FOXQ1, deubiquitinated by USP10, alleviates sepsis-induced acute kidney injury by targeting the CREB5/NF-κB signaling axis.

Sepsis-induced acute kidney injury (S-AKI) is a severe and frequent complication that occurs during sepsis. This study aimed to understand the role of FOXQ1 in S-AKI and its potential upstream and downstream regulatory mechanisms. A cecal ligation and puncture induced S-AKI mouse model in vivo and an LPS-induced HK-2 cell model in vitro were used. FOXQ1 was significantly upregulated in CLP mice and downregulated in the LPS-induced HK-2 cells. Upregulation of FOXQ1 improved kidney injury and dysfunction in CLP mice. Overexpression of FOXQ1 remarkably suppressed the apoptosis and inflammatory response via down-regulating oxidative stress indicators and pro-inflammatory factors (IL-1ß, IL-6, and TNF-α), both in vivo and in vitro. From online analysis, the CREB5/NF-κB axis was identified as the downstream target of FOXQ1. FOXQ1 transcriptionally activated CREB5, upregulating its expression. Overexpression of FOXQ1 suppressed the phosphorylation level and nucleus transport of p65. Rescue experiments showed that CREB5 mediates the protective role of FOXQ1 on S-AKI. Furthermore, FOXQ1 was identified as a substrate of USP10, a deubiquitinating enzyme. Ectopic expression of USP10 reduced the ubiquitination of FOXQ1, promoting its protein stability. USP10 upregulation alleviated LPS-induced cell apoptosis and inflammatory response, while suppression of FOXQ1 augmented these trends. Collectively, our results suggest that FOXQ1, deubiquitinated by USP10, plays a protective role in S-AKI induced inflammation and apoptosis by targeting CREB5/NF-κB axis.

Drug resistance mechanisms and treatment strategies mediated by Ubiquitin-Specific Proteases (USPs) in cancers: new directions and therapeutic options.

Drug resistance represents a significant obstacle in cancer treatment, underscoring the need for the discovery of novel therapeutic targets. Ubiquitin-specific proteases (USPs), a subclass of deubiquitinating enzymes, play a pivotal role in protein deubiquitination. As scientific research advances, USPs have been recognized as key regulators of drug resistance across a spectrum of treatment modalities, including chemotherapy, targeted therapy, immunotherapy, and radiotherapy. This comprehensive review examines the complex relationship between USPs and drug resistance mechanisms, focusing on specific treatment strategies and highlighting the influence of USPs on DNA damage repair, apoptosis, characteristics of cancer stem cells, immune evasion, and other crucial biological functions. Additionally, the review highlights the potential clinical significance of USP inhibitors as a means to counter drug resistance in cancer treatment. By inhibiting particular USP, cancer cells can become more susceptible to a variety of anti-cancer drugs. The integration of USP inhibitors with current anti-cancer therapies offers a promising strategy to circumvent drug resistance. Therefore, this review emphasizes the importance of USPs as viable therapeutic targets and offers insight into fruitful directions for future research and drug development. Targeting USPs presents an effective method to combat drug resistance across various cancer types, leading to enhanced treatment strategies and better patient outcomes.

A pilot trial of neoadjuvant pyrotinib plus trastuzumab, dalpiciclib, and letrozole for triple-positive breast cancer.

Triple-positive breast cancer (TPBC) poorly responds to current standard neoadjuvant therapy (trastuzumab plus pertuzumab and chemotherapy). Our previous MUKDEN 01 study showed a promising total pathological complete response (tpCR) rate of 30.4% with neoadjuvant pyrotinib (pan-human epidermal growth factor receptor tyrosine kinase inhibitor) plus dalpiciclib (cyclin-dependent kinase 4/6 inhibitor) and letrozole, but the efficacy remains suboptimal. This pilot study (NCT05228951) explored adding trastuzumab to this triplet neoadjuvant regimen in patients with stage II-III TPBC. The primary endpoint was tpCR (ypT0/is, ypN0) rate. Between February 2022 and June 2022, 12 patients were enrolled, and seven (58%; 95% confidence interval [CI], 27.7%-84.8%) patients achieved tpCR. The rate of residual cancer burden (RCB) 0-I was 75% (95% CI, 46.8%-91.1%). The objective response rate (ORR) was 92% (95% CI, 64.6%-98.5%). Mean Ki-67 level was significantly reduced from 45.0% (95% CI, 19.5%-70.5%) at baseline to 17.2% (95% CI, 0.7%-33.7%) after neoadjuvant therapy (p = 0.03). The most common grade 3 adverse events were diarrhea (four [33%]) and decreased neutrophil count (three [25%]). No grade 4 adverse events or treatment-related deaths occurred. This four-drug neoadjuvant regimen shows promising pathological response with an acceptable safety profile in patients with TPBC. A randomized controlled trial (NCT05638594) of this regimen is being conducted.

MAGP2 promotes osteogenic differentiation during fracture healing through its crosstalk with the ß-catenin pathway.

Osteogenic differentiation is important for fracture healing. Microfibrial-associated glycoprotein 2 (MAGP2) is found to function as a proangiogenic regulator in bone formation; however, its role in osteogenic differentiation during bone repair is not clear. Here, a mouse model of critical-sized femur fracture was constructed, and the adenovirus expressing MAGP2 was delivered into the fracture site. Mice with MAGP2 overexpression exhibited increased bone mineral density and bone volume fraction (BV/TV) at Day 14 postfracture. Within 7 days postfracture, overexpression of MAGP2 increased collagen I and II expression at the fracture callus, with increasing chondrogenesis. MAGP2 inhibited collagen II level but elevated collagen I by 14 days following fracture, accompanied by increased endochondral bone formation. In mouse osteoblast precursor MC3T3-E1 cells, MAGP2 treatment elevated the expression of osteoblastic factors (osterix, BGLAP and collagen I) and enhanced ALP activity and mineralization through activating ß-catenin signaling after osteogenic induction. Besides, MAGP2 could interact with lipoprotein receptor-related protein 5 (LRP5) and upregulated its expression. Promotion of osteogenic differentiation and ß-catenin activation mediated by MAGP2 was partially reversed by LRP5 knockdown. Interestingly, ß-catenin/transcription factor 4 (TCF4) increased MAGP2 expression probably by binding to MAGP2 promoter. These findings suggest that MAGP2 may interact with ß-catenin/TCF4 to enhance ß-catenin/TCF4's function and activate LRP5-activated ß-catenin signaling pathway, thus promoting osteogenic differentiation for fracture repair. mRNA sequencing identified the potential targets of MAGP2, providing novel insights into MAGP2 function and the directions for future research.

Effects of neoadjuvant stereotactic body radiotherapy plus adebrelimab and chemotherapy for triple-negative breast cancer: A pilot study.

Background: Emerging data have supported the immunostimulatory role of radiotherapy, which could exert a synergistic effect with immune checkpoint inhibitors (ICIs). With proven effective but suboptimal effect of ICI and chemotherapy in triple-negative breast cancer (TNBC), we designed a pilot study to explore the efficacy and safety of neoadjuvant stereotactic body radiotherapy (SBRT) plus adebrelimab and chemotherapy in TNBC patients. Methods: Treatment-naïve TNBC patients received two cycles of intravenous adebrelimab (20 mg/kg, every 3 weeks), and SBRT (24 Gy/3 f, every other day) started at the second cycle, then followed by six cycles of adebrelimab plus nab-paclitaxel (125 mg/m² on days 1 and 8) and carboplatin (area under the curve 6 mg/mL per min on day 1) every 3 weeks. The surgery was performed within 3-5 weeks after the end of neoadjuvant therapy. Primary endpoint was pathological complete response (pCR, ypT0/is ypN0). Secondary endpoints included objective response rate (ORR), residual cancer burden (RCB) 0-I, and safety. Results: 13 patients were enrolled and received at least one dose of therapy. 10 (76.9%) patients completed SBRT and were included in efficacy analysis. 90% (9/10) of patients achieved pCR, both RCB 0-I and ORR reached 100% with three patients achieved complete remission. Adverse events (AEs) of all-grade and grade 3-4 occurred in 92.3% and 53.8%, respectively. One (7.7%) patient had treatment-related serious AEs. No radiation-related dermatitis or death occurred. Conclusions: Adding SBRT to adebrelimab and neoadjuvant chemotherapy led to a substantial proportion of pCR with acceptable toxicities, supporting further exploration of this combination in TNBC patients. Funding: None. Clinical trial number: NCT05132790.

Advances in immunotherapy for triple-negative breast cancer.

BACKGROUND: Immunotherapy has recently emerged as a treatment strategy which stimulates the human immune system to kill tumor cells. Tumor immunotherapy is based on immune editing, which enhances the antigenicity of tumor cells and increases the tumoricidal effect of immune cells. It also suppresses immunosuppressive molecules, activates or restores immune system function, enhances anti-tumor immune responses, and inhibits the growth f tumor cell. This offers the possibility of reducing mortality in triple-negative breast cancer (TNBC). MAIN BODY: Immunotherapy approaches for TNBC have been diversified in recent years, with breakthroughs in the treatment of this entity. Research on immune checkpoint inhibitors (ICIs) has made it possible to identify different molecular subtypes and formulate individualized immunotherapy schedules. This review highlights the unique tumor microenvironment of TNBC and integrates and analyzes the advances in ICI therapy. It also discusses strategies for the combination of ICIs with chemotherapy, radiation therapy, targeted therapy, and emerging treatment methods such as nanotechnology, ribonucleic acid vaccines, and gene therapy. Currently, numerous ongoing or completed clinical trials are exploring the utilization of immunotherapy in conjunction with existing treatment modalities for TNBC. The objective of these investigations is to assess the effectiveness of various combined immunotherapy approaches and determine the most effective treatment regimens for patients with TNBC. CONCLUSION: This review provides insights into the approaches used to overcome drug resistance in immunotherapy, and explores the directions of immunotherapy development in the treatment of TNBC.

Targeting ubiquitin specific proteases (USPs) in cancer immunotherapy: from basic research to preclinical application.

Tumors have evolved in various mechanisms to evade the immune system, hindering the antitumor immune response and facilitating tumor progression. Immunotherapy has become a potential treatment strategy specific to different cancer types by utilizing multifarious molecular mechanisms to enhance the immune response against tumors. Among these mechanisms, the ubiquitin-proteasome system (UPS) is a significant non-lysosomal pathway specific to protein degradation, regulated by deubiquitinating enzymes (DUBs) that counterbalance ubiquitin signaling. Ubiquitin-specific proteases (USPs), the largest DUB family with the strongest variety, play critical roles in modulating immune cell function, regulating immune response, and participating in antigen processing and presentation during tumor progression. According to recent studies, the expressions of some USP family members in tumor cells are involved in tumor immune escape and immune microenvironment. This review explores the potential of targeting USPs as a new approach for cancer immunotherapy, highlighting recent basic and preclinical studies investigating the applications of USP inhibitors. By providing insights into the structure and function of USPs in cancer immunity, this review aims at assisting in developing new therapeutic approaches for enhancing the immunotherapy efficacy.

Neuroinflammation: The central enabler of postoperative cognitive dysfunction.

The proportion of advanced age patients undergoing surgical procedures is on the rise owing to advancements in surgical and anesthesia technologies as well as an overall aging population. As a complication of anesthesia and surgery, older patients frequently suffer from postoperative cognitive dysfunction (POCD), which may persist for weeks, months or even longer. POCD is a complex pathological process involving multiple pathogenic factors, and its mechanism is yet unclear. Potential theories include inflammation, deposition of pathogenic proteins, imbalance of neurotransmitters, and chronic stress. The identification, prevention, and treatment of POCD are still in the exploratory stages owing to the absence of standardized diagnostic criteria. Undoubtedly, comprehending the development of POCD remains crucial in overcoming the illness. Neuroinflammation is the leading hypothesis and a crucial component of the pathological network of POCD and may have complex interactions with other mechanisms. In this review, we discuss the possible ways in which surgery and anesthesia cause neuroinflammation and investigate the connection between neuroinflammation and the development of POCD. Understanding these mechanisms may likely ensure that future treatment options of POCD are more effective.

FSIP1 enhances the therapeutic sensitivity to CDK4/6 inhibitors in triple-negative breast cancer patients by activating the Nanog pathway.

CDK4/6 inhibitors are routinely recommended agents for the treatment of advanced HR+HER2- breast cancer. However, their therapeutic effectiveness in triple-negative breast cancer (TNBC) remains controversial. Here, we observed that the expression level of fibrous sheath interacting protein 1 (FSIP1) could predict the treatment response of TNBC to CDK4/6 inhibitors. High FSIP1 expression level was related to a poor prognosis in TNBC, which was associated with the ability of FSIP1 to promote tumor cell proliferation. FSIP1 downregulation led to slowed tumor growth and reduced lung metastasis in TNBC. FSIP1 knockout caused cell cycle arrest at the G0/G1 phase and reduced treatment sensitivity to CDK4/6 inhibitors by inactivating the Nanog/CCND1/CDK4/6 pathway. FSIP1 could form a complex with Nanog, protecting it from ubiquitination and degradation, which may facilitate the rapid cell cycle transition from G0/G1 to S phase and exhibit enhanced sensitivity to CDK4/6 inhibitors. Our findings suggest that TNBC patients with high FSIP1 expression levels may be suitable candidates for CDK4/6 inhibitor treatment.

KCNJ15 deficiency promotes drug resistance via affecting the function of lysosomes.

The altered lysosomal function can induce drug redistribution which leads to drug resistance and poor prognosis for cancer patients. V-ATPase, an ATP-driven proton pump positioned at lysosomal surfaces, is responsible for maintaining the stability of lysosome. Herein, we reported that the potassium voltage-gated channel subfamily J member 15 (KCNJ15) protein, which may bind to V-ATPase, can regulate the function of lysosome. The deficiency of KCNJ15 protein in breast cancer cells led to drug aggregation as well as reduction of drug efficacy. The application of the V-ATPase inhibitor could inhibit the binding between KCNJ15 and V-ATPase, contributing to the amelioration of drug resistance. Clinical data analysis revealed that KCNJ15 deficiency was associated with higher histological grading, advanced stages, more metastases of lymph nodes, and shorter disease free survival of patients with breast cancer. KCNJ15 expression level is positively correlated with a high response rate after receiving neoadjuvant chemotherapy. Moreover, we revealed that the small molecule drug CMA/BAF can reverse drug resistance by disrupting the interaction between KCNJ15 and lysosomes. In conclusion, KCNJ15 could be identified as an underlying indicator for drug resistance and survival of breast cancer, which might guide the choice of therapeutic strategies.

Direct Knockdown of PDZ and LIM Domain 1 Using an Adenoviral Delivery System Accelerates Osteogenesis and Fracture Healing in Mice.

Substantial advances have been made in understanding the role of partial PDZ and LIM domain family's proteins in skeletal-related diseases. Yet, little is known about the effect of PDZ and LIM Domain 1 (Pdlim1) on osteogenesis and fracture repair. This study aimed to investigate whether direct gene delivery using an adenovirus vector carrying Pdlim1 (Ad-oePdlim1) or encoding shRNA-Pdlim1 (Ad-shPdlim1) could affect the osteogenic activity of preosteoblastic MC3T3-E1 cells in vitro, and influence the fracture healing of mice in vivo. We found that Ad-shPdlim1 transfection contributed to the calcified nodule formation in MC3T3-E1 cells. Downregulation of Pdlim1 enhanced the alkaline phosphatase activity and increased the expression of osteogenic markers (Runt-related transcription factor 2 [Runx2], collagen type I alpha 1 chain [Col1A1], osteocalcin [OCN], and osteopontin [OPN]). Further analysis indicated that Pdlim1 knockdown could activate ß-catenin signaling, as evidenced by the accumulation of ß-catenin in the nucleus and the increase levels of downstream regulators such as Lef1/Tcf7, axis inhibition protein 2, cyclin D1, and SRY-box transcription factor 9. By contrast, Pdlim1 overexpression resulted in inhibition of the osteogenic activity of MC3T3-E1 cells. In vivo, at day 3 after fracture,Ad-shPdlim1 adenovirus particles were injected into the fracture site of the femur of mice, and the process of fracture healing was evaluated by X-ray, micro-computed tomography and histological examination. Local injection of Ad-shPdlim1 promoted the early cartilage callus formation, restored bone mineral density, and accelerated cartilaginous ossification, with the upregulation of osteogenic gene (Runx2, Col1A1, OCN, and OPN) expression and activation of ß-catenin signaling. Thus, we concluded that inhibition of Pdlim1 contributed to osteogenesis and fracture healing by activating the ß-catenin signaling pathway.

KK-LC-1 as a therapeutic target to eliminate ALDH+ stem cells in triple negative breast cancer.

Failure to achieve complete elimination of triple negative breast cancer (TNBC) stem cells after adjuvant therapy is associated with poor outcomes. Aldehyde dehydrogenase 1 (ALDH1) is a marker of breast cancer stem cells (BCSCs), and its enzymatic activity regulates tumor stemness. Identifying upstream targets to control ALDH+ cells may facilitate TNBC tumor suppression. Here, we show that KK-LC-1 determines the stemness of TNBC ALDH+ cells via binding with FAT1 and subsequently promoting its ubiquitination and degradation. This compromises the Hippo pathway and leads to nuclear translocation of YAP1 and ALDH1A1 transcription. These findings identify the KK-LC-1-FAT1-Hippo-ALDH1A1 pathway in TNBC ALDH+ cells as a therapeutic target. To reverse the malignancy due to KK-LC-1 expression, we employ a computational approach and discover Z839878730 (Z8) as an small-molecule inhibitor which may disrupt KK-LC-1 and FAT1 binding. We demonstrate that Z8 suppresses TNBC tumor growth via a mechanism that reactivates the Hippo pathway and decreases TNBC ALDH+ cell stemness and viability.

Microfibril-Associated Glycoprotein-2 Promoted Fracture Healing via Integrin αvß3/PTK2/AKT Signaling.

Fracture healing is a complex physiological process in which angiogenesis plays an essential role. Microfibril-associated glycoprotein-2 (MAGP2) has been reported to possess a proangiogenic activity via integrin αvß3, yet its role in bone repair is unexplored. In this study, a critical-sized femoral defect (2 mm) was created in mice, followed by the delivery of an adenovirus-based MAGP2 overexpression vector or its negative control at the fracture site. At days 7, 14, 21, and 28 postfracture, bone fracture healing was evaluated by radiography, micro-computed tomography, and histopathologic analysis. Adenovirus-based MAGP2 overexpression vector-treated mice exhibited increased bone mineral density and bone volume fraction. MAGP2 overexpression contributed to an advanced stage of endochondral ossification and induced cartilage callus into the bony callus. Further analysis indicated that MAGP2 was associated with enhanced angiogenesis, as evidenced by marked MAGP2 and integrin αvß3 costaining and increased endothelial cell markers such as endomucin and CD31 levls, as well as elevated phosphorylation of protein tyrosine kinase 2 (PTK2) and AKT serine/threonine kinase 1 (AKT) in the callus. In vitro, recombinant human MAGP2 treatment enhanced the viability, migration, and tube formation ability of human microvascular endothelial cells, which was partially reversed by integrin αvß3 inhibition or MK-2206, a specific AKT inhibitor. Inhibition of integrin αvß3 abolished MAGP2-induced PTK2 and AKT activation. Taken together, our data provide the first evidence that MAGP2 promotes angiogenesis and bone formation by activating the integrin αvß3/PTK2/AKT signaling pathway.

CMTM6 overexpression confers trastuzumab resistance in HER2-positive breast cancer.

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is characterized by invasive growth, rapid metastasis and chemoresistance. Trastuzumab is an effective treatment for HER2+ breast cancer; however, trastuzumab resistance leads to cancer relapse and metastasis. CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6) has been considered as a new immune checkpoint for tumor-induced immunosuppression. The role of CMTM6 in trastuzumab resistance remains unknown. Here, we uncover a role of CMTM6 in trastuzumab-resistant HER2+ breast cancer. CMTM6 expression was upregulated in trastuzumab-resistant HER2+ breast cancer cell. Patients with high CMTM6 expressing HER2+ breast cancer had worse overall and progression-free survival than those with low CMTM6 expression. In vitro, CMTM6 knockdown inhibited the proliferation and migration of HER2+ breast cancer cells, and promoted their apoptosis, while CMTM6 overexpression reversed these effects. CMTM6 and HER2 proteins were co-localized on the surface of breast cancer cells, and CMTM6 silencing reduced HER2 protein levels in breast cancer cells. Co-immunoprecipitation revealed that CMTM6 directly interacted with HER2 in HER2+ breast cancer cells, and CMTM6 overexpression inhibited HER2 ubiquitination. Collectively, these findings highlight that CMTM6 stabilizes HER2 protein, contributing to trastuzumab resistance and implicate CMTM6 as a potential prognostic marker and therapeutic target for overcoming trastuzumab resistance in HER2+ breast cancer.

Comprehensive analysis of the expression, prognostic significance, and regulation pathway of G2E3 in breast cancer.

BACKGROUND: Loss of G2-specific E3-like (G2E3) protein sensitizes tumor cells to chemotherapy. However, the role of G2E3 in breast cancer development and patient's prognosis is unclear. Here, we explored the expression, prognostic significance, and regulatory pathway of G2E3 in breast cancer. METHODS: TCGA and UALCAN database were utilized to explore G2E3 expression in breast cancer and normal tissues and its expression in breast cancer based on clinicopathological characteristics, respectively. The Kaplan-Meier plotter database was utilized to determine the effect of G2E3 on the prognosis of breast cancer patients. RT-PCR was utilized to validate the G2E3 expression in cancerous and normal breast tissues. Immunohistochemistry analysis was utilized to validate the prognostic effect of G2E3 expression in breast cancer patients and the relationship between G2E3 expression and lymphocyte infiltration levels. Receiver operating characteristic (ROC) curves were also generated to validate the diagnostic value of G2E3 expression in recurrence/distant organ metastasis and death. The STRING database, DAVID database, and Sanger-box tools were utilized to perform GO functional, KEGG pathway enrichment, and GSEA analysis. The TISIDB database was utilized to determine the relationship between G2E3 expression and tumor immunity. Finally, CTD database was utilized to screen for potential therapeutic compounds that could reduce the G2E3 mRNA expression. RESULTS: TCGA data presented that G2E3 expression was higher in breast cancer tissues than in normal breast tissues. This result was further validated by RT-PCR (P = 0.003). The Kaplan-Meier plotter database suggested that patients with high G2E3 mRNA expression had significantly shorter RFS and OS than patients with low G2E3 mRNA expression. Immunohistochemistry analysis of 156 breast cancer clinical specimens also validated patients with G2E3-positive expression had a significantly shorter DFS and OS than patients with G2E3-negative expression. Thus, G2E3 expression was an independent prognostic predictor of DFS and OS. The G2E3-positive expression also has a high diagnostic value for recurrence/distant organ metastasis and death. GSEA analysis revealed that G2E3 might be enriched in the E2F, PI3K/AKT/mTOR signaling, DNA repair pathways, and other cancer-related signaling pathways. The TISIDB database showed that G2E3 expression was significantly negatively associated with lymphocyte infiltration. This result was further validated in clinical breast cancer samples (P = 0.048; R = -0.158). Using the CTD database, we found that (+)-JQ1 compound, 1,2-dimethylhydrazine, and other compounds may decrease the G2E3 mRNA expression. These compounds could serve as potential therapeutic compounds for the clinical treatment of breast cancer. CONCLUSIONS: G2E3 expression was higher in breast cancer tissues than in normal tissues. G2E3-positive expression was related to a worse survival outcome in patients with breast cancer. Genes co-expressed with G2E3 may be enriched in the breast cancer-related signaling pathways. The G2E3 expression was significantly negatively associated with lymphocyte infiltration. G2E3 may serve as a novel prognostic biomarker and therapeutic target for breast cancer.

A multicentre single arm phase 2 trial of neoadjuvant pyrotinib and letrozole plus dalpiciclib for triple-positive breast cancer.

Current therapies for HER2-positive breast cancer have limited efficacy in patients with triple-positive breast cancer (TPBC). We conduct a multi-center single-arm phase 2 trial to test the efficacy and safety of an oral neoadjuvant therapy with pyrotinib, letrozole and dalpiciclib (a CDK4/6 inhibitor) in patients with treatment-naïve, stage II-III TPBC with a Karnofsky score of ≥70 (NCT04486911). The primary endpoint is the proportion of patients with pathological complete response (pCR) in the breast and axilla. The secondary endpoints include residual cancer burden (RCB)-0 or RCB-I, objective response rate (ORR), breast pCR (bpCR), safety and changes in molecular targets (Ki67) from baseline to surgery. Following 5 cycles of 4-week treatment, the results meet the primary endpoint with a pCR rate of 30.4% (24 of 79; 95% confidence interval (CI), 21.3-41.3). RCB-0/I is 55.7% (95% CI, 44.7-66.1). ORR is 87.4%, (95% CI, 78.1-93.2) and bpCR is 35.4% (95% CI, 25.8-46.5). The mean Ki67 expression reduces from 40.4% at baseline to 17.9% (P < 0.001) at time of surgery. The most frequent grade 3 or 4 adverse events are neutropenia, leukopenia, and diarrhoea. There is no serious adverse event- or treatment-related death. This fully oral, chemotherapy-free, triplet combined therapy has the potential to be an alternative neoadjuvant regimen for patients with TPBC.

The altering in sensory sensitivity: a current issue of female breast surgery.

Breast surgery is an important treatment for women with malignant breast diseases. In addition to breast appearance, the integrity of breast function is increasing in patients with breast diseases. As the basis of breast physiological function, breast skin sensitivity is important to the quality of life of patients after surgery. Breast skin sensitivity gives the patient a "real" breast feeling. The sensory recovery after breast surgery has also become one of the important goals of breast surgery. In this review, we aim to discuss the research progress on recovery of breast skin sensitivity after different treatment modalities for breast disease.

CEMIP as a potential biomarker and therapeutic target for breast cancer patients.

Purpose: We aimed to evaluate whether CEMIP plays any role in the survival outcome of breast cancer (BC) patients, as well as to explore the regulatory mechanism of CEMIP in BC. Methods: We evaluated the expression and prognostic effect of CEMIP in BC patients using the Oncomine, GEPIA, UALCAN, and Kaplan-Meier plotter databases. Additionally, we detected CEMIP mRNA and protein levels in BC and normal tissues via PCR and western blotting analyses. Through immunochemistry analysis, we quantified CEMIP expression in 233 samples from BC patients. We then analyzed the link between the survival outcomes and CEMIP expression based on these clinical samples. Furthermore, we explored the immune-related molecules regulated by CEMIP and its coexpressed genes using the STRING database. Results: CEMIP expression was higher in BC tissues than in normal tissues. Patients with high CEMIP mRNA levels had a worse survival outcome. Similarly, patients expressing CEMIP had significantly shorter overall survival and disease-free survival than those not expressing the protein (P < 0.01). Some lymphocytes, immune inhibitors, immune stimulators, MHC molecules, chemokines, and chemokine receptors can be regulated by CEMIP, and CEMIP and its coexpressed genes can participate in the hyaluronan biosynthetic process, hyaluronan catabolic process, and other related biological processes in the progression of BC. Conclusion: Compared to normal tissues, BC tissues had higher number of CEMIP transcripts. CEMIP expression was associated with an adverse prognosis. CEMIP and its coexpressed genes can participate in the progression of BC. Therefore, CEMIP may be a potential biomarker for the treatment of BC patients.