A systematic analysis of the resistance and sensitivity of HER2YVMA receptor tyrosine kinase mutant to tyrosine kinase inhibitors in HER2-positive lung cancer.

Human epidermal growth factor receptor 2 (HER2) has become a well-established target for the treatment of HER2-positive lung cancer. However, a frequently observed in-frame mutation that inserts amino acid quadruplex Tyr776-Val777-Met778-Ala779 at G776 (G776(YVMA)) in HER2 kinase domain can cause drug resistance and sensitivity, largely limiting the application of reversible tyrosine kinase inhibitors in lung cancer therapy. A systematic investigation of the intermolecular interactions between the HER2(YVMA) mutant and clinical small-molecule inhibitors would help to establish a complete picture of drug response to HER2 G776(YVMA) insertion in lung cancer, and to design new tyrosine kinase inhibitors with high potency and selectivity to target the lung cancer-related HER2(YVMA) mutant. Here, we combined homology modeling, ligand grafting, structure minimization, molecular simulation and binding affinity analysis to profile a number of tyrosine kinase inhibitors against the G776(YVMA) insertion in HER2. It is found that the insertion is far away from HER2 active pocket and thus cannot contact inhibitor ligand directly. However, the insertion is expected to induce marked allosteric effect on some regions around the pocket, including A-loop and hinges connecting between the N- and C-lobes of HER2 kinase domain, which may exert indirect influence to inhibitor binding. Most investigated inhibitors exhibit weak binding strength to both wild-type and mutant HER2, which can be attributed to steric hindrance that impairs ligand compatibility with HER2 active pocket. However, the cognate inhibitor lapatinib and the non-cognate inhibitor bosutinib were predicted to have low affinity for wild-type HER2 but high affinity for HER2(YVMA) mutant, which was confirmed by subsequent kinase assay experiments; the inhibitory potencies of bosutinib against wild-type and mutant HER2 were determined to be IC(50) > 1000 and =27 nM, respectively, suggesting that the bosutinib might be exploited as a selective inhibitor for mutant over wild-type HER2. Structural examination revealed that formation of additional non-bonded interactions such as hydrogen bonds and hydrophobic contacts with HER2 A-loop region due to G776(YVMA) insertion is the primary factor to improve bosutinib affinity upon the mutation.

Comprehensive analysis of UBE2C expression and its potential roles and mechanisms in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) ranks one of the most common and lethal cancers all over the world. Previous studies suggest that ubiquitin-conjugating enzyme E2C (UBE2C) serves as an oncogene in human cancers. However, its expression, diagnosis, prognosis and potential mechanisms in HCC remain largely unknown. In this study, the expression of UBE2C in HCC was first analyzed by comprehensive bioinformatic analysis. ROC curve analysis and survival analysis were employed to assess the diagnostic and prognostic roles of UBE2C in HCC. UBE2C promoter methylation level and upstream regulatory miRNAs of UBE2C in HCC were explored. The present work demonstrated that UBE2C was significantly upregulated in HCC compared with normal controls. We also found significant diagnostic and prognostic values of UBE2C in HCC. Promoter methylation of UBE2C was obviously decreased in HCC and was negatively correlated with UBE2C mRNA expression. 10 miRNAs were predicted to potentially bind to UBE2C. In vitro assay and bioinformatic correlation analysis together revealed that hsa-miR-193b-3p might be another key upstream regulatory mechanism of UBE2C in HCC. In conclusion, UBE2C is overexpressed in HCC and may serve as a key diagnostic/prognostic biomarker for patients with HCC.

Cuproptosis-related gene SLC31A1 is a potential predictor for diagnosis, prognosis and therapeutic response of breast cancer.

Cuproptosis is a recently reported novel way of cell death. A comprehensive study regarding expression, function and mechanism of cuproptosis-related genes in breast cancer is still absent. In this work, a series of in silico analyses were employed and SLC31A1 was selected as the most potential cuproptosis-related gene in breast cancer, which was statistically upregulated and possessed significant abilities to predict diagnosis, prognosis and drug response. Moreover, SLC31A1 was significantly positively correlated with different immune cell infiltration levels, immune cell biomarkers or immune checkpoints in breast cancer. Upstream G2E3-AS1/let-7a-5p and CDKN2B-AS1/let-7b-5p pathways were found to be responsible for SLC31A1 upregulation in breast cancer based on competing endogenous RNA mechanism. Furthermore, we found that SLC31A1 overexpression might be also induced by its high copy number level in breast cancer. Collectively, our current data elucidated that cuproptosis-related SLC31A1 might be a promising diagnostic/prognostic biomarker and drug responsive predictor in breast cancer.

HER2-positive metastatic breast cancer with brain metastases responds favorably to pyrotinib and trastuzumab-based treatment: A case report and literature review.

For HER2-positive metastatic breast cancer patients with the brain involved at initial diagnosis, there was no standard regimen before 2022 when the HER2CLIMB trial published its final overall survival analysis, and the prognosis is relatively poor under the current treatment strategy. We herein reported a case of a female patient who was initially diagnosed with HER2-positive metastatic breast cancer with brain metastases, receiving pyrotinib and trastuzumab-based systematic therapy after palliative craniocerebral radiotherapy as the first-line systematic therapy. During the treatment, the tumor lesions showed obvious regression, and chemotherapy drugs were gradually removed from the regimen. The patient continued receiving trastuzumab and pyrotinib for HER2-targeted therapy. She had achieved more than 26 months of progression-free survival and the disease was stable during the evaluation in April 2022. Radiotherapy followed by dual HER2-targeted therapy of macromolecular monoclonal antibodies trastuzumab and micromolecular TKI pyrotinib plus chemotherapy could be an alternative option for this subtype of patients and need to be further verified by future clinical trials.

Silencing the expression of lncRNA SNHG15 may be a novel therapeutic approach in human breast cancer through regulating miR-345-5p.

Background: Long noncoding RNA (lncRNA) short nucleolar RNA host gene 15 (SNHG15) has been found to have an oncogenic function in numerous malignancies. Nevertheless, the biological function and regulatory mechanisms of SNHG15 in breast cancer have not been fully elucidated. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of SNHG15 and in MDA-MB-231 breast cancer cells. The expression of SNHG15 was silenced using small interfering RNA (siRNA) technology. The proliferation and migration of the cells were examined by colony formation assays, cell counting kit 8 (CCK-8) assays, and transwell assays. For the zebrafish xenograft injection experiments, cultured cells labelled with the fluorescent dye CM-DiI were injected into the perivitelline space of the larvae. Results: This present study revealed that the expression of lncRNA SNHG15 (lnc-SNHG15) was significantly upregulated in breast cancer cells, and its overexpression was associated with the tumor. The relative expression of lnc-SNHG15 could be downregulated using siRNAs, and silencing lnc-SNHG15 inhibited the proliferation and the migration of MDA-MB-231 cells. In vivo experiments using the zebrafish xenograft model showed similar results. Mechanistically, the knockdown effect of lnc-SNHG15 could be restored by inhibiting the expression of the miR-345-5p, confirming the negative regulation between lnc-SNHG15 and miR-345-5p. Interestingly, cisplatin treatment combined with SNHG15 knockdown effectively inhibited MDA-MB-231 cell proliferation and migration in the zebrafish xenograft compared to negative controls. Conclusions: In conclusion, lnc-SNHG15 knockdown increased miR-345-5p expression and negated cisplatin resistance in breast cancer cells, and thus, lnc-SNHG15 may be a potential novel target for breast cancer therapy.

The utility of sentinel Lymph node biopsy in the lateral neck in papillary thyroid carcinoma.

Background: Regional lymph node metastases (LNMs) are very common in papillary thyroid carcinoma (PTC) and associate with locoregional recurrence. The appropriate management of cervical lymph nodes is very important. Therefore, this study evaluated the application of sentinel lymph node biopsy (SLNB) in the lateral neck in PTC patients. Methods: This prospective study was conducted from 1 November 2015 to 31 December 2017 and recruited 78 PTC patients treated with SLNB in the lateral neck and prophylactic lateral neck dissection (compartments II-IV) followed by thyroidectomy or lobectomy and central neck dissection. Results: There were 78 PTC patients enrolled and sentinel lymph nodes (SLNs) were detected among 77 patients. A total of 30 patients were diagnosed with SLN metastases (SLNMs). The remaining 47 patients were pathologically negative of SLN, whereas 4 patients were found with metastases in the non-SLN samples. The detection rate, sensitivity, specificity, and accuracy rate of SLNB in the lateral neck were 98.7%, 87.1%, 98.7%, and 93.6%, respectively. However, the values varied greatly in each specific compartment of the lateral neck, and all of them were no more than 80%. These 34 PTC patients diagnosed with lateral compartment LNM (LLNM) were more likely to be younger (41.38 vs. 48.95 years old, p = 0.002) and exhibit extrathyroidal extension (56.8% vs. 31.7%, p = 0.026) and central compartment LNM (66.7% vs. 12.1%, p < 0.001). Tumors located in the upper third of the thyroid lobe also had a significantly higher probability of LLNM compared with those in middle or inferior location (66.7% vs. 35.3% vs. 34.8%, p = 0.044). At last, age (OR=0.912, p = 0.026), tumor location (upper vs inferior, OR=17.478, p = 0.011), and central compartment LNM (OR=25.364, p < 0.001) were independently predictive of LLNM. Conclusions: SLNB can help surgeons to identify some PTC patients who may benefit from therapeutic lateral neck dissection and protect some patients from prophylactic lateral neck dissection. However, it cannot accurately indicate specific lateral compartment-oriented neck dissection. Meanwhile, LLNM is more likely to occur in PTC patients with younger age or upper pole tumors or central compartment LNM.

Improved Inception V3 method and its effect on radiologists' performance of tumor classification with automated breast ultrasound system.

BACKGROUND: The automated breast ultrasound system (ABUS) is recognized as a valuable detection tool in addition to mammography. The purpose of this study was to propose a novel computer-aided diagnosis (CAD) system by extracting the textural features from ABUS images and to investigate the efficiency of using this CAD for breast cancer detection. METHODS: This retrospective study involved 149 breast nodules [maximum diameter: mean size 18.89 mm, standard deviation (SD) 10.238, and range 5-59 mm] in 135. We assigned 3 novice readers (<3 years of experience and 3 experienced readers (≥10 years of experience to review the imaging data and stratify the 149 breast nodules as either malignant or benign. The Improved Inception V3 (II3) method was developed and used as an assistant tool to help the 6 readers to re-interpret the images. RESULTS: Our method (II3) achieved an accuracy of 88.6% for the final result. The 3 novice readers had an average accuracy of 71.37%±4.067% while the 3 experienced readers was 83.03%±3.371% on the first-reading. With the help of II3 on the second-reading, the average accuracy of the novice readers increased to 84.13%±1.662% and the experienced readers increased to 89.50%±0.346%.The areas under the curve (AUCs) were similar compared with linear algorithms. The mean AUC of the novice readers was improved from 0.7751 (without II3) to 0.8232 (with II3). The mean AUC of the experienced readers was improved from 0.8939 (without II3) to 0.9211 (with II3). The mean AUC for all readers improved in both the second-reading mode (from 0.8345 to 0.8722, P=0.0081<0.05). CONCLUSIONS: With the help of the II3, the diagnostic accuracy of the two groups were both improved, and II3 was more helpful for novice readers than for experienced readers. Our results showed that II3 is valuable in the differentiation of benign and malignant breast nodules and it also improves the experience and skill of some novice radiologists. The II3 cannot completely replace the influence of experience in the diagnostic process and will retain an auxiliary role in the clinic at present.

Prophylactic Central Neck Dissection for cN1b Papillary Thyroid Carcinoma: A Systematic Review and Meta-Analysis.

BACKGROUND: The value of prophylactic central neck dissection (PCND) for papillary thyroid carcinoma (PTC) with clinically evident lateral cervical lymph node metastases (cN1b) remains unclear. Therefore, a systematic review and meta-analysis was conducted to assess the efficacy and safety of PCND. METHODS: A comprehensive systematic search was conducted on PubMed, Web of Science, Cochrane library and Embase databases up to September 2021 to identify eligible studies. Controlled clinical trials assessing therapeutic effects and safety of PCND for cN1b PTC patients were included. The risk of bias for each cohort study was assessed using the Newcastle-Ottawa Scale (NOS). The primary outcomes were indexes related to the locoregional recurrence (LRR) and surgical complications. Review Manager software V5.4.0 was used for statistical analysis. A fixed effects model was adopted for the data without heterogeneity, otherwise a random effects model was used. RESULTS: We included 4 retrospective cohort studies, which comprised 483 PTC patients. There was no statistically significant difference in the central neck recurrence (CNR) (10.2% vs. 3.8%, relative risk (RR) = 1.82; 95%CI 0.90-3.67; P = 0.09), lateral neck recurrence (LNR) (5.1% vs. 7.7%, RR = 0.47; 95% CI 0.13-1.74; P = 0.26), and overall recurrence (OR) (18.9% vs. 16.9%, RR = 0.77; 95%CI 0.34-1.76; P = 0.54), between LND + PCND group and LND group. Simultaneously, PCND increased the risk of permanent hypoparathyroidism (11.4% vs. 4.5%, RR = 2.70, 95%CI 1.05-6.94; P = 0.04) and overall complications (17.0% vs. 5.3%, RR = 3.28; 95%CI 1.37-7.86; P = 0.008). CONCLUSIONS: This meta-analysis showed that PCND did not have any advantage in preventing LRR for cN1b PTC. Meanwhile, PCND may result in the increased rate of surgical complications. However, the current evidence is limited and more clinical trials are still needed to further clarify the true role of PCND. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, CRD42021281825.

Retroperitoneal metastasis synchronous with brain and mediastinal lymph nodes metastasis from breast invasive ductal carcinoma as the first site of distant metastasis: a case report and review of literature.

Breast carcinoma retroperitoneal metastasis is rare. The clinical symptoms of this disease are always non-specific. Laboratory tests are not always helpful for diagnosis and evaluation. We reported a case of a 52 year old Chinese patient who was diagnosed with retroperitoneal metastasis from breast invasive ductal carcinoma as the first site of distant metastasis synchronous with brain and mediastinal lymph nodes metastasis 4 years after modified radical mastectomy. Second-line chemotherapy of docetaxel and capecitabine was recommended. The response evaluation every two to three months was good. Unfortunately, the metastasis in the brain advanced. The patient was transferred to a radiotherapy department to receive radiotherapy and died 10 months later. We also review the related literature.

Low-Grade Adenosquamous Carcinoma of the Axilla of Breast Origin in a Male: A Case Report and Literature Review.

Low-grade adenosquamous carcinoma (LGASC) is a rare invasive tumor that occurs in breast parenchyma. It has previously only been reported in females. Herein, we describe the case of a 52-year-old male who presented with a palpable mass in his right axilla that he reported had been present for 20-years. This is the first report of a male patient with LGASC. Core needle biopsy pathology revealed a benign mass of mammary origin, but its type was initially misdiagnosed. It was only correctly identified via postoperative pathology after local excision, which indicated that the mass exhibited the typical pathological characteristics of LGASC. Immunohistochemical analysis revealed positive expression of estrogen receptor, which was inconsistent with the typical "triple-negative" immunophenotype of LGASC. After resection of the mass the patient was advised to participate in regular outpatient follow-up. In conclusion, LGASC should be considered in male patients with a mass lesion in their breast or axilla, even when core needle biopsy indicates a benign mass of breast origin. One-stage local resection is recommended for the treatment of male patients with LGASC, but it is crucial to ensure that the margins are negative and postoperative adjuvant radiotherapy is not recommended.

MiR-1236-3p serves as a new diagnostic and prognostic biomarker for gastric cancer.

BACKGROUND: The microRNA plays an important role in tumor progression. MiR-1236-3p acts as a tumor suppressor in various malignancies. OBJECTIVE: The aim of present study was to explore the expression of miR-1236-3p in gastric cancer (GC) and its correlation with clinicopathological features, and evaluate the feasibility of using it as a prognostic biomarker in GC. METHODS: Seventy-six pairs of tissue specimens were collected from GC patients. MiR-1236-3p expression level was detected by using qRT-PCR. The diagnostic value of miR-1236-3p was evaluated by receiver operating characteristic curve, and Kaplan-Meier method was used to analyze the overall survival. Prognosis analysis was performed using multivariate cox proportional hazards regression analysis. RESULTS: The expression of miR-1236-3p was significantly reduced in tumor tissues (P< 0.001). In addition, miR-1236-3p expression was correlated with TNM stage (P= 0.001), lymph node metastasis (P= 0.005) and differentiated degree (P= 0.001). The area under the curve was 0.7016, and its specificity and sensitivity were 60.53% and 73.68%. Kaplan-Meier survival curves showed that patients with high miR-1236-3p expression had better overall survival than those with low expression (P= 0.0190). Multivariate Cox regression analysis showed that the miR-1236-3p expression (P= 0.033) was an independent prognostic factor for overall survival of GC prognosis. CONCLUSIONS: The study showed that miR-1236-3p is downregulated in GC tissues, and low expression of miR-1236-3p is associated with a poor prognosis in GC. It may be a new diagnostic and prognostic biomarker for GC.

Transcriptional profiling of differentially expressed long non-coding RNAs in breast cancer.

Long non-coding RNAs (lncRNAs) are subclass of noncoding RNAs that have been recently shown to play critical roles in cancer biology. However, little is known about their mechanistic role in breast cancer pathogenesis, especially in triple-negative breast carcinomas (TNBC) that have particular poor outcomes. This study was specifically designed to identify the signatures relevant lncRNAs in breast cancer and characterize lncRNAs that modulate the phenotype. Here we provide detailed methods and analysis of microarray data, which is deposited in the Gene Expression Omnibus (GEO) with the accession number GSE64790. The basic analysis as contained in the manuscript published in Oncotarget with the PMID 26078338. These data can be used to further elucidate the mechanisms of breast cancer.

The Utility of Sentinel Lymph Node Biopsy in Papillary Thyroid Carcinoma with Occult Lymph Nodes.

BACKGROUND: The sentinel lymph node (SLN) is defined as the first draining node from the primary lesion, and it has proven to be a good indicator of the metastatic status of regional lymph nodes in solid tumors. The aim of this study was to evaluate the clinical application of SLN biopsy (SLNB) in papillary thyroid carcinoma (PTC) with occult lymph nodes. METHODS: From April 2006 to October 2012, 212 consecutive PTC patients were treated with SLNB using carbon nanoparticle suspension (CNS). Then, the stained nodes defined as SLN were collected, and prophylactic central compartment neck dissection (CCND) followed by total thyroidectomy or subtotal thyroidectomy were performed. All the samples were sent for pathological examination. RESULTS: There were 78 (36.8%) SLN metastasis (SLNM)-positive cases and 134 (63.2%) SLNM-negative cases. The sensitivity, specificity, positive and negative predictive values, and false-positive and false-negative rates of SLNB were 78.8%, 100%, 100%, 84.3%, 0%, and 21.2%, respectively. The PTC patients with SLNM were more likely to be male (48.2% vs. 32.7%, p = 0.039) and exhibited multifocality (52.6% vs. 33.3%, p = 0.025) and extrathyroidal extension (56.7% vs. 33.5%, p = 0.015). A greater incidence of non-SLN metastases in the central compartment was found in patients with SLNM (41/78, 52.6%) than in those without SLNM (21/134, 15.7%; p < 0.05). However, the SLNM-negative PTC patients with non-SLN metastases were more likely to be male (37.9% vs. 9.5%, p < 0.05). CONCLUSIONS: The application of SLNB using CNS is technically feasible, safe, and useful, especially for male patients with co-existing multifocality and extrathyroidal extension. However, the sensitivity of SLNB must be improved and its false-negative rate reduced before it can be a routine procedure and replace prophylactic CCND. More attention should be paid to PTC patients (especially males) without SLNM for signs of non-SLN metastases.

Identification of novel long non-coding RNAs in triple-negative breast cancer.

Triple-negative breast carcinomas (TNBC) are characterized by particularly poor outcomes, and there are no established markers significantly associated with prognosis. Long non-coding RNAs (lncRNAs) are subclass of noncoding RNAs that have been recently shown to play critical roles in cancer biology. However, little is known about their mechanistic role in TNBC pathogenesis. In this report, we investigated the expression patterns of lncRNAs from TNBC tissues and matched normal tissues with Agilent Human lncRNA array. We identified 1,758 lncRNAs and 1,254 mRNAs that were differentially expressed (≥ 2-fold change), indicating that many lncRNAs are significantly upregulated or downregulated in TNBC. Among these, XR_250621.1 and NONHSAT125629 were the most upregulated and downregulated lncRNAs respectively. qRT-PCR was employed to validate the microarray analysis findings, and results were consistent with the data from the microarrays. GO and KEGG pathway analysis were applied to explore the potential lncRNAs functions, some pathways including microtubule motor activity and DNA replication were identified in TNBC pathogenesis. Our study revealed that a set of lncRNAs were differentially expressed in TNBC tissues, suggesting that they may play role in TNBC. These results shed light on lncRNAs' biological functions and provide useful information for exploring potential therapeutic targets for breast cancer.

Antitumor effect of FP3 in combination with cetuximab on patient-derived tumor tissue xenograft models of primary colon carcinoma and related lymphatic and hepatic metastases.

FP3 is an engineered protein which contains the extracellular domain 2 of vascular endothelial growth factor (VEGF) receptor 1 (Flt-1) and the extracellular domain 3 and 4 of VEGF receptor 2 (Flk-1, KDR) fused to the Fc portion of human immunoglobulin G1. Previous studies have demonstrated its antiangiogenic effects in vitro and in vivo, and its antitumor activity in vivo. Cetuximab is a monoclonal antibody against epidermal growth factor (EGF) receptor. Combined inhibition of VEGF and EGF signaling may act additively or synergistically. In this study, patient-derived tumor tissue (PDTT) xenograft models of primary colon carcinoma and lymphatic and hepatic metastases were established for assessment of the antitumor activity of FP3 in combination with cetuximab. Xenografts were treated with FP3 and cetuximab, alone or in combination. After tumor growth was confirmed, volume and microvessel density in tumors were evaluated. Levels of VEGF, EGFR and PCNA in the tumor were examined by immunohistochemical staining, and levels of related cell signaling pathway proteins were examined by western blotting. FP3 in combination with cetuximab showed significant antitumor activity in three xenograft models (primary colon carcinoma, lymphatic metastasis and hepatic metastasis). The microvessel density in tumor tissues treated with FP3 in combination with cetuximab was lower compared to that of the control. Antitumor activity of FP3 in combination with cetuximab was significantly higher than that of each agent alone in two xenograft models (colon carcinoma lymphatic metastasis and hepatic metastasis). This study indicated that addition of FP3 to cetuximab significantly improved tumor growth inhibition in the PDTT xenograft models of colon carcinoma lymphatic and hepatic metastases. Combination anti-VEGF (FP3) and anti-EGFR (cetuximab) therapies may represent a novel therapeutic strategy for the management of metastatic colon carcinoma.