Type 1 diabetes mellitus (T1DM) is a chronic and serious condition that is characterized by inadequate pancreatic-β-cells' insulin production. The connection between T1DM and Helicobacter pylori infection remains uncertain. This study aimed to conduct a systematic meta-analysis to examine the association between H. pylori infection, hemoglobin A1c levels, and the development of T1DM. Materials and Methods : The initial search identified 451 articles on the association between H. pylori infection and T1DM. Among them, 12 articles had 2797 participants who met the inclusion criteria for an advanced meta-analysis. Results : A significant association was observed between H. pylori infection and T1DM (OR 1.77, 95% CI 1.47-2.12, p < 0.0001), with heterogeneity: Tau 2 = 0.47; Chi 2 = 57.07, df = 11 ( p < 0.0001); I 2 = 81%. Subgroup analysis showed that H. pylori infection was significantly associated with a longer duration of T1DM and higher hemoglobin A1c levels ( p < 0.001 for both) but not with age at T1DM diagnosis ( p = 0.306). Conclusions: These findings contribute to the understanding of the association between H. pylori infection and T1DM and highlight the potential role of H. pylori in influencing the duration and glycemic control of diabetes. Therefore, pediatric patients who have longstanding T1DM and poor glycemic control should be screened for H. pylori infection.

Background: Capsular contracture is the most common reason for having a secondary breast implant operation. The failure of the implanted device and discomfort are related to foreign body response, which involves a pathologic encapsulation. An up-regulated expression of CD248 was previously demonstrated to modulate inflammation and fibrosis. The authors hypothesized that CD248 contributes to foreign body reaction and contracture during silicone-stimulated capsule formation., Methods: A murine capsular contracture model was established to correlate CD248 with capsular contracture. The timing and site of CD248 expression were characterized by protein analysis and histologic examination. The capsules between wild-type mice and CD248 knockout mice were compared in this model to verify the possible role of CD248 in silicone-related capsule formation., Results: CD248 was expressed in the peri-silicone implant capsule by stromal fibroblast and perivascular fibroblast. CD248 was overexpressed on day 4 and down to a constant level, but it was still up-regulated through day 21 to day 56 after silicone implantation. The CD248 knockout mice showed a prolonged inflammation period, whereas the wild-type mice developed a thinner but more collagenous capsule., Conclusions: In conclusion, an effective murine capsular contracture model was established to study the relationship between CD248 and capsular contracture. CD248 may play a role in inflammation and encapsulation during silicone implantation. CD248 deletion in mice contributed to a loose and irregular collagen bundle in a capsule area, implying a decrease in contracture. Therefore, CD248 could be a potential therapeutic target in capsular contracture., Clinical Relevance Statement: CD248 may play a role in inflammation and encapsulation during silicone implantation. It could be a potential therapeutic target in clinical capsular contracture., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Competing Interests: Conflicts of interest the authors declare no conflicts of interest.

Background: Hidradenitis suppurativa (HS) significantly diminishes the quality of life for patients. Delayed diagnosis represents a significant challenge in effectively managing HS., Objectives: To identify and characterize the key mediator in HS., Methods: Bioinformatic transcriptomic analysis was applied to identify potential candidates contributing to the disease process of HS. Skin samples from 40 patients with HS, four with psoriasis and 29 with normal skin were included. The expression of interleukin (IL)-17A was evaluated and compared among samples of normal skin, psoriatic skin and skin from different stages of HS by immunohistochemistry or dual-colour immunofluorescence. In vitro experiments and RNA sequencing analysis were also conducted to validate the expression of IL-17A and its pathogenic effect in HS., Results: Transcriptomic database analyses identified IL-17 signalling as a potential contributor to HS. In HS, the predominant IL-17A+ cell population was identified as mast cells. IL-17A+ mast-cell density was significantly elevated in HS, especially in samples with advanced Hurley stages, compared with normal skin and psoriasis samples. The close contact between IL-17A+ mast cells and IL-17 receptor A (IL-17RA)-expressing keratinocytes was demonstrated, along with the significant effects of IL-17A on keratinocyte cell proliferation and HS pathogenic gene expression. Treatment with biologics (brodalumab or adalimumab) reduced the severity of the disease and the number of IL-17A+ mast cells in affected tissues., Conclusions: The presence of high-density IL-17A+ mast cells may serve as a valuable pathological marker for diagnosing HS. Moreover, developing therapeutic drugs targeting IL-17A+ mast cells may provide a new approach to treating HS., Competing Interests: Conflicts of interest None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Melanoma, a highly malignant and aggressive form of skin cancer, poses a significant global health threat, with limited treatment options and potential side effects. In this study, we developed a temperature-responsive hydrogel for skin regeneration with a controllable drug release. The hydrogel was fabricated using an interpenetrating polymer network (IPN) of N -isopropylacrylamide (NIPAAm) and poly(vinyl alcohol) (PVA). PVA was chosen for its adhesive properties, biocompatibility, and ability to address hydrophobicity issues associated with NIPAAm. The hydrogel was loaded with doxorubicin (DOX), an anticancer drug, for the treatment of melanoma. The NIPAAm-PVA (N-P) hydrogel demonstrated temperature-responsive behavior with a lower critical solution temperature (LCST) around 34 °C. The addition of PVA led to increased porosity and faster drug release. In vitro biocompatibility tests showed nontoxicity and supported cell proliferation. The N-P hydrogel exhibited effective anticancer effects on melanoma cells due to its rapid drug release behavior. This N-P hydrogel system shows great promise for controlled drug delivery and potential applications in skin regeneration and cancer treatment. Further research, including in vivo studies, will be essential to advance this hydrogel system toward clinical translation and impactful advancements in regenerative medicine and cancer therapeutics., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Skull development coincides with the onset of cerebrospinal fluid (CSF) circulation, brain-CSF perfusion, and meningeal lymphangiogenesis, processes essential for brain waste clearance. How these processes are affected by craniofacial disorders such as craniosynostosis are poorly understood. We report that raised intracranial pressure and diminished CSF flow in craniosynostosis mouse models associate with pathological changes to meningeal lymphatic vessels that affect their sprouting, expansion, and long-term maintenance. We also show that craniosynostosis affects CSF circulatory pathways and perfusion into the brain. Further, craniosynostosis exacerbates amyloid pathology and plaque buildup in Twist1+/-:5xFAD transgenic Alzheimer's disease models. Treating craniosynostosis mice with Yoda1, a small molecule agonist for Piezo1, reduces intracranial pressure and improves CSF flow, in addition to restoring meningeal lymphangiogenesis, drainage to the deep cervical lymph nodes, and brain-CSF perfusion. Leveraging these findings, we show that Yoda1 treatments in aged mice with reduced CSF flow and turnover improve lymphatic networks, drainage, and brain-CSF perfusion. Our results suggest that CSF provides mechanical force to facilitate meningeal lymphatic growth and maintenance. Additionally, applying Yoda1 agonist in conditions with raised intracranial pressure and/or diminished CSF flow, as seen in craniosynostosis or with ageing, is a possible therapeutic option to help restore meningeal lymphatic networks and brain-CSF perfusion.

The meninges lie in the interface between the skull and brain, harboring lymphatic vasculature and skull progenitor cells (SPCs). How the skull and brain communicate remains largely unknown. We found that impaired meningeal lymphatics and brain perfusion drive neurocognitive defects in Twist1 +/- mice, an animal model of craniosynostosis recapitulating human Saethre-Chotzen syndrome. Loss of SPCs leads to skull deformities and elevated intracranial pressure (ICP), whereas transplanting SPCs back into mutant mice mitigates lymphatic and brain defects through two mechanisms: (1) decreasing elevated ICP by skull correction and (2) promoting the growth and migration of lymphatic endothelial cells (LECs) via SPC-secreted vascular endothelial growth factor-C (VEGF-C). Treating Twist1 +/- mice with VEGF-C promotes meningeal lymphatic growth and rescues defects in ICP, brain perfusion, and neurocognitive functions. Thus, the skull functionally integrates with the brain via meningeal lymphatics, which is impaired in craniosynostosis and can be restored by SPC-driven lymphatic activation via VEGF-C., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Loss of expression of the SMARCA4 gene, a subunit of the SWI/SNF complex, has been historically associated with thoracic sarcomas . This loss of expression is extremely rare in gastric cancers, and its role in gastrointestinal tract carcinomas has not been fully elucidated. We report a case of a 73-year-old male with poorly differentiated, SMARCA4 -deficient gastric cancer, showing that this immunophenotype is not limited to thoracic sarcomas or advanced-stage tumors. These tumors are often resistant to conventional FLOT chemotherapy and have poor prognoses, necessitating the need for early identification and alternative therapeutic approaches. New therapies such as EZH2 inhibitors and etoposide should be considered in cases where standard treatments are ineffective., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Gastric neuroendocrine tumors (gNETs) are rare cancers for which surgery may improve survival. We aim to determine if facility type affects treatment and survival outcomes., Methods: The NCDB was queried for patients with gNET from 2004-2016 and stratified into Academic/Research Program (ARP), Community Cancer Program (CCP), Comprehensive Community Cancer Program (CCCP), or Integrated Network Cancer Program (INCP). Overall survival along with clinical and demographic features was compared., Results: Median survival was improved in patients treated at an academic program: 137.3 months versus 88.0, 96.3, and 100.2 for CCP, CCCP, INCP, respectively (P < .0001). Patients treated at academic centers were more likely to have surgery (64.2% vs 59.1%, 57.5%, 51.4%, P < .0001). After propensity matching for age, race, grade, stage, insurance status, and comorbidity score, survival benefit from treatment at an academic center remained (P = .03), particularly for patients undergoing surgery (P < .0001) and chemotherapy (P = .04)., Conclusion: Patients with gNET treated at an academic hospital had improved median survival after propensity matching and may benefit from treatment at academic rather than community medical centers., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The cervical spine plays a critical role in supporting the skull, maintaining horizontal gaze, and facilitating walking. Its unique characteristics, including the widest range of motion among spinal segments, have led to extensive research on cervical sagittal alignment. Various parameters have been proposed to evaluate cervical alignment, with studies investigating their clinical significance, correlation with symptoms, and implications for surgical interventions. Recent findings suggest that cervical sagittal alignment not only impacts the cervical spine but also influences global spine-pelvic alignment through compensatory mechanisms. This comprehensive review examines classical and new parameters of cervical sagittal alignment and considers the dynamic and muscular factors associated with it.

Previous studies have shown how adipocytes can modulate the activity of hair follicle stem cells. However, the role of adipocytes in the pathogenesis of androgenetic alopecia (AGA) remains unknown. We aimed to determine signaling pathways related to the adipose tissue changes in the human scalp with AGA through RNA-seq analysis. RNA was isolated from the adipose tissues derived from the bald (frontal) and normal (occipital) scalps of male patients with AGA ( n = 4). The pooled RNA extracts from these samples were subjected to RNA sequencing, followed by differential gene expression and pathway analysis. Our gene expression analysis identified 1,060 differentially expressed genes, including 522 upregulated and 538 downregulated genes in the bald AGA scalp. Biological pathways pertaining to either adipose tissue metabolism or the hair cycle were generated in our pathway analysis. Downregulation of the peroxisome proliferator-activated receptor (PPAR) signaling pathway was noted to be significant in the bald scalp. Expression of adipogenic markers (e.g., PPARG, FABP4, PLN1 , and ADIPOQ ) was also decreased in the bald site. These findings imply that adipogenesis becomes downregulated in AGA, specifically within the bald scalp adipose. Our results lead to the hypothesis that PPARγ-mediated adipogenesis in the scalp adipose, via crosstalk with signaling pathways involved in hair cycling, might play a role in AGA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cruz, Hong, Aala, Tsai, Chung, Tsai, Hsu and Yang.)

An enzyme-fueled transient volume phase transition (TVPT) of hydrogels under out-of-equilibrium conditions is reported. The approach takes inspiration from the metabolic cycle, comprising nutrient intake and anabolism/catabolism followed by waste excretion. The incorporation of methacrylic acid and acrylated trypsin in a polymeric hydrogel allowed the TVPT of the gel to be fueled by lysozyme. With the intake of lysozyme as fuel, the construction/destruction of electrostatic cross-linkages induced transient shrinkage/swelling of the gel accompanied by the depletion of lysozyme activity. The system's transient response could be flexibly programmed by adjusting not only the fuel concentration but the chemical composition of materials. The lysozyme-fueled TVPT of the gel could be exploited to transient changes in the mechanical properties of the gel. Our work opens a route toward a new class of stimuli-responsive hydrogels for biomedical applications.

Microphysogobio rapidus , an endemic cyprinid fish species found exclusively in Korea, has been identified in only two tributaries of the Nakdong River. The species predominantly occupies the near-gravel bottom waters within shallow sections of the middle and lower reaches of the river, characterized by swift currents. M. rapidus is currently recognized as a critically endangered species due to its distinct habitat preference, as well as the negative impacts of stream dam development and water environment pollution. In this study, we used 10 microsatellite markers to examine the genetic diversity of M. rapidus in the upper Nam (UN), lower Nam (LN), and Deokcheon Rivers (DC) in Korea, with a specific focus on assessment of the impact of dam development. Fish sampled from the UN and LN showed a greater average number of alleles and allelic richness ( A = 18.3-18.4, A R = 13.8) compared to those from DC ( A = 11.8, A R = 11.5). The observed heterozygosity among the fish examined ranged from H O = 0.748 (LN) to 0.766 (DC). All three fish groups exhibited a significant departure from Hardy-Weinberg equilibrium (HWE) ( p < 0.05). Despite having the largest effective population size ( N e = 175 and 157, respectively), the fish sampled from UN and LN showed the highest inbreeding coefficients ( F IS = 0.056-0.053, respectively), which were highly significant ( p < 0.01). In contrast, the fish sampled from DC exhibited the smallest effective population size ( N e = 61) and showed an inbreeding coefficient close to zero ( p > 0.05). BOTTLENECK analysis and estimated M-ratio values (0.341-0.372) revealed indications of past population size reduction in all fish groups examined. No significant genetic differentiation ( F ST < 0.05) was detected using the DAPC, STRUCTURE, and AMOVA among the fish studied. However, pairwise comparisons of F ST between fish sampled from the Nam and Deokcheon Rivers revealed significant values ( p < 0.001) ranging from 0.013 to 0.014. In addition, the closest genetic distance (0.026) was observed between UN and LN, while the greatest distance (0.087) was found between UN and DC. Analysis of gene flow rates among the fish examined indicated asymmetrical gene exchange within the Nam River, which was 31.51% in the downstream direction (from UN to LN), with a minimal gene flow rate (0.41%) in the upstream (from LN to UN) direction. The opposite trend was recorded between DC and LN, with a higher gene flow rate (29.74%) in the upstream direction compared to the downstream direction (0.12%). Our study highlighted the importance of implementing long-term conservation efforts focused on maintaining river integrity by removing water barriers such as weirs that impede fish migration and implementing active protection measures, such as aquaculture breeding and reasonable stocking practices, to preserve M. rapidus in the study area.

Dermatofibromas (DFs) are common, benign fibrous skin tumors that can occur at any skin site. In most cases, DFs are solitary and sporadic, but a few are multiple and familial, and the mechanisms leading to these lesions are currently unclear. Using exome sequencing, we have identified a heterozygous variant in a pedigree with autosomal dominant multiple familial DF within RND3 (c.692C>T,p.T231M) that encodes for the small GTPase RhoE, a regulator of the actin cytoskeleton. Expression of T231M-RhoE or RhoE depletion using CRISPR in human dermal fibroblasts increased proliferation and adhesion to extracellular matrix through enhanced β1 integrin activation and more disorganized matrix. The enzyme PLOD2 was identified as a binding partner for RhoE, and the formation of this complex was disrupted by T231M-RhoE. PLOD2 promotes collagen cross-linking and activation of β1 integrins, and depleting PLOD2 in T231M-RhoE-expressing cells reduced T231M-RhoE-mediated β1 integrin activation and led to increased matrix alignment. Immunohistochemical analysis revealed reduced expression of RhoE but increased expression of PLOD2 in the dermis of DF skin samples compared with that of the controls. Our data show that loss of RhoE function leads to increased PLOD2 activation, enhancing integrin activation and leading to a disorganized extracellular matrix, contributing to DF., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Generalized pustular psoriasis (GPP) is a rare but severe form of psoriasis. An early onset of the diseases is correlated with mutations among IL36RN, CARD14, AP1S3, MPO and SERPINA3 genes. Systemic biological agents including anti-TNF-α, anti-IL-17, anti-IL-12/IL-23, anti-IL1R, anti-IL1β and anti-IL-36R act as novel treatment methods for GPP. Herein we report a female infant clinically diagnosed with GPP since she was 10-month-old. Results of whole-exome sequencing (WES) and Sanger sequencing revealed a reported heterozygous IL36RN (c.115+6T>C) and another reported heterozygous SERPINA3 frame-shifting variant (c.1247&#95;1248del). Initial cyclosporin treatment for the patient led to a partial remission of the symptoms. However, the patient reached nearly total remission of pustules and erythema after anti-TNF-α inhibitor etanercept treatment. Results of further RNA sequencing (RNA-seq) done on peripheral blood mononuclear cells correlated with the clinical responses, showing that cyclosporin suppressed a portion of the neutrophil-related genes, while most genes associated with neutrophil activation, neutrophil-mediated immunity and degranulation were downregulated by the subsequent etanercept treatment. We report this case to demonstrate WES and RNA-seq in combination could come in handy in reaching a precise diagnosis and in evaluating or even predicting the molecular alterations underlying clinical treatment effectiveness., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Central nervous system (CNS) tumor patients commonly undergo multimodality treatment in the course of their disease. Adverse effects and complications from these interventions have not been systematically studied, but pose significant challenges in clinical practice and impact function and quality of life, especially in the management of long-term brain tumor survivors. Here, the European Association of Neuro-Oncology (EANO) has developed recommendations to prevent, diagnose, and manage adverse effects and complications in the adult primary brain CNS tumor (except lymphomas) patient population with a specific focus on surgery, radiotherapy, and pharmacotherapy. Specifically, we also provide recommendations for dose adaptations, interruptions, and reexposure for pharmacotherapy that may serve as a reference for the management of standard of care in clinical trials. We also summarize which interventions are unnecessary, inactive or contraindicated. This consensus paper should serve as a reference for the conduct of standard therapy within and outside of clinical trials., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Purpose: Glioblastoma (GBM) has a poor prognosis after standard treatment. Recently, metformin has been shown to have an antitumor effect on glioma cells. We performed the first randomized prospective phase II clinical trial to investigate the clinical efficacy and safety of metformin in patients with recurrent or refractory GBM treated with low-dose temozolomide., Methods: Included patients were randomly assigned to a control group [placebo plus low-dose temozolomide (50 mg/m 2 , daily)] or an experimental group [metformin (1000 mg, 1500 mg, and 2000 mg per day during the 1st, 2nd, and 3rd week until disease progression, respectively) plus low-dose temozolomide]. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), disease control rate, overall response rate, health-related quality of life, and safety., Results: Among the 92 patients screened, 81 were randomly assigned to the control group (43 patients) or the experimental group (38 patients). Although the control group showed a longer median PFS, the difference between the two groups was not statistically significant (2.66 versus 2.3 months, p = 0.679). The median OS was 17.22 months (95% CI 12.19-21.68 months) in the experimental group and 7.69 months (95% CI 5.16-22.67 months) in the control group, showing no significant difference by the log-rank test (HR: 0.78; 95% CI 0.39-1.58; p = 0.473). The overall response rate and disease control rate were 9.3% and 46.5% in the control group and 5.3% and 47.4% in the experimental group, respectively., Conclusions: Although the metformin plus temozolomide regimen was well tolerated, it did not confer a clinical benefit in patients with recurrent or refractory GBM. Trial registration NCT03243851, registered August 4, 2017., (© 2023. The Author(s).)

Significance: The aberrant inflammation during wound healing results in pathological scarring, such as hypertrophic scars and keloids. This adversely affects the quality of life of patients due to the disfiguring appearance as well as the symptoms of itch and pain. This review summarizes the up-to-date knowledge of the immunopathogenesis and treatment options for pathological scars. Recent Advances: With the advent of new technologies, combined with in vitro and in vivo wound models, several inflammatory cells have been shown to have both direct and indirect effects on both wound healing and pathological scarring. Critical Issues: Expansion of pro-fibrotic immune cells such as M2 macrophages, dendritic cells, mast cells, and Th2 cells leads to fibroblast transition to myofibroblasts via transforming growth factor-β1 signaling pathway. Appropriate management of such inflammatory responses during wound healing remains a critical issue during clinical practice. Future Directions: Regulating inflammation response during wound healing may be a potential therapeutic option for avoiding or reducing pathological scars.