Microarray Chip-Based High-Throughput Screening of Neurofilament Light Chain Self-Assembling Peptide for Noninvasive Monitoring of Alzheimer's Disease.

Alzheimer's disease (AD) starts decades before cognitive symptoms develop. Easily accessible and cost-effective biomarkers that accurately reflect AD pathology are essential for both monitoring and therapeutics of AD. Neurofilament light chain (NfL) levels in blood and cerebrospinal fluid are increased in AD more than a decade before the expected onset, thus providing one of the most promising blood biomarkers for monitoring of AD. The clinical practice of employing single-molecule array (Simoa) technology for routine use in patient care is limited by the high costs. Herein, we developed a microarray chip-based high-throughput screening method and screened an attractive self-assembling peptide targeting NfL. Through directly "imprinting" and further analyzing the sequences, morphology, and affinity of the identified self-assembling peptides, the Pep-NfL peptide nanosheet with high binding affinity toward NfL (KD = 1.39 × 10-9 mol/L), high specificity, and low cost was characterized. The superior binding ability of Pep-NfL was confirmed in AD mouse models and cell lines. In the clinical setting, the Pep-NfL peptide nanosheets hold great potential for discriminating between patients with AD (P < 0.001, n = 37), mild cognitive impairment (P < 0.05, n = 26), and control groups (n = 30). This work provides a high-throughput, high-sensitivity, and economical system for noninvasive tracking of AD to monitor neurodegeneration at different stages of disease. The obtained Pep-NfL peptide nanosheet may be useful for assessing dynamic changes in plasma NfL concentrations to evaluate disease-modifying therapies as a surrogate end point of neurodegeneration in clinical trials.

Microarray-Based CD38 Peptide Probe Screening for Multiple Myeloma Imaging.

Assessing CD38 expression in vivo has become a significant element in multiple myeloma (MM) therapy, as it can be used to detect lesions and forecast the effectiveness of treatment. Accurate diagnosis requires a multifunctional, high-throughput probe screening platform to develop molecular probes for tumor-targeted multimodal imaging and treatment. Here, we investigated a microarray chip-based strategy for high-throughput screening of peptide probes for CD38. We obtained two new target peptides, CA-1 and CA-2, from a 105 peptide library with a dissociation constant (KD) of 10-7 M. The specificity and affinity of the target peptides were confirmed at the molecular and cellular levels. Peptide probes were labeled with indocyanine green (ICG) dye and 68Ga-DOTA, which were injected into a CD38-positive Ramos tumor-bearing mouse via its tail vein, and small animal fluorescence and positron emission tomography (PET) imaging showed that the peptide probes could show specific enrichment in the tumor tissue. Our study shows that a microchip-based screening of peptide probes can be used as a promising imaging tool for MM diagnosis.

Outcomes and prognosis of non-small cell lung cancer patients who underwent curable surgery: a protocol for a real-world, retrospective, population-based and nationwide Chinese National Lung Cancer Cohort (CNLCC) study.

INTRODUCTION: Surgery is one of the main approaches for the comprehensive treatment of early and locally advanced non-small cell lung cancer (NSCLC). This study conducts a nationwide multicentre study to explore factors that could influence the outcomes of patients with I-IIIA NSCLC who underwent curable surgery in real-world scenarios. METHODS AND ANALYSIS: All patients diagnosed with NSCLC between January 2013 and December 2020 will be identified from 30 large public medical services centres in mainland China. The algorithm of natural language processing and artificial intelligence techniques were used to extract data from electronic health records of enrolled patients who fulfil the inclusion criteria. Six categories of parameters are collected and stored from the electronic records, then the parameters will be structured as a high-quality structured case report form. The code book will be compiled and each parameter will be classified and designated a code. In addition, the study retrieves the survival status and causes of death of patients from the Chinese Centre for Disease Control and Prevention. The primary endpoints are overall survival and the secondary endpoint is disease-free survival. Finally, an online platform is formed for data queries and the original records will be stored as secure electronic documents. ETHICS AND DISSEMINATION: The study has been approved by the Ethical Committee of the Chinese Academy of Medical Sciences. Study findings will be disseminated via presentations at conferences and publications in open-access journals. This study has been registered in the Chinese Trial Register (ChiCTR2100052773) on 11 May 2021, http://www.chictr.org.cn/showproj.aspx?proj=136659. TRIAL REGISTRATION NUMBER: ChiCTR2100052773.

Slow Mohs micrographic surgery for nail apparatus melanoma in situ.

BACKGROUND: Nail apparatus melanoma is a malignant tumor with a high incidence in Chinese melanoma patients. Slow Mohs micrographic surgery is an emerging technique for treating nail apparatus melanoma in situ (NAMIS). OBJECTIVE: This study evaluated the efficacy and safety of slow Mohs micrographic surgery for treating NAMIS. METHODS: Patients were enrolled in this retrospective study and treated in a single center from October 1, 2016, to June 30, 2022. Each patient underwent standard slow Mohs micrographic surgery, and follow-up was regularly conducted at clinics. RESULTS: Ten patients were enrolled in the study. Two patients underwent one Mohs stage, seven underwent two Mohs stages, and one underwent seven Mohs stages. The resection margin ranged from 5 to 25 mm. No severe complications were reported in the treatment, and recurrence of NAMIS was not observed during the follow-up period. CONCLUSION: Slow Mohs micrographic surgery is a valuable surgical method to treat NAMIS that preserves digit function and can be well tolerated by patients.

Risk factors for mortality in patients with anti-MDA5 antibody-positive dermatomyositis: A meta-analysis and systematic review.

OBJECTIVES: To determine the prognostic factors of dermatomyositis with anti-melanoma differentiation-associated gene 5 (MDA5) antibody, a rare disease and often complicated by life-threatening, rapidly progressive interstitial lung disease. METHODS: Herein, we searched the Medline, Embase, and Cochrane Library databases and extracted studies published before August 23, 2022. Pooled analysis of hazard ratios (HRs) or odds ratios was used to identify prognostic factors for mortality among patients with anti-MDA5 antibody-positive dermatomyositis (MDA5+ DM). RESULTS: Twenty-nine cohorts with 2,645 patients were included in this meta-analysis. Factors related to poor prognosis included old age (HR 1.54, 95% confidence interval (CI) 1.41-1.69, p < 0.01), male sex (HR 2.07, 95% CI 1.34-3.18, p < 0.01), rapidly progressive interstitial lung disease (RP-ILD) (HR 9.34, 95% CI 6.39-13.6, p < 0.01), high levels of ferritin (HR 1.05, 95% CI 1.01-1.08, p < 0.01), C-reactive protein (CRP) (HR 1.12, 95% CI 1.06-1.19, p < 0.01), creatine kinase (HR 1.05, 95% CI 1.03-1.07, p < 0.01), and lactate dehydrogenase (LDH) (HR 1.27, 95% CI 1.12-1.45, p < 0.01), whereas oxygen index (HR 0.990, 95% CI 0.988-0.992, p < 0.01), partial pressure of oxygen (HR 0.933, 95% CI 0.906-0.961, p < 0.01), forced vital capacity (HR 0.962, 95% CI 0.928-0.998, p = 0.038), and lymphocyte count (HR 0.421, 95% CI 0.282-0.629, p < 0.01) were associated with better outcomes. CONCLUSIONS: Old age, male sex, hypoxemia, low forced vital capacity, lymphocytopenia, and high levels of ferritin, CRP, creatine kinase, and LDH are risk factors for mortality in patients with MDA5+ DM. However, a cautious interpretation of these results and further quality investigation are warranted.

Case report: Checkpoint inhibitor pneumonitis with positive anti-melanoma differentiation-associated gene 5 antibodies in a patient with lung cancer.

With the widespread use of immune checkpoint inhibitors to treat various cancers, pulmonary toxicity has become a topic of increasing concern. Anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibodies are strongly associated with rapidly progressive interstitial lung disease (RP-ILD) in patients with clinically amyopathic dermatomyositis. However, anti-MDA5 antibody expression has not been reported in patients with immune-related adverse events. We present the case of a 74-year-old man with lung adenocarcinoma who developed RP-ILD after treatment with immune checkpoint inhibitors. Further investigation revealed multiple autoantibodies, including anti-MDA5 antibodies. He initially responded to systemic glucocorticoids, immunosuppressants, and tocilizumab but eventually died from worsening pneumomediastinum. This case is the first one to suggest that checkpoint inhibitor pneumonitis can present as RP-ILD with positive anti-MDA5 antibodies, which may be predictive of a poor prognosis.

CaSee: A lightning transfer-learning model directly used to discriminate cancer/normal cells from scRNA-seq.

Single-cell RNA sequencing (scRNA-seq) is one of the most efficient technologies for human tumor research. However, data analysis is still faced with technical challenges, especially the difficulty in efficiently and accurately discriminating cancer/normal cells in the scRNA-seq expression matrix. If we can address these challenges, we can have a deeper understanding of the intratumoral and intertumoral heterogeneity. In this study, we developed a cancer/normal cell discrimination pipeline called pan-Cancer Seeker (CaSee) devoted to scRNA-seq expression matrix, which is based on the traditional high-quality pan-cancer bulk sequencing data using transfer learning. CaSee is the first tool directly used to discriminate cancer/normal cells in the scRNA-seq expression matrix, with much wider application fields and higher efficiency than copy number variation (CNV) method which requires corresponding reference cells. CaSee is user-friendly and can adapt to a variety of data sources, including but not limited to scRNA tissue sequencing data, scRNA cell line sequencing data, scRNA xenograft cell sequencing data and scRNA circulating tumor cell sequencing data. It is compatible with mainstream sequencing technology platforms, 10× Genomics Chromium, Smart-seq2, and Microwell-seq. Here, CaSee pipeline exhibited excellent performance in the multicenter data evaluation of 11 retrospective cohorts and one independent dataset, with an average discrimination accuracy of 96.69%. In general, the development of a deep-learning based, pan-cancer cell discrimination model, CaSee, to distinguish cancer cells from normal cells will be compelling to researchers working in the genomics, cancer, and single-cell fields.

Co-delivery of phagocytosis checkpoint and STING agonist by a Trojan horse nanocapsule for orthotopic glioma immunotherapy.

Rationale: Cancer immunotherapy has demonstrated significant antitumor activity in a variety of tumors; however, extensive infiltration of immunosuppressive tumor-associated macrophages (TAMs) in the glioblastoma (GBM) tumor microenvironment (TME) and the existence of the blood-brain barrier (BBB) might lead to failure of the checkpoint blockade therapy. Methods: Herein, we have developed a smart "Trojan horse" BBB-permeable nanocapsule termed "NAcp@CD47" to deliver anti-CD47 antibodies and stimulator of interferon genes (STING) agonists into GBM tissues in a stealth-like manner to reshaped the immune microenvironment by switching the phenotype of microglia and macrophages. Results: Both in vitro and in vivo studies demonstrate that NAcp@CD47 could effectively penetrate the BBB, increase the polarization of M1-phenotype TAMs, help reduce tumor immunosuppression, and inhibit the orthotopic GBM growth by phagocytosis of macrophages and microglia. Conclusions: Our findings indicate that the well-designed NAcp@CD47 not only enhances the phagocytosis of cancer cells but also efficiently enhance antitumor immunogenicity and reverses immune suppression to convert uninflamed "cold" tumors into "hot" tumors.

Artificial intelligence in melanoma: A systematic review.

BACKGROUND: Melanoma accounts for the majority of skin cancer deaths. Artificial intelligence has been applied in many types of cancers, and in melanoma in recent years. However, no systematic review summarized the application of artificial intelligence in melanoma. AIMS: This study aims to systematically review previously published articles to explore the application of artificial intelligence in melanoma. MATERIALS & METHODS: PubMed database was used to search the eligible publications on August 1, 2020. The query term was "artificial intelligence" and "melanoma." RESULTS: A total of 51 articles were included in this review. Artificial intelligence technique is mainly used in the evaluation of dermoscopic images, other image segmentation and processing, and artificial intelligence diagnosis system. DISCUSSION: Artificial intelligence is also applied in metastasis prediction, drug response prediction, and prognosis of melanoma. Besides, patients' perspectives of artificial intelligence and collaboration of human and artificial intelligence in melanoma also attracted attention. The query term might not include all articles, and we could not examine the algorithms that were built without publication. CONCLUSION: The performance of artificial intelligence in melanoma is satisfactory and the future for potential applications is enormous.

Overexpression of Soybean GmWRI1a Stably Increases the Seed Oil Content in Soybean.

WRINKLED1 (WRI1), an APETALA2/ethylene-responsive-element-binding protein (AP2/EREBP) subfamily transcription factor, plays a crucial role in the transcriptional regulation of plant fatty acid biosynthesis. In this study, GmWRI1a was overexpressed in the soybean cultivar 'Dongnong 50' using Agrobacterium-mediated transformation to generate three transgenic lines with high seed oil contents. PCR and Southern blotting analysis showed that the T-DNA was inserted into the genome at precise insertion sites and was stably inherited by the progeny. Expression analysis using qRT-PCR and Western blotting indicated that GmWRI1a and bar driven by the CaMV 35S promoter were significantly upregulated in the transgenic plants at different developmental stages. Transcriptome sequencing results showed there were obvious differences in gene expression between transgenic line and transgenic receptor during seed developmental stages. KEGG analysis found that the differentially expressed genes mainly annotated to metabolic pathways, such as carbohydrated metabolism and lipid metabolism. A 2-year single-location field trial revealed that three transgenic lines overexpressing GmWRI1a (GmWRI1a-OE) showed a stable increase in seed oil content of 4.97-10.35%. Importantly, no significant effect on protein content and yield was observed. Overexpression of GmWRI1a changed the fatty acid composition by increasing the linoleic acid (C18:2) content and decreasing the palmitic acid (C16:0) content in the seed. The three GmWRI1a-OE lines showed no significant changes in agronomic traits. The results demonstrated that the three GmWRI1a overexpression lines exhibited consistent increases in seed oil content compared with that of the wild type and did not significantly affect the seed yield and agronomic traits. The genetic engineering of GmWRI1a will be an effective strategy for the improvement of seed oil content and value in soybean.

Murine models of rosacea: a review.

Rosacea is a chronic inflammatory disease characterized by facial flushing, erythema, telangiectasia, papules, and pustules. Its pathogenesis has not been fully understood. In 2017, the global ROSacea COnsensus (ROSCO) panel updated the diagnosis, classification, and assessment of rosacea. Phenotype-based treatments and long-term managements have also been recommended. Murine models are a powerful tool in unveiling and dissecting the mechanisms of human diseases. Here, we summarized murine models of rosacea developed or used in previous research, including LL-37 intradermal injection model, KLK-5-induced inflammation model, croton oil inflammation model, 12-O-Tetradecanoylphorbol-13-acetate inflammation model, arachidonic acid inflammation model, RTX-induced vasodilation model, and UVB-induced model. LL-37 injection model has become the most intensively used model in rosacea research. Each model could show the pathophysiological and clinical features of rosacea to some extent. However, no model can show the full picture of the characteristics of rosacea. Improving existed murine models, developing new murine models, and applying them to pathogenesis and treatment research on rosacea are highly warranted in the future.

Research Interest and Public Interest in Melanoma: A Bibliometric and Google Trends Analysis.

INTRODUCTION: Melanoma is a severe skin cancer that metastasizes quickly. Bibliometric analysis can quantify hotspots of research interest. Google Trends can provide information to address public concerns. METHODS: The top 15 most frequently cited articles on melanoma each year from 2015 to 2019, according to annual citations, were retrieved from the Web of Science database. Original articles, reviews, and research letters were included in this research. For the Google Trends analysis, the topic "Melanoma" was selected as the keyword. Online search data from 2004 to 2019 were collected. Four countries (New Zealand, Australia, the United States and the United Kingdom) were selected for seasonal analysis. Annual trends in relative search volume and seasonal variation were analyzed, and the top related topics and rising related topics were also selected and analyzed. RESULTS: The top 15 most frequently cited articles each year were all original articles that focused on immunotherapy (n=8), omics (n=5), and the microbiome (n=2). The average relative search volume remained relatively stable across the years. The seasonal variation analysis revealed that the peak appeared in summer, and the valley appeared in winter. The diseases associated with or manifestations of melanoma, treatment options, risk factors, diagnostic tools, and prognosis were the topics in which the public was most interested. Most of the topics revealed by bibliometric and Google Trends analyses were consistent, with the exception of issues related to the molecular biology of melanoma. CONCLUSION: This study revealed the trends in research interest and public interest in melanoma, which may pave the way for further research.

Immune Checkpoint Inhibitors in Advanced Acral Melanoma: A Systematic Review.

INTRODUCTION: Acral melanoma (AM) has different biological characteristics from cutaneous melanoma. Although systemic therapeutic strategies for advanced AM resemble those for advanced cutaneous melanoma, the evidence of the clinical use of immune checkpoint inhibitors (ICIs) for AM is still inadequate. We aimed to systematically analyze the therapeutic effects and safety profile of ICI treatments in advanced AM. METHODS: This systematic review was conducted in line with a previously registered protocol. Three electronic databases, conference abstracts, clinical trial registers, and reference lists of included articles were searched for eligible studies. The primary outcomes were therapeutic effects, and the secondary outcomes were the safety profiles. RESULTS: This systematic review included six studies investigating anti-CTLA-4 immunotherapy, 12 studies investigating anti-PD-1 immunotherapy, one study investigating the combination therapy of anti-CTLA-4 and anti-PD-1, and one study investigating anti-PD-1 immunotherapy in combination with radiotherapy. In most studies investigating ipilimumab, the anti-CTLA-4 antibody, the objective response rate ranged from 11.4 to 25%, the median progression-free survival ranged from 2.1 to 6.7 months, and the median overall survival was more than 7.16 months. For studies discussing anti-PD-1 immunotherapy with nivolumab, pembrolizumab, or JS001, the objective response rate ranged from 14 to 42.9%, the median progression-free survival ranged from 3.2 to 9.2 months, and the median overall survival was more than 14 months. The combination therapy of anti-CTLA-4 and anti-PD-1 immunotherapy showed better efficacy with an objective response rate of 42.9% than single-agent therapy. The retrospective study investigating the combination therapy of anti-PD-1 immunotherapy and radiation showed no overall response. Few outcomes regarding safety were reported in the included studies. CONCLUSIONS: ICIs, especially anti-CTLA-4 monoclonal antibodies combined with anti-PD-1 antibodies, are effective systematic treatments in advanced AM. However, there remains a lack of high-level evidence to verify their efficacy and safety and support their clinical application.