Liquid-liquid phase separation: A new perspective to understanding aging and pathogenesis.

Mounting evidence has suggested that phase separation, and especially liquid-liquid phase separation (LLPS), underlies the formation of membraneless organelles, which are supramolecular assemblies of proteins and RNA molecules in cells. These membraneless organelles are also called biomolecular condensates. Evidence is now growing that condensates, such as stress granules, P bodies, Cajal bodies, and nucleoli, play vital roles in biological processes, like RNA storage and processing, signaling regulation, transcription regulation, gene regulation, and transport. Conversely, condensates may cause diseases, such as neurodegenerative diseases and tumors, when they go wrong. Condensates initially have liquid-like properties, but accumulating biological and chemical mutations with age render them into a more solid-like state, like amyloids in Alzheimer's disease, Huntington's disease, and Parkinson's disease. Research into phase separation is still in its infancy, but this field is a promising avenue for treatment of aging-related diseases.

CAR-expressing NK cells for cancer therapy: a new hope.

Since the approval in 2017 and the amazing achievement of Kymriah and Yescarta, the number of basic researchers and clinical trials investigating the safety and efficacy of chimeric antigen receptor-expressing T cells (CAR-T cells) has been relentlessly increasing. Up to now, more than 200 clinical trials are listed on clinical trial database of NIH and the basic research is countless. However, the production of allogeneic CAR-T cells products is still expensive and has toxicity. Thus, more effort is needed to develop reliable off-the-shelf cellular therapeutic methods with safety and efficiency for the treatment of patients with cancer. As a kind of innate effector lymphocyte with potent antitumor activity, natural killer cells (NK cells) have attracted much attention. Until now, basic and clinical research has shown that chimeric antigen receptor-expressing NK cell (CAR-NK) therapy may play a significant anti-tumor role and its safety is higher than CAR-T cell therapy. In this review, we discuss advantages and shortages of employing CAR-NK cells as a novel cellular therapy against cancer.

Does immune privilege result in recovered patients testing positive for COVID-19 again?

Recently, an increasing number of reports have indicated that a few patients who were believed to have recovered from COVID-19 initially tested negative but later tested positive. Several hospitals in different countries have detected SARS-CoV-2 RNA in the semen and cerebrospinal fluid of patients with severe COVID-19. Given the fact that the testes and central nervous system are both immune privilege sites and the fact that Ebola virus and Zika virus can avoid immune clearance and continue proliferating and spreading by hiding in those sites, the question of whether SARS-CoV-2 is present in immune privilege sites, it attacks those sites, and it spreads again after proliferating in those sites needs to be investigated.

Stem cell secretome as a new booster for regenerative medicine.

Stem cells are an undifferentiated cell population that has the ability to develop into many different cell types and also has the ability to repair damaged tissues in some cases. For a long time, the stem cell regenerative paradigm has been based on the assumption that progenitor cells play a critical role in tissue repair by means of their plasticity and differentiation potential. However, recent works suggest that the mechanism underlying the benefits of stem cell transplantation might relate to a paracrine modulatory effect rather than the replacement of affected cells at the site of injury. This paracrine modulatory effect derives from secretome which comprises a diverse host of growth factors, cytokines, chemokines, angiogenic factors, and exosomes which are extracellular vesicles that are produced in the endosomal compartment of most eukaryotic cells and are from about 30 to several hundred nanometers in diameter. The role of these factors is being increasingly recognized as key to the regulation of many physiological processes including leading endogenous and progenitor cells to sites of injury as well as mediating apoptosis, proliferation, migration, and angiogenesis. In reality, the immunomodulatory and paracrine role of these factors may mainly account for the therapeutic effects of stem cells and a number of in vitro and in vivo researches have proved limited stem cell engraftment at the site of injury. As a cell-free way for regenerative medicine therapies, stem cell secretome has shown great potential in a variety of clinical applications including prevention of cardiac disfunction, neurodegenerative disease, type 1 diabetes, hair loss, tumors, and joint osteoarthritis.

Carbon dots have antitumor action as monotherapy or combination therapy.

Carbon dots prepared from different sources have been widely studied in various medical applications. Those dots have been reported to be able to inhibit the proliferation of cancer cells, such as prostate cancer cells. The current study used carbon dots prepared from red beans to determine their effect on 16 cell lines including liver cancer cells, pancreatic cancer cells, intrahepatic cholangiocarcinoma cells, and colorectal adenocarcinoma cells. In a cellular viability experiment, carbon dots were found suppress cancer cell viability in a time- and dose-dependent manner. In a cell migration experiment, cancer cells treated with carbon dots had less ability to heal, suggesting that carbon dots inhibit cell migration. In another cellular viability experiment, a combination of carbon dots and doxorubicin resulted in greater inhibition than cells treated with either therapy alone. These findings suggest that carbon dots could be an alternative and complementary medicine for the treatment of cancers.

Shufeng Jiedu Capsule and its active ingredients induce apoptosis, inhibit migration and invasion, and enhances doxorubicin therapeutic efficacy in hepatocellular carcinoma.

BACKGROUND: Shufeng Jiedu Capsule (SFJDC), a traditional Chinese medicine, has been used widely as antiviral, antibacterial, antitumor, and anti-inflammatory drugs. Previous studies indicated that some active ingredients of Shufeng Jiedu Capsule, such as resveratrol and quercetin, could suppress hepatocellular carcinoma (HCC) cells through various signaling pathways. However, anti-HCC activity of SFJDC as a complementary medicine remains unexplored. Here, we use a combination of Shufeng Jiedu Capsule and doxorubicin to treat HCC cells and investigated the effects and mechanisms of SFJDC and its ingredientsin vitro. METHODS: In this study, two HCC cell lines, HepG2 and HepG2.2.15, were employed and all cells were separated into seven groups: doxorubicin group, SFJDC group, combination of doxorubicin and SFJDC group, resveratrol group, quercetin group, resveratrol and quercetin group, and control group. Through this research, the cellular functional experiments, such as MTT assay, Hoechst 33,258 staining, would healing assay, and transwell assay, were took to observe the effects of those agents on proliferation, apoptosis, migration and invasion of cells. Then, apoptosis and invasion related genes and proteins were detected by real-time PCR and western blot to illuminate the signaling pathways. RESULTS: The combination group induced more significant apoptosis and inhibition of migration and invasion by affecting proteins and mRNA of apoptosis, migration, and invasion related elements, such as Bcl-2, Bax, mTOR, and NF-?B. Furthermore, the research suggested SFJDC, as a mixture of a number of ingredients, had stronger activities than particular component or simple mixture of a few components. CONCLUSIONS: SFJDC and its active ingredients could play a role as complementary medicine to increase antitumor effect of doxorubicin by targeting mitochondrial, Akt/mTOR, and NF-?B signaling pathways.

Combination of Cinobufacini and Doxorubicin Increases Apoptosis of Hepatocellular Carcinoma Cells through the Fas- and Mitochondria-Mediated Pathways.

Cinobufacini, a traditional Chinese medicine, has been used widely for cancer treatment, such as hepatocellular carcinoma (HCC), sarcoma, and leukemia. Previous studies done by our lab indicated that cinobufacini could suppress HCC cells through mitochondria-mediated and Fas-mediated apoptotic pathways. Here, we use a combination of cinobufacini and doxorubicin to inhibit the growth of HCC cells. The combination group induced more significant apoptosis by affecting proteins and RNA of apoptosis-related elements, such as Bcl-2, Bax, Bid, and cytochrome c. Furthermore, cinobufacini, as a mixture of a number of components, had stronger apoptosis-inducing activity than particular individual components or a simple mixture of a few components. Overall, these results suggested that the combination of cinobufacini and doxorubicin may provide a new strategy for inhibiting the proliferation of HCC cells.

A novel BMX variant promotes tumor cell growth and migration in lung adenocarcinoma.

The non-receptor tyrosine kinase BMX has been reported in several solid tumors. However, the alternative splicing of BMX and its clinical relevance in lung cancer remain to be elucidated. Exon1.0 array was used to identify a novel alternative splicing of BMX, BMXΔN, which was confirmed by rapid amplification of cDNA ends and reverse transcription-polymerase chain reaction. BMXΔN, resulting from exon skipping with excluding exon 1 to exon 8 of BMX gene, was found in 12% human lung adenocarcinoma specimens. BMXΔN is not found in paired pathologically normal lungs and positively correlated with EGFR mutation in lung adenocarcinomas. Moreover, BMXΔN increases cell proliferation, neoplastic transformation, and migratory property of human non-small cell lung cancer cells. The function of BMXΔN in lung cancer might be presumably due to enhanced ERK signaling.

Researchers of chronic obstructive pulmonary disease gathered at the 2017 Japan-China Joint Medical Workshop on Aging and Health.

As the number of elderly and the size of the total population increase, population aging will become a major problem because of an increase in diseases associated with aging, such as chronic obstructive pulmonary disease (COPD). The 2017 Japan-China Joint Medical Workshop on Aging and Health was held at The University of Tokyo on December 2, 2017 with a focus on management of COPD. More than 50 experts in the fields of respiratory medicine, emergency medicine, traditional Chinese medicine, and Kampo (traditional Japanese medicine) from Japan and China presented the results of their research and shared their experiences treating COPD from different perspectives. Guidelines for diagnosis and management of COPD in different countries were described at the workshop, and advances in recent research into the treatment of COPD with Kampo and traditional Chinese medicine were fully discussed. The results of the workshop should help to improve GOLD guidelines and they should greatly help to optimize COPD treatment.

Linking biological and physical aging: Dynamical scaling of multicellular regeneration.

The fight against biological aging (bio-aging) is long-standing, with the focus of intense research aimed at maintaining high rates of tissue regeneration to promote health and longevity. Nevertheless, there are overwhelming complexities associated with the quantitative analysis of aging. In this study, we sought to quantify bio-aging based on physical aging, by mapping instances of multicellular regeneration to the relaxation of physical systems. An experiment of delayed wound healing assays was devised to obtain delay-dependent healing data. The experiment confirmed the slowdown of healing events, which fitted dynamical scaling just as relaxation events do in physical aging. The scaling exponent, which describes the aging rate in physics, is here similarly proposed as an indicator of the deterioration rate of tissue-regenerative power. Parallel equation-based and cell-based simulations also revealed that asymmetric cell cycle-regulatory mechanisms under strong growth-inhibitory conditions predominantly control the critical slowdown of healing analogous to physical criticality. By establishing a direct link between physical aging and biological aging, we are able to estimate the aging rate of tissues and to achieve an integrated understanding of bio-aging mechanism which may improve the modulation of regeneration for clinical use.

Chinese medicine as complementary therapy for female infertility.

Chinese medicine (CM) has been used in clinical treatment for thousands of years in China, Japan, Korea, and other countries. CM is at present attracting many attentions around the world for reproductive health care and disease prevention, including treatment of female infertility. This review focuses on the CM treatment for female infertility patients, and supplies a summary on the efficacy, safety, and mechanism of some Chinese herbal medicines, herbal medicine-derived active compounds, and acupuncture. A large number of researches have reported that CM could alleviate or even cure female infertility by regulating hormone, improving reproductive outcome of in vivo fertilization, affecting embryonic implantation, curing polycystic ovarian syndrome, endometriosis, pelvic inflammatory disease, relieving mental stress, and regulating immune system. Meanwhile, a few studies claimed that there was little adverse reaction of CM in randomized controlled trials. However, up to present there is a lack of adequate evidences with molecular mechanistic researches and randomized controlled trials to prove the CM as an effective and safe treatment for infertility. Thus, utility of CM as a complementary medicine will be a feasible method to improve the outcome of female infertility treatment.

Identification of TRA2B-DNAH5 fusion as a novel oncogenic driver in human lung squamous cell carcinoma.

Lung squamous cell carcinoma (SCC) is one of the major subtypes of lung cancer. Our current knowledge of oncogenic drivers in this specific subtype of lung cancer is largely limited compared with lung adenocarcinoma (ADC). Through exon array analyses, molecular analyses and functional studies, we here identify the TRA2B-DNAH5 fusion as a novel oncogenic driver in lung SCC. We found that this gene fusion occurs exclusively in lung SCC (3.1%, 5/163), but not in lung ADC (0/119). Through mechanistic studies, we further revealed that this TRA2B-DNAH5 fusion promotes lung SCC malignant progression through regulating a SIRT6-ERK1/2-MMP1 signaling axis. We show that inhibition of ERK1/2 activation using selumetinib efficiently inhibits the growth of lung SCC with TRA2B-DNAH5 fusion expression. These findings improve our current knowledge of oncogenic drivers in lung SCC and provide a potential therapeutic strategy for lung SCC patients with TRA2B-DNAH5 fusion.

Preliminary investigation of five novel long non-coding RNAs in hepatocellular carcinoma cell lines.

Hepatocellular carcinoma (HCC) is a highly prevalent cancer with a high mortality rate and HCC is always accompanied with a hepatitis B virus (HBV) infection, unlike many other types of cancers. Over the past few years, cancer-related long non-coding RNAs (lncRNAs) and virus-related lncRNAs have attracted the attention of many researchers, and a number of previous studies have examined the relationship between lncRNAs and various cancers and viruses. The current study used The Cancer Genome Atlas database to screen for lncRNAs up-regulated in HCC in order to identify cancer biomarkers. Results revealed five lncRNAs that were the most up-regulated. This result was then verified in 10 HCC cell lines and two normal liver cell lines. Quantitative real-time PCR revealed that the five lncRNAs were substantially up-regulated in HCC cell lines. Several of the five lncRNAs were expressed at higher levels in a few HCC cell lines that were infected with HBV or that were positive for its protein or DNA than in HCC cell lines that were not infected with HBV or that were negative for its protein or DNA. These findings suggest that the five lncRNAs might play a role in the progression of HCC and/or HBV infection, and these findings need to be studied in further detail.

Advances of diagnostic and mechanistic studies of γ-glutamyl transpeptidase in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second major cause of cancerous deaths in the world, accounting for 80-90% of all cases of liver cancer with an assessed global incidence of 782,000 new cases and approximate 746,000 deaths in 2012. Preoperative laboratory data (des-γ carboxyprothrombin (DCP), α-fetoprotein (AFP), Indocyanine green retention 15 min (ICG-R15), and γ-glutamyl transferase (GGT)) should be completely assessed before deciding a treatment and predicting prognosis in order to improve the prognosis for patients with HCC. A few recent studies have suggested GGT as an independent prognostic indicator in cases with HCC. And the data of our and other research teams revealed that combination of GGT and ICG-R15 or other factors may improve the efficiency of GGT as a prognostic predictor. In addition of clinical studies, a few mechanistic studies had been performed and GGT was suggested to promote tumor progression and poor prognosis through inducing DNA damage and genome instability, releasing reactive oxygen species to activating invasion-related signaling pathway, blocking chemotherapy, regulating microRNAs, and managing CpG island methylation. Although there were a few mechanistic studies, further and accurate researches were still in need.

Traditional, complementary, and alternative medicine: Focusing on research into traditional Tibetan medicine in China.

As a form of traditional, complementary, and alternative medicine (TCAM), traditional Tibetan medicine has developed into a mainstay of medical care in Tibet and has spread from there to China and then to the rest of the world. Thus far, research on traditional Tibetan medicine has focused on the study of the plant and animal sources of traditional medicines, study of the histology of those plants and animals, chemical analysis of traditional medicines, pharmacological study of those medicines, and evaluation of the clinical efficacy of those medicines. A number of papers on traditional Tibetan medicines have been published, providing some evidence of the efficacy of traditional Tibetan medicine. However, many traditional Tibetan medicines have unknown active ingredients, hampering the establishment of drug quality standards, the development of new medicines, commercial production of medicines, and market availability of those medicines. Traditional Tibetan medicine must take several steps to modernize and spread to the rest of the world: the pharmacodynamics of traditional Tibetan medicines need to be determined, the clinical efficacy of those medicines needs to be verified, criteria to evaluate the efficacy of those medicines need to be established in order to guide their clinical use, and efficacious medicines need to be acknowledged by the pharmaceutical market. The components of traditional Tibetan medicine should be studied, traditional Tibetan medicines should be screened for their active ingredients, and techniques should be devised to prepare and manufacture those medicines.

Advance in studies on traditional Chinese medicines to treat infection with the hepatitis B virus and hepatitis C virus.

Traditional Chinese medicine (TCM), as a type of complementary and alternative medicine (CAM), is a sophisticated and time-honored form of healthcare in China. Many TCMs are widely used to treat hepatitis B and hepatitis C in countries like China, Japan, and South Korea. Since conventional clinical preparations like interferon-α cause obvious dose-dependent adverse reactions and drug resistance, TCMs and related bioactive compounds have garnered increasing attention from physicians and medical researchers. Thus far, a number of TCMs and compounds have been used to inhibit the hepatitis B virus (HBV) or hepatitis C virus (HCV) in vitro, in vivo, and even in clinical trials. The current review summarizes TCMs and related compounds that have been used to inhibit HBV or HCV. Most of these medicines are derived from herbs. HepG2.2.15 cells have been used to study HBV in vitro and Huh7.5 cells have been similarly used to study HCV. Ducks have been used to study the anti-HBV effect of new medication in vivo, but there are few animal models for anti-HCV research at the present time. Thus far, a number of preclinical studies have been conducted but few clinical trials have been conducted. In addition, a few chemically modified compounds have displayed greater efficacy than natural products. However, advances in TCM research are hampered by mechanisms of action of many bioactive compounds that have yet to be identified. In short, TCMs and related active compounds are a CAM that could be used to treat HBV and HCV infections.

Nosocomial infection and its molecular mechanisms of antibiotic resistance.

Nosocomial infection is a kind of infection, which is spread in various hospital environments, and leads to many serious diseases (e.g. pneumonia, urinary tract infection, gastroenteritis, and puerperal fever), and causes higher mortality than community-acquired infection. Bacteria are predominant among all the nosocomial infection-associated pathogens, thus a large number of antibiotics, such as aminoglycosides, penicillins, cephalosporins, and carbapenems, are adopted in clinical treatment. However, in recent years antibiotic resistance quickly spreads worldwide and causes a critical threat to public health. The predominant bacteria include Methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Acinetobacter baumannii. In these bacteria, resistance emerged from antibiotic resistant genes and many of those can be exchanged between bacteria. With technical advances, molecular mechanisms of resistance have been gradually unveiled. In this review, recent advances in knowledge about mechanisms by which (i) bacteria hydrolyze antibiotics (e.g. extended spectrum ß-lactamases, (ii) AmpC ß-lactamases, carbapenemases), (iii) avoid antibiotic targeting (e.g. mutated vanA and mecA genes), (iv) prevent antibiotic permeation (e.g. porin deficiency), or (v) excrete intracellular antibiotics (e.g. active efflux pump) are summarized.

Controversies regarding and perspectives on clinical utility of biomarkers in hepatocellular carcinoma.

The prevalence of hepatocellular carcinoma (HCC) worldwide parallels that of persistent infection with the hepatitis B virus (HBV) and/or hepatitis C virus (HCV). According to recommendations by the World Health Organization guidelines for HBV/HCV, alpha-fetoprotein (AFP) testing and abdominal ultrasound should be performed in routine surveillance of HCC every 6 mo for high-risk patients. These examinations have also been recommended worldwide by many other HCC guidelines over the past few decades. In recent years, however, the role of AFP in HCC surveillance and diagnosis has diminished due to advances in imaging modalities. AFP was excluded from the surveillance and/or diagnostic criteria in the HCC guidelines published by the American Association for the Study of Liver Diseases in 2010, the European Association for the Study of the Liver in 2012, and the National Comprehensive Cancer Network in 2014. Other biomarkers, including the Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), des-γ-carboxyprothrombin, Dickkopf-1, midkine, and microRNA, are being studied in this regard. Furthermore, increasing attention has focused on the clinical utility of biomarkers as pre-treatment predictors for tumor recurrence and as post-treatment monitors. Serum and tissue-based biomarkers and genomics may aid in the diagnosis of HCC, determination of patient prognosis, and selection of appropriate treatment. However, further studies are needed to better characterize the accuracy and potential role of these approaches in clinical practice.

Status of and prospects for cancer vaccines against hepatocellular carcinoma in clinical trials.

Current therapies to treat advanced hepatocellular carcinoma (HCC) are not satisfactory because of the high rate of recurrence after treatment and because of severe complications after surgery. Cancer vaccines have been studied for decades to achieve effective, micro-invasive, long-lasting anti-tumor action. Cancer vaccines are designed to promote tumor-specific immune responses and increase specific cytotoxic CD8-positive T cells. This review summarizes 16 phase I clinical trials of cancer vaccines against HCC that have been conducted over the past 10 years. According to those trials, the Alpha fetoprotein (AFP), Glypican-3 (GPC3), and Multidrug resistance-associated protein 3 (MRP3) vaccines were well tolerated and safe. Some early clinical trials have shown that vaccination resulted in a large number of T cells activated by a specific tumor-associated antigen in the circulation, but clinical outcomes were not satisfactory. This may be because targets for immunosuppressive agents have yet to be clearly determined in HCC. Therapeutic regimens that combine activative agents and suppressive agents may profoundly improve clinical outcomes for patients with HCC in the future.

Sorafenib-based combined molecule targeting in treatment of hepatocellular carcinoma.

Sorafenib is the only and standard systematic chemotherapy drug for treatment of advanced hepatocellular carcinoma (HCC) at the current stage. Although sorafenib showed survival benefits in large randomized phase III studies, its clinical benefits remain modest and most often consist of temporary tumor stabilization, indicating that more effective first-line treatment regimens or second-line salvage therapies are required. The molecular pathogenesis of HCC is very complex, involving hyperactivated signal transduction pathways such as RAS/RAF/MEK/ERK and PI3K/AKT/mTOR and aberrant expression of molecules such as receptor tyrosine kinases and histone deacetylases. Simultaneous or sequential abrogation of these critical pathways or the functions of these key molecules involved in angiogenesis, proliferation, and apoptosis may yield major improvements in the management of HCC. In this review, we summarize the emerging sorafenib-based combined molecule targeting for HCC treatment and analyze the rationales of these combinations.