A Phase II Study of Neoadjuvant PLD/Cyclophosphamide and Sequential nab-Paclitaxel Plus Dual HER2 Blockade in HER2-Positive Breast Cancer.

BACKGROUND: Neoadjuvant trastuzumab/pertuzumab (HP) plus chemotherapy for HER2-positive breast cancer (BC) achieved promising efficacy. The additional cardiotoxicity still existed. Brecan study evaluated the efficacy and safety of neoadjuvant pegylated liposomal doxorubicin (PLD)/cyclophosphamide and sequential nab-paclitaxel based on HP (PLD/C/HP-nabP/HP). PATIENTS AND METHODS: Brecan was a single-arm phase II study. Eligible patients with stages IIA-IIIC HER2-positive BC received 4 cycles of PLD, cyclophosphamide, and HP, followed by 4 cycles of nab-paclitaxel and HP. Definitive surgery was scheduled after 21 days for patients completing treatment or experiencing intolerable toxicity. The primary endpoint was the pathological complete response (pCR). RESULTS: Between January 2020 and December 2021, 96 patients were enrolled. Ninety-five (99.0%) patients received 8 cycles of neoadjuvant therapy and all underwent surgery with 45 (46.9%) breast-conserving surgery and 51 (53.1%) mastectomy. The pCR was 80.2% (95%CI, 71.2%-87.0%). Four (4.2%) experienced left ventricular insufficiency with an absolute decline in LVEF (43%-49%). No congestive heart failure and ≥grade 3 cardiac toxicity occurred. The objective response rate was 85.4% (95%CI, 77.0%-91.1%), including 57 (59.4%) complete responses and 25 (26.0%) partial responses. The disease control rate was 99.0% (95%CI, 94.3%-99.8%). For overall safety, ≥grade 3 AEs occurred in 30 (31.3%) and mainly included neutropenia (30.2%) and asthenia (8.3%). No treatment-related deaths occurred. Notably, age of >30 (P = .01; OR = 5.086; 95%CI, 1.44-17.965) and HER2 IHC 3+ (P = .02; OR = 4.398; 95%CI, 1.286-15.002) were independent predictors for superior pCR (ClinicalTrials.gov Identifier NCT05346107). CONCLUSION: Brecan study demonstrated the encouraging safety and efficacy of neoadjuvant PLD/C/HP-nabP/HP, suggesting a potential therapeutic option in HER2-positive BC.

Immediate breast reconstruction with laparoscopically harvested omental flap: A retrospective analysis with a maximum 12-year follow-up.

PURPOSE: To evaluate the clinical efficacy of immediate breast reconstruction with free or pedicled laparoscopically harvested omental flaps (LHOFs). METHODS: Between March 2011 and 2021, 82 patients who underwent immediate breast reconstruction with free or pediculated omental flaps were enrolled. Breast total or partial mastectomy, laparoscopic greater omentum harvest, and breast reconstruction were carried out in an orderly manner. Postoperative operative results, cosmetic outcomes, and complications were investigated. RESULTS: Seventeen cases of free LHOF and 65 cases of pedicled LHOF were performed. Cosmetic results were mostly satisfactory (61% excellent, 35% good), with a soft breast that was natural in appearance. Satisfaction investigation showed that 96.2% of patients were satisfied with the reconstructed breast. Uneventful follow-up showed no abdominal complications at the donor site, and the surface skin displayed no swelling. No major complications were found, except for three cases of necrosis. One patient developed slight hematoma. Two patients were found to have local recurrence, and one had distant metastasis. Twenty-four patients accepted radiotherapy, but no size reduction was noted after radiotherapy. We followed the patients to determine their survival status. All patients were alive, except for 1 in the free LHOF group who died 31.2 months after surgery. CONCLUSION: Immediate breast reconstruction with LHOF provides a soft reconstructed breast with relatively little donor-site deformity and is useful for breast tumor-specific immediate reconstruction.

Palbociclib plus endocrine therapy in hormone receptor-positive and HER2 negative metastatic breast cancer: a multicenter real-world study in the northwest of China.

BACKGROUND: Real-world data of Palbociclib are insufficient in China. This study aimed to investigate the treatment pattern and real-world outcomes in hormone receptor positive and human epidermal growth factor 2 receptor negative (HR+/HER2-) metastatic breast cancer (MBC) patients treated with Palbociclib in the northwest of China. METHODS: HR+/HER2- MBC patients who received Palbociclib in 8 centers from July 2017 to September 2019 were retrospectively included in this study. Real-world objective response rate (ORR), progression-free survival (PFS) and safety profiles were analyzed. The survival curves were plotted by the Kaplan-Meier method to analyze PFS, which was verified by the log-rank test. RESULTS: In total, 211 women were eligible for the analysis. A total of 85 patients (40.3%), 78 (37.0%), and 48 (22.7%) received Palbociclib in the first-, second-, third- or later-line setting, respectively. 46 patients achieved partial response and 145 patients experienced stable disease, with an ORR of 21.8% and a disease control rate of 90.5%. Following a median follow-up period of 14.2 months, the median PFS was 12.2 months (95% confidence interval, 10.1-14.3 m), and the median overall survival was not reached. Early Palbociclib initiation, sensitivity or acquired resistance to endocrine therapy, estrogen receptor and progesterone receptor double positivity, less than 3 metastatic sites, without visceral metastasis, bone metastasis only, without prior chemotherapy or endocrine therapy were associated with a prolonged PFS in MBC (All P < 0.05). The most common grade 3 or 4 adverse events (AE) was neutropenia (36.5%), and the most common nonhematologic AE was fatigue (10.9%). No patient experienced AE leading to treatment discontinuation. CONCLUSION: Palbociclib plus endocrine therapy exhibited favorable effectiveness and manageable toxicities in the real-world setting, supporting their use in Chinese patients with HR+/HER2 - MBC.

Research Status of Systemic Adjuvant Therapy for Early Breast Cancer.

Breast cancer has surpassed lung cancer as the most common cause of cancer deaths, worldwide. Early breast cancers are treatment sensitive and patients under standardized treatment have prolonged. Breast cancer treatment has significantly evolved from the conventional surgical approach and radiotherapy to local and systemic adjuvant therapies. Though localized breast cancers are clinically manageable, distant recurrence is a cause of morbid concern. Adjuvant systemic therapy is effective in both distant and local recurrences and hence gained significant attention. Early breast cancer prognosis has greatly improved in the past 3 decades with reduced mortality rates due to the widespread use of adjuvant therapy. It can markedly increase the cure rate of breast cancers, and postoperative adjuvant therapy became a part of comprehensive breast cancer treatment. Further research to understand the early breast cancer characteristics could expand the treatment modalities that can improve the outcomes and survival benefits of breast cancer patients.

Estrogen-regulated feedback loop limits the efficacy of estrogen receptor-targeted breast cancer therapy.

Endocrine therapy resistance invariably develops in advanced estrogen receptor-positive (ER+) breast cancer, but the underlying mechanisms are largely unknown. We have identified C-terminal SRC kinase (CSK) as a critical node in a previously unappreciated negative feedback loop that limits the efficacy of current ER-targeted therapies. Estrogen directly drives CSK expression in ER+ breast cancer. At low CSK levels, as is the case in patients with ER+ breast cancer resistant to endocrine therapy and with the poorest outcomes, the p21 protein-activated kinase 2 (PAK2) becomes activated and drives estrogen-independent growth. PAK2 overexpression is also associated with endocrine therapy resistance and worse clinical outcome, and the combination of a PAK2 inhibitor with an ER antagonist synergistically suppressed breast tumor growth. Clinical approaches to endocrine therapy-resistant breast cancer must overcome the loss of this estrogen-induced negative feedback loop that normally constrains the growth of ER+ tumors.

PRMT5 determines the sensitivity to chemotherapeutics by governing stemness in breast cancer.

PURPOSE: Acquired resistance to chemotherapeutic agents in breast cancer is a major clinical challenge. Recent studies have shown that the emergence of cancer stem cells contributes to the development of drug resistance, and the protein arginine methyltransferase 5 (PRMT5) was crucial for the maintenance of stemness. However, the roles of PRMT5 in breast cancer cell stemness and the development of cancer drug resistance have not been clarified. In this study, we investigated the effect of PRMT5 on the sensitivity to doxorubicin and cell stemness in breast cancer. METHODS: PRMT5 expression was assessed in a panel of breast cancer cell lines (MDA-MB-231, MCF7, T-47D, BT-474, Au-565) and normal mammal epithelial cells (MCF10A). For knockdown of PRMT5 expression, two pairs of shRNAs as well as a control shRNA were utilized. Meanwhile, the wild-type PRMT5 and its catalytically dead counterpart (R368A) were stably overexpressed in MDA-MB-231 and MCF7 cells. The sensitivity to doxorubicin was determined by MTT assays, TUNEL assays, and Western blot analyses. To evaluate the degree of cell stemness, CD24/CD44-sorting and mammosphere formation experiments were performed. RESULTS: We demonstrated that PRMT5 regulates OCT4/A, KLF4, and C-MYC in breast cancer to govern stemness and affects the doxorubicin resistance of breast cancer. CONCLUSION: Our study suggests that PRMT5 may play an important role in the doxorubicin resistance of breast cancer.

Regulation of cancerous progression and epithelial-mesenchymal transition by miR-34c-3p via modulation of MAP3K2 signaling in triple-negative breast cancer cells.

Emerging but limited data have evidenced an essential involvement of microRNAs (miRNAs) in the development and progression of triple negative breast cancer (TNBC), which empowers these small regulators as an innovative therapeutic approach, especially for this unique tumor subgroup still lacking an efficient and specific therapeutic target. Herein, we reported the down-regulation of miR-34c-3p level in TNBC tissues, and its expression was closely associated with estrogen receptor alpha (ERα), but not other receptors, in well-characterized breast cancer (BCa) cells. Functionally, ectopic expression of miR-34c-3p inhibited migration, invasion and epithelial-mesenchymal transition (EMT) in TNBC cells. From a mechanistic standpoint, bioinformatics coupled with luciferase and gain-of-function, loss-of-function assays showed that miR-34c-3p may regulate TNBC progression by directly targeting the 3'-untranslated region (UTR) of mitogen-activated protein kinase kinase kinase 2 (MAP3K2). Consistently, MAP3K2 overexpression could effectively rescue miR-34c-3p mimics-induced suppression of cell invasion and EMT. In light of these findings, miR-34c-3p may function as a tumor suppressor in regulating of TNBC invasiveness and EMT through negatively modulating MAP3K2 pathway. Future endeavor in this field may help to identify a novel biomarker to predict prognosis and response to therapy in TNBC.

N-myc downstream-regulated gene 2 expression is associated with glucose transport and correlated with prognosis in breast carcinoma.

INTRODUCTION: N-myc downstream-regulated gene 2 (NDRG2), a novel tumour suppressor and cell stress-related gene, is involved in many cell metabolic processes, such as hormone, ion and fluid metabolism. We investigated whether NDRG2 is involved in any glucose-dependent energy metabolism, as well as the nature of its correlation with breast carcinoma. METHODS: The correlations between NDRG2 expression and glucose transporter 1 (GLUT1) expression in clinical breast carcinoma tissues were analysed. The effects of NDRG2 on glucose uptake were assessed in breast cancer cells and xenograft tumours. The consequences of NDRG2-induced regulation of GLUT1 at the transcription and translation levels and the interaction between NDRG2 and GLUT1 were examined. RESULTS: Data derived from clinical breast carcinoma specimens revealed that (1) patients with high NDRG2 expression had better disease-free survival and overall survival than those with low NDRG2 expression and (2) NDRG2 expression was negatively correlated with GLUT1 expression in these breast carcinoma tissues. NDRG2 inhibited glucose uptake by promoting GLUT1 protein degradation without affecting GLUT1 transcription in both breast cancer cells and xenograft tumours. In addition, NDRG2 protein interacted and partly colocalised with GLUT1 protein in cell cytoplasm areas. CONCLUSIONS: The results of our study support the notion that NDRG2 plays an important role in tumour glucose metabolism, in which GLUT1 is a likely candidate contributor to glucose uptake suppression and tumour growth. Targeting the actions of NDRG2 in cell glucose-dependent energy delivery may provide an attractive strategy for therapeutic intervention in human breast carcinoma.

Notch inhibition promotes fetal liver stem/progenitor cells differentiation into hepatocytes via the inhibition of HNF-1ß.

In a previous study, the Notch pathway inhibited with N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (also called DAPT) was shown to promote the differentiation of fetal liver stem/progenitor cells (FLSPCs) into hepatocytes and to impair cholangiocyte differentiation. The precise mechanism for this, however, was not elucidated. Two mechanisms are possible: Notch inhibition might directly up-regulate hepatocyte differentiation via HGF (hepatocyte growth factor) and HNF (hepatocyte nuclear factor)-4α or might impair cholangiocyte differentiation thereby indirectly rendering hepatocyte differentiation as the dominant state. In this study, HGF and HNF expression was detected after the Notch pathway was inhibited. Although our initial investigation indicated that the inhibition of Notch induced hepatocyte differentiation with an efficiency similar to the induction via HGF, the results of this study demonstrate that Notch inhibition does not induce significant up-regulation of HGF or HNF-4α in FLSPCs. This suggests that Notch inhibition induces hepatocyte differentiation without the influence of HGF or HNF-4α. Moreover, significant down-regulation of HNF-1ß was observed, presumably dependent on an impairment of cholangiocyte differentiation. To confirm this presumption, HNF-1ß was blocked in FLSPCs and was followed by hepatocyte differentiation. The expression of markers of mature cholangiocyte was impaired and hepatocyte markers were elevated significantly. The data thus demonstrate that the inhibition of cholangiocyte differentiation spontaneously induces hepatocyte differentiation and further suggest that hepatocyte differentiation from FLSPCs occurs at the expense of the impairment of cholangiocyte differentiation, probably being enhanced partially via HNF-1ß down-regulation or Notch inhibition.

Ultrasound-guided double-tract percutaneous cholecystostomy combined with a choledochoscope for performing cholecystolithotomies in high-risk surgical patients.

BACKGROUND: Cholecystolithiasis is the most common disease treated by general surgery, with an incidence of about 0.15-0.22%. The most common therapies are open cholecystectomy (OC) or laparoscopic cholecystectomy (LC). However, with a greater understanding of the function of the cholecyst, more and more patients and surgeons are aware that preserving the functional cholecyst is important for young patients, as well as patients who would not tolerate anesthesia associated with either OC or LC. Based on these considerations, we have introduced a notable, minimally invasive treatment for cholecystolithotomy. METHODS: We performed a retrospective review of patients with cholecystolithiasis who were unable to tolerate surgery or who insisted on preserving the functional cholecyst. Our particular approach can be simply described as ultrasound-guided percutaneous cholecystostomy combined with a choledochoscope for performing a cholecystolithotomy under local anesthesia. RESULTS: Ten patients with cholecystolithiasis were treated via this approach. All except one patient had their gallbladder stones totally removed under local anesthesia, without the aggressive procedures associated with OC or LC. The maximum number of gallbladder stones removed was 16, and the maximum diameter was 13 mm without lithotripsy. After the minimally invasive surgery, the cholecyst contractile functions of all patients were normal, confirmed via ultrasound after a high-fat diet. Complications such as bile duct injury, biliary fistula, and bleeding occurred significantly less often than with OC and LC. The recurrence rates for each of 2 post-operative years were about 11.11% (1/9, excluding a failure case) with uncertainty surrounding recurrence or residue, and 22.22% (2/9, including one non-recurrence patient with follow-up time of 22 months), respectively. CONCLUSIONS: Ultrasound-guided percutaneous cholecystostomy combined with choledochoscope is a safe, efficient, and minimally invasive cholecystolithotomy method. We recommend this technique for the management of small stones (less than 15 mm) in high-risk surgical patients.

A historical controlled study of domestic trastuzumab and pertuzumab in combination with docetaxel for the neoadjuvant treatment of early HER2-positive breast cancer.

Background: HER2-positive molecular breast cancer subtypes are characterized by high aggressiveness and malignancy, and their metastasis and mortality rates are among the highest of all types of breast cancer. The use of anti-HER2-targeted agents in neoadjuvant therapy has significantly improved the prognosis of patients with HER2-positive breast cancer. In this study, we investigated the efficacy and safety of a neoadjuvant Chinese THP regimen (docetaxel, trastuzumab biosimilar TQB211 plus the pertuzumab biosimilar TQB2440 or pertuzumab) for ER/PR-negative and HER2-positive breast cancer in China. Method: All enrolled patients received the THP regimen (T: docetaxel 75 mg/m2 per cycle; H: trastuzumab biosimilar TQB211 8 mg/kg in the first cycle and 6 mg/kg maintenance dose in cycles 2 to 4; P: pertuzumab biosimilar TQB2440 or pertuzumab 840 mg in the first cycle, maintenance dose 420 mg in cycles 2 to 4) every 3 weeks for 4 cycles. The biosimilar TQB2440 pertuzumab and pertuzumab were randomly assigned to patients. Docetaxel, TQB211, and TQB2440 were all developed by Chiatai Tianqing. The primary endpoint was the complete pathological response (pCR) in the breast, and the secondary endpoint was cardiac safety. Results: Of the 28 eligible patients, 19 (67.9%) achieved tpCR. The tpCR rate was higher than in the NeoSphere trial (pCR63.2%) and the PEONY study (tpCR52.5%). The adverse events that occurred most frequently were leukopenia and neutropenia, with incidence rates of 82.1% and 75.0%, respectively. Of these, grade 3 leukopenia and neutropenia occupied 46.4% and 35.7%. Other grade 3 or higher adverse events were bone marrow suppression (7.1%), lymphopenia (3.6%), and anemia (3.6%). There were no events of heart failure in patients and no patient died during the neoadjuvant phase. Conclusion: Domestic dual-target HP has a more satisfactory efficacy and safety in the neoadjuvant phase of treatment. Clinical trial registration: https://clinicaltrials.gov/study/NCT05985187, NCT05985187.

Prognostic significance of USP22 as an oncogene in papillary thyroid carcinoma.

Ubiquitin-specific protease 22 (USP22), a novel deubiquitinating enzyme, has been associated with metastasis, therapy resistance, and cell cycle progression. The purpose of this study was to investigate the expression level of USP22 in papillary thyroid carcinoma (PTC) samples and to evaluate its clinical significance in PTC patients. USP22 expression was examined in 30 fresh PTC tissues and paired adjacent noncancerous tissues by real-time quantitative RT-PCR. Immunohistochemistry for USP22 was performed on additional 156 PTC tissues. The clinical significance of USP22 expression was analyzed. We found that the expression levels of USP22 mRNA and protein in PTC tissues were both significantly higher than those in noncancerous tissues. Clinicopathological analysis showed that USP22 expression was significantly correlated with tumor size (p=0.036), extracapsular invasion (p=0.012), multifocality (p=0.014), lymph node metastasis (p=0.022), distant metastasis (p=0.005), and TNM stage (p=0.002). The Kaplan-Meier survival curves revealed that USP22 expression was associated with poor prognosis in PTC patients. USP22 expression was an independent prognostic marker of overall patient survival in a multivariate analysis. Our findings suggest that USP22 is an independent predictor of poor prognosis of PTC patients.

Anesthetic isoflurane posttreatment attenuates experimental lung injury by inhibiting inflammation and apoptosis.

We investigated the effect of 1.4% isoflurane (ISO) on the development of inflammation and apoptosis caused by zymosan (ZY) in mice. We found that ZY-challenged mice exhibited significant body weight loss, markedly high mortality, and significant lung injury characterized by the deterioration of histopathology, histologic scores, and wet-to-dry ratio after ISO treatment. ISO dramatically attenuated ZY-induced lung neutrophil recruitment and inflammation, as evidenced by the reduced levels of total cells, neutrophils, and proinflammatory cytokines (i.e., tumor necrosis factor- α , interleukin- (IL-) 1 ß , IL-6, and macrophage inflammatory protein-2) in bronchoalveolar lavage fluid and of their mRNA expression in lung tissues. ISO also inhibited ZY-induced expression and activation of nuclear factor-kappaB p65 and inducible nitric oxide synthase in pulmonary tissue. ZY administration also resulted in the upregulation of heme oxygenase-1 expression and activity in the lung, which was further enhanced by ISO treatment. Moreover, ISO markedly prevented ZY-induced pulmonary cell apoptosis in mice, as reflected by the decrease in expression of procaspase-8, procaspase-3, cleaved caspase-8, and cleaved caspase-3, as well as in caspase-3 activity and Bcl-2-associated X/B-cell lymphoma 2 ratio. These results indicate that ISO is a potential therapeutic drug for treating ZY-induced lung injury, and further investigations are warranted.

A subanesthetic dose of isoflurane during postconditioning ameliorates zymosan-induced neutrophil inflammation lung injury and mortality in mice.

Anesthetic isoflurane (ISO) has immunomodulatory effects. In the present study, we investigated whether a subanesthetic dose of ISO (0.7%) protected against zymosan (ZY) induced inflammatory responses in the murine lung and isolated neutrophils. At 1 and 6 hrs after ZY administration intraperitoneally, ISO was inhaled for 1 hr, and 24 hrs later, lung inflammation and injury were assessed. We found that ISO improved the survival rate of mice and mitigated lung injury as characterized by the histopathology, wet-to-dry weight ratio, protein leakage, and lung function index. ISO significantly attenuated ZY-induced lung neutrophil recruitment and inflammation. This was suggested by the downregulation of (a) endothelial adhesion molecule expression and myeloperoxidase (MPO) activity in lung tissue and polymorphonuclear neutrophils (b) chemokines, and (c) proinflammatory cytokines in BALF. Furthermore, ZY-induced nuclear translocation and DNA-binding activity of NF- κ B p65 were also reduced by ISO. ISO treatment inhibited iNOS expression and activity, as well as subsequent nitric oxide generation. Consistent with these in vivo observations, in vitro studies confirmed that ISO blocked NF- κ B and iNOS activation in primary mouse neutrophils challenged by ZY. These results provide evidence that 0.7% ISO ameliorates inflammatory responses in ZY-treated mouse lung and primary neutrophils.

Pyrotinib for HER2-positive metastatic breast cancer: a systematic review and meta-analysis.

Background: Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer patients continue to progress despite multiple anti-HER2-targeted treatments. A number of studies have found that Pyrotinib, a small-molecule pan-ErbB receptor tyrosine kinase inhibitor (TKI), is effective in treating patients with HER2-positive metastatic breast cancer. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of Pyrotinib in the treatment of HER2-positive metastatic breast cancer. Methods: PubMed, Embase, Web of Science, and Cochrane Library databases were searched until February 2022. Research on HER2-positive metastatic breast cancer being treated with Pyrotinib in any line of therapy was included, both prospective and retrospective. Statistical pooling and meta-analysis of data from the included studies were performed to explore the efficacy and safety of Pyrotinib in HER2-positive metastatic breast cancer. Results: In this meta-analysis, 23 studies were included. The overall objective response rate was 0.49 (95% CI: 0.40, 0.58) for Pyrotinib in HER2-positive metastatic breast cancer and 0.52 (95% CI: 0.32, 0.71) in those with brain metastases. The objective response rate of Pyrotinib was superior to that of other second-line therapeutics in comparison (RR =1.38, 95% CI: 1.25, 1.52), but was relatively inferior to trastuzumab emtansine (T-DM1) (RR =0.82, 95% CI: 0.36, 1.85). The combined median progression-free survivals (PFSs) for Pyrotinib in metastatic breast cancer and those with brain metastases were 8.2 (95% CI: 6.8, 9.5) months and 8.9 (95% CI: 6.2, 11.7) months, respectively. The most common adverse reaction was diarrhea with an all-grade incidence of 0.84 (95% CI: 0.74, 0.92), followed by nausea and vomiting of 0.52 (95% CI: 0.36, 0.68). Conclusions: In any line of treatment for HER2-positive metastatic breast cancer, the Pyrotinib-containing regimens demonstrated considerable tumor response, disease control, and survival with manageable adverse effects.

The Potent Novel CDK4/6 Inhibitor TQB3616 in Hormone Receptor Positive Breast Cancer: Preclinical Characterization with in vitro and Human Tumor Xenograft Models.

Purpose: Inhibition of the cyclin-dependent kinase (CDK) 4/6-retinoblastoma (RB) pathway exerts a considerable inhibitory effect, preventing the spread and metastasis of breast cancer cells and promoting tumor regression. In this study, we examined the antitumor activity of TQB3616, a novel inhibitor of CDK4/6 activity, which showed a greater efficacy improvement in antitumor effects. Methods: TQB3616 group, abemaciclib group and endocrine or HER-2 targeted combination therapy group were set up respectively. The effects of drugs on cell proliferation activity, cell cycle, apoptosis, downstream protein expression and gene expression of HR positive (T47D, MCF-7) and HER-2 positive (BT474, MDA-MB-361) breast cancer cell lines were studied. The antiproliferative effect of TQB3616 was also measured in vivo. Results: TQB3616 showed a remarkable inhibitory effect on the proliferation of hormone receptor-positive breast cancer cells in vitro. In addition, TQB3616 combined with endocrine therapy or Human Epidermal Growth Factor Receptor 2 (HER2) targeted therapy showed significant synergistic antitumor activity in estrogen receptor (ER)-positive/HER2-negative or HER2-positive breast cancer. In contrast to abemaciclib, which targets the CDK4/6 pathway with proven efficacy, the oral agent TQB3616 not only induced G1 stalling, leading to a profound reduction in the level of RB protein phosphorylated at Ser807/811, but also showed enhanced tumor killing effects by promoting cell apoptosis. Oral administration of TQB3616 showed more potent antitumor activity than abemaciclib in an in vitro breast cancer xenograft model, causing significant tumor regression associated with sustained target inhibition in tumor tissue and manageable in vivo toxicity. Conclusion: The results of this study indicate that TQB3616 is a novel CDK4/6 inhibitor, and its highly effective antitumor activity against breast cancer is expected to yield promising therapeutic effects in clinical studies.

Design, strategies, and therapeutics in nanoparticle-based siRNA delivery systems for breast cancer.

Utilizing small interfering RNA (siRNA) as a treatment for cancer, a disease largely driven by genetic aberrations, shows great promise. However, implementing siRNA therapy in clinical practice is challenging due to its limited bioavailability following systemic administration. An attractive approach to address this issue is the use of a nanoparticle (NP) delivery platform, which protects siRNA and delivers it to the cytoplasm of target cells. We provide an overview of design considerations for using lipid-based NPs, polymer-based NPs, and inorganic NPs to improve the efficacy and safety of siRNA delivery. We focus on the chemical structure modification of carriers and NP formulation optimization, NP surface modifications to target breast cancer cells, and the linking strategy and intracellular release of siRNA. As a practical example, recent advances in the development of siRNA therapeutics for treating breast cancer are discussed, with a focus on inhibiting cancer growth, overcoming drug resistance, inhibiting metastasis, and enhancing immunotherapy.

Sevoflurane preconditioning improves mitochondrial function and long-term neurologic sequelae after transient cerebral ischemia: role of mitochondrial permeability transition.

OBJECTIVE: Anesthetic preconditioning appears to be a viable strategy to treat ischemic cerebral injury. Here we investigated 1) whether the protection conferred by sevoflurane preconditioning sustains in time; 2) whether sevoflurane preconditioning diminishes mitochondrial dysfunction following cerebral ischemia; and 3) whether mitochondrial permeability transition pore plays a crucial role in the sevoflurane preconditioning. DESIGN: Laboratory investigation. SETTING: University research laboratory. SUBJECTS: : Sprague-Dawley rats. INTERVENTIONS: Rats underwent 2 hrs of focal cerebral ischemia induced by middle cerebral artery occlusion. Preconditioning was elicited with sevoflurane (2.3%) for 60 mins at 24 hrs before ischemia. The involvement of mitochondrial permeability transition pore was determined with a mitochondrial permeability transition pore opener atractyloside and a specific mitochondrial permeability transition pore inhibitor cyclosporin A. In vitro study was performed on acutely isolated mitochondria subjected to calcium overload. MEASUREMENTS AND MAIN RESULTS: Sevoflurane preconditioning significantly decreased the infarct size by 35.9% (95% confidence interval 6.5-28.4, p < .001). This reduction of injury volume was associated with a long-term improvement of neurological function according to modified neurological severity score (F = 13.6, p = .001) and sticky-tape test (F = 29.1, p < .001) for 42 days after ischemia. Furthermore, sevoflurane preconditioning markedly protected mitochondria, as indicated by preserved respiratory chain complex activities and membrane potential, lowered mitochondrial hydrogen-peroxide production, and attenuated mitochondrial permeability transition pore opening. Isolated mitochondria also demonstrated a reduced sensitivity to Ca-induced mitochondrial permeability transition pore opening after pre-exposure to sevoflurane in vitro (95% confidence interval 24.2-196.5,p = .006). Inhibiting mitochondrial permeability transition pore using cyclosporin A resulted in protective effects similar to those seen with sevoflurane preconditioning, whereas pharmacologically opening the mitochondrial permeability transition pore with atractyloside abrogated all the positive effects of sevoflurane preconditioning and cyclosporin A, including suppression of mitochondrial permeability transition pore opening, counteraction of mitochondria-dependent apoptotic pathway, and subsequent histological and behavioral improvements. CONCLUSIONS: Sevoflurane preconditioning protects mitochondria from cerebral ischemia/reperfusion injury and ameliorates long-term neurological deficits. Inhibition of mitochondrial permeability transition pore opening is a crucial step in mediating the neuroprotection of sevoflurane preconditioning.

Notch is the key factor in the process of fetal liver stem/progenitor cells differentiation into hepatocytes.

Cell transplantation is efficient method to therapy end-stage liver disease (ESLD). How to punctually induce stem cell differentiation into hepatocyte is still a challenge. Notch plays important roles in embryonic development and cell differentiation. However, during the differentiation process from fetal liver stem/progenitor cells (FLSPCs) to mature hepatocytes, the contribution of Notch, especially which Notch receptor is primarily responsible, is unknown. First, specific Notch receptor responsible for FLSPCs differentiation was identified. On both tissue level and cell level, we found that Notch3 was the only receptor greater expressed in liver tissue at embryonic day (ED) 14 and FLSPCs, compared with the adult liver and BRL cells, respectively. Second, morphological phenotypic and functional aspects were analyzed to evaluate whether Notch inhibition by GSIs (γ-secretase inhibitors, inhibitor of Notch) promotes the differentiation of FLSPCs into hepatocytes. Results showed that N-[N-(3, 5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) as GSIs was able to induce FLSPCs differentiation into hepatocytes. The differentiated FLSPCs showed similar morphology to mature hepatocytes, expressed hepatic markers indicative of a mature developmental stage, and displayed similar functionality to mature hepatocytes. The differentiation efficiency by GSIs was similar to that by hepatocyte growth factor (HGF) induction. More specifically, as the differentiation of FLSPCs progressed towards hepatocytes, the expression of Notch3 was gradually down-regulated, consistent with the down-regulation of other stem cell markers. These findings imply that Notch3 may not only be a regulator of FLSPCs differentiation into hepatocytes, but also be a potential marker of FLSPCs.

Loss of human epidermal receptor-2 in human epidermal receptor-2+ breast cancer after neoadjuvant treatment: A case report.

BACKGROUND: Human epidermal receptor-2 (HER-2) expression has been reported to be discordant between primary tumor and metastatic tissue. CASE SUMMARY: We presented a case diagnosed with the HER-2+ breast cancer patient who exhibited changes in the expression of HER-2 receptors on tumour samples from surgical specimens obtained after neoadjuvant treatment (NAT) compared with initial biopsy. The patient underwent a HER-2-targeted therapy consequently, in spite of HER+ gene loss. After the surgery, the patient subsequently underwent endocrine therapy and radiotherapy. CONCLUSION: Changes in HER-2 expression after NAT should be retested by physicians and pathologists before systemic treatment instead of avoiding further HER-2-targeted therapy, and we will perform immunohistochemical multiple-spot biopsy analyses of other important clinical issues to better define prognosis and tailor subsequent adjuvant therapy.