Covalent targeted radioligands potentiate radionuclide therapy.

Targeted radionuclide therapy, in which radiopharmaceuticals deliver potent radionuclides to tumours for localized irradiation, has addressed unmet clinical needs and improved outcomes for patients with cancer1-4. A therapeutic radiopharmaceutical must achieve both sustainable tumour targeting and fast clearance from healthy tissue, which remains a major challenge5,6. A targeted ligation strategy that selectively fixes the radiopharmaceutical to the target protein in the tumour would be an ideal solution. Here we installed a sulfur (VI) fluoride exchange (SuFEx) chemistry-based linker on radiopharmaceuticals to prevent excessively fast tumour clearance. When the engineered radiopharmaceutical binds to the tumour-specific protein, the system undergoes a binding-to-ligation transition and readily conjugates to the tyrosine residues through the 'click' SuFEx reaction. The application of this strategy to a fibroblast activation protein (FAP) inhibitor (FAPI) triggered more than 80% covalent binding to the protein and almost no dissociation for six days. In mice, SuFEx-engineered FAPI showed 257% greater tumour uptake than did the original FAPI, and increased tumour retention by 13-fold. The uptake in healthy tissues was rapidly cleared. In a pilot imaging study, this strategy identified more tumour lesions in patients with cancer than did other methods. SuFEx-engineered FAPI also successfully achieved targeted ß- and α-radionuclide therapy, causing nearly complete tumour regression in mice. Another SuFEx-engineered radioligand that targets prostate-specific membrane antigen (PSMA) also showed enhanced therapeutic efficacy. Considering the broad scope of proteins that can potentially be ligated to SuFEx warheads, it might be possible to adapt this strategy to other cancer targets.

PAX2 is regulated by estrogen/progesterone through promoter methylation in endometrioid adenocarcinoma and has an important role in carcinogenesis via the AKT/mTOR signaling pathway.

Endometrioid adenocarcinoma (EEC) is one of the most common cancers of the female reproductive system. In recent years, much emphasis has been placed on early diagnosis and treatment. PAX2 (Paired box 2) inactivation is reportedly an important biomarker for endometrioid intraepithelial neoplasia (EIN) and EEC. However, the role of PAX2 in EEC carcinogenesis remains unclear. PAX2 expression and associated clinical characteristics were analyzed via The Cancer Genome Atlas, Gene Expression Omnibus, and Cancer Cell Line Encyclopedia databases and clinical paired EIN/EEC tissue samples. Bioinformatic analysis was conducted to identify the putative molecular function and mechanism of PAX2. Cell proliferation, colony formation, cell migration, and invasion assays in vitro, and mouse xenograft models were utilized to study the biological functions of PAX2 in vivo. Pyrosequencing and the demethylating drug 5-Aza-dc were used to verify promoter methylation in clinical tissues and cell lines, respectively. The mechanism underlying the regulatory effect of estrogen (E2) and progesterone (P4) on PAX2 expression was investigated by receptor block assay and double luciferase reporter assay. PAX2 expression was found to be significantly downregulated in EIN and EEC tissues, its overexpression inhibited EEC cell malignant behaviors in vivo and in vitro and inhibited the AKT/mTOR signaling pathway. PAX2 inactivation in EEC was related to promoter methylation, and its expression was regulated by E2 and P4 through their receptors via promoter methylation. Our findings elucidated the expression and function of PAX2 in EEC and have provided hitherto undocumented evidence of the underlying molecular mechanisms. PAX2 expression is suppressed by estrogen prompting its methylation through estrogen receptor. Furthermore, PAX2 regulates the AKT/mTOR signaling pathway to influence EEC progression. © 2024 The Pathological Society of Great Britain and Ireland.

Stimulated Raman Scattering Microscopy Reveals Aberrant Triglyceride Accumulation in Lymphatic Metastasis of Papillary Thyroid Carcinoma.

Lipid metabolic alterations are known to play a crucial role in cancer metastasis. As a key hub in lipid metabolism, intracellular neutral lipid accumulation in lipid droplets (LDs) has become a signature of aggressive human cancers. Nevertheless, it remains unclear whether lipid accumulation displays distinctive features in metastatic lesions compared to the primary ones. Here, we integrated multicolor stimulated Raman scattering (SRS) imaging with confocal Raman spectroscopy on the same platform to quantitatively analyze the amount and composition of LDs in intact human thyroid tissues in situ without any processing or labeling. Inspiringly, we found aberrant accumulation of triglycerides (TGs) in lymphatic metastases but not in normal thyroid, primary papillary thyroid carcinoma (PTC), or normal lymph node. In addition, the unsaturation degree of unsaturated TGs was significantly higher in the lymphatic metastases from patients diagnosed with late-stage (T3/T4) PTC compared to those of patients diagnosed with early-stage (T1/T2) PTC. Furthermore, both public sequencing data analysis and our RNA-seq transcriptomic experiment showed significantly higher expression of alcohol dehydrogenase-1B (ADH1B), which is critical to lipid uptake and transport, in lymphatic metastases relative to the primary ones. In summary, these findings unravel the lipid accumulation as a novel marker and therapeutic target for PTC lymphatic metastasis that has a poor response to the regular radioactive iodine therapy.

Extension of Endocardium-Derived Vessels Generate Coronary Arteries in Neonates.

BACKGROUND: Unraveling how new coronary arteries develop may provide critical information for establishing novel therapeutic approaches to treating ischemic cardiac diseases. There are 2 distinct coronary vascular populations derived from different origins in the developing heart. Understanding the formation of coronary arteries may provide insights into new ways of promoting coronary artery formation after myocardial infarction. METHODS: To understand how intramyocardial coronary arteries are generated to connect these 2 coronary vascular populations, we combined genetic lineage tracing, light sheet microscopy, fluorescence micro-optical sectioning tomography, and tissue-specific gene knockout approaches to understand their cellular and molecular mechanisms. RESULTS: We show that a subset of intramyocardial coronary arteries form by angiogenic extension of endocardium-derived vascular tunnels in the neonatal heart. Three-dimensional whole-mount fluorescence imaging showed that these endocardium-derived vascular tunnels or tubes adopt an arterial fate in neonates. Mechanistically, we implicate Mettl3 (methyltransferase-like protein 3) and Notch signaling in regulating endocardium-derived intramyocardial coronary artery formation. Functionally, these intramyocardial arteries persist into adulthood and play a protective role after myocardial infarction. CONCLUSIONS: A subset of intramyocardial coronary arteries form by extension of endocardium-derived vascular tunnels in the neonatal heart.

Impact of lateral cervical lymph node metastasis on lung metastasis in pediatric thyroid cancer: A correlation study.

BACKGROUND: Thyroid cancer (TC) frequently manifests with lung metastases in the pediatric population, occurring at a significant rate of 30 %. This study aims to evaluate the impact of regional patterns of cervical lymph node metastases on lung metastases in pediatric TC. METHODS: Retrospective analysis was conducted on data from pediatric TC patients spanning the years 2000 to 2018. We compared the rates of lymph node metastasis (LNR), the number of lymph node metastases, and the number of dissected lymph nodes in the central and lateral cervical regions between patients with and without lung metastases. Statistical methods were employed to adjust for confounders during hypothesis testing. RESULTS: A total of 227 pediatric patients, with a median age of 15.12 ± 2.84 years, were included in the study. Of these, 202 (89 %) exhibited LN metastasis, with 40(17.62 %) patients presenting with lung metastasis. Patients with lung metastases were found to be younger (13.40 ± 3.11 vs. 15.50 ± 2.64, p < 0.001), had larger primary tumor diameters (3.49 ± 1.98 vs. 2.31 ± 1.45, p < 0.001), and exhibited a higher number of lymph node metastases (23.40 ± 10.75 vs. 14.65 ± 13.16, p < 0.001). Notably, in patients with LN metastases, the presence of >12 lateral cervical lymph node metastases emerged as a significant risk factor for lung metastases. Among children with metachronous lung metastases, the median time to detection of lung metastases was 43 (12-132) months, and they appeared to receive a greater proportion of radioactive iodine (RAI) treatment compared to those with synchronous lung metastases. CONCLUSION: Lateral cervical lymph node metastasis independently predicts the likelihood of lung metastases in pediatric TC. Furthermore, our findings emphasize the importance of thorough examination of the lungs during follow-up, particularly when the number of metastatic lateral cervical lymph nodes exceeds 12.

The frequency of risk pathological characteristics in clinically low-risk papillary thyroid microcarcinoma suitable for active surveillance.

PURPOSE: Active surveillance has emerged as an initial management strategy for patients with low-risk papillary thyroid microcarcinoma (PTMC). The main objective of this research was to investigate the frequency of risk pathological characteristics among patients with clinically low-risk PTMC who are suitable for Active Surveillance. METHODS: A retrospective review was conducted on patients who underwent lobectomy for PTMC between January 2013 and December 2018. Patients with bilateral tumors, macroscopic multifocal tumors, macroscopic extrathyroidal extension (ETE), clinical lymph node metastases, macroscopic extranodal extension (ENE), distant metastases, a history of neck radiation or familial thyroid cancer were excluded. Pathological characteristics were collected from the postoperative pathological results. Aggressive variants, multifocality, ETE, lymphovascular invasion (LVI), perineural invasion (PNI), metastatic lymph nodes (LNs) ≥ 5, and ENE were defined as risk characteristics. RESULTS: The study included 4923 patients, of whom 1229 (25.0%) were male. The mean age was 43 years. A total of 2250 patients (45.7%) exhibited risk characteristics. Among them, 15 patients presented with aggressive variants, and 1813 patients (36.8%) had ETE. Multifocality, LVI, and PNI were observed in 551 (11.2%), 21 (0.4%), and 40 (0.8%) patients, respectively. A total of 139 patients (2.8%) had five or more metastatic LNs, and ENE was identified in 140 patients. Notably, 172 patients (3.5%) fulfilled the criteria for completion thyroidectomy, as they had aggressive variants, LVI, or five or more metastatic LNs. CONCLUSIONS: Nearly half of the patients diagnosed with clinically low-risk PTMC exhibited risk pathological characteristics, and a small proportion of patients met the criteria for completion thyroidectomy.

A nomogram for predicting lateral lymph node metastasis in cN0 unifocal papillary thyroid microcarcinoma.

BACKGROUND: Identifying risk factors for occult lateral lymph node metastasis (LLNM) in papillary thyroid microcarcinoma (PTMC) can provide valuable insights into the necessity of lateral neck dissection (LND). The objective of this study was to develop a nomogram for predicting the probability of LLNM in patients with cN0 unifocal PTMC. METHODS: We conducted a retrospective analyzed a total of 4872 patients with cN0 unifocal PTMC who were treated at our center from January 2013 to June 2018. Logistic regression analysis was used to determine the risk factors for LLNM, and a nomogram was constructed based on these risk factors. RESULTS: The rate of LLNM was 3.2%. Tumors located in the upper lobe(odds ratio [OR] = 2.56, 95% confidence interval [CI] 1.80-3.62; p < 0.001) and size greater than 7 mm (OR = 2.59, 95% CI 1.85-3.62; p < 0.001) had a significantly higher risk of LLNM compared to tumors in the lower or middle lobe and size less than or equal to 7 mm. Tumors with extrathyroidal extension (ETE) had a significantly higher risk of LLNM (OR = 1.41, 95% CI 1.01-1.99; p = 0.044). The presence of three or more central lymph node metastases (CLNMs) (OR = 5.84, 95% CI 3.83-8.93; p < 0.001) or one or two CLNMs (OR = 2.91, 95% CI 1.93-4.42; p < 0.001) also increased the risk of LLNM compared to having no CLNMs. A nomogram incorporating these risk factors was developed, and the receiver operating characteristic (ROC) curve demonstrated an area under the curve (AUC) of 0.777, indicating a high degree of predictive accuracy. CONCLUSION: Tumor location in the upper lobe, greater than 7 mm in size, ETE, and CLNMs, especially three or more, were independent risk factors for LLNM in cN0 unifocal PTMC. The nomogram based on these factors exhibited favorable predictive value and consistency.

Association between surgical extent and recurrence in unilateral intermediate- to high-risk papillary thyroid cancer.

BACKGROUND: Guidelines recommend total thyroidectomy (TT) to facilitate radioactive ablation and serological follow-up for intermediate- to high-risk papillary thyroid carcinoma (PTC). However, the association between surgical extent and tumor recurrence in these patients has not been well validated. We aimed to examine the association between the extent of surgery and recurrence in patients with completely resected unilateral intermediate- to high-risk PTC. METHODS: Patients with completely resected unilateral PTC from 2000 to 2017 in a single institute were reviewed. Those who had extrathyroidal extension (ETE) or lymph node metastasis (LNM, cN1 or pN1 > 5 lymph nodes involved) were included for analysis. Cox proportional hazards models were applied to measure the association between surgical extent and recurrence-free survival (RFS) while adjusting for patient demographic, clinicopathological and treatment variables. RESULTS: A total of 4550 patients (mean[SD] age, 43.0[11.7] years; 3379 women[74.3%]) were included. Of these patients, 2262(49.7%), 656(14.4%), 1032(22.7%), and 600 (13.2%) underwent lobectomy, TT, lobectomy + neck dissection (ND) and TT + ND, respectively. With a median follow-up period of 68 months, after multivariate adjustment, lobectomy was associated with a compromised RFS compared with other surgical extents (HR[95%CI], TT 0.537[0.333-0.866], P = 0.011, lobectomy + ND 0.531[0.392-0.720] P < 0.0001, TT + ND 0.446[0.286-0.697] P < 0.0001). RFS was similar between the two extents with ND (lobectomy + ND, HR [95%CI], 1.196 [0.759-1.885], P = 0.440). CONCLUSION: Lobectomy alone is associated with an elevated recurrence risk in patients with unilateral intermediate- to high-risk PTC compared with larger surgical extents. However, lobectomy and ND may provide similar tumor control compared with the conventional approach of TT and ND.

CT-based quantification of trachea shape to detect invasion by thyroid cancer.

OBJECTIVE: This study aims to develop a CT-based method for quantifying tracheal shape and evaluating its ability to distinguish between cases with or without tracheal invasion in patients with thyroid carcinoma. METHODS: A total of 116 quantitative shape features, including 56 geometric moments and 60 bounding shape features, were defined. The tracheal lumen was semi-automatically defined with a CT threshold of less than - 500 HU. Three contiguous slices with the 1st, 2nd, and 3rd smallest trachea lumen areas were contiguously selected, and the appropriate number of slices to be included was determined. Fifty-six patients with differentiated thyroid carcinoma (DTC) invading the trachea and 22 patients with DTC but without invasion were retrospectively included. A receiver operating characteristic (ROC) curve was applied to select the representative shape features and determine the optimal threshold. RESULTS: 23.3%, 25.9%, and 24.1% of the features displayed an area under the ROC curve (AUC) ≥ 0.800 when derived from 1, 2, and 3 slices, respectively. Calculating feature values from two slices with the 1st and 2nd smallest tracheal lumen area were considered appropriate. Six final features, including 3 geometric moments and 3 bounding shape features, were selected to determine the tracheal invasion status of DTC and displayed AUCs of 0.875-0.918, accuracies of 0.821-0.891, sensitivities of 0.813-0.893, and specificities of 0.818-0.932, outperforming the visual evaluation results. CONCLUSIONS: Geometric moments and bounding shape features can quantify the tracheal shape and are reliable for identifying DTC tracheal invasion. The selected features quantified the extent of tracheal deformity in DTC patients with and without tracheal invasion. CLINICAL RELEVANCE STATEMENT: Six geometric features provide a non-invasive, semi-automated evaluation of the tracheal invasion status of thyroid cancer. KEY POINTS: • A novel method for quantifying tracheal shape using 56 geometric moments and 60 bounding shape features was developed. • Six features identify tracheal invasion by thyroid carcinoma. • The selected features quantified the extent of tracheal deformity in differentiated thyroid carcinoma patients with and without tracheal invasion.

A prediction model for identifying high-risk lymph node metastasis in clinical low-risk papillary thyroid microcarcinoma.

BACKGROUND: The presence of high-volume lymph node metastasis (LNM) and extranodal extension (ENE) greatly increases the risk of recurrence in patients with low-risk papillary thyroid microcarcinoma (PTMC). The goal of this research was to analyze the factors that contribute to high-risk lymph node metastasis in patients with low-risk PTMC. METHODS: We analyzed the records of 7344 patients who were diagnosed with low-risk PTMC and treated at our center from January 2013 to June 2018.LNM with a high volume or ENE was classified as high-risk lymph node metastasis (hr-LNM). A logistic regression analysis was conducted to identify the risk factors associated with hr-LNM. A nomogram was created and verified using risk factors obtained from LASSO regression analysis, to predict the likelihood of hr-LNM. RESULTS: The rate of hr-LNM was 6.5%. LASSO regression revealed six variables that independently contribute to hr-LNM: sex, age, tumor size, tumor location, Hashimoto's thyroiditis (HT), and microscopic capsular invasion. A predictive nomogram was developed by integrating these risk factors, demonstrating its excellent performance. Upon analyzing the receiver operating characteristic (ROC) curve for predicting hr-LNM, it was observed that the area under the curve (AUC) had a value of 0.745 and 0.730 in the training and testing groups showed strong agreement, affirming great reliability. CONCLUSION: Sex, age, tumor size, tumor location, HT, and microscopic capsular invasion were determined to be key factors associated with hr-LNM in low-risk PTMC. Utilizing these factors, a nomogram was developed to evaluate the risk of hr-LNM in patients with low-risk PTMC.

Intraparotid node metastasis affects the long-term survival of patients with resectable recurrent parotid gland carcinoma.

PURPOSE: The recurrence rate of parotid gland cancer is high, but research on the prognosis of recurrent parotid gland cancer (RPC) is relatively limited. We aim to determine the potential prognosis factors of RPC. STUDY DESIGN: Retrospective cohort analysis. SETTING: Tertiary cancer center. METHODS: We conducted a retrospective review from 2012 to 2021 on RPC patients treated at the China National Cancer Center (CNCC). To analyze the impact of various variables on overall survival (OS) after recurrence, a univariate and multivariate Cox proportional hazard model was employed. RESULTS: A total of 50/218 (23.0%) patients diagnosed with RPC and underwent surgery. The 5-year OS of all RPC patients in this cohort was 61.9%. 5 of 50 patients (10%) exhibited intraparotid node (IPN) metastasis. By univariate and multivariate analyses, we found that IPN metastasis was one of the prognostic factors of OS (p = 0.039) in RPC patients. The presence of IPN metastasis was also related to poor survival in individuals with negative cervical lymph nodes (CN0) (p = 0.011). In terms of the influence of surgical margins on prognosis, our findings revealed that RPC patients with negative margins exhibited a higher survival result than those with positive margins (p = 0.002). CONCLUSION: According to this study, IPN metastasis indicate a high incidence of mortality in recurrent parotid cancer patients. Particularly, in CN0 patients, the presence of IPN metastasis was associated with poor survival in CN0 patients.

Risk stratification of lateral neck recurrence for patients with pN1a papillary thyroid cancer.

BACKGROUND: Lateral neck is not recommended for dissection in patients with pN1a papillary thyroid cancer (PTC), but its recurrence risk has not been well stratified. We aimed to develop a risk stratification system for lateral neck recurrence in patients with pN1a PTC. METHODS: Patients with pN1a PTC who underwent thyroidectomy and unilateral central compartment dissection from 2000-2016 were enrolled. The association between number of central lymph node metastases (CLNMs) and lateral neck recurrence was comprehensively assessed using a Cox proportional hazards model with restricted cubic spline. Stratification was then performed based on CLNMs and other significant risk factors selected by multivariate analysis. Lateral neck recurrent-free survival (LRFS) rate of each stratification was estimated with Kaplan-Meier curve and comparison was performed using log-rank test. RESULTS: Ninety-six (3.8%) lateral neck recurrences were identified during a median follow-up of 62 months among a total of 2500 admitted cases. An increasing number of CLNMs was associated with compromised LRFS for up to 6 CLNMs (P < 0.001), and CLNMs > 3 indicated significantly worse 5-year LRFS than that of CLNM ≤ 3 (90.6% vs. 98.1%, P < 0.001). When stratification with CLNMs and primary tumor size (selected by multivariate analysis, HR (95%CI) = 4.225(2.460-7.256), P < 0.001), 5-year LRFS rates of high- (CLNMs > 3 and primary tumor size > 2 cm), intermediate- (CLNMs > 3 and primary tumor size 1-2 cm) and low-risk (primary tumor size ≤ 1 cm or CLNMs ≤ 3) groups were 78.5%, 90.0% and 97.9%, respectively (P < 0.05). CONCLUSIONS: The number of CLNMs combined with primary tumor size seems to effectively stratify lateral neck recurrence risk for patients with pN1a PTC.

Induction TPF followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locally advanced hypopharyngeal cancer: a preliminary analysis of a randomized phase 2 trial.

PURPOSE: Concurrent chemoradiotherapy (CCRT) is a standard treatment choice for locally advanced hypopharyngeal carcinoma. The aim of this study was to investigate whether induction chemotherapy (IC) followed by CCRT is superior to CCRT alone to treat locally advanced hypopharyngeal carcinoma. METHODS AND MATERIALS: Patients (n = 142) were randomized to receive two cycles of paclitaxel/cisplatin/5-fluorouracil (TPF) IC followed by CCRT or CCRT alone. The primary end point was overall survival (OS). The secondary end points included the larynx-preservation rate, progression-free survival (PFS), distant metastasis-free survival (DMFS), and toxicities. RESULTS: Ultimately, 113 of the 142 patients were analyzed. With a median follow-up of 45.6 months (interquartile range 26.8-57.8 months), the 3-year OS was 53.1% in the IC + CCRT group compared with 54.8% in the CCRT group (hazard ratio, 1.004; 95% confidence interval, 0.573-1.761; P = 0.988). There were no statistically significant differences in PFS, DMFS, and the larynx-preservation rate between the two groups. The incidence of grade 3-4 hematological toxicity was much higher in the IC+ CCRT group than in the CCRT group (54.7% vs. 10%, P < 0.001). CONCLUSIONS: Adding induction TPF to CCRT did not improve survival and the larynx-preservation rate in locally advanced hypopharyngeal cancer, but caused a higher incidence of acute hematological toxicities. TRIAL REGISTRATION: ClinicalTrials.gov , number NCT03558035. Date of first registration, 15/06/2018.

Solute Carrier Family 27 Member 6 (SLC27A6) Possibly Promotes the Proliferation of Papillary Thyroid Cancer by Regulating c-MYC.

To investigate the expression and mechanism of LSC27A6 in papillary thyroid cancer (PTC). We analyzed the differential expression of SLC27A6 in PTC tissues and normal tissues based on the TCGA database and validated it using immunohistochemistry. Wilcoxon rank sum, chi-square test, or Fisher exact exam were used to analyze the relationship between the expression of SLC27A6 and clinicopathological information. Samples were divided into two groups according to whether BRAF was mutated or not, and Wilcoxon rank sum was used to determine whether the expression of SLC27A6 was related to BRAF mutation. The effects of SLC27A6 on the proliferation, migration, and apoptosis of PTC cells were detected by cell counting kit-8 (CCK8), colony formation assay, transwell assay, and flow cytometry. Spearman correlation analysis was used to evaluate the relationship between SLC27A6 and c-MYC. Protein expression was detected by Western blot. The expression of SLC27A6 was higher in PTC and positively correlated with N stage. SLC27A6 expression was higher in samples with BRAF mutations. Down-regulation of SLC27A6 inhibited cell proliferation, migration, and invasion and induced apoptosis. Spearman correlation analysis showed that SLC27A6 was positively correlated with c-MYC. Knockdown of SLC27A6 inhibited c-MYC expression. Our results suggest that SLC27A6 is overexpressed in PTC tissues and affects the progression of PTC by regulating c-MYC.

Organ preservation surgery for pyriform sinus carcinoma with vocal cord fixation: functional and oncological outcomes.

BACKGROUND: Pyriform sinus carcinoma with vocal cord fixation is stratified as stage T3 and above, and non-surgical treatment is generally preferred according to the guidelines, aiming to preserve laryngeal function. However, long-term survival is often compromised by deep infiltration of the tumor. Vertical hemipharyngolaryngectomy (VHPL) was previously reported to be a feasible surgical approach for organ preservation. The aim of this study was to evaluate the functional and oncological outcomes of VHPL in patients. METHODS: Patients who underwent VHPL type II (total VHPL, which includes the removal of a vertical section of the thyroid cartilage through the anterior commissure to the upper border of the cricoid cartilage) for pyriform sinus cancer with vocal cord fixation at the authors' institute between 1999 and 2015 were retrospectively analyzed. Functional outcomes concerning swallowing and decannulation were evaluated. Successful functional preservation was defined as laryngeal preservation as well as oral realimentation and decannulation within 6 months after surgery. The oncological outcomes were measured by overall survival (OS) and disease-free survival (DFS) with Kaplan-Meier curves and comparisons were performed between the VHPL-treated patients and patients who underwent non-surgical treatment within the same period. RESULTS: A total of 23 patients (stage T3, 17 patients; stage T4, 6 patients) whose initial treatment was VHPL type II were studied, and a cohort of 123 patients was selected as the control group. Pedicle and free flap reconstructions were performed on 12 and 11 patients, respectively. Postoperative radiation and chemoradiation was performed on 14 and 3 patients, respectively. Flap failure and pharyngeal fistula were detected in 2 and 5 patients, respectively. Oral realimentation and decannulation within 6 months were achieved in 82.6% (19 patients) and 87.0% (20 patients) of patients, respectively, and the total functional preservation rate of the study cohort at 6 months was similar to that of the control cohort. (78.3% vs. 82.9%, p = 0.28). After a median follow-up period of 49 months, 9 recurrences and 8 deaths had occurred in the study cohort. According to the Kaplan-Meier analysis, the study cohort had superior DFS (5-year DFS 60.3% vs. 44.6%, p = 0.04) and similar OS (5-year OS 63.8% vs 57.0% p = 0.28) compared with those in the control group. CONCLUSION: VHPL yielded favorable oncological and functional outcomes in patients with unilateral pyriform sinus carcinoma and vocal cord fixation.

Dominant point mutation in a tetraspanin gene associated with field-evolved resistance of cotton bollworm to transgenic Bt cotton.

Extensive planting of crops genetically engineered to produce insecticidal proteins from the bacterium Bacillus thuringiensis (Bt) has suppressed some major pests, reduced insecticide sprays, enhanced pest control by natural enemies, and increased grower profits. However, rapid evolution of resistance in pests is reducing these benefits. Better understanding of the genetic basis of resistance to Bt crops is urgently needed to monitor, delay, and counter pest resistance. We discovered that a point mutation in a previously unknown tetraspanin gene in the cotton bollworm (Helicoverpa armigera), a devastating global pest, confers dominant resistance to Cry1Ac, the sole Bt protein produced by transgenic cotton planted in China. We found the mutation using a genome-wide association study, followed by fine-scale genetic mapping and DNA sequence comparisons between resistant and susceptible strains. CRISPR/Cas9 knockout of the tetraspanin gene restored susceptibility to a resistant strain, whereas inserting the mutation conferred 125-fold resistance in a susceptible strain. DNA screening of moths captured from 23 field sites in six provinces of northern China revealed a 100-fold increase in the frequency of this mutation, from 0.001 in 2006 to 0.10 in 2016. The correspondence between the observed trajectory of the mutation and the trajectory predicted from simulation modeling shows that the dominance of the mutation accelerated adaptation. Proactive identification and tracking of the tetraspanin mutation demonstrate the potential for genomic analysis, gene editing, and molecular monitoring to improve management of resistance.

Recurrent granular cell tumor of the thyroid: a case report and literature review.

BACKGROUND: Granular cell tumor (GCT) of the thyroid is a rare benign tumor of Schwann cell origin with a favorable prognosis and only 10 cases have been reported so far in scientific literature. The present case study describes the first case of recurrent thyroid GCT. CASE PRESENTATION: Our case describes a 20-year-old woman who had undergone lobectomy for GCT of the thyroid 4 years ago. Hematoxylin-eosin (HE) staining revealed that the lesion was composed of epithelioid cells with an abundance of eosinophilic granular cytoplasm. Immunohistochemical analysis showed that tumor cells tested positive for S-100 protein and negative for desmin. Both histological and immunohistochemical analyses supported the diagnosis of recurrent GCT of the thyroid. CONCLUSIONS: Our case suggested that a tumor-free margin excision and post-operative follow-up are necessary for the treatment of GCT of the thyroid.

Primary hyperoxaluria diagnosed after kidney transplantation failure: lesson from 3 case reports and literature review.

BACKGROUND: Primary hyperoxaluria (PH) is a rare inborn disorder of the metabolism of glyoxylate, which causes the hallmark production oxalate and forms insoluble calcium oxalate crystals that accumulate in the kidney and other organs. Since the manifestation of PH varies from recurrent nephrolithiasis, nephrocalcinosis, and end-stage renal disease with age at onset of symptoms ranging from infancy to the sixth decade, the disease remains undiagnosed until after kidney transplantation in some cases. CASE PRESENTATION: Herein, we report 3 cases of PH diagnosed after kidney transplantation failure, providing the comprehensive clinical course, the ultrasonic image of renal graft and pathologic image of the biopsy, highlighting the relevance of biopsy findings and the results of molecular genetic testing. We also focus on the treatment and the unfavorable outcome of the patients. Meanwhile, we review the literature and show the additional 10 reported cases of PH diagnosed after kidney transplantation. Additionally, we discuss the progressive molecular understanding of the mechanisms involved in PH and molecular therapy. CONCLUSIONS: Overall, the necessity of preoperative screening of PH in all patients even with a minor history of nephrolithiasis and the importance of proper treatment are the lessons we learn from the 3 cases, which prompt us to avoid tragedies.

MicroRNA-183 induces epithelial-mesenchymal transition and promotes endometrial cancer cell migration and invasion in by targeting CPEB1.

The aim of this study is to evaluate the ability of microRNA-183 (miR-183) to influence epithelial-mesenchymal transition (EMT) and cell proliferation, migration, invasion, and apoptosis in endometrial cancer (EC) by targeting cytoplasmic polyadenylation element binding protein 1(CPEB1). EC tissues with matched nonmalignant tissues were collected from 208 EC patients. Ishikawa and RL95-2 cells were selected for cell experiments in vitro and each kind of cells were grouped into blank, negative control (NC), miR-183 mimic, miR-183 inhibitor, CPEB1 overexpression, and miR-183 mimic + CPEB1 overexpression groups. Expressions of miR-183, CPEB1, E-cadherin, and Vimentin were determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Cell viability, colony formation ability, migration, invasion, and apoptosis were assessed by MTT assay, clone formation assay, scratch test, Transwell assay, and flow cytometry. In vivo tumorigenesis of Ishikawa cells was evaluated by tumor formation in nude mice. The miR-183 expression was higher, but the CPEB1 expression was lower in EC tissues than in adjacent nonmalignant tissues. CPEB1 was confirmed as the target of miR-183 by dual-luciferase reporter assay. The miR-183 mimic group had increased cell viability, colony formation ability, cell invasion and migration, tumor volume and weight in nude mice, but decreased cell apoptosis when compared with the blank group. The expression of E-cadherin was down-regulate, but expression of Vimentin was up-regulate in the miR-183 mimic group in comparison with the blank group. In terms of a comparison between the blank group and CPEB1 overexpression group, the CPEB1 overexpression group had suppressed cell viability, colony formation ability, cell invasion and migration, tumor volume and weight, but increased cell apoptosis. The expression of E-cadherin was up-regulated, but the expression of Vimentin was down-regulated in the CPEB1 overexpression group in comparison with the blank group. The miR-183 mimic + CPEB1 overexpression group had higher miR-183 expression than the blank group. These findings indicate that miR-183 induces EMT, inhibits apoptosis, and promotes cell proliferation, migration, invasion, and in vivo tumorigenesis in EC by targeting CPEB1.

Recovery from Talaromyces marneffei involving the kidney in a renal transplant recipient: A case report and literature review.

Talaromyces marneffei is an emerging opportunistic infection among immunocompromised patients. We observe the first native case of disseminated T. marneffei involving the kidney in a renal transplant recipient in mainland China. We describe the comprehensive clinical course, and ultrasound imaging of renal transplant biopsy, pathologic images, and electron microscopy observation of the biopsy specimen, highlighting the relevance of biopsy findings and the blood culture. We also focus on the treatment and good outcome of the patient. Then we review the literature and show the additional 10 reported cases of T. marneffei in renal transplant recipients. In addition, we discuss the new methods of rapid diagnosis of T. marneffei. In brief, timely diagnosis and proper treatment of T. marneffei infection is important in renal transplant recipients.