Chinese Academy of Medical Sciences Dermatology Hospital

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

OBJECTIVE: For prevention of obesity in Chinese population, it is necessary to define the optimal range of healthy weight and the appropriate cut-off points of BMI and waist circumference for Chinese adults. The Working Group on Obesity in China under the support of International Life Sciences Institute Focal point in China organized a meta-analysis on the relation between BMI, waist circumference and risk factors of related chronic diseases (e.g., high diabetes, diabetes mellitus, and lipoprotein disorders). METHODS: 13 population studies in all met the criteria for enrollment, with data of 239,972 adults (20-70 year) surveyed in the 1990s. Data on waist circumference was available for 111,411 persons and data on serum lipids and glucose were available for more than 80,000. The study populations located in 21 provinces, municipalities and autonomous regions in mainland China as well as in Taiwan. Each enrolled study provided data according to a common protocol and uniform format. The Center for data management in Department of Epidemiology, Fu Wai Hospital was responsible for statistical analysis. RESULTS AND CONCLUSION: The prevalence of hypertension, diabetes, dyslipidemia and clustering of risk factors all increased with increasing levels of BMI or waist circumference. BMI at 24 with best sensitivity and specificity for identification of the risk factors, was recommended as the cut-off point for overweight, BMI at 28 which may identify the risk factors with specificity around 90% was recommended as the cut-off point for obesity. Waist circumference beyond 85 cm for men and beyond 80 cm for women were recommended as the cut-off points for central obesity. Analysis of population attributable risk percent illustrated that reducing BMI to normal range (< 24) could prevent 45%-50% clustering of risk factors. Treatment of obese persons (BMI > or = 28) with drugs could prevent 15%-17% clustering of risk factors. The waist circumference controlled under 85 cm for men and under 80 cm for women, could prevent 47%-58% clustering of risk factors. According to these, a classification of overweight and obesity for Chinese adults is recommended.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with droplets and contact as the main means of transmission. Since the first case appeared in Wuhan, China, in December 2019, the outbreak has gradually spread nationwide. Up to now, according to official data released by the Chinese health commission, the number of newly diagnosed patients has been declining, and the epidemic is gradually being controlled. Although most patients have mild symptoms and good prognosis after infection, some patients developed severe and die from multiple organ complications. The pathogenesis of SARS-CoV-2 infection in humans remains unclear. Immune function is a strong defense against invasive pathogens and there is currently no specific antiviral drug against the virus. This article reviews the immunological changes of coronaviruses like SARS, MERS and other viral pneumonia similar to SARS-CoV-2. Combined with the published literature, the potential pathogenesis of COVID-19 is inferred, and the treatment recommendations for giving high-doses intravenous immunoglobulin and low-molecular-weight heparin anticoagulant therapy to severe type patients are proposed.

OBJECTIVES: To quantify global, regional and country-specific estimates of epidemiology of systemic lupus erythematosus (SLE). METHODS: Four databases were systematically searched, and a Bayesian hierarchical linear mixed model was constructed to estimate the global, regional, and country-specific incidence and prevalence of SLE. RESULTS: 112 studies met the inclusion criteria. The global SLE incidence and newly diagnosed population were estimated to be 5.14 (1.4 to 15.13) per 100 000 person-years and 0.40 million people annually, respectively. In women, the values were 8.82 (2.4 to 25.99) per 100 000 person-years and 0.34 million people annually, while in men, the estimates were 1.53 (0.41 to 4.46) per 100 000 person-years and 0.06 million people annually, respectively. Poland, the USA and Barbados had the highest estimates of SLE incidence. Regarding prevalence, the global SLE prevalence and affected population were estimated to be 43.7 (15.87 to 108.92) per 100 000 persons and 3.41 million people, respectively. In women, the values were 78.73 (28.61 to 196.33) per 100 000 persons and 3.04 million people, while in men the estimates were 9.26 (3.36 to 22.97) per 100 000 persons and 0.36 million people, respectively. The United Arab Emirates, Barbados and Brazil had the highest SLE prevalence. In addition to regional and sex differences, age and prevalence estimation method (period or point prevalence) differences could also lead to variations in epidemiological SLE findings. CONCLUSIONS: Epidemiological data on SLE are lacking for 79.8% of countries worldwide. The epidemiology of SLE varies substantially between different sex and age groups and is distributed unequally among geographical regions; specifically, SLE occurs more frequently in high-income countries.

Incidence of hepatocellular carcinoma (HCC) is on the rise due to the prevalence of chronic hepatitis and cirrhosis. Although there are surgical and chemotherapy treatment avenues the mortality rate of HCC remains high. Immunotherapy is currently the new frontier of cancer treatment and the immunobiology of HCC is emerging as an area for further exploration. The tumor microenvironment coexists and interacts with various immune cells to sustain the growth of HCC. Thus, immunosuppressive cells play an important role in the anti-tumor immune response. This review will discuss the current concepts of immunosuppressive cells, including tumor-associated macrophages, marrow-derived suppressor cells, tumor-associated neutrophils, cancer-associated fibroblasts, and regulatory T cell interactions to actively promote tumorigenesis. It further elaborates on current treatment modalities and future areas of exploration.

Until recently, Histoplasma capsulatum was believed to harbour three varieties, var. capsulatum (chiefly a New World human pathogen), var. duboisii (an African human pathogen) and var. farciminosum (an Old World horse pathogen), which varied in clinical manifestations and geographical distribution. We analysed the phylogenetic relationships of 137 individuals representing the three varieties from six continents using DNA sequence variation in four independent protein-coding genes. At least eight clades were idengified: (i) North American class 1 clade; (ii) North American class 2 clade; (iii) Latin American group A clade; (iv) Latin American group B clade; (v) Australian clade; (vi) Netherlands (Indonesian?) clade; (vii) Eurasian clade and (viii) African clade. Seven of eight clades represented genetically isolated groups that may be recognized as phylogenetic species. The sole exception was the Eurasian clade which originated from within the Latin American group A clade. The phylogenetic relationships among the clades made a star phylogeny. Histoplasma capsulatum var. capsulatum individuals were found in all eight clades. The African clade included all of the H. capsulatum var. duboisii individuals as well as individuals of the other two varieties. The 13 individuals of var. farciminosum were distributed among three phylogenetic species. These findings suggest that the three varieties of Histoplasma are phylogenetically meaningless. Instead we have to recognize the existence of genetically distinct geographical populations or phylogenetic species. Combining DNA substitution rates of protein-coding genes with the phylogeny suggests that the radiation of Histoplasma started between 3 and 13 million years ago in Latin America.

Health professions preventing and controlling Coronavirus Disease 2019 are prone to skin and mucous membrane injury, which may cause acute and chronic dermatitis, secondary infection and aggravation of underlying skin diseases. This is a consensus of Chinese experts on protective measures and advice on hand-cleaning- and medical-glove-related hand protection, mask- and goggles-related face protection, UV-related protection, eye protection, nasal and oral mucosa protection, outer ear, and hair protection. It is necessary to strictly follow standards of wearing protective equipment and specification of sterilizing and cleaning. Insufficient and excessive protection will have adverse effects on the skin and mucous membrane barrier. At the same time, using moisturizing products is highly recommended to achieve better protection.

Psoriasis is a chronic autoimmune inflammatory disease that remains active for a long period, even for life in most patients. The impact of psoriasis on health is not only limited to the skin, but also influences multiple systems of the body, even mental health. With the increasing of literature on the association between psoriasis and extracutaneous systems, a better understanding of psoriasis as an autoimmune disease with systemic inflammation is created. Except for cardiometabolic diseases, gastrointestinal diseases, chronic kidney diseases, malignancy, and infections that have received much attention, the association between psoriasis and more systemic diseases, including the skin system, reproductive system, and oral and ocular systems has also been revealed, and mental health diseases draw more attention not just because of the negative mental and mood influence caused by skin lesions, but a common immune-inflammatory mechanism identified of the two systemic diseases. This review summarizes the epidemiological evidence supporting the association between psoriasis and important and/or newly reported systemic diseases in the past 5 years, and may help to comprehensively recognize the comorbidity burden related to psoriasis, further to improve the management of people with psoriasis.

OBJECTIVE: To describe the current epidemiology of sexually transmitted diseases (STDs), we analyzed the time trends in distribution of reported cases of STDs in China from 1989 to 1998. STUDY DESIGN: Based on the computerized database of the National System of STD Surveillance, a retrospective study of STD cases reported from 1989 to 1998 was carried out. RESULTS: From 1989 to 1998, STD incidence increased significantly in men and women and demonstrated nonlinear growth trends, with the exception of gonorrhea incidence. Between 1990 and 1998, the incidence increased more in females (4.20 times) than that in males (3.79 times). Syphilis incidence increased approximately 20 times during this period at an average annual rate of 52.7%. Gonorrhea incidence increased 2.6 times during this period at an average annual rate of 11.4%, which reached a plateau from 1994 to 1997. Extramarital transmission as source of STD infection has significantly increased from 1995 to 1998. CONCLUSION: The incidence of STDs has continued to increase in China from 1989 to 1998. The epidemic patterns are different from rates in developed counties in which behavior interventions have been successfully implemented, suggesting the need for active behavioral-intervention programs in China.

Background and Aims The development and progression of hepatocellular carcinoma (HCC) is dependent on its local microenvironment. Tumor‐associated macrophages (TAMs) are deemed a key factor for the tumor microenvironment and attribute to contribute to tumor aggressiveness. However, the detailed mechanism underlying the pro‐metastatic effect of TAMs on HCC remains undefined. Approach and Results The present study proved that TAMs were enriched in HCC. TAMs were characterized by an M2‐polarized phenotype and accelerated the migratory potential of HCC cells in vitro and in vivo . Furthermore, we found that M2‐derived exosomes induced TAM‐mediated pro‐migratory activity. With the use of mass spectrometry, we identified that integrin, α M β 2 (CD11b/CD18), was notably specific and efficient in M2 macrophage–derived exosomes (M2 exos). Blocking either CD11b and/or CD18 elicited a significant decrease in M2 exos–mediated HCC cell metastasis. Mechanistically, M2 exos mediated an intercellular transfer of the CD11b/CD18, activating the matrix metalloproteinase‐9 signaling pathway in recipient HCC cells to support tumor migration. Conclusions Collectively, the exosome‐mediated transfer of functional CD11b/CD18 protein from TAMs to tumor cells may have the potency to boost the migratory potential of HCC cells, thus providing insights into the mechanism of tumor metastasis.

Macrophage-stimulator of interferon genes (STING) signaling mediated sterile inflammation has been implicated in various age-related diseases. However, whether and how macrophage mitochondrial DNA (mtDNA) regulates STING signaling in aged macrophages remains largely unknown. We found that hypoxia-reoxygenation (HR) induced STING activation in macrophages by triggering the release of macrophage mtDNA into the cytosol. Aging promoted the cytosolic leakage of macrophage mtDNA and enhanced STING activation, which was abrogated upon mtDNA depletion or cyclic GMP-AMP Synthase (cGAS) inhibition. Aged macrophages exhibited increased mitochondrial injury with impaired mitophagy. Mechanistically, a decline in the PTEN-induced kinase 1 (PINK1)/Parkin-mediated polyubiquitination of mitochondria was observed in aged macrophages. Pink1 overexpression reversed the inhibition of mitochondrial ubiquitination but failed to promote mitolysosome formation in the aged macrophages. Meanwhile, aging impaired lysosomal biogenesis and function in macrophages by modulating the mTOR/transcription factor EB (TFEB) signaling pathway, which could be reversed by Torin-1 treatment. Consequently, Pink1 overexpression in combination with Torin-1 treatment restored mitophagic flux and inhibited mtDNA/cGAS/STING activation in aged macrophages. Moreover, besides HR-induced metabolic stress, other types of oxidative and hepatotoxic stresses inhibited mitophagy and promoted the cytosolic release of mtDNA to activate STING signaling in aged macrophages. STING deficiency protected aged mice against diverse types of sterile inflammatory liver injuries. Our findings suggest that aging impairs mitophagic flux to facilitate the leakage of macrophage mtDNA into the cytosol and promotes STING activation, and thereby provides a novel potential therapeutic target for sterile inflammatory liver injury in aged patients.

OBJECTIVES: Antimicrobial resistance (AMR) is a priority for surveillance in bacterial infections. For leprosy, AMR has not been assessed because Mycobacterium leprae does not grow in vitro. We aim to obtain AMR data using molecular detection of resistance genes and to conduct a prospective open survey of resistance to antileprosy drugs in countries where leprosy is endemic through a WHO surveillance network. METHODS: From 2009 to 2015, multi-bacillary leprosy cases at sentinel sites of 19 countries were studied for resistance to rifampicin, dapsone and ofloxacin by PCR sequencing of the drug-resistance-determining regions of the genes rpoB, folP1 and gyrA. RESULTS: Among 1932 (1143 relapse and 789 new) cases studied, 154 (8.0%) M. leprae strains were found with mutations conferring resistance showing 182 resistance traits (74 for rifampicin, 87 for dapsone and 21 for ofloxacin). Twenty cases showed rifampicin and dapsone resistance, four showed ofloxacin and dapsone resistance, but no cases were resistant to rifampicin and ofloxacin. Rifampicin resistance was observed among relapse (58/1143, 5.1%) and new (16/789, 2.0%) cases in 12 countries. India, Brazil and Colombia reported more than five rifampicin-resistant cases. CONCLUSIONS: This is the first study reporting global data on AMR in leprosy. Rifampicin resistance emerged, stressing the need for expansion of surveillance. This is also a call for vigilance on the global use of antimicrobial agents, because ofloxacin resistance probably developed in relation to the general intake of antibiotics for other infections as it is not part of the multidrug combination used to treat leprosy.

Syphilis was nearly eliminated from China 50 years ago but is now the most commonly reported communicable disease in Shanghai. Dr. Joseph Tucker and colleagues write that the Chinese syphilis epidemic holds important lessons about social and environmental influences on sexual health.

BACKGROUND AND AIMS: Liver metastasis is a frequent occurrence in patients with colorectal cancer (CRC), with 15%-25% of CRC patients having liver metastases at the time of initial diagnosis. Specifically, some regional-stage patients with mild symptoms (stage 1 or 2) will also advance to liver metastases rapidly, even if the CRC lesion in situ is resected in time. Nevertheless, the precise mechanism of liver metastasis is still unclear. APPROACH AND RESULTS: Fresh tumor tissues from patients with CRC, adjacent noncancerous tissues, and colorectal adenoma tissues were subjected to microarray analysis to identify differentially expressed microRNA. Exosomes from human serum and cell culture medium were separated, quantitated, and verified by transmission electronic microscopy and Zetasizer Nano. Luciferase reporter assay, real-time quantitative PCR, western blot, immunoprecipitation, chromatin and re-chromatin immunoprecipitation, migration and invasion assay, PDX mouse model, flow cytometry, immunohistochemistry, and immunofluorescence staining were employed to explore the regulation among CRC liver metastases, immunosuppression, and cell adhesion. In this study, we demonstrated that the hypoxic microenvironment in primary CRC lesions boosted exosome release, selectively initiated favorable premetastatic niche formation in the liver but not in other organs. Mechanistically, Kupffer cells (KCs) can phagocytose exosomes containing highly expressed miR-135a-5p from the blood circulation into the liver. Exosomal miR-135a-5p initiated the large tumor suppressor kinase 2-yes-associated protein-matrix metalloproteinase 7 axis to promote the occurrence of CRC liver metastasis, and cluster of differentiation 30-TNF receptor-associated factor 2-p65-mediated immunosuppression signaling also contributed to this process. CONCLUSIONS: Hypoxia-induced exosomal miR-135a-5p correlates with the development, clinical severity, and prognosis of CRC liver metastases through the premetastatic niche; and our findings revealed that miR-135a-5p might be a promising target in halting CRC liver metastases.

Although aggravated liver injury has been reported in aged livers post-ischemia and reperfusion (IR), the underlying mechanism of innate immune activation of aged macrophages is not well understood. Here, we investigated whether and how Stimulator of interferon genes (STING) signaling regulated macrophage proinflammatory activation and liver IR injury. Mice were subjected to hepatic IR in vivo. Macrophages isolated from IR-stressed livers and bone marrow-derived macrophages (BMDMs) from young and aged mice were used for in vitro studies. Enhanced nucleotide-binding domain and leucine-rich repeat containing protein 3 (NLRP3) activation was found in both livers and macrophages of aged mice post-IR. NLRP3 knockdown in macrophages inhibited intrahepatic inflammation and liver injury in both young and aged mice. Interestingly, enhanced activation of the STING/ TANK-binding kinase 1 (TBK1) signaling pathway was observed in aged macrophages post-IR and mitochondria DNA (mtDNA) stimulation. STING suppression blocked over-activation of NLRP3 signaling and excessive secretion of proinflammatory cytokines/chemokines in the mtDNA-stimulated BMDMs from aged mice. More importantly, STING knockdown in macrophages abrogated the detrimental role of aging in aggravating liver IR injury and intrahepatic inflammation. Finally, peripheral blood from the recipients undergoing liver transplantation was collected and analyzed. The results showed that the elderly recipients had much higher levels of TNF-α, IL-6, IL-1β, and IL-18 post-transplantation, indicating increased NLRP3 activation in lR-stressed livers of elderly recipients. In summary, our study demonstrated that the STING-NLRP3 axis was critical for the proinflammatory response of aged macrophages and would be a novel therapeutic target to reduce IR injury in elderly patients.

Wound healing is vital for human health, yet the details of cellular dynamics and coordination in human wound repair remain largely unexplored. To address this, we conducted single-cell multi-omics analyses on human skin wound tissues through inflammation, proliferation, and remodeling phases of wound repair from the same individuals, monitoring the cellular and molecular dynamics of human skin wound healing at an unprecedented spatiotemporal resolution. This singular roadmap reveals the cellular architecture of the wound margin and identifies FOSL1 as a critical driver of re-epithelialization. It shows that pro-inflammatory macrophages and fibroblasts sequentially support keratinocyte migration like a relay race across different healing stages. Comparison with single-cell data from venous and diabetic foot ulcers uncovers a link between failed keratinocyte migration and impaired inflammatory response in chronic wounds. Additionally, comparing human and mouse acute wound transcriptomes underscores the indispensable value of this roadmap in bridging basic research with clinical innovations.

Abstract Hepatocellular death is a sensitive parameter for detecting acute liver injury (ALI) of toxic, viral, metabolic, and autoimmune origin. Ferroptosis has recently been implicated in carbon tetrachloride (CCl 4 )-induced ALI. However, the underpinning mechanism and mechanistic basis remain elusive. In this study, bicyclol, a proprietary hepatoprotectant in China, and ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) were administered in CCl 4 -injured mice. A panel of ferroptosis-related markers, including mitochondria morphology, reactive oxygen species production, protein adducts in response to lipid peroxidation, and key modulators of ferroptotic process, was determined in vivo. Erastin-treated L-O2 hepatocytes were transfected with glutathione peroxidase 4 (GPx4) or nuclear factor erythroid 2-related factor 2 (Nrf2) siRNA to delineate the pathway of bicyclol against ferroptosis in vitro. As a result, CCl 4 led to iron accumulation, excessive reactive oxygen species production, enhanced lipid peroxidation, and characteristic morphological changes in mitochondria, along with a decrease in GPx4 and xCT protein levels in ALI mice liver, all of which were generally observed in ferroptosis. The use of Fer-1 further corroborated that ferroptosis is responsible for liver damage. Bicyclol exerted its hepatoprotection by preventing the aforesaid ferroptotic process. Furthermore, bicyclol alleviated erastin-induced cellular inviability, destruction, and lipid peroxidation in vitro. Knockdown of GPx4 diminished these protective activities against perturbations associated with ferroptosis in L-O2 hepatocytes. Additionally, Nrf2 silencing drastically reduced GPx4 levels, and further impeded the medicinal effects of bicyclol. In summary, positively regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in CCl 4 -induced ALI in mice.

Porokeratosis (PK) is a heterogeneous group of keratinization disorders. No causal genes except MVK have been identified, even though the disease was linked to several genomic loci. Here, we performed massively parallel sequencing and exonic CNV screening of 12 isoprenoid genes in 134 index PK patients (61 familial and 73 sporadic) and identified causal mutations in three novel genes (PMVK, MVD, and FDPS) in addition to MVK in the mevalonate pathway. Allelic expression imbalance (AEI) assays were performed in 13 lesional tissues. At least one mutation in one of the four genes in the mevalonate pathway was found in 60 (98%) familial and 53 (73%) sporadic patients, which suggests that isoprenoid biosynthesis via the mevalonate pathway may play a role in the pathogenesis of PK. Significantly reduced expression of the wild allele was common in lesional tissues due to gene conversion or some other unknown mechanism. A G-to-A RNA editing was observed in one lesional tissue without AEI. In addition, we observed correlations between the mutations in the four mevalonate pathway genes and clinical manifestations in the PK patients, which might support a new and simplified classification of PK under the guidance of genetic testing.

China has experienced an increasing epidemic of sexually transmitted infections (STIs), including HIV. High risk groups likely to be infected include female sex workers (FSWs) and their clients, men who have sex with men (MSM), drug users and migrant workers. Prevention can be achieved through education of the population, condom promotion, early detection of symptomatic and asymptomatic people, and effective diagnosis and treatment of these patients and their partners. This article aims to describe the profile of the epidemic in high-risk groups in China as well as to detail the contributing factors and the implications for control. Programmes for the control of STIs should be immediate priorities in China, and primary and secondary prevention strategies are vital to this process.

Abstract Cutaneous malignant melanoma (hereafter called melanoma) is one of the most aggressive cancers with increasing incidence and mortality rates worldwide. In this study, we performed a systematic investigation of the tumor microenvironmental and genetic factors associated with melanoma to identify prognostic biomarkers for melanoma. We calculated the immune and stromal scores of melanoma patients from the Cancer Genome Atlas (TCGA) using the ESTIMATE algorithm and found that they were closely associated with patients’ prognosis. Then the differentially expressed genes were obtained based on the immune and stromal scores, and prognostic immune‐related genes further identified. Functional analysis and the protein–protein interaction network further revealed that these genes enriched in many immune‐related biological processes. In addition, the abundance of six infiltrating immune cells was analyzed using prognostic immune‐related genes by TIMER algorithm. The unsupervised clustering analysis using immune‐cell proportions revealed eight clusters with distinct survival patterns, suggesting that dendritic cells were most abundant in the microenvironment and CD8 + T cells and neutrophils were significantly related to patients’ prognosis. Finally, we validated these genes in three independent cohorts from the Gene Expression Omnibus database. In conclusion, this study comprehensively analyzed the tumor microenvironment and identified prognostic immune‐related biomarkers for melanoma.