Engineering a cell-penetrating hyperstable antibody scFv(Ras)-An extraordinary approach to cancer therapeutics

In the modern pharmaceutical industry,monoclonal antibodies are often used as therapeutic agents.However,they are restricted to cell surface antigens due to their inability to penetrate the outer cell membrane and maintain normal function in the reducing environment.Additionally,it can lead to cytotoxicity since it attacks cancerous cells by mimicking the human immune system.As an alternative,this study modifies the hyperstable single-chain fragment variable(scFv)antibody to eliminate cancer using its linear shape.The scFv(F8)antibody model was modified to recognize human Ras protein by altering residues in the antigen-binding site.Furthermore,a cell-penetrating peptide(CPP)was attached to the scFv(Ras)antibody model to allow entrance to the cell,creating CPP-scFv(Ras).Sodium dodecyl sulfate polyacrylamide gel electrophoresis(SDS-PAGE),western blotting,and the binding assay were performed to prove its effectiveness.As a result,CPP-scFv(Ras)was successfully engineered and bound to the antigen,HRas(G12V).

Development of therapeutic cancer vaccines using nanomicellar preparations

Cancer treatment is a multifaceted challenge,and therapeutic vaccines have emerged as a promising approach.The micellar preparation efficiently encapsulates antigen polypeptides and enhances antigen presentation through the major histocompatibility class I pathway,promoting cytotoxic T lymphocyte immune responses.Moreover,it enables codelivery of both antigen and adjuvant to the same target antigen-presenting cells.Combining themicellar vaccine with traditional cancer treatments(such as chemotherapy,radiotherapy,and surgery)has demonstrated improved efficacy in murine tumor models.Overall,the polyethylene glycol-phosphatidylethanolamine micelle-based vaccine presents a promising platformfor cancer therapeutic vaccines.By leveraging the strengths of various treatmentmodalities,this innovative vaccine approach holds the potential to revolutionize cancer therapy and bring new possibilities for cancer patients.

Immunotherapy and therapeutic vaccines in prostate cancer： an update on current strategies and clinical implications

In recent years, immunotherapy has emerged as a viable and attractive strategy for the treatment of prostate cancer. While there are multiple ways to target the immune system, therapeutic cancer vaccines and immune checkpoint inhibitors have been most successful in late-stage clinical trials. The landmark Food and Drug Administration approval of sipuleuceI-T for asymptomatic or minimally symptomatic metastatic prostate cancer set the stage for ongoing phase III trials with the cancer vaccine PSA-TRICOM and the immune checkpoint inhibitor ipilimumab. A common feature of these immune-based therapies is the appearance of improved overall survival without short-term changes in disease progression. This class effect appears to be due to modulation of tumor growth rate kinetics, in which the activated immune system exerts constant immunologic pressure that slows net tumor growth. Emerging data suggest that the ideal population for clinical trials of cancer vaccines is patients with lower tumor volume and less aggressive disease. Combination strategies that combine immunotherapy with standard therapies have been shown to augment both immune response and clinical benefit.

Evolving role of adiponectin in cancer-controversies and update

Adiponectin(APN), an adipokine produced by adipocytes, has been shown to have a critical role in the pathogenesis of obesityassociated malignancies. Through its receptor interactions, APN may exert its anti-carcinogenic effects including regulating cell survival, apoptosis and metastasis via a plethora of signalling pathways. Despite the strong evidence supporting this notion, some work may indicate otherwise. Our review addresses all controversies critically. On the whole, hypoadiponectinaemia is associated with increased risk of several malignancies and poor prognosis. In addition, various genetic polymorphisms may predispose individuals to increased risk of obesity-associated malignancies. We also provide an updated summary on therapeutic interventions to increase APN levels that are of key interest in this field. To date efforts to manipulate APN levels have been promising, but much work remains to be done.

A New Statistical Modeling Approach for Survival Analysis of Cancer Patients—Multiple Myeloma Cancer

Background: The Cox Proportional Hazard (Cox-PH) model has been a popularly used method for survival analysis of cancer data given the survival times as a function of covariates or risk factors. However, it is very seldom to see the assumptions for the application of the Cox-PH model satisfied in most of the research studies, raising questions about the effectiveness, robustness, and accuracy of the model predicting the proportion of survival times. This is because the necessary assumptions in most cases are difficult to satisfy, as well as the assessment of interaction among covariates. Methods: To further improve the therapeutic/treatment strategy for cancer diseases, we proposed a new approach to survival analysis using multiple myeloma (MM) cancer data. We first developed a data-driven nonlinear statistical model that predicts the survival times with 93% accuracy. We then performed a parametric analysis on the predicted survival times to obtain the survival function which is used in estimating the proportion of survival times. Results: The new proposed approach for survival analysis has proved to be more robust and gives better estimates of the proportion of survival than the Cox-PH model. Also, satisfying the proposed model assumptions and finding interactions among risk factors is less difficult compared to the Cox-PH model. The proposed model can predict the real values of the survival times and the identified risk factors are ranked according to the percent of contribution to the survival time. Conclusion: The new proposed nonlinear statistical model approach for survival analysis of cancer diseases is very efficient and provides an improved and innovative strategy for cancer therapeutic/treatment.

MicroRNA-216a: a potential therapeutic target for drug resistance and recurrent of liver cancer

The Editor welcomes submissions for possible publication in the Letters to the Editor section.Letters commenting on an article published in the Journal or other interesting pieces will be considered if they are received within 6 weeks of the time the article was published.Authors of the article being commented on will be given an opportunity to offer a timely response to the letter.Authors of letters will be notified that the letter has been received.Unpublished letters cannot be returned.

Atypical artificial cells:Novel biomimetic materials for combating cancer

The functional concept of using synthetic entities to supplement or replace certain functions or structures of biological cells is realized by the development of atypical artificial cells using a bottom-up approach.Tremendous progress has been achieved over the past 5 years that focuses on the therapeutic applications of atypical artificial cells,especially in the anticancer arena.Artificial cell-based anticancer strategies have demon-strated eminent advantages over conventional anticancer tactics,with excellent biocompatibility and targeting capability.The present review commences with introducing the constructing principles and classification of artificial cells.Artificial cell-based applications in cancer prophylaxis,diagnosis,and treatment are subsequently highlighted.These stimulating outcomes may inspire the development of next-generation anticancer ther-apeutic strategies.

Hepatocellular carcinoma in patients with renal dysfunction: Pathophysiology, prognosis, and treatment challenges

The population of patients with hepatocellular carcinoma(HCC)overlaps to a high degree with those for chronic kidney disease(CKD)and end-stage renal disease(ESRD).The degrees of renal dysfunction vary,from the various stages of CKD to dialysis-dependent ESRD,which often affects the prognosis and treatment choice of patients with HCC.In addition,renal dysfunction makes treatment more difficult and may negatively affect treatment outcomes.This study summarized the possible causes of the high comorbidity of HCC and renal dysfunction.The possible mechanisms of CKD causing HCC involve uremia itself,long-term dialysis status,immunosuppressive agents for postrenal transplant status,and miscellaneous factors such as hormone alterations and dysbiosis.The possible mechanisms of HCC affecting renal function include direct tumor invasion and hepatorenal syndrome.Finally,we categorized the risk factors that could lead to both HCC and CKD into four categories:Environmental toxins,viral hepatitis,metabolic syndrome,and vasoactive factors.Both CKD and ESRD have been reported to negatively affect HCC prognosis,but more research is warranted to confirm this.Furthermore,ESRD status itself ought not to prevent patients receiving aggressive treatments.This study then adopted the well-known Barcelona Clinic Liver Cancer guidelines as a framework to discuss the indicators for each stage of HCC treatment,treatment-related adverse renal effects,and concerns that are specific to patients with pre-existing renal dysfunction when undergoing aggressive treatments against CKD and ESRD.Such aggressive treatments include liver resection,simultaneous liver kidney transplantation,radiofrequency ablation,and transarterial chemoembolization.Finally,focusing on patients unable to receive active treatment,this study compiled information on the latest systemic pharmacological therapies,including targeted and immunotherapeutic drugs.Based on available clinical studies and Food and Drug Administration labels,this study details the drug indications,side effects,and dose adjustments for patients with renal dysfunction.It also provides a comprehensive review of information on HCC patients with renal dysfunction from disease onset to treatment.

Bidirectional crosstalk between therapeutic cancer vaccines and the tumor microenvironment:Beyond tumor antigens

Immunotherapy has rejuvenated cancer therapy,especially after anti-PD-(L)1 came onto the scene.Among the many therapeutic options,therapeutic cancer vaccines are one of the most essential players.Although great progress has been made in research on tumor antigen vaccines,few phase III trials have shown clinical benefits.One of the reasons lies in obstruction from the tumor microenvironment(TME).Meanwhile,the therapeutic cancer vaccine reshapes the TME in an ambivalent way,leading to immune stimulation or immune escape.In this review,we summarize recent progress on the interaction between therapeutic cancer vaccines and the TME.With respect to vaccine resistance,innate immunosuppressive TME components and acquired resistance caused by vaccination are both involved.Understanding the underlying mechanism of this crosstalk provides insight into the treatment of cancer by directly targeting the TME or synergizing with other therapeutics.

Advances in the prerequisite and consequence of STING downstream signalosomes

The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)pathway is an evolving DNA-sensing mechanism involved in innate immunity and pathogen defense that has been optimized while remaining conserved.Aside from recognizing pathogens through conserved motifs,these receptors also detect aberrant or misplaced self-molecules as possible signs of perturbed homeostasis.Upon binding external or self-derived DNA,a mobile sec-ondary messenger 2′3′-cyclic GMP-AMP(cGAMP)is produced by cGAS and in turn activates its adapter STING in the endo-plasmic reticulum(ER).Resting-state or activated STING protein isfinely restricted by multiple degradation machin-eries.The post-translational changes of the STING protein,along with the regulatory machinery ofthe secret routes,limit the onset,strength and sustention of STING signal.STING experiences a conformational shift and relocates with TBK1 from the ER to perinuclear vesicles containing transcription factors,provoking the transcription activity of IRF3/IFN-I and NF-κB pathways,as well as to initiate a number of cellular processes that have been shown to alter the immune landscape in cancer,such as autophagy,NLRP3 inflamma-some,ER stress,and cell death.STING signal thus serves as a potent activator for immune mobilization yet also triggers immune-mediated pathology in tissues.Recent advances have established the vital role of STING in immune surveil-lance as well as tumorigenic process.This review provides an overview of the disparate outcomes of cancer attributed to the actions of pleiotropic and coordinated STING downstream signalosomes,along with the underlying mechanisms of STING function in pathologies,providing therapeutic impli-cations for new approaches in hunt for the next generation of cancer immunotherapy base on STING.

Development of polyvinylpyrrolidone/paclitaxel self-assemblies for breast cancer

The goal of this investigation was to develop and demonstrate a polymer/paclitaxel selfassembly(PTX-SA) formulation. Polymer/PTX-SAs were screened based on smaller size of formulation using dynamic light scattering analysis. Additionally, fluorescence microscopy and flow cytometry studies exhibited that polyvinylpyrrolidone(PVP)-based PTX-SAs(PVP/PTX-SAs) had superior cellular internalization capability in MCF7 and MDA-MB-231 breast cancer cells. The optimized PVP/PTXSAs exhibited less toxicity to human red blood cells indicating a suitable formulation for reducing systemic toxicity. The formation of PVP and PTX self-assemblies was confirmed using fluorescence quenching and transmission electron microscopy which indicated that the PVP/PTX-SAs were spherical in shape with an average size range of 53.81 nm as detected by transmission electron microscopy(TEM).FTIR spectral analysis demonstrates incorporation of polymer and paclitaxel functional groups in PVP/PTX-SAs. Both proliferation(MTS) and clonogenic(colony formation) assays were used to validate superior anticancer activity of PVP/PTX-SAs in breast cancer cells over paclitaxel. Such superior anticancer activity was also demonstrated by downregulation of the expression of pro-survival protein(Bcl-x L), upregulation of apoptosis-associated proteins(Bid, Bax, cleaved caspase 7, and cleaved PARP)and β-tubulin stabilization. These results support the hypothesis that PVP/PTX-SAs improved paclitaxel delivery to cancer cells.

Signaling pathways downstream to receptor tyrosine kinases:targets for cancer treatment

Mammalian cells have the ability to respond to a myriad of diverse extracellular stimuli that modulate cell function.This often involves ligands binding to cell surface receptors and subsequent activation of intracellular signaling pathways.These pathways can lead to changes in gene expression patterns that in turn regulate cell growth,differentiation,migration,and function.One important type of cell surface receptor is the receptor tyrosine kinase(RTK).In response to in response to ligand binding,RTKs dimerize,then trans-phosphorylate each other,leading to activation of downstream pathways.While the signaling proteins in these pathways are important for normal cell growth control,when improperly regulated they can lead to uncontrolled growth and sometimes cancer.For this reason,they are often considered to be good candidates for drug targets for chemotherapeutic drugs.RTKs can activate multiple different signaling pathways.Some of the signaling proteins in these pathways can have crosstalk with other RTK activated pathways,and some of them can be activated by multiple mechanisms in addition to activation by RTKs.While there is a wide array of different signaling proteins and pathways activated by RTKs,in this review we will discuss components of several key pathways including the MAPK pathway,the Her2/Neu pathway,mTOR,and Pak kinases.We provide an overview of the roles for these pathways in cell signaling and discuss how different components of these pathways are being considered as targets for cancer treatment.

Application of Response Evaluation Criteria of Traditional Chinese Medicine for Solid Tumor in Advanced Non-Small Cell Lung Cancer

Objective：To evaluate the objectivity and comprehensiveness of Response Evaluation Criteria of Traditional Chinese Medicine for Solid Tumor（Draft,REC-TCM-ST） in application of Chinese medicine therapeutic effect in patients with advanced non-small cell lung cancer（NSCLC）.Methods：A retrospective clinical research was used in 104 NSCLC patients in stages of Ⅲ-Ⅳ,53 cases were in Chinese medicine（CM） group and 51 cases were in Western medicine（WM） group.The therapeutic effect of the two groups was evaluated with both REC-TCM-ST and Response Evaluation Criteria in Solid Tumor（RECIST）.Kaplan-Meier method was used to analyze the survival time.Kappa test method was used to test the consistency of the two kinds of evaluation results.Results：According to REC-TCM-ST,the effective rate on relieving tumor mass in the CM group was significantly lower than that in the WM group（P〈0.05）,but there was no significant difference in tumor-mass stable rate（P〉0.05）;the symptom of weakness in the CM group was improved significantly,indicating better therapeutic effect than that in the WM group（P〈0.01）.Karnofsky score in the CM group was significantly better than that in the WM group（P〈0.01）.In terms of survival conditions,the median survival time and the survival rate of 6 months,1 year and 2 years of the CM group were higher than the WM group.The total effective rate was 9.62%,and the total stable rate was 72.12%for 104 cases according to RECIST;while the total effective rate was 34.62%,and the total stable rate was 84.62%according to REC-TCM-ST,thus there were significant differences between the results of the two criteria（P〈0.01）,and there was also some consistency between them,but not satisfactory.Conclusions：REC-TCM-ST was used to evaluate the therapeutic effect of CM in the treatment of advanced NSCLC,which shows that its evaluation results can better reflect the advantages and disadvantages of CM,and the effectiveness of CM is more objective and comprehensive than RECIST,so REC-TCM-ST is worthy of further improvement and clinical expansion.

Molecular mechanism revealing therapeutic opportunities of histone deacetylases inhibitors in triple-negative breast cancer

Subject Code:H31With the support by the National Natural Science Foundation of China,Ministry of Science and Technology of China and Chinese Academy of Sciences,the research team led by Prof.Geng Meiyu(耿美玉)and Ding Jian(丁健)from Shanghai Institute of Materia Medica,Chinese Academy of Sciences,demonstrated the therapeutic opportunities of histone deacetylases(HDACs)inhibitors in

Leveraging Metabolomics to Assess the Next Generation of Temozolomide-based Therapeutic Approaches for Glioblastomas

Glioblastoma multiforme （GBM） is the most common adult primary tumor of the cen- tral nervous system. The current standard of care for glioblastoma patients involves a combination of surgery, radiotherapy and chemotherapy with the alkylating agent temozolomide. Several mech- anisms underlying the inherent and acquired temozolomide resistance have been identified and con- tribute to treatment failure. Early identification of temozolomide-resistant GBM patients and improvement of the therapeutic strategies available to treat this malignancy are of uttermost impor- tance. This review initially looks at the molecular pathways underlying GBM formation and devel- opment with a particular emphasis placed on recent therapeutic advances made in the field. Our focus will next be directed toward the molecular mechanisms modulating temozolomide resistance in GBM patients and the strategies envisioned to circumvent this resistance. Finallyl we highlight the diagnostic and prognostic value of metabolomics in cancers and assess its potential usefulness in improving the current standard of care for GBM patients.