Therapeutic resistance in cancer is responsible for numerous cancer deaths in clinical practice. While target mutations are well recognized as the basis of genetic resistance to targeted therapy, nontarget mutation resistance (or nongenetic resistance) remains poorly characterized. Despite its complex and unintegrated mechanisms in the literature, nongenetic resistance is considered from our perspective to be a collective response of innate or acquired resistant subpopulations in heterogeneous tumors to therapy. These subpopulations, e.g., cancer stem-like cells, cancer cells with epithelial-to-mesenchymal transition, and drug-tolerant persisters, are protected by their resistance traits at cellular and molecular levels. This review summarizes recent advances in the research on resistant populations and their resistance traits. NOTCH signaling, as a central regulator of nongenetic resistance, is discussed with a special focus on its canonical maintenance of resistant cancer cells and noncanonical regulation of their resistance traits. This novel view of canonical and noncanonical NOTCH signaling pathways is translated into our proposal of reshaping therapeutic strategies targeting NOTCH signaling in resistant cancer cells. We hope that this review will lead researchers to study the canonical and noncanonical arms of NOTCH signaling as an integrated resistant mechanism, thus promoting the development of innovative therapeutic strategies.
Neoplasms/metabolism* ; Receptors, Notch/metabolism* ; Disease Resistance/physiology* ; Signal Transduction/physiology* ; Humans ; Drug Resistance, Neoplasm/physiology* ; Molecular Targeted Therapy/methods*

Objective:To study the efficiency and biosafety of Electrochemical advanced oxidation processes(EAOP)in dental bleaching,and conduct preliminary application.Methods:Indigo carmine and coffee were used as the indicator to assess the effi-cacy of EAOP.High resistance meter was used to measure the resistance of the tooth to verify the safety of the working voltage.Twenty wisdom teeth after tooth extraction were collected,dyed and bleached in vitro to verify the bleaching efficiency.Subsequent-ly,the bleached teeth were examined by scanning electron microscopy,hardness testing,and bacterial adhesion experiments to as-sess surface damage.To determine its cytotoxicity,cells were co-cultured with electrolyte.Initial samples of bleaching tray was prepared,and its durability were verified.Results:The EAOP could bleach indigo carmine within 10 min and coffee within 90 min at an operating voltage of 8 V.The resistance at the groove of the tooth socket was(3.4±1.2)MΩ,and the theoretical calculated current was less than 3 μA.The efficiency of EAOP tooth bleaching was slightly lower than that of traditional office bleaching and higher than that of home bleaching.Compared with the traditional bleaching method,scanning electron microscopy showed that EAOP had less demineralization effect on tooth surface.The tooth hardness before and after bleaching had no statistical difference(P=0.912).The bacterial adhesion test after tooth bleaching showed that EAOP method could reduce about 60％bacterial adhe-sion(P＜0.001).The cytotoxicity test showed that EAOP electrolyte had no obvious toxic effect.The durability test shows that the bleached denture still has good bleaching effect after 20 h of use.Conclusion:Compared with the traditional bleaching method,EAOP bleaching had excellent tooth bleaching effect,little effect on tooth damage,high safety,and the related bleaching devices had good durability.

Objective:To study the efficiency and biosafety of Electrochemical advanced oxidation processes(EAOP)in dental bleaching,and conduct preliminary application.Methods:Indigo carmine and coffee were used as the indicator to assess the effi-cacy of EAOP.High resistance meter was used to measure the resistance of the tooth to verify the safety of the working voltage.Twenty wisdom teeth after tooth extraction were collected,dyed and bleached in vitro to verify the bleaching efficiency.Subsequent-ly,the bleached teeth were examined by scanning electron microscopy,hardness testing,and bacterial adhesion experiments to as-sess surface damage.To determine its cytotoxicity,cells were co-cultured with electrolyte.Initial samples of bleaching tray was prepared,and its durability were verified.Results:The EAOP could bleach indigo carmine within 10 min and coffee within 90 min at an operating voltage of 8 V.The resistance at the groove of the tooth socket was(3.4±1.2)MΩ,and the theoretical calculated current was less than 3 μA.The efficiency of EAOP tooth bleaching was slightly lower than that of traditional office bleaching and higher than that of home bleaching.Compared with the traditional bleaching method,scanning electron microscopy showed that EAOP had less demineralization effect on tooth surface.The tooth hardness before and after bleaching had no statistical difference(P=0.912).The bacterial adhesion test after tooth bleaching showed that EAOP method could reduce about 60％bacterial adhe-sion(P＜0.001).The cytotoxicity test showed that EAOP electrolyte had no obvious toxic effect.The durability test shows that the bleached denture still has good bleaching effect after 20 h of use.Conclusion:Compared with the traditional bleaching method,EAOP bleaching had excellent tooth bleaching effect,little effect on tooth damage,high safety,and the related bleaching devices had good durability.

Femoral neck fracture (FNF) in the elderly patients is currently a major health challenge worldwide, with excessive consumption of medical resources, high incidence of complications as well as suboptimal outcome and prognosis. Hip joint arthroplasty (HJA) has been the mainstream treatment for FNF in the elderly, but the conventional surgical approaches and techniques are still confronted with a series of bottlenecks such as dislocation, limp and limb length discrepancy. In recent years, direct anterior approach (DAA) for HJA (DAA-HJA) has been a major new choice in the field of joint replacement, which achieves improved clinical effectiveness of HJA in the treatment of elderly FNF, due to the fact that DAA approach involves the neuromuscular interface and accords with the idea of soft tissue retention and enhanced recovery after surgery. However, there is still a lack of unified understanding of standard technique and procedure of DAA-HJA in the treatment of elderly FNF. Therefore, relevant experts from the Hip Joint Group of Chinese Orthopedics Association of Chinese Medical Association, Youth Arthrology Group of Orthopedic Committee of PLA, Orthopedic Committee of Chongqing Medical Association, Branch of Orthopedic Surgeons of Chongqing Medical Doctor Association and Sport Medicine Committee of Chongqing Medical Association were organized to formulate the " Chinese expert consensus on the technical standard of direct anterior hip arthroplasty for elderly femoral neck fracture ( version 2023)" based on evidence-based medicine. This consensus mainly proposed 13 recommendations covering indications, surgical plans, prosthesis selections, surgical techniques and processes, and postoperative management of DAA-HJA in elderly patients with FNF, aiming to promote standardized, systematic and patient-specific diagnosis and treatment to improve the functional prognosis of the patients.

OBJECTIVE： To prepare Zingiber officinale oil microcapsules and to evaluate its quality. METHODS： Z. officinale oil microcapsules were prepared by spray drying method with sodium starch octenyl succinate as capsule material. The preparation technology was optimized by orthogonal test with mixing temperature of capsule material and capsule core， mass ratio of capsule material and capsule core， stirring speed as factors， using encapsulation efficiency as index. The drug loading， encapsulation efficiency， appearance， particle size distribution and stability of light， heat and humidity （using iodine value and peroxide value as indexes） were evaluated. RESULTS： The optimal preparation technology of Z. officinale oil microcapsules was that the mixing temperature of capsule material and core was 60 ℃； mass ratio of capsule material and capsule core was 10 ∶ 1； stirring speed was 12 000 r/min. Average drug-loading amount and encapsulation efficiency of Z. officinale oil microcapsules prepared by optimal technology were 17.97％ and 73.57％ （n＝3）. The morphology of Z. officinale oil microcapsules was round， smooth， non-sticky and uniform in size distribution. The average diameter of microcapsules was （6.30±0.27） μm. Under light， heat and humidity conditions， the iodine value and peroxide value of Z. officinale oil microcapsules changed slightly. CONCLUSIONS： The optimal preparation technology of Z. officinale oil microcapsules is simple and reproducible. The prepared microcapsules have good encapsulation efficiency， high drug loading amount and good stability.

Objective: To study the effects of platelet-rich fibrin extract (PRFe) and platelet-derived growth factor (PDGF) released from PRFe on the proliferation of human gingival fibroblasts (HGFs) and to provide an experimental basis for its application in promoting gingival soft tissue increment. Methods: Platelet-rich fibrin (PRF) was transformed into PRFe by tissue culture. The three-dimensional structure of PRF was observed by electron microscopy, and the content of PDGF in PRF was quantitatively determined by ELISA. The ratios of PRFe examined were 2.5% PRFe, 5% PRFe, 7.5% PRFe, 10% PRFe, 12.5% PRFe and 15% PRFe. Gingival fibrosis was detected by the CCK-8 method. After determining the optimal concentration of PRFe, flow cytometry was used to detect the effect of PRFe on the proliferation cycle of human gingival fibroblasts, and the effect of PDGF on the proliferative activity of gingival fibroblasts was observed by neutralizing the release of PDGF. Results : PRF is a three-dimensional reticular structure that contains a large number of growth factors. PDGF release peaked on the 7th day. The proliferative activity of HGFs cultured with different concentrations of PRFe was concentration-dependent, but the effect was optimal at 5% PRFe (P < 0.05). There were no significant differences in the effect of subsequent concentration increases on the proliferation of HGFs (P > 0.05). The flow cytometry results showed that 5% PRFe could significantly stimulate the S-phase division and proliferation of gingival fibroblasts, while the PDGF neutralization test showed that the proliferation of gingival fibroblasts was significantly inhibited by the neutralization of PDGF. Conclusion Overall 5% PRFe had the best effect on promoting gingival fibroblast proliferation in vitro. PDGF released from PRF plays an important role in promoting the proliferation of gingival fibroblasts.

Objective : To construct a Miller class Ⅲ gingival recession animal model and to lay the foundation for exploring the treatment of Miller class Ⅲ gingival recession. Methods: Two adult male beagle dogs were selected, and four teeth from each beagle dog were selected to establish an experimental Miller class Ⅲ gingival recession model. The root surface was revealed by removing the soft and hard tissues of the buccal side. The success of the model was determined by measuring the vertical gingival retraction (VGR), horizontal retraction (HGR), keratosis tissue width (KTW), gingival tissue thickness (GTT), and probing depth (PD) at 1, 2, 4, 6, and 8 weeks after modeling. Results: After observing the clinical indexes, the PDs before and after the modeling were all smaller than 3 mm and no deep-period pockets were formed. The VGR before modeling was 0 mm, and the VGR range after modeling was 5-6.38 mm. A comparison of the before and after modeling results showed that this difference was statistically significant (P < 0.05). The postoperative VGR results were grouped according to timepoint. A comparison between the two groups showed that the differences at 2, 4, 6 and 8 weeks postoperatively were not statistically significant (P > 0.05). The HGR before the modeling was 0 mm, and the HGR fluctuated around 10.5 mm after the modeling, and this difference was statistically significant (P < 0.05). The HGR results were grouped by timepoint after surgery, and a one-way analysis of showed that the differences between the two groups were not statistically significant (P > 0.05). The KTW range before modeling was 6~9 mm, and it fluctuated around 2 mm after modeling, and this difference was statistically significant (P < 0.05). The KTW results were grouped by timepoint after surgery, and they indicated that significant differences did not occur between the groups postoperatively (P > 0.05). The pre-modeling GTT was 1.5 mm, and the GTT range after modeling was 1.5-2 mm. The preoperative and postoperative GTT results were grouped by timepoint, and the results showed that significant differences did not occur between 1 week and 2 weeks after surgery (P = 0.123), although a statistically significant difference was observed at 1 week postoperatively between this group and the other groups (P < 0.05). Conclusion The method used in this experiment can successfully build a Miller class III gingival recession animal model, and the model remains stable after wound healing.