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Progress and challenges in RET-targeted cancer therapy

《医学前沿（英文）》 2023年 第17卷 第2期   页码 207-219 doi: 10.1007/s11684-023-0985-y

摘要： The rearranged during transfection (RET) is a receptor protein tyrosine kinase. Oncogenic RET fusions or mutations are found most often in non-small cell lung cancer (NSCLC) and in thyroid cancer, but also increasingly in various types of cancers at low rates. In the last few years, two potent and selective RET protein tyrosine kinase inhibitors (TKIs), pralsetinib (BLU-667) and selpercatinib (LOXO-292, LY3527723) were developed and received regulatory approval. Although pralsetinib and selpercatinib gave high overall response rates (ORRs), < 10% of patients achieved a complete response (CR). The RET TKI-tolerated residual tumors inevitably develop resistance by secondary target mutations, acquired alternative oncogenes, or MET amplification. RET G810 mutations located at the kinase solvent front site were identified as the major on-target mechanism of acquired resistance to both selpercatinib and pralsetinib. Several next-generation of RET TKIs capable of inhibiting the selpercatinib/pralsetinib-resistant RET mutants have progressed to clinical trials. However, it is likely that new TKI-adapted RET mutations will emerge to cause resistance to these next-generation of RET TKIs. Solving the problem requires a better understanding of the multiple mechanisms that support the RET TKI-tolerated persisters to identify a converging point of vulnerability to devise an effective co-treatment to eliminate the residual tumors.

关键词： pralsetinib     selpercatinib     RET-alteration     lung cancer     thyroid cancer     tumor-agnostic therapy     drug resistance    

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甲状腺乳头状癌菌群失调及与肿瘤信号通路异常的相关性研究 Article

喻爽, 丁彦强, 王雪洁, Siu Kin Ng, 曹思婷, 刘伟鑫, 郭朱明, 谢宇彬, 洪澍彬, 许丽霞, 李晓星, 李杰, 吕伟明, 彭穗, 李延兵, 沈祖尧, 于君, 肖海鹏

《工程（英文）》 2023年 第28卷 第9期   页码 179-192 doi: 10.1016/j.eng.2023.01.007

摘要：

研究表明微生态失调在多种肿瘤的发生发展中起至关重要的作用。然而，对于甲状腺肿瘤中细菌是否参与肿瘤的发生仍不清楚。本研究中，我们旨在探索甲状腺组织中的菌群特征及其对甲状腺乳头状癌（PTC）的作用。我们同时对 340 例PTC和甲状腺良性结节 （BTN） 患者的肿瘤组织及其邻近正常组织进行菌群分析和转录组测序。在PTC、BTN及其邻近无肿瘤组织中鉴定出明显不同的菌群特征。我们通过免疫组化染色、细菌原位杂交和电镜观察验证了甲状腺组织内细菌的存在。与BTN相比，我们发现在PTC中有17个菌属存在显著丰度差异，其中PTC中富集菌Rhodococcus、Neisseria、Streptococcus、Halomonas和Devosia存在促癌作用；以及丰度降低的Amycolatopsis则可能有抑癌作用。这些丰度存在明显差异的细菌可以鉴别PTC组织（PTC-T）与BTN组织（BTN-T），曲线下面积（AUC）为81.66%。微生物网络分析表明，PTC组织内细菌间的相互关联性高于BTN组织。同时，在合并桥本甲状腺炎组织的PTC中发现与免疫相关的菌属（Erwinia、Bacillus 和 Acinetobacter）明显富集。此外，我们联合转录组测序分析提示PTC富集菌与肿瘤相关信号通路的关键基因如BRAF、KRAS、IRAK4、CTNNB1、PIK3CA、MAP3K7 和 EGFR存在正相关性。总的来说，我们的研究结果表明，甲状腺肿瘤组织内存在菌群失调，并可能通过肿瘤相关信号通路参与PTC的发生。

关键词： 甲状腺乳头状癌     甲状腺良性结节     细菌     转录组     桥本甲状腺炎    

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The effect of orbital radiation therapy on thyroid-associated orbitopathy complicated with dysthyroid

null

《医学前沿（英文）》 2017年 第11卷 第3期   页码 359-364 doi: 10.1007/s11684-017-0528-5

摘要：

Thyroid-associated orbitopathy (TAO) is an inflammatory autoimmune disorder. The most serious complication of TAO is dysthyroid optic neuropathy (DON), which can lead to permanent vision loss because of volume expansion in the orbital apex. Orbital radiation therapy (ORT) is an anti-inflammatory treatment used in the treatment of active TAO. Clinical studies support radiotherapy as having a modest effect on DON, and early radiotherapy may protect against disease progression to DON. Current studies suggest that radiotherapy is generally safe. However, risks still exist in some cases. The possible effects of radiotherapy on TAO, especially complicated with DON, are reviewed. The effects of radiotherapy on DON are not completely known, and evidence from standardized, prospective, and multicenter clinical trials is still lacking.

关键词： thyroid-associated orbitopathy     dysthyroid optic neuropathy     orbital radiation therapy    

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Are the SNPs of NKX2-1 associated with papillary thyroid carcinoma in the Han population of Northern

null

《医学前沿（英文）》 2014年 第8卷 第1期   页码 113-117 doi: 10.1007/s11684-014-0310-x

摘要：

Papillary thyroid carcinoma (PTC) is one of the most common tumors of the thyroid gland. The common risk factors of PTC include ionizing radiation, positive family history, and thyroid nodular disease. PTC was identified in Europeans by conducting a genome-wide association study, and a strong association signal with PTC was observed in rs944289 and NKX2-1 (located at the 14q13.3 locus), which was probably the genetic risk factor of PTC. This study aimed to examine the association of this gene with PTC in Chinese. A total of 354 patients with PTC and 360 healthy control subjects from the Han population of Northern China were recruited in the study. These individuals were genotyped to determine rs12589672, rs12894724, rs2076751, and rs944289. The association of rs944289 with PTC was obtained (C vs. T, P=0.027, OR=1.264, 95% CI=1.026-1.557; and C/C-C/T vs. T/T, P=0.034, OR=1.474, 95% CI=1.028-2.112). Conducting a subgroup analysis, we found a marginal difference in the allele frequency distribution of rs944289 (adjusted P=0.062) between the patients with PTC and multi-nodular goiter and the control subjects. We also observed an interaction (P=0.029; OR=2.578, 95% CI=1.104-6.023) between rs944289 and diabetes in patients with PTC. In conclusion, rs944289 was associated with an increased risk of PTC in the Han population of Northern China, but no clear association was observed in either of the tag single nucleotide polymorphisms of NKX2-1.

关键词： NKX2-1     papillary thyroid carcinoma     the Han population of Northern China     association    

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Analyses of levels of thyroid hormones and its receptor expression in puerperants and newborns from an

JU Ying, CHEN Lan, JIANG Qi, YANG Kedi, CHEN Xuemin, XU Guojian, LI Liping

《医学前沿（英文）》 2008年 第2卷 第3期   页码 276-282 doi: 10.1007/s11684-008-0052-8

摘要： In this study, the serum levels, including thyroid hormones free triiodothyronine (FT), free thyroxine(FT),thyroid stimulating hormone(TSH)among the subjects from the exposed group ( = 48) and the control group ( = 45) were detected by immuno radiometric assay (IRMA). The expression levels of TR?1, TR?1, TSHR mRNA in placentas and umbilical cords were detected by fluorescent quantitative real-time PCR (FQ-PCR). The correlations between the thyroid hormone levels in maternal serum and umbilical serum, and between the expression levels of its receptors mRNA in placentas and umbilical cords were determined. We found that the FT levels of both maternal serum and umbilical cord serum in the exposed group were lower than those in the control ( < 0.05). However, the increased TSH levels in the exposed group had statistically significance compared to those in the control group ( < 0.05). The TR?1 and TR?1 mRNA levels both in placentas and umbilical cords in the exposed group were lower than those in the control group ( < 0.05 and 0.01). However, the TSHR mRNA levels in the exposed group were significantly different compared to those in the control group ( < 0.01). The serum FT4 and TSH levels of parturient women were positively correlated with those of the newborns in both groups ( < 0.05 and 0.01). The mRNA levels of TR?1, TR?1 and TSHR in the placentas were positively correlated with those in umbilical cords in both groups ( < 0.01). The findings suggest that some environmental pollutants existing in the electronic waste (e-waste) dismantling region may affect the health of local parturient women and newborns, representing changes both in serum levels of thyroid hormones and in mRNA expression of its receptors.

关键词： control     immuno radiometric     FT     TSH     exposed    

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mesenchymal stem cells promotes the expression of tumor-suppressive FAT1 and inhibits stemness maintenance in thyroid

《医学前沿（英文）》 doi: 10.1007/s11684-023-0999-5

摘要： Through bioinformatics predictions, we identified that GTF2I and FAT1 were downregulated in thyroid carcinoma (TC). Further, Pearson’s correlation coefficient revealed a positive correlation between GTF2I expression and FAT1 expression. Therefore, we selected them for this present study, where the effects of bone marrow mesenchymal stem cell-derived EVs (BMSDs-EVs) enriched with GTF2I were evaluated on the epithelial–to–mesenchymal transition (EMT) and stemness maintenance in TC. The under-expression of GTF2I and FAT1 was validated in TC cell lines. Ectopically expressed GTF2I and FAT1 were found to augment malignant phenotypes of TC cells, EMT, and stemness maintenance. Mechanistic studies revealed that GTF2I bound to the promoter region of FAT1 and consequently upregulated its expression. MSC-EVs could shuttle GTF2I into TPC-1 cells, where GTF2I inhibited TC malignant phenotypes, EMT, and stemness maintenance by increasing the expression of FAT1 and facilitating the FAT1-mediated CDK4/FOXM1 downregulation. In vivo experiments confirmed that silencing of GTF2I accelerated tumor growth in nude mice. Taken together, our work suggests that GTF2I transferred by MSC-EVs confer antioncogenic effects through the FAT1/CDK4/FOXM1 axis and may be used as a promising biomarker for TC treatment.

关键词： thyroid carcinoma     mesenchymal stem cell     extracellular vesicle     GTF2I     FAT1     CDK4    

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Sensitivity of supplementation of thyroid hormone on treatment of idiopathic short-stature children during

Wei Wang, Shuqin Jiang, Zhirui Cui, Xiangyang Luo, Lingli Shi, Heli Zheng

《医学前沿（英文）》 2018年 第12卷 第5期   页码 580-585 doi: 10.1007/s11684-017-0585-9

摘要：

This study aimed to evaluate the effects of thyroid hormone supplementation on growth rate of children with idiopathic short stature (ISS) and low-normal serum free thyroxine FT4 who were receiving growth hormone therapy. We selected 64 prepubertal children with FT4 levels in the lowest third of the normal range as the lower FT4 group, and these children were divided randomly into two subgroups: L-thyroxine (L-T4)-treated subgroup was treated with L-T4 (0.5–3.0 g/(kg·d)) from the beginning of the study, and the non-L-T4-treated subgroup received placebo. We also selected 39 ISS children with FT4 in the upper two-thirds of the normal range as the higher FT4 group. During the first year, the lower FT4 group featured lower FT3, FT4, thyroid stimulating hormone (TSH), and insulin-like growth factor-I standard deviation score (IGF-I SDS) and significantly lower height velocity (HV) compared with the higher FT4 group. However, in the lower FT4 group, the L-T4-treated subgroup presented higher FT4, FT3, TSH, and IGF-I SDS concentrations and significantly higher HV compared with children in the non-L-T4-treated subgroup. In children with ISS, the negative effect of thyroid hormone deficiency on growth rate should be considered when FT4 level lies in the low-normal range prior to recombinant human growth hormone treatment.

关键词： therapeutic     idiopathic short-stature children     free T4     the first year     recombinant human growth hormone    

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Atypical pituitary hormone–target tissue axis

《医学前沿（英文）》 2023年 第17卷 第1期   页码 1-17 doi: 10.1007/s11684-022-0973-7

摘要： A long-held belief is that pituitary hormones bind to their cognate receptors in classical target glands to actuate their manifold functions. However, a number of studies have shown that multiple types of pituitary hormone receptors are widely expressed in non-classical target organs. Each pituitary gland-derived hormone exhibits a wide range of nonconventional biological effects in these non-classical target organs. Herein, the extra biological functions of pituitary hormones, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, adrenocorticotrophic hormone, and prolactin when they act on non-classical organs were summarized, defined by the novel concept of an “atypical pituitary hormone–target tissue axis.” This novel proposal explains the pathomechanisms of abnormal glucose and lipid metabolism, obesity, hypertension, fatty liver, and atherosclerosis while offering a more comprehensive and systematic insights into the coordinated regulation of environmental factors, genetic factors, and neuroendocrine hormones on human biological functions. The continued exploration of the physiology of the “atypical pituitary hormone–target tissue axis” could enable the identification of novel therapeutic targets for metabolic diseases.

关键词： thyroid-stimulating hormone     follicle-stimulating hormone     luteinizing hormone     adrenocorticotrophic hormone     prolactin    

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Midline2 is overexpressed and a prognostic indicator in human breast cancer and promotes breast cancer

《医学前沿（英文）》 2021年 第15卷 第6期   页码 942-942 doi: 10.1007/s11684-021-0876-z

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Epithelial-to-mesenchymal transition in cancer: complexity and opportunities

Yun Zhang, Robert A. Weinberg

《医学前沿（英文）》 2018年 第12卷 第4期   页码 361-373 doi: 10.1007/s11684-018-0656-6

摘要：

The cell-biological program termed the epithelial-to-mesenchymal transition (EMT) plays an important role in both development and cancer progression. Depending on the contextual signals and intracellular gene circuits of a particular cell, this program can drive fully epithelial cells to enter into a series of phenotypic states arrayed along the epithelial-mesenchymal phenotypic axis. These cell states display distinctive cellular characteristics, including stemness, invasiveness, drug-resistance and the ability to form metastases at distant organs, and thereby contribute to cancer metastasis and relapse. Currently we still lack a coherent overview of the molecular and biochemical mechanisms inducing cells to enter various states along the epithelial-mesenchymal phenotypic spectrum. An improved understanding of the dynamic and plastic nature of the EMT program has the potential to yield novel therapies targeting this cellular program that may aid in the management of high-grade malignancies.

关键词： epithelial-to-mesenchymal transition     cancer     metastasis     cancer stem cell    

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Long-term results of suppressing thyroid-stimulating hormone during radiotherapy to prevent primary hypothyroidism

Maura Massimino, Marta Podda, Lorenza Gandola, Emanuele Pignoli, Ettore Seregni, Carlo Morosi, Filippo Spreafico, Andrea Ferrari, Emilia Pecori, Monica Terenziani

《医学前沿（英文）》 2021年 第15卷 第1期   页码 101-107 doi: 10.1007/s11684-020-0752-2

摘要： Primary hypothyroidism commonly occurs after radiotherapy (RT), and coincides with increased circulating thyroid-stimulating hormone (TSH) levels. We tested therefore the protective effect of suppressing TSH with L-thyroxine during RT for medulloblastoma/PNET and Hodgkin lymphoma (HL) in a prospective cohort study. From 1998 to 2001, a total of 37 euthyroid children with medulloblastoma/PNET plus 14 with HL, scheduled for craniospinal irradiation and mediastinum/neck radiotherapy, respectively, underwent thyroid ultrasound and free triiodothyronine (FT3), free thyroxine (FT4), and TSH evaluation at the beginning and end of craniospinal iiradiation. From 14 days before and up to the end of radiotherapy, patients were administered L-thyroxine checking every 3 days TSH to ensure a value<0.3 μIU/mL. During follow-up, blood tests and ultrasound were repeated; primary hypothyroidism was considered an increased TSH level greater than normal range. Twenty-two/37 patients with medulloblastoma/PNET and all the 14 patients with HL were alive after a median 231 months from radiotherapy with 7/22 and 8/14 having correctly reached TSH levels ˂ 0.3 μIU/mL and well matched for other variables. Twenty years on, hypothyroidism-free survival rates differed significantly, being 60%±15% and 15.6%±8.2% in TSH-suppressed vs. not-TSH suppressed patients, respectively ( =0.001). These findings suggest that hypothyroidism could be durably prevented in two populations at risk of late RT sequelae, but it should be confirmed in a larger cohort.

关键词： iatrogenic primary hypothyroidism     late effects of radiotherapy     long-term follow-up     medulloblastoma     Hodgkin lymphoma    

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Metformin for cancer prevention

Yonghua Yang

《医学前沿（英文）》 2011年 第5卷 第2期   页码 115-117 doi: 10.1007/s11684-011-0112-3

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Orlistat induces ferroptosis-like cell death of lung cancer cells

《医学前沿（英文）》 2021年 第15卷 第6期   页码 922-932 doi: 10.1007/s11684-020-0804-7

摘要： Aberrant de novo lipid synthesis is involved in the progression and treatment resistance of many types of cancers, including lung cancer; however, targeting the lipogenetic pathways for cancer therapy remains an unmet clinical need. In this study, we tested the anticancer activity of orlistat, an FDA-approved anti-obesity drug, in human and mouse cancer cells in vitro and in vivo, and we found that orlistat, as a single agent, inhibited the proliferation and viabilities of lung cancer cells and induced ferroptosis-like cell death in vitro. Mechanistically, we found that orlistat reduced the expression of GPX4, a central ferroptosis regulator, and induced lipid peroxidation. In addition, we systemically analyzed the genome-wide gene expression changes affected by orlistat treatment using RNA-seq and identified FAF2, a molecule regulating the lipid droplet homeostasis, as a novel target of orlistat. Moreover, in a mouse xenograft model, orlistat significantly inhibited tumor growth and reduced the tumor volumes compared with vehicle control (P<0.05). Our study showed a novel mechanism of the anticancer activity of orlistat and provided the rationale for repurposing this drug for the treatment of lung cancer and other types of cancer.

关键词： orlistat     ferroptosis     FAF2     lung cancer    

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Role of the forkhead transcription factor FOXO-FOXM1 axis in cancer and drug resistance

null

《医学前沿（英文）》 2012年 第6卷 第4期   页码 376-380 doi: 10.1007/s11684-012-0228-0

摘要：

The forkhead transcription factors FOXO and FOXM1 have pivotal roles in tumorigenesis and in mediating chemotherapy sensitivity and resistance. Recent research shows that the forkhead transcription factor FOXM1 is a direct transcriptional target repressed by the forkhead protein FOXO3a, a vital downstream effector of the PI3K-AKT-FOXO signaling pathway. Intriguingly, FOXM1 and FOXO3a also compete for binding to the same gene targets, which have a role in chemotherapeutic drug action and sensitivity. An understanding of the role and regulation of the FOXO-FOXM1 axis will impact directly on our knowledge of chemotherapeutic drug action and resistance in patients, and provide new insights into the design of novel therapeutic strategy and reliable biomarkers for prediction of drug sensitivity.

关键词： FOXO3a     FOXM1     transcription factor     cancer     drug resistance     tumorigenesis    

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Improving the prognosis of pancreatic cancer: insights from epidemiology, genomic alterations, and therapeutic

《医学前沿（英文）》 doi: 10.1007/s11684-023-1050-6

摘要： Pancreatic cancer, notorious for its late diagnosis and aggressive progression, poses a substantial challenge owing to scarce treatment alternatives. This review endeavors to furnish a holistic insight into pancreatic cancer, encompassing its epidemiology, genomic characterization, risk factors, diagnosis, therapeutic strategies, and treatment resistance mechanisms. We delve into identifying risk factors, including genetic predisposition and environmental exposures, and explore recent research advancements in precursor lesions and molecular subtypes of pancreatic cancer. Additionally, we highlight the development and application of multi-omics approaches in pancreatic cancer research and discuss the latest combinations of pancreatic cancer biomarkers and their efficacy. We also dissect the primary mechanisms underlying treatment resistance in this malignancy, illustrating the latest therapeutic options and advancements in the field. Conclusively, we accentuate the urgent demand for more extensive research to enhance the prognosis for pancreatic cancer patients.

关键词： pancreatic cancer     cancer screening     single cell     molecular alterations     precancerous lesion     therapy resistance    

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标题 作者 时间 类型 操作

Progress and challenges in RET-targeted cancer therapy

期刊论文

甲状腺乳头状癌菌群失调及与肿瘤信号通路异常的相关性研究

喻爽, 丁彦强, 王雪洁, Siu Kin Ng, 曹思婷, 刘伟鑫, 郭朱明, 谢宇彬, 洪澍彬, 许丽霞, 李晓星, 李杰, 吕伟明, 彭穗, 李延兵, 沈祖尧, 于君, 肖海鹏

期刊论文

The effect of orbital radiation therapy on thyroid-associated orbitopathy complicated with dysthyroid

null

期刊论文

Are the SNPs of NKX2-1 associated with papillary thyroid carcinoma in the Han population of Northern

null

期刊论文

Analyses of levels of thyroid hormones and its receptor expression in puerperants and newborns from an

JU Ying, CHEN Lan, JIANG Qi, YANG Kedi, CHEN Xuemin, XU Guojian, LI Liping

期刊论文

mesenchymal stem cells promotes the expression of tumor-suppressive FAT1 and inhibits stemness maintenance in thyroid

期刊论文

Sensitivity of supplementation of thyroid hormone on treatment of idiopathic short-stature children during

Wei Wang, Shuqin Jiang, Zhirui Cui, Xiangyang Luo, Lingli Shi, Heli Zheng

期刊论文

Atypical pituitary hormone–target tissue axis

期刊论文

Midline2 is overexpressed and a prognostic indicator in human breast cancer and promotes breast cancer

期刊论文

Epithelial-to-mesenchymal transition in cancer: complexity and opportunities

Yun Zhang, Robert A. Weinberg

期刊论文

Long-term results of suppressing thyroid-stimulating hormone during radiotherapy to prevent primary hypothyroidism

Maura Massimino, Marta Podda, Lorenza Gandola, Emanuele Pignoli, Ettore Seregni, Carlo Morosi, Filippo Spreafico, Andrea Ferrari, Emilia Pecori, Monica Terenziani

期刊论文

Metformin for cancer prevention

Yonghua Yang

期刊论文

Orlistat induces ferroptosis-like cell death of lung cancer cells

期刊论文

Role of the forkhead transcription factor FOXO-FOXM1 axis in cancer and drug resistance

null

期刊论文

Improving the prognosis of pancreatic cancer: insights from epidemiology, genomic alterations, and therapeutic

期刊论文