Branch Chain Amino Acid Metabolism Promotes Brain Metastasis of NSCLC through EMT Occurrence by Regulating ALKBH5 activity.

Metabolic reprogramming is one of the essential features of tumors that may dramatically contribute to cancer metastasis. Employing liquid chromatography-tandem mass spectrometry-based metabolomics, we analyzed the metabolic profile from 12 pairwise serum samples of NSCLC brain metastasis patients before and after CyberKnife Stereotactic Radiotherapy. We evaluated the histopathological architecture of 144 surgically resected NSCLC brain metastases. Differential metabolites were screened and conducted for functional clustering and annotation. Metabolomic profiling identified a pathway that was enriched in the metabolism of branched-chain amino acids (BCAAs). Pathologically, adenocarcinoma with a solid growth pattern has a higher propensity for brain metastasis. Patients with high BCAT1 protein levels in lung adenocarcinoma tissues were associated with a poor prognosis. We found that brain NSCLC cells had elevated catabolism of BCAAs, which led to a depletion of α-KG. This depletion, in turn, reduced the expression and activity of the m6A demethylase ALKBH5. Thus, ALKBH5 inhibition participated in maintaining the m6A methylation of mesenchymal genes and promoted the occurrence of epithelial-mesenchymal transition (EMT) in NSCLC cells and the proliferation of NSCLC cells in the brain. BCAA catabolism plays an essential role in the metastasis of NSCLC cells.

Different prognosis in cutaneous early-onset and late-onset Merkel cell carcinoma: a population-based retrospective study.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare and highly aggressive form of skin cancer. However, there is limited research on the clinicopathological features of early-onset MCC (EOMCC) and the differences between EOMCC and late-onset MCC (LOMCC). Our objective was to evaluate the clinicopathological features and cancer-specific survival (CSS) of EOMCC. METHODS: Our cohort study analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database from January 1, 2018, to December 31, 2020. Data from 1941 patients who were diagnosed with primary cutaneous MCC were included. We then divided the patients with MCC into two groups: those with EOMCC (526 patients) and those with LOMCC (1415 patients). CSS is used as the primary outcome. RESULTS: The EOMCC group exhibited trends toward advanced tumor progression, an expanded surgical scope, increased lymph node retrieval, intensified radiotherapy, greater utilization of systemic therapy, and a better prognosis. Multivariate analysis revealed that LOMCC (HR 3.305 [2.002-5.456], P < 0.001), advanced T stage (HR 1.430 [1.139-1.797], P = 0.002), advanced N stage (HR 1.522 [1.221-1.897], P < 0.001), M1 stage (HR 2.587 [1.480-4.521], P < 0.001), and radiation (HR 0.586 [0.410-0.837], P = 0.003) were significantly associated with CSS. Among these factors, EOMCC/LOMCC was most strongly associated with CSS, indicating that LOMCC is an independent risk factor for CSS. Interestingly, we found that regional EOMCC and localized or in situ LOMCC had almost completely overlapping survival curves (Plog-rank = 0.620). Additionally, we observed that the TNM staging + age model was a more accurate predictor of CSS among MCC patients than using TNM staging alone. CONCLUSIONS: We found that EOMCC has distinct clinicopathological features compared to LOMCC. EOMCC is associated with better CSS. The combination of TNM staging and age was more accurate for predicting patient outcomes than TNM staging alone.

Defining Ideal Pretarsal Rolls Through a Morphometric Analysis in Asians.

BACKGROUND: Pretarsal rolls are a crucial aesthetic feature. Despite numerous studies conducted on periorbital aesthetics, there remains a dearth of research on the ideal pretarsal rolls. OBJECTIVES: This study aimed to investigate 4 aesthetic characteristics of ideal pretarsal rolls: presence, width, proportion, and morphology. METHODS: Respondents (385, including 80 aesthetic specialists) were presented with 7 series of images of pretarsal rolls, including 2 series of pretarsal roll existence, 2 series of varying widths, 2 series of different ratios between pretarsal roll and palpebral fissure height, and 1 series about morphology. Participants were asked to rank each image within a given series from most attractive to least attractive. The rankings were then analyzed according to population demographics. RESULTS: The majority of respondents deemed images with pretarsal rolls to be more aesthetically pleasing (P < .001) than those without such features. Additionally, pretarsal rolls with a width of 5 mm (P < .001), a ratio to palpebral fissure height of 0.5:1 (P < .001), and a crescent shape (P < .001) were perceived as the most attractive. Moreover, individuals aged 40 or younger exhibited a significant preference for images with pretarsal rolls compared to older groups (P < .001), and females displayed a greater inclination toward a medium ratio of pretarsal roll to palpebral fissure height than males did (0.5:1 P = .003, 0.618:1 P < .001). CONCLUSIONS: This study validates the optimal characteristics of pretarsal rolls, which provides insight into pretarsal roll aesthetics and holds significant implications for surgical planning and effect assessment in future periocular procedures involving pretarsal rolls.

Defining Ideal Double Eyelids With a Morphometric Analysis in Asians.

BACKGROUND: Double eyelids are always considered crucial aesthetic symbols. Despite numerous studies conducted on the attractiveness of double eyelids, there remains a dearth of research on quantitative and morphological evaluation of ideal double eyelids. OBJECTIVES: In this we study aimed to investigate the optimal height and morphological characteristics of ideal double eyelids. METHODS: Participants were presented with a total of 9 images, consisting of 1 single eyelid image and 8 double eyelid images, featuring 2 distinct shapes and 4 varied pretarsal shows. Respondents were instructed to assign scores ranging from 1 (least attractive) to 5 (most attractive) for each image. Subsequently, the scores for each image were analyzed based on population demographics, followed by the calculation of aesthetic metrics. RESULTS: The whole cohort deemed images with a 2-mm fold to be more attractive than 1 mm (P < .001), followed by 3 mm and 0 mm (single eyelid), and finally, 4 mm. Morphologically, significant differences were found between images with the same pretarsal shows of 3 mm (P < .001) and 4 mm (P = .026). Most subgroup analysis results were aligned with those of the cohort, with gender being the most significant factor in distinguishing double eyelid aesthetics. Additionally, aesthetic characteristics of 2-mm folds were found to be comparable to appealing double eyelids in previous studies. CONCLUSIONS: In this study we validated the optimal heights and morphology of double eyelids, thereby addressing the existing gap in aesthetic studies on double eyelids. These findings hold significant implications for surgical planning, effect assessment, and other periocular procedures related to upper blepharoplasty.

Exosomes from human adipose-derived mesenchymal stem cells attenuate localized scleroderma fibrosis by the let-7a-5p/TGF-ßR1/Smad axis.

BACKGROUND: Inflammation and fibrosis of the skin are characteristics of localized scleroderma (LS). Emerging evidence has demonstrated that exosomes from human adipose tissue-derived mesenchymal stem cells (ADSC-Exo) could alleviate skin fibrosis. OBJECTIVE: The impact and potential mechanism of ADSC-Exo on LS fibrosis was examined. METHODS: ADSC-Exo was isolated and identified. The effects of ADSC-Exo on the abilities of proliferation and migration of LS-derived fibroblasts (LSFs) were assessed by CCK-8 and scratch assays, respectively. qRT-PCR, western blot, and immunofluorescence were conducted to detect LSFs stimulated with ADSC-Exo, ADSC-ExoAnti-let-7a-5p, let-7a-5p mimic/TGF-ßR1 shRNA virus, and negative controls. The impact of ADSC-Exo on C57BL/6j LS mice was evaluated by photographic morphology, hematoxylin-eosin (H&E), Masson's trichrome, and immunohistochemical staining. RESULTS: The verified ADSC-Exo limited the proliferation and migration of LSFs and reduced the expression of COL1, COL3, α-SMA, TGF-ßR1, and p-Smad2/ 3 in vitro and in vivo. TGF-ßR1 knockdown and let-7a-5p mimic in LSFs reduced the expression of COL1, COL3, α-SMA, and p-Smad2/3. However, compared with the ADSC-ExoNC group, the dermal thickness was increased, collagen arrangement was disordered, and α-SMA and TGF-ßR1 levels were increased after exposure to ADSC-ExoAnti-let-7a-5p. CONCLUSIONS: In this study, it might show that ADSC-Exo may successfully prevent LSF bioactivity, collagen deposition, and myofibroblast trans-differentiation. Additionally, we confirmed that let-7a-5p in ADSC-Exo could directly target TGF-R1 to control the Smad pathway and reduce fibrosis in LSFs. Our work offered a brand-new therapeutic approach and clarified the unique mechanism for the clinical management of LS.

Fat Grafting Reduces Skin Hyperpigmentation of Localized Scleroderma Patients: A Prospective Self-controlled Study.

BACKGROUND: Localized scleroderma (LS) is characterized by skin fibrosis, hyperpigmentation and soft tissue atrophy. Fat grafting has been widely used to correct LS deformity. OBJECTIVE: To investigate the effect of fat grafting on the skin pigmentation of LS lesions. METHODS: A prospective self-controlled study was conducted. Skin melanin and erythema indexes were measured by Mexameter® MX18 before and 3 months after surgery. Differences between lesions and contralateral normal sites were compared to evaluate changes induced by fat grafting. Localized Scleroderma Cutaneous Assessment Tool and PUMC Localized Scleroderma Facial Aesthetic Index were used for clinical evaluation. RESULTS: Fourteen frontal linear LS patients participated in the study. Before surgery, the melanin index of the lesions was significantly higher than the contralateral sites (p = 0.023), while the erythema indexes were not significantly different (p = 0.426). Three months post-operation, the melanin index of the lesions significantly decreased (p = 0.008). There was no significant change in the erythema index of the lesions before and after fat grafting (p = 0.322). The LoSCAT and PUMC LSFAI scores demonstrated improved disease condition and facial esthetics after surgery. CONCLUSION: Fat grafting could alleviate skin hyperpigmentation and skin damage of LS lesions while having little effect on skin erythema and disease activity. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

A Study Based on Network Pharmacology Decoding the Multi-Target Mechanism of Duhuo Jisheng Decoction for the Treatment of Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IDD) poses a grim public health impact. Duhuo Jisheng Decoction (DJD), a traditional Chinese medicine formula, has recently received significant attention for its efficacy and safety in treating IDD. However, the pathological processes of IDD in which DJD interferes and molecular mechanism involved are poorly understood, which brings difficulties to the clinical practice of DJD for the treatment of IDD. This study systematically investigated the underlying mechanism of DJD treatment of IDD. Network pharmacology approaches were employed, integrating molecular docking and random walk with restart (RWR) algorithm, to identify key compounds and targets for DJD in the treatment of IDD. Bioinformatics approaches were used to further explore the biological insights in DJD treatment of IDD. The analysis identifies AKT1, PIK3R1, CHUK, ALB, TP53, MYC, NR3C1, IL1B, ERBB2, CAV1, CTNNB1, AR, IGF2, and ESR1 as key targets. Responses to mechanical stress, oxidative stress, cellular inflammatory responses, autophagy, and apoptosis are identified as the critical biological processes involved in DJD treatment of IDD. The regulation of DJD targets in extracellular matrix components, ion channel regulation, transcriptional regulation, synthesis and metabolic regulation of reactive oxygen products in the respiratory chain and mitochondria, fatty acid oxidation, the metabolism of Arachidonic acid, and regulation of Rho and Ras protein activation are found to be potential mechanisms in disc tissue response to mechanical stress and oxidative stress. MAPK, PI3K/AKT, and NF-κB signaling pathways are identified as vital signaling pathways for DJD to treat IDD. Quercetin and Kaempferol are assigned a central position in the treatment of IDD. This study contributes to a more comprehensive understanding of the mechanism of DJD in treating IDD. It provides a reference for applying natural products to delay the pathological process of IDD.

What factors will influence patients when choosing plastic surgeons? A behaviour analysis of Chinese patients.

PURPOSE: To analyze the factors that patients consider when choosing plastic surgeons and investigate patients' attitudes toward physicians' aesthetic ability and their adherence toward same-gender physicians. METHODS: A cross-sectional study was conducted. All patients who presented for evaluation and management between January and April 2022 were eligible for study enrolment. Data collected include demographical information and specific questions related to choosing plastic surgeons, including physician's education, surgical ability, research, title, appearance, dress, age, aesthetics, the patient's preference for physicians' gender, and the way of learning about physicians. RESULTS: 1006 valid respondents participated, and the average age was 46.44 ±â€¯15.51 years old (participation rate 99.60%). 72.5% were female. Plastic surgery history (OR 3.242, 95%CI: 1.664-6.317, p = 0.001), education (OR 1.895, 95%CI: 1.064-3.375, p = 0.030), income (OR 1.340, 95%CI: 1.026-1.750, p = 0.032), sexual orientation (OR 1.662, 95%CI: 1.066-2.589, p = 0.025), and concern for the physicians' appearance (OR 1.564, 95%CI: 1.160-2.107, p = 0.003) were significantly associated with patients' tendency to value physicians' aesthetic ability. Marital status (OR 0.766, 95% CI: 0.616-0.951, p = 0.016), income (OR 0.896,95% CI: 0.811-0.990, p = 0.031), the attention to physicians' age (OR 1.191,95% CI: 1.031-1.375, p = 0.017), and the attention to physicians' aesthetic ability (OR 0.775,95% CI: 0.666-0.901, p = 0.001) were significantly associated with the respondents' same-gender adherence degree. CONCLUSION: These findings suggest that patients with plastic surgery history, higher income, higher education background, and more diverse sexual orientation paid more attention to physicians' aesthetic ability. Marriage and income would affect the same-gender adherence degree, which would further influence patients' attention to the doctor's age and aesthetic ability.

Platelet-Rich Plasma Combined Fat Transplantation for the Treatment of Bleomycin-Induced Murine Scleroderma.

BACKGROUND: Low-fat retention induced by inflammation limits the clinical application of fat grafting for treating localized scleroderma (LS) patients. Novel methods to improve the therapeutic outcome are needed. OBJECTIVE: The aim of the study is to investigate the effect of platelet-rich plasma (PRP)-assisted fat transplantation on skin fibrosis and adipose survival in the LS model. METHODS: The LS model was established by the injection of bleomycin into BALB/C nude mice, which were randomly divided into the following 4 groups: healthy control, LS disease group model, fat transplantation group, and PRP+ fat transplantation group. The mice received a subcutaneous injection at back with phosphate-buffered saline, fat, or 20% PRP+ fat. Factors of immunoregulation, angiogenesis and adipogenesis were measured. RESULTS: Platelet-rich plasma-combined fat transplantation significantly attenuated dermis fibrosis by reducing the production of type III collagen. The fat retention in the PRP+ fat transplantation group was 43 ± 4 mg, significantly higher than 22 ± 15 mg in the fat transplantation group (P = 0.0416). The level of tumor necrosis factor α and interleukin 2 showed no significant difference between the groups. The expression of angiogenesis factors, vascular endothelial growth factor, hepatocyte growth factor, platelet-derived growth factor, and CD31, significantly increased in the PRP+ fat transplantation group. The expression of adipogenesis factors, insulin-like growth factor 1 receptor, extracellular signal-regulated kinase, anti-CCAAT-enhancer-binding proteins, and peroxisome proliferator-activated receptor γ, also significantly increased in the PRP+ fat transplantation group. CONCLUSIONS: The results demonstrated that PRP-combined fat transplantation attenuated dermis fibrosis and raised fat survival in the LS model by promoting angiogenesis and adipogenesis through insulin-like growth factor 1 receptor/extracellular signal-regulated kinase signaling pathway.

Nuclear Translocation of LDHA Promotes the Catabolism of BCAAs to Sustain GBM Cell Proliferation through the TxN Antioxidant Pathway.

Glutamate is excitotoxic to neurons. The entry of glutamine or glutamate from the blood into the brain is limited. To overcome this, branched-chain amino acids (BCAAs) catabolism replenishes the glutamate in brain cells. Branched-chain amino acid transaminase 1 (BCAT1) activity is silenced by epigenetic methylation in IDH mutant gliomas. However, glioblastomas (GBMs) express wild type IDH. Here, we investigated how oxidative stress promotes BCAAs' metabolism to maintain intracellular redox balance and, consequently, the rapid progression of GBMs. We found that reactive oxygen species (ROS) accumulation promoted the nuclear translocation of lactate dehydrogenase A (LDHA), which triggered DOT1L (disruptor of telomeric silencing 1-like)-mediated histone H3K79 hypermethylation and enhanced BCAA catabolism in GBM cells. Glutamate derived from BCAAs catabolism participates in antioxidant thioredoxin (TxN) production. The inhibition of BCAT1 decreased the tumorigenicity of GBM cells in orthotopically transplanted nude mice, and prolonged their survival time. In GBM samples, BCAT1 expression was negatively correlated with the overall survival time (OS) of patients. These findings highlight the role of the non-canonical enzyme activity of LDHA on BCAT1 expression, which links the two major metabolic pathways in GBMs. Glutamate produced by the catabolism of BCAAs was involved in complementary antioxidant TxN synthesis to balance the redox state in tumor cells and promote the progression of GBMs.

Wip1 regulates wound healing by affecting activities of keratinocytes and endothelial cells through ATM-p53 and mTOR signaling.

BACKGROUND: As a p53-regulated gene, Wip1 regulates proliferation, migration, apoptosis, and senescence of several type cells, but its biological functions in keratinocytes and endothelial cells which are involved wound healing are not fully understood. This study aims to reveal the function and underlying mechanism of Wip1 in wound healing using models of transgenic animal, keratinocytes, and endothelial cells. METHODS: Using Wip1 knockout C57 BL/6 mice, we investigated effect of Wip1 deficiency on wound healing and angiogenesis; And using HaCaT and HUVEC as keratinocytes and endothelial cells, combined using primary keratinocytes from Wip1 knockout mice, we studied the effects of Wip1 knockdown/knockout or overexpression on proliferation, migration, and protein expressions of signaling components in ATM-p53 and mTOR pathway. RESULTS: Wip1 deficiency in mice impaired the wound repair and endothelial angiogenesis, reduced the thickness of granulation tissue, and decreased the number of Ki67-positive cells and CD31 positive vessels in granulation tissue. Knockdown of Wip1 by shRNAs suppressed the proliferation and migration of HaCaT and HUVEC cells and induced notably apoptosis in the two cells. In western blot, Wip1 knockdown enriched p53 and ATM proteins, while decreased activated AKT, mTOR and activated S6 ribosomal protein (pS6) levels in HaCaT and HUVEC cells. Ectopic expression of Wip1 decreased the p53 and ATM proteins, while increased activated AKT, mTOR and pS6 levels in HaCaT and HUVEC cells. And in primary keratinocytes from mice tail skin, Wip1 knockout increased p53 and ATM, while decreased activated AKT, mTOR and pS6 protein levels. CONCLUSION: Our study directly supports that Wip1 regulated skin wound healing possibly by affecting bioactivities including proliferation, migration and apoptosis of keratinocytes and endothelial cells at least through by modulating ATM-p53 and mTOR signaling.

Hypoxia-induced reprogramming of glucose-dependent metabolic pathways maintains the stemness of human bone marrow-derived endothelial progenitor cells.

The benefits of hypoxia for maintaining the stemness of cultured human bone marrow-derived endothelial progenitor cells (BM EPCs) have previously been demonstrated but the mechanisms responsible remain unclear. Growing evidences suggest that cellular metabolism plays an important role in regulating stem cell fate and self-renewal. Here we aimed to detect the changes of glucose metabolism and to explore its role on maintaining the stemness of BM EPCs under hypoxia. We identified the metabolic status of BM EPCs by using extracellular flux analysis, LC-MS/MS, and 13C tracing HPLC-QE-MS, and found that hypoxia induced glucose metabolic reprogramming, which manifested as increased glycolysis and pentose phosphate pathway (PPP), decreased tricarboxylic acid (TCA) and mitochondrial respiration. We further pharmacologically altered the metabolic status of cells by employing various of inhibitors of key enzymes of glycolysis, PPP, TCA cycle and mitochondria electron transport chain (ETC). We found that inhibiting glycolysis or PPP impaired cell proliferation either under normoxia or hypoxia. On the contrary, inhibiting pyruvate oxidation, TCA or ETC promoted cell proliferation under normoxia mimicking hypoxic conditions. Moreover, promoting pyruvate oxidation reverses the maintenance effect of hypoxia on cell stemness. Taken together, our data suggest that hypoxia induced glucose metabolic reprogramming maintains the stemness of BM EPCs, and artificial manipulation of cell metabolism can be an effective way for regulating the stemness of BM EPCs, thereby improving the efficiency of cell expansion in vitro.

Individualized High Double Eyelid Fold Correction in Secondary Blepharoplasty: A Free-Style Design.

BACKGROUND: High crease correction is difficult to achieve in secondary blepharoplasty. Currently, patients tend to have more precise requirements for crease-lowering procedures, such as low in-fold or low out-fold creases. For the out-fold crease, the height of the central crease is similar with the height of the medial crease, whereas for the in-fold crease, the height of the medial crease is lower than the height of the central crease. OBJECTIVES: In this study, the authors developed a strategy to create low in-fold or out-fold creases to satisfy patients' individualized requirements. METHODS: The medical records of patients who received crease-lowering secondary blepharoplasty from January 2015 to January 2021 were reviewed. The results were grouped by preoperative condition (high in-fold/out-fold) and patients' expectations for postoperative outcome (low in-fold/out-fold). Preoperative and postoperative images were collected, and patient satisfaction, complications and revisions were evaluated. RESULTS: In total, 297 consecutive patients were included in this study with an average follow-up duration of 12.3 months. Eighteen patients had high in-fold creases, and 279 patients had high out-fold creases. Regarding patients with high out-folds, 233 patients wanted to have low out-folds, and 46 patients wanted to have low in-folds. Two hundred and sixty-six (89.6%) patients were satisfied with their results. Complications included complete crease loss (n = 3, 1.0%), partial crease loss (n = 5, 1.7%), multiple creases (n = 6, 2.0%), asymmetric creases (n = 7, 2.4%), and upper eyelid skin laxity (n = 10, 3.4%). CONCLUSIONS: This flexible, novel technique for customizing low out-fold or in-fold creases is reliable in high double-eyelid crease correction based on preoperative upper eyelid skin tightness, scar positions, and the patient's expected double-eyelid crease shape. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

A Comprehensive Ultrasound Evaluation Approach of Lower Facial Structure Before Masseter Muscle Botulinum Toxin Injection.

BACKGROUND: Masseter reduction by botulinum neurotoxin A (BoNT-A) injection is a popular procedure in East Asia. Inappropriate injection can result in various complications. OBJECTIVES: The aim of this study was to develop an approach for comprehensively evaluating the lower facial structure based on the shape of the mandible angle, the thickness of the masseter, and the thickness of subcutaneous fat. METHODS: Clinical profiles and standard ultrasound images were collected from patients seeking masseter BoNT-A injections. Lower facial structures were evaluated based on 3 aspects: mandible, masseter, and subcutaneous fat and skin. The mandibular angle was classified as extroverted, straight, or introverted. The starting point of the middle part of the masseter was recorded. The thickness of the deep inferior tendon, the superficial and deep belly of the superficial part of the masseter, and their contractility were measured. Overall thickness and the thickness of subcutaneous fat and skin were also measured. RESULTS: Eighty-four masseters from 42 patients were included. Straight mandibular angles were the most common type of angle (48.81%), followed by introverted (26.19%) and extroverted angles (25.00%). The middle part of the masseter starts from 2.33 [0.36] cm (mean [standard deviation]) above the mandible edge, which is above the usual injection points. The superficial belly was thicker than the deep belly in both static and clenching states (P = .048, P = .001) and had greater contractility. The average overall thickness was 1.87 [0.29] cm. CONCLUSIONS: Comprehensive evaluation of the lower facial contour and structure based on ultrasound examination could be a reliable and replicable assessment approach.

The prognostic impact of tumor-infiltrating B lymphocytes in patients with solid malignancies: A systematic review and meta-analysis.

This study reviewed the prognostic effect of tumor-infiltrating B lymphocytes (TIBLs) on solid malignancies, to determine the potential role of TIBLs in predicting cancer patient's prognosis and their response to immunotherapy. A total of 45 original papers involving 11,099 individual patients were included in this meta-analysis covering 7 kinds of cancer. The pooled results suggested that high levels of TIBLs were correlated with favorable OS in lung, esophageal, gastric, colorectal, liver, and breast cancer; improved RFS in lung cancer; and improved DFS in gastrointestinal neoplasms. Additionally, TIBLs were significantly correlated with negative lymphatic invasion in gastric cancer, small tumor size in hepatocellular carcinoma, and negative distant metastasis in colorectal cancer. Additionally, TIBLs were reported as a discriminative feature of patients treated with immunotherapy with improved survival. We concluded that TIBLs play a favorable prognostic role among the common solid malignancie, providing theoretical evidence for further prognosis prediction for solid tumors.

The 100 Most-Cited Manuscripts on Blepharoptosis: A Bibliometric analysis.

BACKGROUND: We conducted a bibliometric analysis of blepharoptosis, obtained the top 100 most-cited articles, and then researched the characteristics of every article. MATERIALS AND METHODS: The Web of Science Citation Index was utilized to identify articles related to blepharoptosis written in English published from 1900 to 2021 using predefined search terms. Then, the returned results were screened, and the top 100 most-cited articles were individually classified based on publication year, country of publication, source journal, total citations, authors' specialty, level of evidence, main subject, and type of study. RESULTS: The 100 most-cited articles were published between 1948 and 2014. The number of citations/articles ranged from 49 to 743. Ophthalmology journals made the greatest contributions to landmark literature (n=61). The primary focus of these 100 studies was the surgical technique (n=41). The majority of them (n=52) only achieved level 4 evidence, as a high proportion of these articles were case series (n=52). The most common country of publication was the United States (n=59). CONCLUSIONS: Our bibliometric analysis provides insight into the citation frequency of the most-cited articles on blepharoptosis. The landmark, highly cited articles that have shaped the landscape of blepharoptosis were identified. The results from these top 100 cited articles are helpful for present current surgical decision-making.

Single-cell RNA sequencing of subcutaneous adipose tissues identifies therapeutic targets for cancer-associated lymphedema.

Cancer-associated lymphedema frequently occurs following lymph node resection for cancer treatment. However, we still lack effective targeted medical therapies for the treatment or prevention of this complication. An in-depth elucidation of the cellular alterations in subcutaneous adipose tissues of lymphedema is essential for medical development. We performed single-cell RNA sequencing of 70,209 cells of the stromal vascular fraction of adipose tissues from lymphedema patients and healthy donors. Four subpopulations of adipose-derived stromal cells (ASCs) were identified. Among them, the PRG4+/CLEC3B+ ASC subpopulation c3 was significantly expanded in lymphedema and related to adipose tissue fibrosis. Knockdown of CLEC3B in vitro could significantly attenuate the fibrogenesis of ASCs from patients. Adipose tissues of lymphedema displayed a striking depletion of LYVE+ anti-inflammatory macrophages and exhibited a pro-inflammatory microenvironment. Pharmacological blockage of Trem1, an immune receptor predominantly expressed by the pro-inflammatory macrophages, using murine LR12, a dodecapeptide, could significantly alleviate lymphedema in a mouse tail model. Cell-cell communication analysis uncovered a perivascular ligand-receptor interaction module among ASCs, macrophages, and vascular endothelial cells. We provided a comprehensive analysis of the lineage-specific changes in the adipose tissues from lymphedema patients at a single-cell resolution. CLEC3B was found to be a potential target for alleviating adipose tissue fibrosis. Pharmacological blockage of TREM1 using LR12 could serve as a promising medical therapy for treating lymphedema.

Double Eyelid Shape Preference: A Large Sample Survey.

BACKGROUND: Double eyelid blepharoplasty is a popular procedure among Asian population. Double eyelid shape is important to achieving high satisfaction rate. Currently, there lacks large sample survey and detailed analysis on preferred double eyelid shape. This study aims to investigate the double eyelid shape preference using the "in-fold," "on-fold," and "out-fold" classification and analyze the preferred shape of different demographic groups. METHODS: A large sample survey was conducted with a questionnaire of nine questions in three sections: demographic characteristics, desired double eyelid shape, and assessment of the classification. The preference for each type of double eyelid shape was analyzed and compared among different groups. RESULTS: A total of 11153 (9698 female and 1455 male) respondents finished the questionnaire, including 382 plastic surgeons. In-fold double eyelid was the most popular choice overall. Out-fold was the least preferred, except for specific groups such as actors and heavy makeup wearers. No significant difference was observed between the preference of patients and plastic surgeons. The majority of respondents cared much about postoperative double eyelid shape and considered the classification useful. CONCLUSIONS: In-fold was the most preferred double eyelid shape, especially for patients who met one or more of the following criteria: male, older than 40, divorced, or housewives. However, heavy makeup wearers or actors/actresses tend to prefer out-fold double eyelids. The "in-fold," "on-fold," and "out-fold" classification was precise and beneficial to doctor-patient communication. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Ibrutinib reverses IL-6-induced osimertinib resistance through inhibition of Laminin α5/FAK signaling.

Osimertinib, a 3rd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the first-line standard-of-care for EGFR-mutant non-small cell lung cancer (NSCLC) patients, while acquired drug resistance will inevitably occur. Interleukin-6 (IL-6) is a keystone cytokine in inflammation and cancer, while its role in osimertinib efficacy was unknown. Here we show that clinically, plasma IL-6 level predicts osimertinib efficacy in EGFR mutant NSCLC patients. Highly increased IL-6 levels are found in patients with acquired resistance to osimertinib. Addition of IL-6 or exogenous overexpression of IL-6 directly induces osimertinib resistance. Proteomics reveals LAMA5 (Laminin α5) and PTK2, protein tyrosine kinase 2, also called focal adhesion kinase (FAK), are activated in osimertinib-resistant cells, and siRNA knockdown of LAMA5 or PTK2 reverses IL-6-mediated osimertinib resistance. Next, using a large-scale compound screening, we identify ibrutinib as a potent inhibitor of IL-6 and Laminin α5/FAK signaling, which shows synergy with osimertinib in osimertinib-resistant cells with high IL-6 levels, but not in those with low IL-6 levels. In vivo, this combination inhibits tumor growth of xenografts bearing osimertinib-resistant tumors. Taken together, we conclude that Laminin α5/FAK signaling is responsible for IL-6-induced osimertinib resistance, which could be reversed by combination of ibrutinib and osimertinib.