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CLDN6 is a member of the CLDNs family that is specifically and highly expressed in cancers such as ovarian, testicular, endocervical, liver and lung adenocarcinoma, but hardly expressed in adult normal tissues. CLDN6 is able to activate multiple signaling pathways, which take part in the development and progression of cancer, including promoting tumor growth, migration and invasion, and promoting chemoresistance in cancer. In recent years, CLDN6 has received much attention as a novel target for cancer therapeutics. Many types of anticancer drugs targeting CLDN6 have been developed, including antibody-conjugated drugs (ADC), monoclonal antibodies, bispecific antibodies, and chimeric antigen receptor T-cell immunotherapy (CAR-T). This paper briefly summarizes the structure, expression and function of CLDN6 in tumors, and reviews the current status and ideas of developing targeted CLDN6 anticancer drugs.
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Signal Transduction , Immunotherapy , Antibodies, Monoclonal , Neoplasms/drug therapyABSTRACT
Idiopathic intracranial hypertension (IIH) is a syndrome of unexplained increased intracranial pressure with normal cerebrospinal fluid and without organic brain lesions. The etiology and pathogenesis of IIH remain unclear, and IIH patients may develop irreversible visual impairment. At present, there are no guidelines and expert consensus on diagnosis and treatment of IIH in China. This review aims to introduce the pathogenesis, diagnosis and treatment of IIH, in order to help clinicians improve their understanding of the disease and to identify, diagnose and treat IIH as early as possible, and improve the prognosis of patients.
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ObjectiveTo evaluate the clinical efficacy and safety of Zisheng Pill Formula （资生丸方， ZPF） in the treatment of malignant tumor targeted drugs-related diarrhea with spleen-stomach weakness syndrome. MethodsThis was an randomized controlled study， involving 34 cases in the treatment group and 33 cases in the control group. The treatment group was given ZPF decoction， one dose daily by twice， 200 ml each time， while the control group was given montmorillonite powder， three times per day， 3 g each time， with the first dose doubled， both groups for two weeks. The diarrhea frequency， stool characteristics， common terminology criteria for adverse events （CTCAE） for diarrhea， traditional Chinese medicine （TCM） syndrome score， the European organization for research on treatment of cancer （EORTC） quality of life questionnaire （EORTC QOL-C30） score， levels of serum intestinal functional indicators including diamine oxidase （DAO）， D-lactic acid （D-LA）， endotoxin （ET） levels were evaluated before and after treatment， and the safety was assessed. ResultsThere were 33 cases in the treatment group and 32 cases in the control group in terms of the per-protocol set （PPS）. The total effective rate of diarrhea of the treatment group and control group was 84.85% and 37.50%， respectively， and the total effective rate of TCM syndromes was 93.94% and 34.38%， with statistically significant differences between the groups （P＜0.01）. After treatment， the frequency of diarrhea and CTCAE grade decreased in both groups， with improved stool characteristics， increased overall health score， and decreased DAO， D-LA and ET levels； in the treatment group， the frequency of diarrhea， the TCM symptom scores in terms of stool characteristics， fear of cold and cold limbs， fatigue， numbness， nausea and vomiting， abdominal distension and abdominal pain were reduced， while the physical function score increased； in the control group， the frequency of diarrhea， stool characteristics and abdominal pain score decreased （P＜0.05 or P＜0.01）. The results favored the treatment group than the control group in all the outcomes except for the nausea and vomiting score， abdominal pain score， overall health score， physical function score， and ET level （P＜0.05 or P＜0.01）. During the treatment， one case of gastrointestinal infection and one case of constipation occurred in the treatment group， while one case of tumor progression in the control group. ConclusionZPF can effectively improve the clinical symptoms， increase quality of life， decrease serum DAO， D-LA and ET levels， and is safe when treating malignant tumor targeted drug-related diarrhea with spleen-stomach weakness syndrome. The possible mechanism may be related to the repair of intestinal mucosa barrier function.
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Tyrosine kinase inhibitors (TKIs) are a class of molecular targeted drugs that inhibit the activation of downstream signaling pathways by inhibiting oncogene-related receptor tyrosine kinases to exert anti-cancer effects. TKIs are superior to traditional chemotherapeutics in terms of selectivity, effectiveness and safety, and are widely used in the treatment of cancer. However, TKIs-induced liver injury is one of the difficult problems in its clinical application. In this article, relevant literatures from domestic and abroad are reviewed and the research progress in the classification, clinical application of TKIs and the mechanism of TKIs-induced liver injury are summarized. This review intends to provide a reference for further elucidating the mechanism of TKIs-induced liver injury, and seeking effective prevention and treatment methods.
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【Objective】 To explore the therapeutic effects of lactate dehydrogenase A (LDHA) inhibitor and targeted drugs on fumarate-hydratase-deficient renal cell carcinoma (FH-d RCC). 【Methods】 RNA-sequencing was used to detect the mRNA expression in FH-d RCC tissues, which was further validated with real-time fluorescence quantitative PCR and immunohistochemistry. Human-derived FH-d RCC cell line UOK262 and murine-derived FH-d RCC cell line FH1-/-CL19 (CL19) were treated with LDHA inhibitor [(R)-GNE-140] and listed kidney cancer targeted drugs (Axitinib, Cabozantinib, Sunitinib, Sorafenib, Pazopanib, Everolimus) respectively, and then treated with LHDA inhibitor in combination with the targeted drugs to observe the alteration of cell proliferation. The combination index (CI) of different dose groups of the combination drugs were analyzed with CompuSyn software to determine the optimal combination regimen. 【Results】 LDHA inhibitor and targeted drugs, including Cabozantinib, Sorafenib and Sunitinib, had a significant inhibitory effect on the proliferation of FH-d RCC cells, and the combination of Cabozantinib and Sorafenib or Pazopanib had a significant anti-tumor effect. 【Conclusion】 LDHA inhibitor combined with targeted drugs can significantly inhibit the growth of FH-d RCC cells, indicating that LDHA may be a potential therapeutic target of FH-d RCC.
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Being the most common solid malignant tumor in the digestive system and the third leading cause of cancer-related death worldwide， hepatocellular carcinoma （HCC） is characterized by insidious onset， early recurrence/metastasis and poor prognosis. With the advantages of targeted precision， high specificity， minimal drug resistance， remarkable therapeutic efficacy and fewer side effects， molecular targeted drugs have become the hotspot and focus of tumor therapy research in recent years. As more is learned about the mechanism and clinical efficacy， some molecular targeted drugs have been recommended by HCC treatment guidelines. This paper reviewed the mechanism of HCC targeted therapy， molecular targeted drugs， relevant therapeutic protocols and outcomes so as to provide reference and evidence for subsequent research.
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In recent years, with the emergence of new research evidence, the domestic and foreign guidelines in the field of gastrointestinal stromal tumors (GISTs) have been updated. The adjusted contents cover almost every link of GISTs management, from GISTs diagnosis, biological behavior, surgical treatment to targeted drug treatment. Since 2020, the NCCN of the United States has separated the contents related to GISTs from the clinical practice guide for soft tissue sarcoma for the first time to form 2021 V.1 versions. The CSCO has also adjusted and upgraded the previous consensus of Chinese experts on the diagnosis and treatment of GISTs to 2020 and 2021 versions of the guidelines for the diagnosis and treatment of GISTs. This opens a new model of accurate diagnosis and treatment of GISTs under the guidance of evidence-based medicine. The listing of new targeted drugs afatinib and ripretinib is expected to get rid of the drug-resistant treatment dilemma of metastatic GISTs, enrich the back-line treatment camp, provide more opportunities for surgical intervention, and then bring survival benefits to patients with advanced GISTs.
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Genodermatoses are a relatively independent type of skin diseases, with early onset, complex clinical manifestations and multiple system involvement. Current treatments of genodermatoses are still limited with poor therapeutic effect, and the quality of life of patients is greatly affected. This review summarizes prospective treatment methods of some hereditary skin diseases and related research progress, including innovative application of traditional medicines, biologics and small-molecule targeted drugs, stem cell therapy and gene editing, aiming to provide more reference for clinicians.
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In recent years, with the continuous in-depth research on the pathogenesis of rheumatism and the rapid development of biopharmaceutical technology, the development of targeted drugs for rheumatism is in full swing. In order to better standardize the diagnosis and treatment of rheumatism and the rational application of targeted drugs, the Chinese Rheumatology Association will introduce the targeted drugs for rheumatism that have been approved by the China National Medical Products Administration so far, and provide clinicians with standardized diagnosis and treatment reference.
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Objective:To study the effect of crizotinib on acute radiation-induced lung injury in mice and its possible mechanism.Methods:A total of 72 mice were randomly divided into 4 groups by the random number table method: healthy control group (NC group, n=12), crizotinib-only group (CRZ group, n=12), radiotherapy-only group (RT group, n=24), and radiotherapy pluscrizotinib group (RT+ CRZ group, n=24). The whole lungs were exposed to a single dose of 12 Gy X-rays. Lung tissue and bronchoalveolar lavage fluid (BALF) were obtained at 1, 2, 4, and 8 weeks after radiotherapy. The total number of nucleated cells was counted under a light microscope, and the total protein content of BALF was detected by bicinchoninic acid (BCA) protein assay. The pathological changes of lung tissue were observed by HE staining and MASSON staining. The expressions of TGF-β1 and ICAM-1 mRNA in lung tissue were detected by real-time quantitative polymerase chain reaction (qPCR), the locations and expressions of MPO and ICAM-1 proteins were observed by immunohistochemical staining, and the expressions of TGF-β1, Smad3, p-Smad3 and ICAM-1 proteins in lung tissue were detected by Western blot. Results:At different time points after irradiation, the pathological manifestations such as inflammation and exudation of lung tissue in the RT+ CRZ group were significantly increased, and the total number of cells and protein content in BALF was higher than that of the other three groups, compared with RT group, the difference was statistically significant at 4 week ( t=-5.031, -2.814, P<0.05). Compared with RT group, the expressions of ICAM-1 and TGF-β1 mRNA in lung tissue of the RT+ CRZ group were significantly increased, while the expression of TGF-β1 increased significantly at 1, 4 and 8 weeks after irradiation ( t=-2.687, -7.032, -5.221, P<0.05), and the expression of ICAM-1 increased significantly at 2 and 4 weeks after irradiation ( t=-4.819, -6.057, P<0.05). The expressions of these two gradually increased from 1 to 4 weeks and peaked in 4 weeks, then decreased at 8 weeks. At the same time, the trend of the expression of MPO mRNA was consistent with ICAM-1 and TGF-β1. At 4 week, there was no difference in the expression of Smad3 protein in these four groups ( P>0.05). The expressions of TGF-β1, p-Smad3, ICAM-1 and p-Smad3/Smad3 proteins of the RT+ CRZ group were all higher than those of the other three groups ( F=14.74, 10.03, 35.29, 22.94, P<0.05). Conclusions:Crizotinib combined with radiotherapy can aggravate acute radiation-induced lung injury, which may due to the increase of ICAM-1 expression by up-regulating the TGF-β1 signaling pathway.
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Osteoarthritis (OA) is one of the most disabling dis¬eases with high incidence, which involves the entire joint and its diseased tissues include cartilage, subchondral bone and synovi¬um.For the exploration of its pathogenesis, the current research focuses on: ( 1 ) cartilage damage caused by cartilage metabo¬lism imbalance.'Hie reasons include aging, trauma, obesity, biological rhythm changes, biological mechanics and other fac¬tors: (2) abnonnal bone remodeling of subchondral bone, resul¬ting in subchondral bone sclerosis and bone spurs; ( 3 ) cartilage debris leads to synovial inflammation caused by synovial macro¬ phages and T cells.At present, there have been clinical and pre-clinical studies of a variety of targeted small molecule drugs for the above symptoms.This review focuses on the current un¬derstanding of the underlying pathogenesis of OA, and emphasi-zes the important role of chondrocytes, macrophages, and osteo¬clasts, as well as the latest research progress in drug therapy at this stage.
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G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors in mammals that contain seven transmembrane helices. The human genome encodes about 800 different types of GPCRs, which are widely involved in the pathological processes underlying different diseases, e.g. metabolic diseases and tumors, rendering them popular therapeutic targets. Peptides are organic substances consisted of two to dozens of amino acids linked by peptide bonds. They are bioactive substances involved in various cellular activities. To date, over 7 000 natural peptides have been identified as hormones, neurotransmitters, growth factors, ion channel ligands and antibiotics. Peptide drugs are valued for being selective and efficacious, and at the same time relatively safe and with low costs of production. In recent years, based on the increased understanding of GPCR structures, the development of GPCR-targeting peptide drugs has made great progress. Up to now, there have been nearly 50 peptide drugs targeting GPCRs approved by FDA for the treatment of metabolic diseases, nervous system diseases, cancer or other diseases. The research and development of peptide drugs have gone through three stages: development based on human peptides, on natural peptides and by modern biotechnology. At present, most of the marketed GPCR-targeting peptide drugs are derivatives of human natural peptides. In this review, we sum up the recent marketed GPCR-targeting peptide drugs, and also summarize the current strategies and further directions of peptide drug development.
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Objective@#The purpose of this review of COVID-19 related research is to deepen our understanding of SARS-CoV-2, which would be inspire new ideas for targeted drug development and vaccine design, and further empower the prevention and control COVID-19.@*Methods@#Through literature research and data analysis, we explored the process and mechanism of epitranscriptomics modification to regulate the replication and infectivity of COVID-19.@*Results@#Provide important ideas and technical support for the prevention and control of SARS-CoV-2 infections and emerging epidemic diseases.@*Conclusions@#Taking the new research direction of epitranscriptomics as the starting point, it is expected to open up new scientific research concepts and paradigms.
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Since sorafenib has been first-line molecular-targeted drug for advanced hepatocellular carcinoma (HCC), clinical studies in the last 10 years failed to confirm that a new molecular-targeted drug or immune checkpoint inhibitor was superior or non-inferior to sorafenib, or approved second-line treatment for patients with the failure of sorafenib. However, many clinical studies published in 2017 have changed people′s previous understanding. REFLECT trial showed that as the first-line treatment of advanced HCC, lenvatinib was non-inferior than sorafenib. In addition, RESORCE trial and CheckMate-040 trial confirmed respectively that regorafenib and PD-1 inhibitor nivolumab were options of second-line treatment for patients with advanced HCC after sorafenib treatment. The development of these drugs will bring a new prospect for advanced HCC patients.
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Microvascular invasion (MVI) is one of the invasive characteristics of hepatocellular carcinoma (HCC) and also an independent risk factor for intrahepatic and distant metastasis of hepatocellular carcinoma.The occurrence of MVI in patients with hepatocellular carcinoma is universal and can occur in different stages of hepatocellular carcinoma,which is the result of the joint action of multiple factors,including tumor diameter,tumor morphology,tumor pathological grading,and hepatitis B virus activity and replication.For patients with preoperative assessment of MVI risk factors,reasonable surgical plans should be made according to the basic conditions of patients.Non-anatomic hepatectomy is performed to expand the resection scope as far as possible (at least ＞ 1 cm),and anatomic hepatectomy is performed with complete Laennec cystectomy along the Glisson system.Pathological examination is the gold standard of MVI diagnosis,and standardized diagnosis can improve the detection rate of MVI.MVI is mainly related to early postoperative recurrence of hepatocellular carcinoma (within 1 year).For patients with positive MVI after HCC resection,selective combination with transcatheter arterial chemoembolization,radiotherapy and molecular targeted drugs can reduce tumor recurrence and prolong the survival time of patients with liver cancer without recurrence.Therefore,MVI has important clinical significance for the comprehensive diagnosis and treatment of hepatocellular carcinoma.
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Larotrectinib (also called LOxO-101, ARRY-470, and VITRAKVI?) is a kind of new high selective and broad-spectrum small molecule that is administered orally. Larotrectinib is tropomyosin receptor kinase (TRK) inhibitor and is used in the treatment of neuro-trophin tyrosine kinase receptor (NTRK) gene fusion in children and in adults. Based on use of larotrectinib against solid tumor in a vari-ety of NTRK gene fusion, larotrectinib has a good curative effect and security. On November 27, 2018, the drug was approved by the Food and Drug Administration (FDA) for the first time in the world. It is used in the treatment of no unknown drug resistant mutations, a broader shift, or partial surgical treatment, and after the treatment of disease progress of NTRK gene fusion in children and adult pa-tients with solid tumor. This article reviews the latest research progress in the research background, structure, and mechanism of ac-tion, clinical trials, adverse reactions and treatment, and drug resistance mechanism of larotrectinib.
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Objective: Invasive pulmonary Aspergillus infection has the characteristics of high morbidity, difficult to be treated, poor prognosis and high mortality. This study aims to investigate the effects of cinnamaldehyde on 1,3-β-D-glucans in the pulmonary Aspergillus fumigatus cell wall to provide a basis for developing novel antifungal drugs. Methods: Immunosuppressed ICR mice were intranasally inoculated with 50 µL of A. fumigatus suspension (1 × 107 CFU/mL) and then separated into two groups, for the experimental group cinnamaldehyde was orally administered at 240 mg/kg/d consecutively for 14 d. While for the control group, voriconazole was used to treat the fungus infection. Pulmonary tissues were then extracted for 1,3-β-D-glucans assay and electron microscopy. Results: The concentration of 1,3-β-D-glucans was significantly different between the cinnamaldehyde and voriconazole groups, which was (1160.89 ± 364.96) pg/mL and (3885.94 ± 845.45) pg/mL, respectively (P < 0.01). Electron microscopy showed that 2−3 outer layers (1,3-β-D-glucan layer) of A. fumigatus cell wall were damaged and fell off, resulting in serious defect of the cell wall, but the cell membrane was clear and intact. Conclusion: Cinnamaldehyde has a significant influence on the integrity of 1,3-β-D-glucans in the pulmonary A. fumigatus cell wall, but the cell membrane is unaffected, suggesting that cinnamaldehyde has unique antifungal properties depending on its action against the 1,3-β-D-glucans on the pulmonary A. fumigatus cell wall.
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With the advent of the era of accurate medical treatment,molecular targeted therapy has become a new trend of cancer treatment.The abnormal status of cancer metabolism and metabolic drug together with tumor targeted therapy are becoming the hotspot in cancer.A large number of studies have shown that metformin,a targeted metabolic drug,has synergistic anti-tumor effects when it is used in combination with various target drugs.The combination of targeted metabolic drugs and anti-tumor drugs can provide new strategies for tumor treatment.
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OBJECTIVE:To evaluate the affordability of 3 anti-tumor targeted drugs gefitinib,trastuzumab and sunitinib in ur-ban and rural residents of Hubei province,and to provide reference for medical insurance price admission of anti-malignant tumor targeted drugs in China. METHODS:Referring to the incidence of malignant tumor stated in statistical yearbook of Hubei province and income data of urban and rural residents in Hubei province,based on the policy of reducing the price of imported drugs by 50% mentioned in the national drug price negotiations,and assume the drugs are included in the medical insurance reimbursement list,WHO/HAI standard survey method,catastrophic expenditure evaluation method and poverty effect evaluation method were ad-opted to calculate the affordability of 3 drugs. RESULTS:According to WHO/HAI standard survey method,increment of payment for 3 drugs were 64.00%-74.00% before and after 50% discount and reimbursement. According to catastrophic expenditure evalua-tion method,50% discount of gefitinib and reimbursement gefitinib,trastuzumab and sunitinib in urban area would result in cata-strophic expenditures of 20.00%、59.28% and 35.48% patients;in rural area,would result in catastrophic expenditures of 50.63%、74.72% and 75.93% patients. According to poverty effect evaluation method,50% discount of 3 drugs and reimbursement caused less than 31.95% urban and rural patients falling to poverty. CONCLUSIONS:Fifty percentage discount of 3 anti-tumor targeted drugs mentioned in the national drug price negotiations cause the economic burden more serious for rural residents than urban resi-dents. In the formulation of policies,the corresponding reimbursement ratio should be adjusted according to urban and rural areas, drug price and disease types for a balance of patients with different economic burden.
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Objective To adopt the network meta analysis method to compare the incidence difference of cutaneous squamous-cell carcinoma(SCC)and rash in 5 kinds of targeted drugs regimen for treating malignant melanoma.Methods PubMed and Cochrane Library databases were retrieved by computer.The retrieval range was from their establishment to November 2015.The network meta analysis pooled the evidences of direct and indirect comparison for evaluating the pooled odds ratio(OR)and cumulative probability of cutaneous complications occurrence difference in 5 kinds of targeted drugs regimen for treating malignant melanoma.Results Six randomized controlled trials(RCTs)conforming to the inclusion criteria were included.The meta analysis results revealed that compared with Dabrafenib+Trametinib,the cutaneous SCC occurrence rate of Vemurafenib was higher(OR=9.20,95％CI=1.26-52.53),while the rash occurrence rate of Vemurafenib+Cobimetinib was higher(OR=6.81,95％CI=1.01-41.87).The surface under the cumulative ranking curves(SUCRA)value showed that adopting Trametinib had the lowest occurrence rate for SCC,and adopting Dabrafenib+Trametinib had the lowest occurrence rate of rash.Conclusion Dabrafenib+Trametinibis generate the lowest complication incidence rate of malignant melanoma.