State Key Laboratory of Biotherapy

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.

MicroRNAs (miRNAs) are endogenous, small non-coding RNAs that function in regulation of gene expression. Compelling evidences have demonstrated that miRNA expression is dysregulated in human cancer through various mechanisms, including amplification or deletion of miRNA genes, abnormal transcriptional control of miRNAs, dysregulated epigenetic changes and defects in the miRNA biogenesis machinery. MiRNAs may function as either oncogenes or tumor suppressors under certain conditions. The dysregulated miRNAs have been shown to affect the hallmarks of cancer, including sustaining proliferative signaling, evading growth suppressors, resisting cell death, activating invasion and metastasis, and inducing angiogenesis. An increasing number of studies have identified miRNAs as potential biomarkers for human cancer diagnosis, prognosis and therapeutic targets or tools, which needs further investigation and validation. In this review, we focus on how miRNAs regulate the development of human tumors by acting as tumor suppressors or oncogenes.

NF-κB pathway consists of canonical and non-canonical pathways. The canonical NF-κB is activated by various stimuli, transducing a quick but transient transcriptional activity, to regulate the expression of various proinflammatory genes and also serve as the critical mediator for inflammatory response. Meanwhile, the activation of the non-canonical NF-κB pathway occurs through a handful of TNF receptor superfamily members. Since the activation of this pathway involves protein synthesis, the kinetics of non-canonical NF-κB activation is slow but persistent, in concordance with its biological functions in the development of immune cell and lymphoid organ, immune homeostasis and immune response. The activation of the canonical and non-canonical NF-κB pathway is tightly controlled, highlighting the vital roles of ubiquitination in these pathways. Emerging studies indicate that dysregulated NF-κB activity causes inflammation-related diseases as well as cancers, and NF-κB has been long proposed as the potential target for therapy of diseases. This review attempts to summarize our current knowledge and updates on the mechanisms of NF-κB pathway regulation and the potential therapeutic application of inhibition of NF-κB signaling in cancer and inflammatory diseases.

Programmed cell death (PCD), referring to apoptosis, autophagy and programmed necrosis, is proposed to be death of a cell in any pathological format, when mediated by an intracellular program. These three forms of PCD may jointly decide the fate of cells of malignant neoplasms; apoptosis and programmed necrosis invariably contribute to cell death, whereas autophagy can play either pro-survival or pro-death roles. Recent bulk of accumulating evidence has contributed to a wealth of knowledge facilitating better understanding of cancer initiation and progression with the three distinctive types of cell death. To be able to decipher PCD signalling pathways may aid development of new targeted anti-cancer therapeutic strategies. Thus in this review, we present a brief outline of apoptosis, autophagy and programmed necrosis pathways and apoptosis-related microRNA regulation, in cancer. Taken together, understanding PCD and the complex interplay between apoptosis, autophagy and programmed necrosis may ultimately allow scientists and clinicians to harness the three types of PCD for discovery of further novel drug targets, in the future cancer treatment.

Ferroptosis is an iron-dependent cell death, which is different from apoptosis, necrosis, autophagy, and other forms of cell death. The process of ferroptotic cell death is defined by the accumulation of lethal lipid species derived from the peroxidation of lipids, which can be prevented by iron chelators (e.g., deferiprone, deferoxamine) and small lipophilic antioxidants (e.g., ferrostatin, liproxstatin). This review summarizes current knowledge about the regulatory mechanism of ferroptosis and its association with several pathways, including iron, lipid, and cysteine metabolism. We have further discussed the contribution of ferroptosis to the pathogenesis of several diseases such as cancer, ischemia/reperfusion, and various neurodegenerative diseases (e.g., Alzheimer's disease and Parkinson's disease), and evaluated the therapeutic applications of ferroptosis inhibitors in clinics.

Pseudomonas aeruginosa (P. aeruginosa) is a Gram-negative opportunistic pathogen that infects patients with cystic fibrosis, burn wounds, immunodeficiency, chronic obstructive pulmonary disorder (COPD), cancer, and severe infection requiring ventilation, such as COVID-19. P. aeruginosa is also a widely-used model bacterium for all biological areas. In addition to continued, intense efforts in understanding bacterial pathogenesis of P. aeruginosa including virulence factors (LPS, quorum sensing, two-component systems, 6 type secretion systems, outer membrane vesicles (OMVs), CRISPR-Cas and their regulation), rapid progress has been made in further studying host-pathogen interaction, particularly host immune networks involving autophagy, inflammasome, non-coding RNAs, cGAS, etc. Furthermore, numerous technologic advances, such as bioinformatics, metabolomics, scRNA-seq, nanoparticles, drug screening, and phage therapy, have been used to improve our understanding of P. aeruginosa pathogenesis and host defense. Nevertheless, much remains to be uncovered about interactions between P. aeruginosa and host immune responses, including mechanisms of drug resistance by known or unannotated bacterial virulence factors as well as mammalian cell signaling pathways. The widespread use of antibiotics and the slow development of effective antimicrobials present daunting challenges and necessitate new theoretical and practical platforms to screen and develop mechanism-tested novel drugs to treat intractable infections, especially those caused by multi-drug resistance strains. Benefited from has advancing in research tools and technology, dissecting this pathogen's feature has entered into molecular and mechanistic details as well as dynamic and holistic views. Herein, we comprehensively review the progress and discuss the current status of P. aeruginosa biophysical traits, behaviors, virulence factors, invasive regulators, and host defense patterns against its infection, which point out new directions for future investigation and add to the design of novel and/or alternative therapeutics to combat this clinically significant pathogen.

Epigenetic alternations concern heritable yet reversible changes in histone or DNA modifications that regulate gene activity beyond the underlying sequence. Epigenetic dysregulation is often linked to human disease, notably cancer. With the development of various drugs targeting epigenetic regulators, epigenetic-targeted therapy has been applied in the treatment of hematological malignancies and has exhibited viable therapeutic potential for solid tumors in preclinical and clinical trials. In this review, we summarize the aberrant functions of enzymes in DNA methylation, histone acetylation and histone methylation during tumor progression and highlight the development of inhibitors of or drugs targeted at epigenetic enzymes.

PURPOSE: Tumor associated macrophages (TAMs) are considered with the capacity to have both negative and positive effects on tumor growth. The prognostic value of TAM for survival in patients with solid tumor remains controversial. EXPERIMENTAL DESIGN: We conducted a meta-analysis of 55 studies (n = 8,692 patients) that evaluated the correlation between TAM (detected by immunohistochemistry) and clinical staging, overall survival (OS) and disease free survival (DFS). The impact of M1 and M2 type TAM (n = 5) on survival was also examined. RESULTS: High density of TAM was significantly associated with late clinical staging in patients with breast cancer [risk ratio (RR) = 1.20 (95% confidence interval (CI), 1.14-1.28)] and bladder cancer [RR = 3.30 (95%CI, 1.56-6.96)] and with early clinical staging in patients with ovarian cancer [RR = 0.52 (95%CI, 0.35-0.77)]. Negative effects of TAM on OS was shown in patients with gastric cancer [RR = 1.64 (95%CI, 1.24-2.16)], breast cancer [RR = 8.62 (95%CI, 3.10-23.95)], bladder cancer [RR = 5.00 (95%CI, 1.98-12.63)], ovarian cancer [RR = 2.55 (95%CI, 1.60-4.06)], oral cancer [RR = 2.03 (95%CI, 1.47-2.80)] and thyroid cancer [RR = 2.72 (95%CI, 1.26-5.86)],and positive effects was displayed in patients with colorectal cancer [RR = 0.64 (95%CI, 0.43-0.96)]. No significant effect was showed between TAM and DFS. There was also no significant effect of two phenotypes of TAM on survival. CONCLUSIONS: Although some modest bias cannot be excluded, high density of TAM seems to be associated with worse OS in patients with gastric cancer, urogenital cancer and head and neck cancer, with better OS in patients with colorectal cancer.

Abstract Nicotinamide adenine dinucleotide (NAD + ) and its metabolites function as critical regulators to maintain physiologic processes, enabling the plastic cells to adapt to environmental changes including nutrient perturbation, genotoxic factors, circadian disorder, infection, inflammation and xenobiotics. These effects are mainly achieved by the driving effect of NAD + on metabolic pathways as enzyme cofactors transferring hydrogen in oxidation-reduction reactions. Besides, multiple NAD + -dependent enzymes are involved in physiology either by post-synthesis chemical modification of DNA, RNA and proteins, or releasing second messenger cyclic ADP-ribose (cADPR) and NAADP + . Prolonged disequilibrium of NAD + metabolism disturbs the physiological functions, resulting in diseases including metabolic diseases, cancer, aging and neurodegeneration disorder. In this review, we summarize recent advances in our understanding of the molecular mechanisms of NAD + -regulated physiological responses to stresses, the contribution of NAD + deficiency to various diseases via manipulating cellular communication networks and the potential new avenues for therapeutic intervention.

Epithelial-mesenchymal transition (EMT) is an essential process in normal embryonic development and tissue regeneration. However, aberrant reactivation of EMT is associated with malignant properties of tumor cells during cancer progression and metastasis, including promoted migration and invasiveness, increased tumor stemness, and enhanced resistance to chemotherapy and immunotherapy. EMT is tightly regulated by a complex network which is orchestrated with several intrinsic and extrinsic factors, including multiple transcription factors, post-translational control, epigenetic modifications, and noncoding RNA-mediated regulation. In this review, we described the molecular mechanisms, signaling pathways, and the stages of tumorigenesis involved in the EMT process and discussed the dynamic non-binary process of EMT and its role in tumor metastasis. Finally, we summarized the challenges of chemotherapy and immunotherapy in EMT and proposed strategies for tumor therapy targeting EMT.

Mechanistic target of rapamycin (mTOR) is a protein kinase regulating cell growth, survival, metabolism, and immunity. mTOR is usually assembled into several complexes such as mTOR complex 1/2 (mTORC1/2). In cooperation with raptor, rictor, LST8, and mSin1, key components in mTORC1 or mTORC2, mTOR catalyzes the phosphorylation of multiple targets such as ribosomal protein S6 kinase β-1 (S6K1), eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), Akt, protein kinase C (PKC), and type-I insulin-like growth factor receptor (IGF-IR), thereby regulating protein synthesis, nutrients metabolism, growth factor signaling, cell growth, and migration. Activation of mTOR promotes tumor growth and metastasis. Many mTOR inhibitors have been developed to treat cancer. While some of the mTOR inhibitors have been approved to treat human cancer, more mTOR inhibitors are being evaluated in clinical trials. Here, we update recent advances in exploring mTOR signaling and the development of mTOR inhibitors for cancer therapy. In addition, we discuss the mechanisms underlying the resistance to mTOR inhibitors in cancer cells.

Myeloid-derived suppressor cells (MDSCs) are a heterogenic population of immature myeloid cells with immunosuppressive effects, which undergo massive expansion during tumor progression. These cells not only support immune escape directly but also promote tumor invasion via various non-immunological activities. Besides, this group of cells are proved to impair the efficiency of current antitumor strategies such as chemotherapy, radiotherapy, and immunotherapy. Therefore, MDSCs are considered as potential therapeutic targets for cancer therapy. Treatment strategies targeting MDSCs have shown promising outcomes in both preclinical studies and clinical trials when administrated alone, or in combination with other anticancer therapies. In this review, we shed new light on recent advances in the biological characteristics and immunosuppressive functions of MDSCs. We also hope to propose an overview of current MDSCs-targeting therapies so as to provide new ideas for cancer treatment.

Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies, including cancer vaccines, adoptive cell therapy and antibody-based therapies, especially for solid tumors. Neoantigens are newly formed antigens generated by tumor cells as a result of various tumor-specific alterations, such as genomic mutation, dysregulated RNA splicing, disordered post-translational modification, and integrated viral open reading frames. Neoantigens are recognized as non-self and trigger an immune response that is not subject to central and peripheral tolerance. The quick identification and prediction of tumor-specific neoantigens have been made possible by the advanced development of next-generation sequencing and bioinformatic technologies. Compared to tumor-associated antigens, the highly immunogenic and tumor-specific neoantigens provide emerging targets for personalized cancer immunotherapies, and serve as prospective predictors for tumor survival prognosis and immune checkpoint blockade responses. The development of cancer therapies will be aided by understanding the mechanism underlying neoantigen-induced anti-tumor immune response and by streamlining the process of neoantigen-based immunotherapies. This review provides an overview on the identification and characterization of neoantigens and outlines the clinical applications of prospective immunotherapeutic strategies based on neoantigens. We also explore their current status, inherent challenges, and clinical translation potential.

Traditional drug discovery mainly focuses on direct regulation of protein activity. The development and application of protein activity modulators, particularly inhibitors, has been the mainstream in drug development. In recent years, PROteolysis TArgeting Chimeras (PROTAC) technology has emerged as one of the most promising approaches to remove specific disease-associated proteins by exploiting cells' own destruction machinery. In addition to PROTAC, many different targeted protein degradation (TPD) strategies including, but not limited to, molecular glue, Lysosome-Targeting Chimaera (LYTAC), and Antibody-based PROTAC (AbTAC), are emerging. These technologies have not only greatly expanded the scope of TPD, but also provided fresh insights into drug discovery. Here, we summarize recent advances of major TPD technologies, discuss their potential applications, and hope to provide a prime for both biologists and chemists who are interested in this vibrant field.

Regulated cell death (RCD), also well-known as programmed cell death (PCD), refers to the form of cell death that can be regulated by a variety of biomacromolecules, which is distinctive from accidental cell death (ACD). Accumulating evidence has revealed that RCD subroutines are the key features of tumorigenesis, which may ultimately lead to the establishment of different potential therapeutic strategies. Hitherto, targeting the subroutines of RCD with pharmacological small-molecule compounds has been emerging as a promising therapeutic avenue, which has rapidly progressed in many types of human cancers. Thus, in this review, we focus on summarizing not only the key apoptotic and autophagy-dependent cell death signaling pathways, but the crucial pathways of other RCD subroutines, including necroptosis, pyroptosis, ferroptosis, parthanatos, entosis, NETosis and lysosome-dependent cell death (LCD) in cancer. Moreover, we further discuss the current situation of several small-molecule compounds targeting the different RCD subroutines to improve cancer treatment, such as single-target, dual or multiple-target small-molecule compounds, drug combinations, and some new emerging therapeutic strategies that would together shed new light on future directions to attack cancer cell vulnerabilities with small-molecule drugs targeting RCD for therapeutic purposes.

The therapeutic use of messenger RNA (mRNA) has fueled great hope to combat a wide range of incurable diseases. Recent rapid advances in biotechnology and molecular medicine have enabled the production of almost any functional protein/peptide in the human body by introducing mRNA as a vaccine or therapeutic agent. This represents a rising precision medicine field with great promise for preventing and treating many intractable or genetic diseases. In addition, in vitro transcribed mRNA has achieved programmed production, which is more effective, faster in design and production, as well as more flexible and cost-effective than conventional approaches that may offer. Based on these extraordinary advantages, mRNA vaccines have the characteristics of the swiftest response to large-scale outbreaks of infectious diseases, such as the currently devastating pandemic COVID-19. It has always been the scientists' desire to improve the stability, immunogenicity, translation efficiency, and delivery system to achieve efficient and safe delivery of mRNA. Excitingly, these scientific dreams have gradually been realized with the rapid, amazing achievements of molecular biology, RNA technology, vaccinology, and nanotechnology. In this review, we comprehensively describe mRNA-based therapeutics, including their principles, manufacture, application, effects, and shortcomings. We also highlight the importance of mRNA optimization and delivery systems in successful mRNA therapeutics and discuss the key challenges and opportunities in developing these tools into powerful and versatile tools to combat many genetic, infectious, cancer, and other refractory diseases.

Compared to the available protein sequences of different organisms, the number of revealed protein-protein interactions (PPIs) is still very limited. So many computational methods have been developed to facilitate the identification of novel PPIs. However, the methods only using the information of protein sequences are more universal than those that depend on some additional information or predictions about the proteins. In this article, a sequence-based method is proposed by combining a new feature representation using auto covariance (AC) and support vector machine (SVM). AC accounts for the interactions between residues a certain distance apart in the sequence, so this method adequately takes the neighbouring effect into account. When performed on the PPI data of yeast Saccharomyces cerevisiae, the method achieved a very promising prediction result. An independent data set of 11,474 yeast PPIs was used to evaluate this prediction model and the prediction accuracy is 88.09%. The performance of this method is superior to those of the existing sequence-based methods, so it can be a useful supplementary tool for future proteomics studies. The prediction software and all data sets used in this article are freely available at http://www.scucic.cn/Predict_PPI/index.htm.

Importance: Laparoscopic distal gastrectomy is accepted as a more effective approach to conventional open distal gastrectomy for early-stage gastric cancer. However, efficacy for locally advanced gastric cancer remains uncertain. Objective: To compare 3-year disease-free survival for patients with locally advanced gastric cancer after laparoscopic distal gastrectomy or open distal gastrectomy. Design, Setting, and Patients: The study was a noninferiority, open-label, randomized clinical trial at 14 centers in China. A total of 1056 eligible patients with clinical stage T2, T3, or T4a gastric cancer without bulky nodes or distant metastases were enrolled from September 2012 to December 2014. Final follow-up was on December 31, 2017. Interventions: Participants were randomized in a 1:1 ratio after stratification by site, age, cancer stage, and histology to undergo either laparoscopic distal gastrectomy (n = 528) or open distal gastrectomy (n = 528) with D2 lymphadenectomy. Main Outcomes and Measures: The primary end point was 3-year disease-free survival with a noninferiority margin of -10% to compare laparoscopic distal gastrectomy with open distal gastrectomy. Secondary end points of 3-year overall survival and recurrence patterns were tested for superiority. Results: Among 1056 patients, 1039 (98.4%; mean age, 56.2 years; 313 [30.1%] women) had surgery (laparoscopic distal gastrectomy [n=519] vs open distal gastrectomy [n=520]), and 999 (94.6%) completed the study. Three-year disease-free survival rate was 76.5% in the laparoscopic distal gastrectomy group and 77.8% in the open distal gastrectomy group, absolute difference of -1.3% and a 1-sided 97.5% CI of -6.5% to ∞, not crossing the prespecified noninferiority margin. Three-year overall survival rate (laparoscopic distal gastrectomy vs open distal gastrectomy: 83.1% vs 85.2%; adjusted hazard ratio, 1.19; 95% CI, 0.87 to 1.64; P = .28) and cumulative incidence of recurrence over the 3-year period (laparoscopic distal gastrectomy vs open distal gastrectomy: 18.8% vs 16.5%; subhazard ratio, 1.15; 95% CI, 0.86 to 1.54; P = .35) did not significantly differ between laparoscopic distal gastrectomy and open distal gastrectomy groups. Conclusions and Relevance: Among patients with a preoperative clinical stage indicating locally advanced gastric cancer, laparoscopic distal gastrectomy, compared with open distal gastrectomy, did not result in inferior disease-free survival at 3 years. Trial Registration: ClinicalTrials.gov Identifier: NCT01609309.

Oral squamous cell carcinoma (OSCC) develops on the mucosal epithelium of the oral cavity. It accounts for approximately 90% of oral malignancies and impairs appearance, pronunciation, swallowing, and flavor perception. In 2020, 377,713 OSCC cases were reported globally. According to the Global Cancer Observatory (GCO), the incidence of OSCC will rise by approximately 40% by 2040, accompanied by a growth in mortality. Persistent exposure to various risk factors, including tobacco, alcohol, betel quid (BQ), and human papillomavirus (HPV), will lead to the development of oral potentially malignant disorders (OPMDs), which are oral mucosal lesions with an increased risk of developing into OSCC. Complex and multifactorial, the oncogenesis process involves genetic alteration, epigenetic modification, and a dysregulated tumor microenvironment. Although various therapeutic interventions, such as chemotherapy, radiation, immunotherapy, and nanomedicine, have been proposed to prevent or treat OSCC and OPMDs, understanding the mechanism of malignancies will facilitate the identification of therapeutic and prognostic factors, thereby improving the efficacy of treatment for OSCC patients. This review summarizes the mechanisms involved in OSCC. Moreover, the current therapeutic interventions and prognostic methods for OSCC and OPMDs are discussed to facilitate comprehension and provide several prospective outlooks for the fields.

As an evolutionarily conserved signalling network, the Hippo pathway plays a crucial role in the regulation of numerous biological processes. Thus, substantial efforts have been made to understand the upstream signals that influence the activity of the Hippo pathway, as well as its physiological functions, such as cell proliferation and differentiation, organ growth, embryogenesis, and tissue regeneration/wound healing. However, dysregulation of the Hippo pathway can cause a variety of diseases, including cancer, eye diseases, cardiac diseases, pulmonary diseases, renal diseases, hepatic diseases, and immune dysfunction. Therefore, therapeutic strategies that target dysregulated Hippo components might be promising approaches for the treatment of a wide spectrum of diseases. Here, we review the key components and upstream signals of the Hippo pathway, as well as the critical physiological functions controlled by the Hippo pathway. Additionally, diseases associated with alterations in the Hippo pathway and potential therapies targeting Hippo components will be discussed.