Non-coding RNAs as therapeutic targets in cancer and its clinical application

Cancer genomics has led to the discovery of numerous oncogenes and tumor suppressor genes that play critical roles in cancer development and progression.Oncogenes promote cell growth and proliferation,whereas tumor suppressor genes inhibit cell growth and division.The dysregulation of these genes can lead to the development of cancer.Recent studies have focused on non-coding RNAs(ncRNAs),including circular RNA(circRNA),long non-coding RNA(lncRNA),and microRNA(miRNA),as therapeutic targets for cancer.In this article,we discuss the oncogenes and tumor suppressor genes of ncRNAs associated with different types of cancer and their potential as therapeutic targets.Here,we highlight the mechanisms of action of these genes and their clinical applications in cancer treatment.Understanding the molecular mechanisms underlying cancer development and identifying specific therapeutic targets are essential steps towards the development of effective cancer treatments.

Improving the accuracy and consistency of clinical target volume delineation for rectal cancer by an education program

BACKGROUND Accurate target volume delineation is the premise for the implementation of precise radiotherapy.Inadequate target volume delineation may diminish tumor control or increase toxicity.Although several clinical target volume(CTV)delineation guidelines for rectal cancer have been published in recent years,significant interobserver variation(IOV)in CTV delineation still exists among radiation oncologists.However,proper education may serve as a bridge that connects complex guidelines with clinical practice.AIM To examine whether an education program could improve the accuracy and consistency of preoperative radiotherapy CTV delineation for rectal cancer.METHODS The study consisted of a baseline target volume delineation,a 150-min education intervention,and a follow-up evaluation.A 42-year-old man diagnosed with stage IIIC(T3N2bM0)rectal adenocarcinoma was selected for target volume delineation.CTVs obtained before and after the program were compared.Dice similarity coefficient(DSC),inclusiveness index(IncI),conformal index(CI),and relative volume difference[ΔV(%)]were analyzed to quantitatively evaluate the disparities between the participants’delineation and the standard CTV.Maximum volume ratio(MVR)and coefficient of variation(CV)were calculated to assess the IOV.Qualitative analysis included four common controversies in CTV delineation concerning the upper boundary of the target volume,external iliac area,groin area,and ischiorectal fossa.RESULTS Of the 18 radiation oncologists from 10 provinces in China,13 completed two sets of CTVs.In quantitative analysis,the average CTV volume decreased from 809.82 cm3 to 705.21 cm3(P=0.001)after the education program.Regarding the indices for geometric comparison,the mean DSC,IncI,and CI increased significantly,whileΔV(%)decreased remarkably,indicating improved agreement between participants’delineation and the standard CTV.Moreover,an 11.80%reduction in MVR and 18.19%reduction in CV were noted,demonstrating a smaller IOV in delineation after the education program.Regarding qualitative analysis,the greatest variations in baseline were observed at the external iliac area and ischiorectal fossa;61.54%(8/13)and 53.85%(7/13)of the participants unnecessarily delineated the external iliac area and the ischiorectal fossa,respectively.However,the education program reduced these variations.CONCLUSION Wide variations in CTV delineation for rectal cancer are present among radiation oncologists in China's Mainland.A well-structured education program could improve delineation accuracy and reduce IOVs.

Reducing intrathecal pressure after traumatic spinal cord injury: a potential clinical target to promote tissue survival

Spinal cord injury （SCI） is an unexpected event that is both devastating and debilitating, resulting in not just motor and sensory loss, but also autonomic dysfunction of the bladder, bowel and sexual organs. Currently, there are no treatments available to improve outcome follow- ing SCI, leaving individuals with permanent and lifelong physical disability. Worldwide it is estimated that more than 500,000 people sustain a SCI each year, with average lifetime cost of paraplegia and quadriplegia estimated at $5 million and $9.5 million respectively. We therefore urgently need effective therapies to improve quality of life following SCI, and this requires a greater understanding of how cell and axonal injury develops after the traumatic event.

Effects of age and sex on clinical high-risk for psychosis in the community

BACKGROUND Recent reports of both heightened prevalence rates and limited clinical relevance of clinical high-risk(CHR)criteria and their relevant symptoms in children and adolescents indicate an important role of neurodevelopment in the early detection of psychoses.Furthermore,sex effects in CHR symptoms have been reported,though studies were inconclusive.As sex also impacts on neurodevelopment,we expected that sex might have an additional contribution to age in the prevalence and clinical relevance of CHR symptoms and criteria.AIM To investigate age and sex effects on CHR criteria and symptoms and their association with psychosocial impairment and mental disorder.METHODS In this cross-sectional cohort study,n=29168-to 40-year-olds,randomly drawn from the population register of the Swiss canton Bern,were assessed in semistructured interviews by phone or face-to-face for CHR symptoms and criteria using the Structured Interview for Psychosis-Risk Syndromes and the Schizophrenia Proneness Instrument in its child and youth,and adult version,respectively.Furthermore,social and occupational functioning and DSM-IV axis I disorders were assessed.Simple and interaction effects of age and sex on CHR symptoms and criteria,and interaction effects of age,sex,and CHR symptoms and criteria on presentation of functional impairment and of non-psychotic disorder were investigated using logistic regression analyses.RESULTS Altogether,542(18.6%)participants reported any CHR symptom;of these,261(9.0%)participants reported any one of the 11 criteria relevant cognitive and perceptual basic symptoms,and 381(13.1%)any one of the five attenuated or transient psychotic symptoms(attenuated psychotic symptoms/brief intermittent psychotic symptoms).Fewer participants met any one of the CHR criteria(n=82,2.8%)or any one of the three recently recommended CHR criteria(n=38,1.3%).Both age and sex were significantly(P<0.05)associated with CHR symptoms and criteria,mostly by younger age and female sex.Though slightly differing between symptom groups,age thresholds were detected around the turn from adolescence to adulthood;they were highest for cognitive basic symptoms and CHR criteria.With the exception of the infrequent speech disorganization attenuated psychotic symptom,the interaction of age with CHR symptoms and criteria predicted functional impairment;whereas,independent of each other,sex and CHR symptoms mostly predicted mental disorders.CONCLUSION Age and sex differentially impact on CHR symptoms and criteria;these differences may support better understanding of causal pathways.Thus,future CHR studies should consider effects of sex and age.

Locoregional extension patterns of nasopharyngeal carcinoma and suggestions for clinical target volume delineation

Clinical target volume (CTV) delineation is crucial for tumor control and normal tissue protection. This study aimed to define the locoregional extension patterns of nasopharyngeal carcinoma (NPC) and to improve CTV delineation. Magnetic resonance imaging scans of 2366 newly diagnosed NPC patients were reviewed. According to incidence rates of tumor invasion, the anatomic sites surrounding the nasopharynx were classified into high-risk (>30%), medium-risk (5%-30%), and low-risk (<5%) groups. The lymph node (LN) level was determined according to the Radiation Therapy Oncology Group guidelines, which were further categorized into the upper neck (retropharyngeal region and level Ⅱ), middle neck (levels Ⅲ and Va), and lower neck (levels Ⅳ and Vb and the supraclavicular fossa). The high-risk anatomic sites were adjacent to the nasopharynx, whereas those at medium- or low-risk were separated from the nasopharynx. If the high-risk anatomic sites were involved, the rates of tumor invasion into the adjacent medium-risk sites increased; if not, the rates were significantly lower (P < 0.01). Among the 1920 (81.1%) patients with positive LN, the incidence rates of LN metastasis in the upper, middle, and lower neck were 99.6% , 30.2%, and 7.2%, respectively, and skip metastasis happened in only 1.2% of patients. In the 929 patients who had unilateral upper neck involvement, the rates of contralateral middle neck and lower neck involvement were 1.8% and 0.4%, respectively. Thus, local disease spreads stepwise from proximal sites to distal sites, and LN metastasis spreads from the upper neck to the lower neck. Individualized CTV delineation for NPC may be feasible.

Cancer stem cell impact on clinical oncology

Cancer is a widespread worldwide chronic disease. In most cases, the high mortality rate from cancer correlates with a lack of clear symptoms, which results in late diagnosis for patients, and consequently, advanced tumor disease with poor probabilities for cure, since many patients will show chemo-and radio-resistance. Several mechanisms have been studied to explain chemo-and radio-resistance to anti-tumor therapies, including cell signaling pathways, anti-apoptotic mechanisms, stemness, metabolism, and cellular phenotypes. Interestingly, the presence of cancer stem cells(CSCs), which are a subset of cells within the tumors, has been related to therapy resistance. In this review, we focus on evaluating the presence of CSCs in different tumors such as breast cancer, gastric cancer, lung cancer, and hematological neoplasias, highlighting studies where CSCs were identified in patient samples. It is evident that there has been a great drive to identify the cell surface phenotypes of CSCs so that they can be used as a tool for anti-tumor therapy treatment design. We also review the potential effect of nanoparticles, drugs, natural compounds, aldehyde dehydrogenase inhibitors, cell signaling inhibitors, and antibodies to treat CSCs from specific tumors. Taken together, we present an overview of the role of CSCs in tumorigenesis and how research is advancing to target these highly tumorigenic cells to improve oncology patient outcomes.

Current evidence and challenges of systematic therapies for adult recurrent glioblastoma: Results from clinical trials

Recurrence is a major concern for adult patients with glioblastomas(GBMs), and the prognosis remains poor.Although several therapies have been assessed, most of them have not achieved satisfactory results. Therefore, there is currently no standard treatment for adult recurrent GBM(r GBM). Here, we review the results of clinical trials for the systematic therapy of r GBM. Regorafenib, rindopepimut and neoadjuvant programmed death 1(PD-1)inhibitors are promising agents for r GBM, while regorafenib is effective in both O6-methylguanine DNA methyltransferase(MGMT) promoter methylated and unmethylated patients. Temozolomide rechallenge and alkylating agents combined with bevacizumab can be useful for patients with MGMT methylation, and patients with isocitrate dehydrogenase(IDH) mutations or second recurrence can benefit from vocimagene amiretrorepvec(Toca511). Some phase I trials on targeted therapy and immunotherapy have shown positive results, and results from further studies are expected. In addition to the analysis of existing clinical trial results, forthcoming trials should be well designed, and patients are encouraged to participate in appropriate clinical trials.

Clinical nutrition in the hepatogastroenterology curriculum

Gastroenterology(GE) used to be considered a subspecialty of internal medicine. Today, GE is generally recognized as a wide-ranging specialty incorporating capacities, such as hepatology, oncology and interventional endoscopy, necessitating GEexpert differentiation. Although the European Board of Gastroenterology and Hepatology has defined specific expertise areas in Advanced endoscopy, hepatology, digestive oncology and clinical nutrition, training for the latter topic is lacking in the current hepatogastroenterology(HGE) curriculum. Given its relevance for HGE practice, and being at the core of gastrointestinal functioning, there is an obvious need for training in nutrition and related issues including the treatment of disease-related malnutrition and obesity and its associated metabolic derangements. This document aims to be a starting point for the integration of nutritional expertise in the HGE curriculum, allowing a central role in the management of malnutrition and obesity. We suggest minimum endpoints for nutritional knowledge and expertise in the standard curriculum and recommend a focus period of training in nutrition issues in order to produce well-trained HGE specialists. This article provides a road map for the organization of such a training program. We would highly welcome the World Gastroenterology Organisation, the European Board of Gastroenterology and Hepatology, the American Gastroenterology Association and other(inter)national Gastroenterology societies support the necessary certifications for this item in the HGE-curriculum.

Vascular targeted photochemotherapy using padoporfin and padeliporfin as a method of the focal treatment of localised prostate cancer-clinician's insight

Vascular targeted photochemotherapy(VTP) holds promise as a novel strategy of the focal treatment of localised prostate cancer(LPCa). It is convenient to perform, minimally invasive and can be conduct in ambulatory conditions. In this review, methodologic aspects of padoporfin- and padeliporfin-mediated VTP and its clinical application in focal treatment of LPCa as well as future perspective of this method were presented. Physicochemical and pharmacokinetic parameters of padoporphin and padeliporfin using as VTP photosensitizers were described, as well as methodologic question of radiation delivery and dosimetry, and oxygen monitoring in cancer tissue in context of VTP safety and efficiency of LPCa focal therapy were discussed. The results of clinical trials concerning application of padoporfin- and padeliporfin-mediated VTP in LPCa were also presented. The future of VTP is development of protocols, founded on the realtime feedback and rules-based approach to make this strategy a standard procedure in LPCa treatment. To evaluate clinical potential of this procedure, a costeffectiveness analysis is also necessary.

Thinking and practice on clinical safety evaluation of combination of traditional Chinese medicine and western medicine

China is gradually establishing a multidisciplinary diagnosis and treatment system of traditional Chinese medicine(TCM)and western medicine.TCM-drug combination is prone to adverse reactions.Clinical feature is the appearance of adverse reactions,and target is the internal mechanism.The establishment of feature and target correlation model will contribute to the development of this field.This paper introduces the four steps of feature-target correlation method that risk identification,feature extraction,sign target correlation and experimental research.Xiyanping-Ribavirin combination is as an example to illustrate this method.It is expected that the method will be popularized and applied to protect clinical safety.

New advances in targeted gastric cancer treatment

Despite a decrease in incidence over past decades,gastric cancer remains a major global health problem. In the more recent period, survival has shown only minor improvement, despite significant advances in diagnostic techniques, surgical and chemotherapeutic approaches, the development of novel therapeutic agents and treatment by multidisciplinary teams. Because multiple genetic mutations, epigenetic alterations, and aberrant molecular signalling pathways are involved in the development of gastric cancers, recent research has attempted to determine the molecular heterogeneity responsible for the processes of carcinogenesis, spread and metastasis. Currently, some novel agents targeting a part of these dysfunctional molecular signalling pathways have already been integrated into the standard treatment of gastric cancer, whereas others remain in phases of investigation within clinical trials. It is essential to identify the unique molecular patterns of tumours and specific biomarkers to develop treatments targeted to the individual tumour behaviour. This review analyses the global impact of gastric cancer, as well as the role of Helicobacter pylori infection and the efficacy of bacterial eradication in preventing gastric cancer development. Furthermore, the paper discusses the currently available targeted treatments and future directions of research using promising novel classes of molecular agents for advanced tumours.

Hepatocellular carcinoma: Therapeutic advances in signaling,epigenetic and immune targets

Hepatocellular carcinoma(HCC)remains a global medical burden with rising incidence due to chronic viral hepatitis and non-alcoholic fatty liver diseases.Treatment of advanced disease stages is still unsatisfying.Besides first and second generation tyrosine kinase inhibitors,immune checkpoint inhibitors have become central for the treatment of HCC.New modalities like epigenetic therapy using histone deacetylase inhibitors(HDACi)and cell therapy approaches with chimeric antigen receptor T cells(CAR-T cells)are currently under investigation in clinical trials.Development of such novel drugs is closely linked to the availability and improvement of novel preclinical and animal models and the identification of predictive biomarkers.The current status of treatment options for advanced HCC,emerging novel therapeutic approaches and different preclinical models for HCC drug discovery and development are reviewed here.

Targeted treatments for metastatic esophageal squamous cell cancer

Squamous cell carcinoma, one of the two major subtypes of esophageal carcinomas, constitutes the great majority of tumors in the upper and middle third of the organ. Declining in incidence in western countries, it continues to be a significant public health problem in the far east. Targeted treatments are novel therapies introduced in the clinical therapeutic armamentarium of oncology in the last 10-15 years. They represent a rational way of treating various cancers based on their molecular lesions. Although no such agent has been approved so far for the treatment of esophageal squamous cell carcinomas (ESCC), several are in clinical trials and several others have displayed pre-clinical activity that would justify the efforts and risks of pursuing their clinical development in this disease. This paper discusses some of these targeted agents in more advanced development in metastatic ESCC, as well as some promising drugs with pre-clinical or initial clinical data in the disease.

Development of targeted therapies in treatment of glioblastoma

Glioblastoma （GBM） is a type of tumor that is highly lethal despite maximal therapy. Standard therapeutic approaches provide modest improvement in progression-free and overall survival, necessitating the investigation of novel therapies. Oncologic therapy has recently experienced a rapid evolution toward ＂targeted therapy＂, with drugs directed against specific targets which play essential roles in the proliferation, survival, and invasiveness of GBM cells, including numerous molecules involved in signal transduction pathways. Inhihitors of these molecules have already entered or are undergoing clinical trials. However, significant challenges in their development remain because several preclinical and clinical studies present conflicting results. In this article, we will provide an up-to-date review of the current targeted therapies in GBM.

Immune checkpoint and inflammation as therapeutic targets in pancreatic carcinoma

Pancreatic adenocarcinoma(PAC) is one of the most deadly malignant neoplasms,and the efficacy of conventional cytotoxic chemotherapy is far from satisfactory. Recent research studies have revealed that immunosuppression and inflammation are associated with oncogenesis,as well as tumor development,invasion,and metastasis in PAC. Thus,immunosuppressionrelated signaling,especially that involving immune checkpoint and inflammation,has emerged as novel treatment targets for PAC. However,PAC is an immuneresistant tumor,and it is still unclear whether immune checkpoint or anti-inflammation therapies would be an ideal strategy. In this article,we will review immune checkpoint and inflammation as potential targets,as well as clinical trials and the prospects for immunotherapy in PAC.

Combining chemotherapy and targeted therapies in metastatic colorectal cancer

Colorectal cancer remains one of the major causes of cancer death worldwide. During the past years, the development of new effective treatment options has led to a considerable improvement in the outcome of this disease. The advent of agents such as capecitabine, irinotecan, oxaliplatin, cetuximab and bevacizumab has translated into median survival times in the range of 2 years. Intense efforts have focused on identifying novel agents targeting specific growth factor receptors, critical signal transduction pathways or mediators of angiogenesis. In addition, several clinical trials have suggested that some of these molecularly targeted drugs can be safely and effectively used in combination with conventional chemotherapy. In this article we review various treatment options combining cytotoxic and targeted therapies currently available for patients with metastatic colorectal cancer.

Targeted therapy of gastric cancer:current and prospective strategies

Gastric cancer is the third leading cause of cancer-related death worldwide. Surgery is currently the only curative treatment strategy. Chemotherapy has shown limited efficacy in advanced gastric cancer patients with a median overall survival of less than one year. Thus, new treatments are urgently needed. Trastuzumab and Ramucirumab are the only targeted therapies approved currently. Most Phase Ⅲ clinical trials evaluating targeted drugs in gastric cancer have failed. This review will evaluate relevant clinical trials with targeted therapies performed in gastric cancer patients, discuss the possible reasons for the failure, and indicate new possibilities to enhance gastric cancer treatment.

Efficacy and safety of Lianhuaqingwen capsules in high-risk common type COVID-19 pneumonia:A multicenter retrospective study

Objective:To evaluate the clinical safety and efficacy of Lianhuaqingwen(LHQW)capsules in patients with high-risk common type COVID-19 pneumonia.Methods:A retrospective multicenter study on 383 high-risk common type COVID-19 pneumonia cases was conducted.Patients were categorized as the standard treatment(SDT)group(n=168)and the LHQW+SDT group(n=215).The primary endpoint was the rate of symptom(fever,fatigue,coughing)recovery and the secondary endpoints included the time to symptom recovery,the proportion of patients with improvement in chest CT images,the proportion of patients with clinical cure,the timing and rate of negative conversion of SARS-CoV-2 RNA assay.Results:The recovery rate was significantly higher in the LHQW+SDT group as compared with the SDT group(89.7%vs.72.0%,P<0.01).The combined use of LHQW+SDT also showed shorter time for symptom recovery,as well as shorter time for individual symptom of fever,fatigue and coughing recovery than use of SDT alone.A higher proportion of patients in the LHQW+SDT group with improvements in chest CT images and clinical cure(77.7%vs.57.1%,P<0.01)but the proportion of patients deteriorating to severe cases(1%vs.25%,P<0.01)in this group was significant lower than those in the SDT group.No significant difference in negative conversion rate of viral assay results was observed(76.8%vs.75.0%,P>0.05).No serious adverse events were reported.Conclusions:LHQW capsules could be recommended to ameliorate clinical symptoms and reduce the rate of deteriorating to severe cases for high-risk common type COVID-19 pneumonia.

Preliminary Findings on the Use of Targeted Therapy in Combination with Sodium Phenylbutyrate in Advanced Malignant Mesothelioma: A Strategy for Improved Survival

Advanced malignant mesothelioma (MM) is among the most aggressive and difficult-to-treat diseases. Industrialization and exposure to asbestos is the main causative factor for the dramatic increase in the incidence of MM, which carries a poor prognosis and a median survival of less than 12 months. Combination chemotherapy offers only palliative results;however, targeted therapy carries more promise for future successful treatment. This paper presents preliminary findings of improved overall survival (OS) using a combination of sodium phenylbutyrate (PB) with various chemotherapeutic and targeted agents in advanced MM. The data suggest using a strategy of simultaneous interruption of signal transduction involving RAS-MEK-ERK, PI3K-AKT, mTOR, Merlin, and angiogenesis pathways and interference in cell cycle and epigenetic processes. Complete response was determined in 15.4% and stable disease in 46.2% in the group of 13 evaluable patients. Median OS for MM was higher compared to other treatments (17 months compared to between 6 and 12.1 months). The longest surviving patient continues to be in complete response and in excellent condition for over 12.5 years from the treatment start. These findings are only preliminary and validation of the results using a well-designed phase I/II trial in advanced MM is proposed.

Development of a risk score to guide targeted hepatitis C testing among human immunodeficiency virus patients in Cambodia

BACKGROUND The World Health Organization recommends testing all human immunodeficiency virus(HIV)patients for hepatitis C virus(HCV).In resource-constrained contexts with low-to-intermediate HCV prevalence among HIV patients,as in Cambodia,targeted testing is,in the short-term,potentially more feasible and cost-effective.AIM To develop a clinical prediction score(CPS)to risk-stratify HIV patients for HCV coinfection(HCV RNA detected),and derive a decision rule to guide prioritization of HCV testing in settings where‘testing all’is not feasible or unaffordable in the short term.METHODS We used data of a cross-sectional HCV diagnostic study in the HIV cohort of Sihanouk Hospital Center of Hope in Phnom Penh.Key populations were very rare in this cohort.Score development relied on the Spiegelhalter and Knill-Jones method.Predictors with an adjusted likelihood ratio≥1.5 or≤0.67 were retained,transformed to natural logarithms,and rounded to integers as score items.CPS performance was evaluated by the area-under-the-ROC curve(AUROC)with 95% confidence intervals(CI),and diagnostic accuracy at the different cut-offs.For the decision rule,HCV coinfection probability≥1% was agreed as test-threshold.RESULTS Among the 3045 enrolled HIV patients,106 had an HCV coinfection.Of the 11 candidate predictors(from history-taking,laboratory testing),seven had an adjusted likelihood ratio≥1.5 or≤0.67:≥50 years(+1 point),diabetes mellitus(+1),partner/household member with liver disease(+1),generalized pruritus(+1),platelets<200×10^(9)/L(+1),aspartate transaminase(AST)<30 IU/L(-1),AST-to-platelet ratio index(APRI)≥0.45(+1),and APRI<0.45(-1).The AUROC was 0.84(95%CI:0.80-0.89),indicating good discrimination of HCV/HIV coinfection and HIV mono-infection.The CPS result≥0 best fits the test-threshold(negative predictive value:99.2%,95%CI:98.8-99.6).Applying this threshold,30%(n=926)would be tested.Sixteen coinfections(15%)would have been missed,none with advanced fibrosis.CONCLUSION The CPS performed well in the derivation cohort,and bears potential for other contexts of low-to-intermediate prevalence and little onward risk of transmission(i.e.cohorts without major risk factors as injecting drug use,men having sex with men),and where available resources do not allow to test all HIV patients as recommended by WHO.However,the score requires external validation in other patient cohorts before any wider use can be considered.