Homogentisic acid metabolism inhibits papillary thyroid carcinoma proliferation through ROS and p21-induced cell cycle arrest.

Thyroid cancer is one of the most common primary endocrine malignancies worldwide, and papillary thyroid carcinoma (PTC) is the predominant histological type observed therein. Although PTC has been studied extensively, our understanding of the altered metabolism and metabolic profile of PTC tumors is limited. We identified that the content of metabolite homogentisic acid (HGA) in PTC tissues was lower than that in adjacent non-cancerous tissues. We evaluated the potential of HGA as a novel molecular marker in the diagnosis of PTC tumors, as well as its ability to indicate the degree of malignancy. Studies have further shown that HGA contributes to reactive oxygen species (ROS) associated oxidative stress, leading to toxicity and inhibition of proliferation. In addition, HGA caused an increase in p21 expression levels in PTC cells and induced G1 arrest. Moreover, we found that the low HGA content in PTC tumors was due to the low expression levels of tyrosine aminotransferase (TAT) and p-hydroxyphenylpyruvate hydroxylase (HPD), which catalyze the conversion of tyrosine to HGA. The low expression levels of TAT and HPD are strongly associated with a higher probability of PTC tumor invasion and metastasis. Our study demonstrates that HGA could be used to diagnose PTC and provides mechanisms linking altered HGA levels to the biological behavior of PTC tumors.

68Ga-Labeled Fibroblast Activation Protein Inhibitor PET/CT for the Early and Late Prediction of Pathologic Response to Neoadjuvant Chemotherapy in Breast Cancer Patients: A Prospective Study.

68Ga-labeled fibroblast activation protein inhibitor (68Ga-FAPI) PET/CT has demonstrated promising clinical results, with a higher SUVmax and tumor-to-background ratio (TBR) in breast cancer (BC) patients than 18F-FDG PET/CT. Here, we aimed to evaluate the suitability of 68Ga-FAPI PET/CT for the early and late prediction of the pathologic response to neoadjuvant chemotherapy (NAC) in BC. Methods: Twenty-two consecutive patients with newly diagnosed BC and an indication for NAC were prospectively included. All patients underwent standard chemotherapy and 68Ga-FAPI PET/CT at baseline, after 2 cycles of NAC (PET2), and 1 wk before surgery (PET3). SUVmax was measured in the primary tumor region and positive regional lymph nodes. The expression of fibroblast activation protein in the primary lesion was analyzed by immunohistochemistry. Results: Seven patients (31.8%) achieved a pathologic complete response (pCR), and 15 (68.2%) had residual tumors. Thirteen patients (59.1%) showed concentric withdrawal of the primary tumor, and 9 (40.9%) showed diffuse withdrawal. Between PET2 and PET3, the ΔSUVmax of the primary tumor (R 2 = 0.822; P = 0.001) and metastatic lymph nodes (R 2 = 0.645; P = 0.002) were significantly correlated. The absolute values of SUVmax and TBR at PET2 and PET3 were lower in patients with pCR than in those without pCR (P < 0.05). Moreover, a larger ΔSUVmax at any time point was strongly associated with pCR (P < 0.05). Similar downward trends in SUVmax, TBR, and ΔSUVmax were observed in the pattern of primary tumor reduction. For predicting pCR, the optimal cutoff values for ΔSUVmax after 2 chemotherapy cycles, ΔSUVmax before surgery, TBR after 2 chemotherapy cycles, and TBR before surgery of the primary tumor were 3.4 (area under the curve [AUC], 0.890), 1.1 (AUC, 0.978), -63.8% (AUC, 0.879), -90.8% (AUC, 0.978), 7.6 (AUC, 0.848), and 1.4 (AUC, 0.971), respectively. Immunohistochemistry showed that the SUVmax and TBR of 68Ga-FAPI PET/CT were positively correlated with fibroblast activation protein expression (P < 0.001 for both). Conclusion: Assessment of early changes in 68Ga-FAPI uptake during NAC by 68Ga-FAPI PET/CT can predict pCR and primary tumor concentric withdrawal in BC patients. 68Ga-FAPI PET/CT has great potential for the early and late prediction of the pathologic response to NAC in BC.

Targeting c-Jun inhibits fatty acid oxidation to overcome tamoxifen resistance in estrogen receptor-positive breast cancer.

Tamoxifen-based endocrine therapy remains a major adjuvant therapy for estrogen receptor (ER)-positive breast cancer (BC). However, many patients develop tamoxifen resistance, which results in recurrence and poor prognosis. Herein, we show that fatty acid oxidation (FAO) was activated in tamoxifen-resistant (TamR) ER-positive BC cells by performing bioinformatic and functional studies. We also reveal that CPT1A, the rate-limiting enzyme of FAO, was significantly overexpressed and that its enzymatic activity was enhanced in TamR cells. Mechanistically, the transcription factor c-Jun was activated by JNK kinase-mediated phosphorylation. Activated c-Jun bound to the TRE motif in the CPT1A promoter to drive CPT1A transcription and recruited CBP/P300 to chromatin, catalysing histone H3K27 acetylation to increase chromatin accessibility, which ensured more effective transcription of CPT1A and an increase in the FAO rate, eliminating the cytotoxic effects of tamoxifen in ER-positive BC cells. Pharmacologically, inhibiting CPT1A enzymatic activity with the CPT1 inhibitor etomoxir or blocking c-Jun phosphorylation with a JNK inhibitor restored the tamoxifen sensitivity of TamR cells. Clinically, high levels of phosphorylated c-Jun and CPT1A were observed in ER-positive BC tissues in patients with recurrence after tamoxifen therapy and were associated with poor survival. These results indicate that the assessment and targeting of the JNK/c-Jun-CPT1A-FAO axis will provide promising insights for clinical management, increased tamoxifen responses and improved outcomes for ER-positive BC patients.

Construction of a risk model based on N6 -methyladenosinerelated lncRNAs for predicting the prognosis of breast cancer.

N6-methyladenosine modification and lncRNAs are closely related to the prognosis and immunotherapy response of breast cancer patients. LncRNAs related to m6 A-associated genes were predicted based on coexpression analysis of the TCGA database. We established a novel 7-m6 A-associated lncRNA signature for predicting patient prognosis and validated it. The model was significantly correlated with survival time and survival status and was an independent predictor of overall survival (OS). Except for the M1 disease group, the model had good predictive value for OS in different subgroups. We constructed a prognostic model based on 7 m6 A-associated lncRNAs in breast cancer. This model could serve as an independent prognostic factor with tremendous predictive ability for breast cancer patients.

SENP3 promotes tumor progression and is a novel prognostic biomarker in triple-negative breast cancer.

Background: The clinical outcome of triple-negative breast cancer (TNBC) is poor. Finding more targets for the treatment of TNBC is an urgent need. SENPs are SUMO-specific proteins that play an important role in SUMO modification. Among several tumor types, SENPs have been identified as relevant biomarkers for progression and prognosis. The role of SENPs in TNBC is not yet clear. Methods: The expression and prognosis of SENPs in TNBC were analyzed by TCGA and GEO data. SENP3 coexpression regulatory networks were determined by weighted gene coexpression network analysis (WGCNA). Least absolute shrinkage and selection operator (LASSO) and Cox univariate analyses were used to develop a risk signature based on genes associated with SENP3. A time-dependent receiver operating characteristic (ROC) analysis was employed to evaluate a risk signature's predictive accuracy and sensitivity. Moreover, a nomogram was constructed to facilitate clinical application. Results: The prognostic and expression effects of SENP family genes were validated using the TCGA and GEO databases. SENP3 was found to be the only gene in the SENP family that was highly expressed and associated with an unfavorable prognosis in TNBC patients. Cell functional experiments showed that knockdown of SENP3 leads to growth, invasion, and migration inhibition of TNBC cells in vitro. By using WGCNA, 273 SENP3-related genes were identified. Finally, 11 SENP3-related genes were obtained from Cox univariate analysis and LASSO regression. Based on this, a prognostic risk prediction model was established. The risk signature of SENP3-related genes was verified as an independent prognostic marker for TNBC patients. Conclusion: Among SENP family genes, we found that SENP3 was overexpressed in TNBC and associated with a worse prognosis. SENP3 knockdown can inhibit tumor proliferation, invasion, and migration. In TNBC patients, a risk signature based on the expression of 11 SENP3-related genes may improve prognosis prediction. The established risk markers may be promising prognostic biomarkers that can guide the individualized treatment of TNBC patients.

Vascularized composite allograft rejection is delayed by infusion of IFN-γ-conditioned BMSCs through upregulating PD-L1.

Mesenchymal stromal cells (MSCs) have been applied in prevention from allograft rejection based on their immunomodulatory effects. However, conflicting results have been presented among recent studies, for which one possibility being acknowledged is that the exact effect is determined by the microenvironment when MSCs are applied in vivo. Using a hind limb composite tissue allograft model, we investigate the influence of IFN-γ-preconditioning on the immunomodulatory effects of MSCs and the subsequent allograft survival. Firstly, different doses of IFN-γ were respectively used to incubate with bone marrow-derived MSCs (BMSCs). We found that IFN-γ altered the expression of PD-L1, a major suppressor gene in the immune system during allograft rejection, in a strictly dose-dependent manner in BMSCs. Ten nanograms per milliliter IFN-γ-incubated BMSCs significantly stimulated PD-L1 expression and suppressed T cell proliferation and differentiation, while 50 ng/mL IFN-γ-incubated BMSCs sharply reduced PD-L1 expression. Moreover, we observed that, in contrast to the naive BMSC transplantation group, BMSCs pre-conditioned with 10 ng/mL IFN-γ (BMSCs-IFN-γ) significantly delayed the allograft rejection in vivo. In vitro mixed lymphocyte reaction (MLR) indicated that BMSCs-IFN-γ inhibited T lymphocyte proliferation and activation via PD-L1. Moreover, BMSCs-IFN-γ did not influence the proliferation and activation of T lymphocytes when PD-L1 protein was neutralized by the PD-L1 antibody. These data collectively reveal a role of recipient ongoing immune microenviroment in BMSC-based immunesuppressive therapy. Graphical abstract ᅟ.

[Effectiveness of posterior intercostal artery perforator flap in repair of donor defect after latissimus dorsi myocutaneous flap transfer].

Objective: To investigate the feasibility and effectiveness of the latissimus dorsi myocutaneous flap in repair of large complex tissue defects of limb and the relaying posterior intercostal artery perforator flap in repair of donor defect after latissimus dorsi myocutaneous flap transfer. Methods: Between January 2016 and May 2017, 9 patients with large complex tissue defects were treated. There were 8 males and 1 female with a median age of 33 years (range, 21-56 years). The injury caused by traffic accident in 8 cases, and the time from post-traumatic admission to flap repair was 1-3 weeks (mean, 13 days). The defect in 1 case was caused by the resection of medial vastus muscle fibrosarcoma. There were 5 cases of upper arm defects and 4 cases of thigh defects. The size of wounds ranged from 20 cm×12 cm to 36 cm×27 cm. There were biceps brachii defect in 2 cases, triceps brachii defect in 3 cases, biceps femoris defect in 2 cases, quadriceps femoris defect in 2 cases, humerus fracture in 2 cases, brachial artery injury in 2 cases, and arteria femoralis split defect combined with nervus peroneus communis and tibia nerve split defect in 1 case. The latissimus dorsi myocutaneous flaps were used to repair the wounds and reconstruct the muscle function. The size of the skin flaps ranged from 22 cm×13 cm to 39 cm×28 cm; the size of the muscle flaps ranged from 12 cm×3 cm to 18 cm×5 cm. The wounds were repaired with pedicle flaps and free flaps in upper limbs and lower limbs, respectively. The donor sites were repaired with posterior intercostal artery perforator flaps. The size of flaps ranged from 10 cm×5 cm to 17 cm×8 cm. The second donor sites were sutured directly. Results: All the flaps survived smoothly and the wounds and donor sites healed by first intention. All patients were followed up 10-19 months (mean, 13 months). At last follow-up, the flaps had good appearances and textures. The muscle strength recovered to grade 4 in 5 cases and to grade 3 in 4 cases. After latissimus dorsi myocutaneous flap transfer, the range of motion of shoulder joint was 40-90°, with an average of 70°. The two-point discrimination of latissimus dorsi myocutaneous flap was 9-15 mm (mean, 12.5 mm), and that of posterior intercostal artery perforator flap was 8-10 mm (mean, 9.2 mm). There were only residual linear scars at the second donor sites. Conclusion: The latissimus dorsi myocutaneous flap combined with posterior intercostal artery perforator flap for the large complex tissue defects and donor site can not only improve the appearance of donor and recipient sites, but also reconstruct muscle function, and reduce the incidence of donor complications.

The clinicopathologic differences of central lymph node metastasis in predicting lateral lymph node metastasis and prognosis in papillary thyroid cancer associated with or without Hashimoto's thyroiditis.

This study aims to evaluate the difference of central lymph node metastases (LNM) in papillary thyroid carcinoma (PTC) associated with or without Hashimoto's thyroiditis (HT) in predicting lateral node metastasis. A retrospective case control study was performed. Patients (1276) with PTC who underwent a total or near-total thyroidectomy with at least one lymph node dissection in our institution were retrospectively reviewed. All patients were divided into two groups (HT-group and non-HT group) according to the pathological diagnosis. In HT-group, the incidence of both central and lateral LNM was lower compared with non-HT group. The average of central metastatic lymph node radio (LNR) was also lower than that in Non-HT group. The multivariate analysis showed that the number of metastatic central LNs (HT ≥ 4, Non-HT ≥ 2) and the central LNR (HT ≥ 0.4, Non-HT ≥ 0.6) were independently associated with lateral LNM. Patients with HT need larger primary tumor size, more positive central LN and higher LNR to predict the presence of lateral LNM. HT may protect against central and lateral LNM in PTC. The number of positive central LNs and central LNR in PTC could be used to determine the presence of lateral LNM and inform postoperative follow-up.