ObjectiveAutoimmune thyroiditis (AIT), a prevalent autoimmune disorder that frequently leads to hypothyroidism. A critical unmet need exists for disease-modifying therapies that target its underlying pathogenesis. This study aimed to identify and validate novel therapeutic targets for AIT.MethodsWe employed an integrative genomics approach, combining genome-wide association studies (GWAS) with molecular quantitative trait loci (QTL) analyses, including expression (eQTL), protein (pQTL), and DNA methylation QTL (mQTL), across two independent AIT cohorts for discovery and replication. We performed two-sample bidirectional Mendelian randomization (MR) with sensitivity analyses, followed by summary-data-based MR (SMR) and heterogeneity in dependent instruments (HEIDI) tests. Top candidates were further evaluated via phenome-wide association study (PheWAS) and computational drug screening. Guided by these findings, we quantified plasma levels of the top-priority candidate, Ribonuclease T2 (RNASET2), via ELISA in AIT patients and non-AIT controls. To functionally validate its therapeutic potential, we developed a novel three-dimension (3D) inflammatory thyrocyte spheroid model and evaluated potential therapeutic effects of recombinant RNASET2. Loss-of-function (small interfering RNA-mediated knockdown) and gain-of-function (recombinant protein RNASET2 rescue) experiments further supported RNASET2 as a therapeutic target.ResultsMulti-omics integration consistently nominated RNASET2 as a causal protective factor against AIT. Signals of pQTL and eQTL for RNASET2 were associated with decreased AIT risk, while three mQTLs were correlated with increased risk. PheWAS indicated minimal pleiotropic effects, supporting its therapeutic suitability. Computational drug screening nominated genistein, a soy isoflavone known to upregulate RNASET2 expression, as a repurposing candidate. Empirically, plasma RNASET2 levels were moderately elevated in AIT patients, potentially reflecting a compensatory anti-inflammatory response. Crucially, recombinant RNASET2 effectively mitigated inflammation and apoptosis in the thyrocyte spheroid model, confirming its functional protective role. Consistently, RNASET2 knockdown heightened susceptibility to inflammatory cell death and cytokine expression, a phenotype reversed by recombinant RNASET2 supplementation.ConclusionsBy integrating large-scale genomic analyses with functional validation, our study establishes RNASET2 as a promising therapeutic target for AIT. RNASET2 augmentation represents a potential disease-modifying strategy, providing a translational bridge from genetic discovery to clinical application.

Introduction: Autoimmune thyroiditis (AIT), clinically termed Hashimoto’s thyroiditis (HT), is a chronic autoimmune condition characterized by progressive immune-mediated degeneration of thyroid tissue. The association between AIT and cancer risk, particularly thyroid cancer, remains controversial. Objective: This study is aimed to investigate potential causal associations between AIT/HT and thyroid cancers or extra-thyroidal cancers comprehensively. Methods: To clarify this uncertainty, we employed Mendelian randomization (MR) analysis to evaluate causal associations between genetic predisposition to AIT and pan-cancer risk, including subtypes of thyroid cancer and extra-thyroidal malignancies. Summary statistics were pooled from comprehensive genome-wide studies, including two independent AIT/HT datasets, 10 thyroid neoplasm datasets, and 33 extra-thyroidal cancer datasets. Bidirectional two-sample MR analyses were conducted to mitigate confounding and reverse causation. Quality control was reinforced through sensitivity analyses. Results: Contrary to previous observational studies, our study found no genetically supported causal link between AIT/HT and the development of thyroid carcinoma. However, elevated risks of non-Hodgkin lymphoma, primary lymphoid/hematopoietic malignancies, testicular cancer, and brain cancer might be associated with AIT/HT. Sensitivity analyses confirmed the robustness of these results, although some associations exhibited heterogeneity or pleiotropy. Conclusion: These findings reveal tissue-specific effects of thyroid autoimmunity on cancer development, suggesting distinct biological pathways beyond thyroid malignancies. This study provides genetic evidence that refines cancer risk assessment in patients with AIT/HT and emphasizes the need for further mechanistic research to elucidate underlying biological processes.

A Chinese multicenter prospective cohort study of supraclavicular oblique incision sternocleidomastoid intermuscular approach (SOI-SMIA) versus traditional low collar incision linea alba cervicalis approach (TCLI-LACA) in thyroid lobectomy for papillary thyroid carcinoma (LATERAL study) has been initiated. The aim is to compare surgical approach-related outcomes in thyroid lobectomy. We here outline the detailed protocol for this study. PTC which can be treated by lobectomy is considered for inclusion in the study. Eligible patients will receive printed materials that detail the advantages and disadvantages of each management option, allowing them to select their preferred intervention. Thyroid lobectomy by SOI-SMIA or TCLI-LACA will be performed within 24 h after grouping. We designed a composite index of surgical approach-related trauma as the primary endpoint. It includes both the superficial (scar consciousness and appearance satisfaction) component and the deep component (neck impairment), and will be assessed at 1 month and 6 months after surgery. The LATERAL study will be conducted in three hospitals in China. We plan to recruit 80 patients per group and enroll patients consecutively over time and will conclude once the group with the smaller number of participants reaches 80 cases. The results of this trial will contribute to confirming the role of SOI-SMIA in thyroid lobectomy for PTC, and provide evidence to support its wider adoption.

PGC1α, a central player in mitochondrial biology, holds a complex role in the metabolic shifts seen in cancer cells. While its dysregulation is common across major cancers, its impact varies. In some cases, downregulation promotes aerobic glycolysis and progression, whereas in others, overexpression escalates respiration and aggression. PGC1α’s interactions with distinct signaling pathways and transcription factors further diversify its roles, often in a tissue-specific manner. Understanding these multifaceted functions could unlock innovative therapeutic strategies. However, challenges exist in managing the metabolic adaptability of cancer cells and refining PGC1α-targeted approaches. This review aims to collate and present the current knowledge on the expression patterns, regulators, binding partners, and roles of PGC1α in diverse cancers. We examined PGC1α’s tissue-specific functions and elucidated its dual nature as both a potential tumor suppressor and an oncogenic collaborator. In cancers where PGC1α is tumor-suppressive, reinstating its levels could halt cell proliferation and invasion, and make the cells more receptive to chemotherapy. In cancers where the opposite is true, halting PGC1α’s upregulation can be beneficial as it promotes oxidative phosphorylation, allows cancer cells to adapt to stress, and promotes a more aggressive cancer phenotype. Thus, to target PGC1α effectively, understanding its nuanced role in each cancer subtype is indispensable. This can pave the way for significant strides in the field of oncology.

Background: The present study aimed to construct a novel pyroptosis-related gene signature to predict the prognosis of papillary thyroid cancer (PTC). Methods: The gene expression level and survival and prognosis information of PTC were obtained from TCGA. The differentially expressed pyroptosis-related genes (DEPs) between cancer and control groups were selected, followed by subtype analysis. A prognostic model was built using LASSO regression analysis. The samples were then divided into high- and low-risk groups, and the differences in immune cell distribution in different risk groups were compared. The chemical drugs associated with genes in the prognostic model were extracted from the Comparative Toxicogenomics Database. Results: A total of 31 DEPs were selected, and 3 different subtypes were obtained. A prognostic model based on 6 pyroptosis-related genes was constructed. The risk grouping was significantly correlated with the actual prognosis, and the model was found to be an independent prognostic factor. Six immune cells with significant differences in distribution in different risk groups were screened. CGP52608 could target four genes in the prognostic model, including GSDMB, NLRC4, IL1A, and IL6. Conclusion: The present study constructed a pyroptosis-related gene signature that could predict the prognosis of PTC. Additionally, this signature was correlated with tumor immunity.

Background Hashimoto's thyroiditis (HT) is a thyroid autoimmune disease characterized by lymphocytic infiltration and thyroid destruction. Prunella vulgaris (PV) is a traditional Chinese herbal medicine with documented clinical efficacy in treating HT. We previously reported an immunoregulatory effect of PV in thyrocytes; however, the bioactive components of PV remained unclear. This study aimed to elucidate key components of PV for treating HT and their acting mechanisms. Methods Network pharmacology was used to predict key PV components for HT. The predicted components were tested to determine whether they could exert an immunoregulatory effect of PV in human thyrocytes. Limited proteolysis-mass spectrometry (Lip-MS) was used to explore interacting proteins with PV components in human thyrocytes. Microscale thermophoresis binding assay was used to evaluate the affinity of PV components with the target protein. Results Eleven PV components with 192 component targets and 3415 HT-related genes were gathered from public databases. With network pharmacology, a ‘component-target-disease’ network was established wherein four flavonoids including quercetin, luteolin, kaempferol, morin, and a phytosterol, β-sitosterol were predicted as key components in PV for HT. In stimulated primary human thyrocytes or Nthy-ori-31 cells, key components inhibited gene expressions of inflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and interferon-β (IFN-β), cellular apoptosis, and activation of nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF-3). Heat shock protein 90 alpha, class A, member 1 (HSP90AA1), was identified to interact with flavonoids in PV by Lip-MS. Morin had the highest affinity with HSP90AA1 (KD = 122.74 μM), followed by kaempferol (KD = 168.53 μM), luteolin (KD = 293.94 μM), and quercetin (KD = 356.86 μM). Conclusion Quercetin, luteolin, kaempferol, morin, and β-sitosterol reproduced an anti-inflammatory and anti-apoptosis effect of PV in stimulated human thyrocytes, which potentially contributed to the treatment efficacy of PV in HT.

Background:There is much debate on the optimal treatment approach of papillary thyroid carcinoma (PTC). Different guidelines base recommendations on various risk factors. While diagnosing the various risk factors is difficult due to the technical limitations, intraoperative frozen section (IFS) may be a feasible method. We aim to real-time evaluate the multiple risk factors, including lymph node metastasis (LNM), extrathyroidal extension (ETE), multifocality using IFS, and then identify a more effective surgical plan, which may help avoid the need for a second surgery and improve prognosis of patients. Methods:We retrospectively reviewed the medical records of 364 patients from January 1, 2021 to December 31, 2021. All the patients were initially recommended to undergo a hemithyroidectomy (HT) with isthmusectomy and ipsilateral central compartment neck dissection (CCND). IFS would be executed immediately. Further total thyroidectomies (TTs) would be performed if: (I) results of IFS showed >5 LNM, or (II) there are 1≤ LNM ≤5 but with ETE and/or multifocal carcinoma. The patients were divided and investigated according to the extent of surgery. Results:Based on the results of IFS, 72 patients underwent TT. The TT group displayed larger average tumor diameter, greater age, higher average body mass index (BMI), and elevated incidence of hypertension and hyperlipidemia compared to the HT group. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of IFS were 77.61%, 100%, 100%, and 88.46%, respectively. Conclusions:IFS is a highly reliable procedure. Comprehensively evaluating central compartment LNM, ETE, and multifocal carcinoma through IFS helps identify a more reasonable surgical option under the current clinical consensus, which may thus help avoid the need for a second surgery.

Purpose Sex hormones are thought to be responsible for the unique gender differences in papillary thyroid cancer(PTC). Most previous studies on these have focused on the expression of estrogen receptors, or have been limited to animal studies. The aim of our study was to explore the relationship between serum sex hormones and the pathological features of PTC in the clinical setting, as further evidence of the role of sex hormones in PTC. Methods Retrospective data analysis of patients who underwent thyroid surgery at the Department of Thyroid Surgery, Nanjing Drum Tower Hospital from January 2022 to September 2022 Correlation between serum sex hormone and pathological features was analyzed in male patients and in menopausal female patients. Serum sex hormones include luteinizing hormone(LH), follicle stimulating hormone(FSH), estradiol(E 2 ), total testosterone(TT), progesterone(P), and prolactin(PRL). Tumor pathological characteristics include the number and size of tumor, presence of extrathyroidal extension(ETE), presence of lymph node metastasis(LNM). Results Preoperative serum E2 in male patients was positively correlated with tumor size in PTC, LH was negatively correlated with LNM, while TT and P were negatively correlated with ETE. Similar findings were not observed in menopausal female patients. Conclusion We observed that serum sex hormones correlate with the pathological features of PTC in male patients, for the first time in a clinical study. High serum estrogens may be a risk factor for PTC, while androgens are the opposite. This somewhat corroborates previous research and provides new variables for future PTC prediction models.

[This corrects the article DOI: 10.3389/fcell.2020.591239.].

BACKGROUND:Emerging studies have demonstrated the critical role of RNA m6A methylation in tumor progression, whereas lncRNA m6A modification profiles in breast cancer remain largely unknown. Our previous study has shown that METTL14 accelerates breast cancer migration and invasion in an m6A-dependent manner, making it critical to analyze METTL14-mediated m6A modification at a transcriptome-wide scale in breast cancer.METHODS:Here, we performed MeRIP-seq analysis in METTL14 overexpressed and control MDA-MB-231 cells. Conjoint analysis of MeRIP-seq and RNA-seq data was used to select lncRNAs with m6A methylation and differential expression. Finally, the screened lncRNA was verified by MeRIP-PCR and its function was studied via transwell assay.RESULTS:Our results determined that high expression of METLL14 results in 3996 hypermethylation peaks from 3107 transcripts, and 4100 hypomethylation peaks from 2918 transcripts. Furthermore, conjoint analysis of MeRIP-seq and RNA-seq data identified 25 lncRNAs with discrepant methylation and simultaneously discrepant expression, among which the top 10 differentially expressed LncRNAs were AC026401.3, CYTOR, LINC01943, AC084125.2, FLJ20021, LINC00472, and NORAD, MALAT1, AL161431.1, and LINC01764. Moreover, over-expressed METTL14 stimulated the m6A modification of AC084125.2, while decreasing its expression. Compared to adjacent tissues, AC084125.2 was lowly expressed in tumors and could be used as a biomarker in the diagnosis of breast cancer. Meanwhile, AC084125.2 inhibited the migration and invasion of cancer cells.CONCLUSION:In conclusion, METTL14-mediated m6A modification of lncRNAs, which might provide reference for future intervention in tumor progression.

Methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1 like (MTHFD1L) is a mitochondrial enzyme involved in the synthesis of tetrahydrofolate (THF). This study aimed to investigate the effect of MTHFD1L in papillary thyroid cancer (PTC). Tumor tissues and adjacent tissues from 11 patients with PTC were collected, the expression level of MTHFD1L mRNA was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The cancer genome atlas (TCGA) database was used for analysis MTHFD1L differentially expressed be-tween tumor tissue and adjacent tissues. MTHFD1L was knocked down by a lentivirus-based system and CRISPR-Cas9. Affymetrix genechip human transcriptome array 2.0 was used to assess gene expression. Cell growth and motility were evaluated in vivo and in vitro. Cell apoptosis and cell cycle were investigated by flow cytometry assay. The expression levels of proteins were detected by western blotting. MTHFD1L mRNA and protein expression levels significantly increased in tumor tissues and CAL-62, K1 and TPC-1 cell lines. After knockdown MTHFD1L, the growth of cells were reduced while cell apoptosis was increased. In addition, tumor growth was inhibited after MTHFD1L knockdown in nude mice. Affymetrix genechip human transcriptome array 2.0 was founded that MTHFD1L knockdown can inhibit the expression levels of CCND1 and Notch2. Furthermore, we identified that MTHFD1L knockdown inhibited cells growth and induced cell apoptosis in PTC. Importantly, MTHFD1L knockdown decreased the expression levels of Notch2, Hes1 CCND1, Bcl-2, and PCNA protein, whereas the level of Bax increased. Our study suggested MTHFD1L knockdown could diminished PTC cell proliferation. MTHFD1L serves as a valuable therapeutic target.

Background:Various incisions and approaches for thyroidectomy have been developed to treat differentiated thyroid cancer (DTC). Supraclavicular oblique incision (SOI) thyroidectomy (SOIT) has been applied in DTC patients over the past ten years. However, the safety and efficacy of this approach were yet to be confirmed.Aim:This study aimed to compare the surgical and patient-related outcomes between SOIT and traditional low collar incision thyroidectomy (TLCIT) in patients with DTC.Methods:We retrospectively screened all patients with DTC who received thyroid lobectomy from October 2020 to October 2021. The surgical results and patient-related outcomes assessed at 1 and 6 months after surgery by questionnaire were compared between the SOIT and TLCIT groups.Results:A total of 128 patients were included in this study, of whom 38 patients (30.5%) were operated on with SOIT and 89 patients (69.5%) with TLCIT. There was no significant difference in demographic characteristics and thyroid features between the two groups. Despite comparable operative time (61.9 ± 12.1 vs. 59.9 ± 15.0 min, p = 0.425), the SOIT group had a smaller neck incision (4.4 ± 0.7 vs. 5.0 ± 1.0 cm, p = 0.002), a shorter duration of postoperative drainage (2.4 ± 0.5 vs. 2.7 ± 0.9 days, p = 0.019), less volume of postoperative drainage (48.4 ± 24.6 vs. 60.3 ± 22.8 ml, p = 0.040), and shorter postoperative hospitalization (3.2 ± 0.5 vs. 3.6 ± 0.9 days p = 0.006), as compared with the TLCIT group. At 1-month follow-up after surgery, SOIT showed better performance in preventing hypoparathyroidism (p = 0.026) and abnormal neck sensation (p = 0.010) and in improving cosmetic satisfaction (p = 0.036) than TLCIT. At 6-month follow-up, SOIT was feedback with better cosmetic satisfaction (p < 0.001) and a lower percent of abnormal neck sensation (p = 0.031) or movement (p = 0.005).Conclusion:Our study suggests that minimally invasive surgery using the SOI provides superior surgical and patient-related outcomes compared with surgery using a traditional low collar incision (TLCI) in patients with DTC.

We aimed to evaluate the effects of long-chain non-coding RNA (lncRNA) anti-differentiation non-coding RNA (ANCR) on the proliferation, invasion, and migration of breast cancer cells by targeting miR-331. Forty-eight breast cancer and paracancerous tissue samples were collected. LncRNA ANCR expressions in breast cancer and adjacent tissues, human breast cancer cells and mammary epithelial cells, and miR-331 expressions in interfering cell line MDA-MB-231 (MCF-7)-shANCR, negative control MDA-MB-231 (MCF-7)-shNC and blank control MDA-MB-231 (MCF-7) were detected by real-time quantitative PCR. The correlations between lncRNA ANCR expression and clinicopathological characteristics were analyzed. Cell proliferation was detected by MTT and colony formation assays. Invasion and migration were tested by Transwell and scratch assays, respectively. The targeting relationship between ANCR and miR-331 was analyzed using the TargetScan database, and their interaction was studied using a dual-luciferase reporter assay. The expression of lncRNA ANCR in breast cancer tissue was significantly lower than that in adjacent normal tissue (p < 0.05). LncRNA ANCR was lowly expressed in various human breast cancer cell lines, being lowest in high-metastatic cell line (MDA-MB-231HM) (p < 0.05). Silencing lncRNA ANCR significantly enhanced the proliferation and invasion capacities of breast cancer cells, and promoted their tumor formation abilities in nude mice (p < 0.05). ANCR bound miR-331 targetedly, and the former negatively regulated the expression of the latter. LncRNA ANCR is lowly expressed upon breast cancer, and inhibits cell proliferation, invasion, and migration in vitro and in vivo. LncRNA ANCR exerts antitumor effects by targetedly binding miR-331 and then inhibiting its expression.

目的 探讨低位直肠癌保留部分肛提肌重建盆底的改良经肛提肌外腹会阴联合切除(ELAPE)手术操作的技术要点和临床效果.方法 2018年1月至2019年12月于南京大学医学院附属鼓楼医院胃肠外科收治的不能保肛的低位直肠癌患者,按腹腔镜直肠癌根治术常规清扫和分离,至肿瘤平面时根据肿瘤位于直肠的部位,分离健侧直肠系膜与肛提肌;完成腹部操作后,改折刀位行会阴部操作,切除患侧肛提肌,并保留部分健侧肛提肌行重建盆底的改良ELAPE手术.结果 共26例患者行保留部分肛提肌重建盆底的改良ELAPE手术,其中男19例,女7例,年龄29～76岁,肿瘤距肛门距离平均(2.54±1.05)cm,平均手术时间(285.0±35.8)min,平均出血(92.3±39.2)ml;术后病理Ⅰ～Ⅱ期8(30.8％)例,Ⅲ期18(69.2％)例.平均淋巴结清扫(13.6±3.6)枚,环周切缘均阴性.术后住院时间(11.6±2.9)d,出现尿潴留2例.中位随访时间26(12～33)个月,1例出现肝脏转移,其余均无局部及远处复发转移征象;均无盆底疝发生.结论 低位直肠癌保留部分肛提肌重建盆底的改良ELAPE手术安全可靠,具有较高临床应用价值.

所谓肠梗阻,通俗地讲就是肠子堵了,不通了.肠梗阻有四大症状,叫做“痛、吐、胀、闭”,即腹痛、呕吐、腹胀和肛门停止排气排便.如果肠子完全堵死了,就是完全性肠梗阻,四大症状俱全,这种情况的患者必须立即到医院处理,多半需要急诊手术;有的患者肠道没有完全堵住,就是不全性肠梗阻,相应症状要轻得多,这时可以先行保守治疗.

结肠憩室是指结肠黏膜疝出形成的囊状结构,憩室开口被堵塞、内容物无法排出时可继发炎症反应,即结肠憩室炎,并导致相应的临床表现.憩室的发生主要与患者的饮食结构(低膳食纤维饮食)、年龄以及肠道内环境紊乱等因素有关.结肠憩室目前常用的检查手段有CT、结肠镜、MRI和超声检查[1].憩室炎的治疗方式包括药物治疗和手术治疗.本文总结2例结肠憩室炎病例诊断过程中的疑难点和治疗策略,为临床疑似结肠肿瘤的结肠憩室炎的诊断和治疗提供参考.

G protein coupled estrogen receptor (GPER1) is a membrane estrogen receptor, belonging to the seven-transmembrane G protein-coupled receptors family, and has important biological functions in cancer. However, the functional role of GPER1 in gastric cancer (GC) remain incompletely understood. In the present study, we employed gene set enrichment analysis and discovered that GPER1 expression was concomitant with EMT process and was positively correlated with activation of the PI3K/AKT pathway in GC. Knockdown of GPER1 with siRNA suppressed the proliferation, migration, and invasion of AGS and MGC-803 GC cells. Knockdown of GPER1 also downregulated the mesenchymal markers N-cadherin and vimentin, upregulated E-cadherin, an epithelial marker, and suppressed expression of the Snail, Slug and Twist1 transcription factors, indicating that knockdown of GPER1 inhibited EMT. Moreover, 740Y-P, a PI3K activator, reversed the effects of GPER1 knockdown on EMT processes. Overexpression of GPER1 with plasmid can further prove these findings. In summary, these data demonstrate that GPER1 inhibition suppresses the proliferation, migration, and invasion of gastric cancer cells by inhibiting PI3K/AKT-mediated EMT. Our study elucidated the function of GPER1 in gastric cancer, and we identified PI3K/AKT-mediated EMT as a novel mechanism by which GPER1 contributes to proliferation, migration, and invasion of gastric cancer. These data suggest that combining inhibition of GPER1 and PI3K may be a potential therapeutic approach to inhibit gastric cancer metastasis.