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*

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.

Objectives:This study aimed to assess the efficacy and safety of bendamustine in combination with rituximab (BR regimen) for the treatment of newly diagnosed indolent B-cell non-Hodgkin's lymphoma (B-iNHL) and elderly mantle cell lymphoma (eMCL) .Methods:From December 1, 2020 to September 10, 2022, a multi-center prospective study was conducted across ten Grade A tertiary hospitals in Shandong Province, China. The BR regimen was administered to evaluate its efficacy and safety in newly diagnosed B-iNHL and eMCL patients, and all completed at least four cycles of induction therapy.Results:The 72 enrolled patients with B-iNHL or MCL were aged 24-74 years, with a median age of 55 years. Eastern Cooperative Oncology Group (ECOG) performance status scores of 0-1 were observed in 76.4% of patients, while 23.6% had scores of 2. Disease distribution included follicular lymphoma (FL) (51.4% ), marginal zone lymphoma (MZL) (33.3% ), eMCL (11.1% ), and the unknown subtype (4.2% ). According to the Ann Arbor staging system, 16.7% and 65.3% of patients were diagnosed with stage Ⅲ and stage Ⅳ lymphomas, respectively. Following four cycles of BR induction therapy, the overall response rate was 98.6%, with a complete response (CR) rate of 83.3% and a partial response (PR) rate of 15.3%. Only one eMCL patient experienced disease progression during treatment, and only one FL patient experienced a relapse. Even when evaluated using CT alone, the CR rate was 63.9%, considering the differences between PET/CT and CT assessments. The median follow-up duration was 11 months (range: 4-22), with a PFS rate of 96.8% and an OS rate of 100.0%. The main hematologic adverse reactions included grade 3-4 leukopenia (27.8%, with febrile neutropenia observed in 8.3% of patients), grade 3-4 lymphopenia (23.6% ), grade 3-4 anemia (5.6% ), and grade 3-4 thrombocytopenia (4.2% ). The main non-hematologic adverse reactions such as fatigue, nausea/vomiting, rash, and infections occurred in less than 20.0% of patients.Conclusion:Within the scope of this clinical trial conducted in China, the BR regimen demonstrated efficacy and safety in treating newly diagnosed B-iNHL and eMCL patients.

Background: Cardiopulmonary resuscitation (CPR) strategies in COVID-19 patients differ from those in patients suffering from cardiogenic cardiac arrest. During CPR, both healthcare and non-healthcare workers who provide resuscitation are at risk of infection. The Working Group for Expert Consensus on Prevention and Cardiopulmonary Resuscitation for Cardiac Arrest in COVID-19 has developed this Chinese Expert Consensus to guide clinical practice of CPR in COVID-19 patients. Main recommendations: 1) A medical team should be assigned to evaluate severe and critical COVID-19 for early monitoring of cardiac-arrest warning signs. 2) Psychological counseling and treatment are highly recommended, since sympathetic and vagal abnormalities induced by psychological stress from the COVID-19 pandemic can induce cardiac arrest. 3) Healthcare workers should wear personal protective equipment (PPE). 4) Mouth-to-mouth ventilation should be avoided on patients suspected of having or diagnosed with COVID-19. 5) Hands-only chest compression and mechanical chest compression are recommended. 6) Tracheal-intubation procedures should be optimized and tracheal-intubation strategies should be implemented early. 7) CPR should be provided for 20-30 min. 8) Various factors should be taken into consideration such as the interests of patients and family members, ethics, transmission risks, and laws and regulations governing infectious disease control. Changes in management: The following changes or modifications to CPR strategy in COVID-19 patients are proposed: 1) Healthcare workers should wear PPE. 2) Hands-only chest compression and mechanical chest compression can be implemented to reduce or avoid the spread of viruses by aerosols. 3) Both the benefits to patients and the risk of infection should be considered. 4) Hhealthcare workers should be fully aware of and trained in CPR strategies and procedures specifically for patients with COVID-19.

Objective:To investigate the effects of of anti tumor necrosis factor-α (TNF-α) in adjuvant treatment of strangulated intestinal obstruction combined with ischemic intestinal necrosis.Methods:From February 2011 to August 2016 in Huadu District People′s Hospital Affiliated with Southern Medical University, 122 patients with strangulated intestinal obstruction combined with ischemic intestinal necrosis were selected and were equally divided into the experimental group and control group with 61 cases in each group according to the random draw envelope principle. Conventional surgical resection and anastomosis was used in control group, the postoperative anti TNF-α therapy was given for 2 weeks based on the treatment in control group.Results:All patients completed surgery and there were no serious complications during operation.The postoperative anal exhaust time and symptom remission time in experimental group were significantly lower than those in control group: (2.14 ± 0.41) d vs. (6.24 ± 1.28) d and (3.54 ± 0.77) d vs. (6.99 ± 0.91) d ( P<0.05). The incidence of postoperative 14 d complications such as anastomotic leakage, wound infection, anastomotic stenosis and pulmonary infection in the experimental group was 4.9%(3/61), and that of the control group was 18%(11/61), and the incidence of postoperative complications in the experimental group was significantly lower than that in the control group ( P<0.05). The postoperative 1d and 7 d serum TNF-α content in the experimental group was significantly lower than that in the control group ( P<0.05). The postoperative 14 d anal function in the experimental group was significantly better than that in the control group ( P<0.05). MRASP and MSP of postoperative 14 d in experimental group were all significantly higher than those in the control group: (80.24 ± 11.39) mmHg (1 mmHg=0.133 kPa) vs. (76.24 ± 12.11) mmHg, (231.98 ± 45.29) mmHg vs. (226.39 ± 41.87) mmHg ( P<0.05). Conclusions:The anti TNF-α in adjuvant treatment of strangulated intestinal obstruction combined with ischemic intestinal necrosis can promote the recovery of clinical symptoms and inhibit the release of TNF-α. It also can reduce the incidence of postoperative complications and improve gastrointestinal motility of patients.

Objective To observe the early effect of organ donation after pancreas-kidney transplantation.Methods Eight cases of diabetic nephropathy received combined pancreas kidney transplantation.There were 8 donors,including 6 males and 2 females,with an average age of (26 10) years old (range from 15 to 42 years).There were 4 cases of donors with China during the transition period of brain heart double death organ donation (C-Ⅲ) standard,3 cases of donors in line with the international standard of brain death organ donation (C-Ⅰ) standard,1 case of international standard of heart death organ donation (C-lⅡ M-Ⅲ) citizen donors.There were 6 men and 2 women for recipients of the same blood type.Results Eight cases were awake 4-6 h postoperation and the ventilator was removed 8-14 h after operation.The rehabilitation therapy began 2 days postoperation from surgery intensive care unit (SICU) to the common wards.Serum C-peptide and insulin levels achieved normal range in 1-2 weeks after transplant.Blood glucose returned to the normal level in 2-3 weeks,and the creatinine level decreased to the normal level in 2 weeks postoperation.Duodenal intramural hematoma occurred in one patient intraoperatively,and the pancreatic graft was removed for safe consideration.Other patients had no serious surgical complications within 2 weeks after transplantation.Conclusion For organ donation after death of pancreas kidney transplantation,early organ function recovered well.Under the strict preoperative evaluation,the young donors can be safely used in combined pancreas and kidney transplantation.

Objective To evaluate the effect on salvage treatment of sudden deafness with comprehensive Chinese medicine therapy. Methods Fifty-three sudden deafness patients failing in conventional western medicine treatment were given comprehensive Chinese medicine therapy, and the salvage treatment followed by oral use of Chinese medicine, intravenous injection of Chinese patent medicine, acupoint injection, ear acupoint plastering, acupoint application, acupuncture, sound healing, and massage. The therapeutic effect and the relief of major accompanying symptoms were evaluated after treatment, and the relationship of disease course with clinical efficacy was also investigated. Results (1) After treatment, 4 cases were cured, 9 were markedly effective, 13 were effective, 27 were ineffective, and the total effective rate was 49.06%. (2) Except for the 2 excluded cases, the major accompanying symptoms such as tinnitus, auricular distress, and vertigo were relieved to various degrees in other cases. ( 3) Twenty-two patients had a course of disease within 14 days, and the total effective rate for them was 72.73%. A total effective rate of 32.26% was achieved in 31 cases with disease course over 14 days. It is indicated that the therapeutic effect for patients with a disease course less than 14 days was superior to that with a disease course over 14 days (P<0.01). Conclusion Comprehensive Chinese medicine therapy exerts inspiring therapeutic effect on salvage treatment of sudden deafness, and earlier intervention results into better effect.

Objective To investigate the methods used for evaluating the severity of the patients with acute pancreatitis induced by hyperlipidemia in order to find out some simple and practical biomarkers for predicting the severity of the illness.Methods Sixty-two patients with acute pancreatitis resulted from hyperlipidemia were selected from the in-patients of our hospital from January 2007 to July 2011 and were divided into two groups,namely the mild acute pancreatitis group(MAP,n =32)and the severe acute pancreatitis group(SAP,n =30)as per the Chinese Acute Pancreatitis Guideline.Two groups were comparable verified by the test of homogeneity of variance after grouping.Arterial blood gas analyses were done immediately after admission:Venous blood was taken from forearm for determining renal function and blood coagulation at 6 o＇lock of next day after admission.The data of base excess(BE),creatinine(CR),C-reactive protein(CRP),fibrin(FIB)and D-Dmmer(D-D)were documented.The contrast CT imaging of pancreas was done within 48 hours after admission in all patients.APACHE Ⅱ scores and computed tomography severity index(CTSI)were calculated.The differences in BE,CR,CRP,FIB and D-D between 2 groups were analyzed by using t-test,and the correlation among them and APACHE Ⅱ score and CTSI were analyzed by Spearman test done with SPSS 18.0 software.As BE ＜-4.5 mnol/L,CR ＞ 120μmol/L,CRP ＞ 100 mg/L,FIB ＞5.5 g/L and D-D 800 ng/L were set respectively as a positive screening criterion,positive prediction value(PPV),negative prediction value(NPV),sensitivity and specificity of each marker and combined markers were calculated after they were set at different positive scales in order to get the optimal predictors for evaluating the severity of acute pancreatitis induced by hyperlipidemia.Results The absolute values of BE,CR,CRP,FIB and D-D in group SAP were much higher than those in group MAP(P ＜ 0.01).Each of them had good correlation with APACHE Ⅱ score and CTSI,especially BE and D-D more significant.Each of them used separately for predicting the severity of acute pancreatitis showed PPV and NPV with high specificity but the sensitivity was hot high.The joint use of BE,CR and CRP,and joint use of FIB and D-D could be more valid as PPV and NPV with high specificity for predicting the severity of acute pancreatitis,but the sensitivity decreased.Conclusions BE,CR,CRP,FIB and D-D were good biomarkers for quickly and accurately evaluating and predicting the severity of the acute pancreatitis caused by hyperlipidemia.

Objective To evaluate the therapeutic methods for stones in congenital anomalous kidneys. Methods The clinical outcomes of 126 patients(75 males and 51 females: mean age 39 years, range 12-66 years)who underwent extracorporeal shock wave lithotripsy (ESWL, n= 37), minimally invasive percutaneous nephrolithotomy (MPCNL, n = 41) or open surgery (n = 48) were retrospectively reviewed. There were 40 horseshoe kidneys(31.8%), 51 duplex kidneys(40.5%), 35 malrotated kidneys(27.8%). Seventyl calculi were located in left kidneys(55.6%)and 56 in right kid-neys(44.4%). There were 96 single stones(76.2%)and 30 complex stones(23.8%). The greatest di-ameter of stone ranged from0.8 cm to 2.2 cm(mean 1.5 cm) in ESWL group, 1.0 cm to 4.0 cm (mean 2.5 cm) in MPCNL group and 1.5 cm to 3.8 cm(mean 2.7 cm) in open surgery group. The therapeutic effects of 3 methods were compared. Results The stone-free rate at 1 session was 78.4%(29/31) in ESWL group, 85.4%(35/41) in MPCNL group and 87.5%(42/48) in open sur-gery group. No significant difference was found among the 3 groups(x2 = 1.39,P=0.50). The inci-dence of complications was 13.5% in ESWL group, 9.7% in MPCNL group and 6.3% in open sur-gery group(x2=1.28, P=0.53). Only 1 case of malrotated kidney suffered massive hemorrhage and was cured by selective embolism of renal artery. No major complications occurred in the other pa-tients. Conclusions With rigorous indication, ESWL or MPCNL is as safe and effective as open sur-gery in the management of stones in congenital anomalous kidneys. It should be considered as the pri-mary therapy. But the treatment must be individualized in terms of the type anomalous kidney, stone characteristics and obstruction.

Objective To analyze the blood perfusion characteristics of retroperitoneal benign and malignant tumors by real-time contrast enhanced ultrasonography and discuss its value in the differential diagnosis.Methods The study involved 42 patients with pathological evidence through surgery or needle biopsy,including 12 patients with benign retroperitoneal tumors and 30 patients with malignant retroperitoneal tumors.The blood perfusion characteristics of two groups were observed under low mechanical index after the injection of contrast ultrasound agent(SonoVue),and the changes of twodimensional ultrasonography and the time-intensity curve(TIC)were analyzed. Results During real time contrast enhancement,the different characteristics of retroperitoneal benign and malignant tumors were observed.Malignant tumors in retro peritoneum presented the pattern of ultrasound contrast agent(UCA) enhancement from center to periphery and enhanced overall uneven mainly,begin tumors presented peripheral enhancement pattern or uniformity and overall strengthening of the main.TIC curve between benign and malignant tumors displayed that contrast enhanced intensity of region of interest(P＜0.00 1),ascending slop and halftime of descending were statistically significant(P＜0.05).Conclusions Real-time contrast-enhanced ultrasonography is a valued method to provide information for the differential diagnosis in retroperitoneal benign and malignant tumors.