The tumor microenvironment (TME) is a critical determinant of tumor initiation, progression, and therapeutic response, and serves as the basis for designing precise delivery strategies. Its marked heterogeneity underscores the need for a more comprehensive understanding of its composition and function. In addition to the extensively studied classical TME, emerging evidence highlights the significant roles of the tumor mechanical microenvironment and the tumor microbial microenvironment in modulating treatment efficacy. These non-classical dimensions not only independently influence tumor behavior but also interact dynamically with classical TME components. Mechanical cues within the TME, including matrix stiffness and solid stress, significantly affect drug distribution and treatment efficacy, suggesting that mechanical remodeling represents a potential strategy to enhance therapeutic outcomes. Concurrently, tumor-associated microbiota and their metabolites participate in immune regulation and metabolic reprogramming, contributing to tumor development and offering novel therapeutic targets. Moreover, recent advances have broadened our understanding on the multilayered regulatory landscape of the TME through the investigation of previously underappreciated factors such as neural regulation, metabolic niche dynamics, spatiotemporal heterogeneity, and epigenetic modulation. This review systematically summarizes the characteristics of these diverse TME dimensions and highlights recent progress in targeted delivery strategies, to facilitate the development of more personalized and effective anticancer therapies.
Humans ; Tumor Microenvironment ; Neoplasms/pathology* ; Drug Delivery Systems ; Antineoplastic Agents/administration & dosage*

Poorly differentiated and advanced thyroid cancers are characterized by high malignan-cy,progress rapidly,and resistance to radiotherapy and chemotherapy.These characteristics pose sig-nificant challenges,severely limiting effective treat-ment options.Various kinase inhibitors have been used in the treatment of refractory thyroid cancer were used accompanying by the carcinogenic mechanisms'studies investigating in thyroid cancer,such as Dabrafenib(BRAF inhibitor),Trametinib(MEK inhibitor),Vandetanib(RET inhibitor),Lenva-tinib(VEGF inhibitor),and multi-target kinase inhib-itors.However,drug resistance remains an inevita-ble issue,significantly limiting the efficacy and ap-plication of kinase inhibitors.Therapeutic approach-es such as immunotherapy,redifferentiation strate-gies for thyroid cancer,radiopharmaceutical conju-gates,and the application of nanotechnology are currently in the clinical research stage,requiring further clarification of their efficacy.Comprehen-sive understanding of therapeutic strategies and available treatment combinations for refractory thy-roid cancer is of paramount importance in the diag-nosis and treatment of thyroid cancer.Therefore,this article reviews technologies and methods for treating refractory thyroid cancer,focusing on che-motherapy,molecular targeted therapy,immuno-therapy,and radiopharmaceutical therapy,aiming to provide a reference for selecting treatment strat-egies for refractory thyroid cancer.

Poorly differentiated and advanced thyroid cancers are characterized by high malignan-cy,progress rapidly,and resistance to radiotherapy and chemotherapy.These characteristics pose sig-nificant challenges,severely limiting effective treat-ment options.Various kinase inhibitors have been used in the treatment of refractory thyroid cancer were used accompanying by the carcinogenic mechanisms'studies investigating in thyroid cancer,such as Dabrafenib(BRAF inhibitor),Trametinib(MEK inhibitor),Vandetanib(RET inhibitor),Lenva-tinib(VEGF inhibitor),and multi-target kinase inhib-itors.However,drug resistance remains an inevita-ble issue,significantly limiting the efficacy and ap-plication of kinase inhibitors.Therapeutic approach-es such as immunotherapy,redifferentiation strate-gies for thyroid cancer,radiopharmaceutical conju-gates,and the application of nanotechnology are currently in the clinical research stage,requiring further clarification of their efficacy.Comprehen-sive understanding of therapeutic strategies and available treatment combinations for refractory thy-roid cancer is of paramount importance in the diag-nosis and treatment of thyroid cancer.Therefore,this article reviews technologies and methods for treating refractory thyroid cancer,focusing on che-motherapy,molecular targeted therapy,immuno-therapy,and radiopharmaceutical therapy,aiming to provide a reference for selecting treatment strat-egies for refractory thyroid cancer.

Objective:To investigate the application value of enhanced recovery after surgery (ERAS) in perioperative period of laparoscopic sleeve gastrectomy (LSG).Method:The retrospective cohort study was conducted. The clinical data of 1 181 patients undergoing LSG in the Sir Run Run Shaw Hospital, Affiliated with the Zhejiang University School of Medicine from January 2021 to December 2023 were collected. There were 242 males and 939 females, aged (31±8)years. Of 1 181 patients, 598 cases receiving routine perioperative care were divided into the control group, and 583 cases receiving perioperative care with ERAS were divided into the ERAS group. Measurement data with normal distribution were represented as Mean± SD, and the independent sample t test was used for comparison between the groups. Measurement data with skewed distribution were represented as M( Q1, Q3), and the Mann-Whitney rank sum test was used for comparison between the groups. Count data were expressed as absolute numbers or percentages, and the chi-square test or Fisher exact probability were used for comparison between the groups. Repeated measurement data were analyzed using the repeated ANOVA, with baseline scores as covariates. Simple effects analysis was conducted in case of interaction, and multiple comparisons were adjusted using the Bonferroni method. Results:(1) Postoperative outcomes. The numerical rating scale (NRS) scores for pain at immediate return to the ward and on the third postoperative mornings changed from 5.35±0.93 to 2.57±0.83 in the control group, versus changed from 3.15±0.93 to 0.70±0.65 in the ERAS group, showing significant difference between the two groups ( Ftime=66.58, Fgroup=1 765.85, Finteraction=6.90, P<0.05). After adjusting NRS scores for pain at immediate return to the ward as the baseline, results of simple effects analysis showed that on the third postoperative mornings, the NRS scores in the ERAS group were lower by 1.89, 1.53, and 1.76 respectively compared to the control group ( P<0.05). Cases with nausea at immediate return to the ward and on the third postoperative mornings changed from 497 to 97 in the control group, versus changed from 198 to 11 in the ERAS group, showing signifi-cant difference between the two groups ( χ2=294.45, 398.76,209.39, 73.00, P<0.05). Cases with vomiting at immediate return to the ward and on the third postoperative mornings changed from 243 to 41 in the control group, versus changed from 51 to 2 in the ERAS group, showing significant difference between the two groups ( χ2=160.54, 149.37, 71.76, 35.69, P<0.05). The duration of postoperative hospital stay was (3.22±0.65)days in the control group, versus (2.17±0.49)days in the ERAS group, showing a significant difference between the two groups ( t=-11.89, P<0.05). (2) Complications. The incidence of cases with dehydration within postoperative 30 days was 0.50%(3/598) in the control group, versus 0.69%(4/583) in the ERAS group, showing no significant difference between the two groups ( P>0.05). None of patient in the control group and the ERAS group experienced bleeding, gastric leakage, intra-abdominal infection, and no patient had unplanned secondary surgery within postoperative 30 days. Conclusions:ERAS in perioperative period of LSG are safe and feasible. Compared to routine care, ERAS can significantly reduce postoperative pain, decrease the incidence of postoperative nausea and vomiting, shorten the postoperative hospital stay, and do not increase the rate of postoperative complications or unplanned secondary surgeries within postoperative 30 days.

Objective: To investigate the use of additives and microbiologic contamination in prepared beverages around campus in Wuxi City, so as to provide reference for ensuring the physical health of primary and secondary school students. Methods: From August to September 2022, 108 prepared beverage were randomly collected from beverage stores around campus in four districts of Wuxi City. The food additives and microbiologic contamination were detected by the national standard method and evaluated according to the National Food Safety Standards for the Use of Food Additives and Local Food Safety Standards for Ready made Beverages. Chi squared test was used for statistical analysis. Results: The use of 13 additives in prepared beverages didn t exceed the limits specified in relevant standards. The detection rate of preservatives in fruit juice (52.78%) was higher than that in tea (16.67%), and milk tea (27.78%), while the detection rate of pigments in milk tea (16.67%) was lower than that in tea (52.78%) and fruit juice (47.22%)( χ 2=11.24, 11.46, P <0.05). The overlapping use of the same functional additive did not exceed the specified limit. The exceeding rate of total bacterial count was 9.26%, and Escherichia coli was 14.81%. Conclusion There are certain food safety risks in prepared beverages around the campus in Wuxi City. Relevant enterprises and shops should strengthen supervision and management to ensure food safety for students.

Objective:To correlate multiphase CT angiography (mCTA), serum lipid peroxidation (LPO) and thrombus precursor protein (TpP) levels with recurrence of acute cerebral infarction (ACI) in older adults and investigate the value of these indicators in the predication of ACI recurrence.Methods:A total of 128 older adult patients with ACI who received treatment in Ningbo Medical Center Lihuili Hospital, China between January 2019 and January 2020 were included in this study. All of them were followed up for 1 year. They were divided into ACI recurrence group ( n = 29) and no ACI recurrence group ( n = 99) according to whether they had recurrent cerebral infarction. All patients underwent mCTA. Maas system and Tan score were used according to mCTA images. Serum TpP level was measured using enzyme-linked immunosorbent assay. Serum LPO level was measured using Yagi's fluorescence method. Multiple linear regression analysis was used for correlation analysis. The receiver operating characteristic (ROC) curve was used to evaluate the efficacy of mCTA and serum LPO and TpP levels in the diagnosis of ACI. Results:Tan score in the ACI recurrence group was significantly lower than that in the no ACI recurrence group [(1.06 ± 0.26) points vs. (1.89 ± 0.82) points, t = 5.35, P < 0.05]. Serum TpP and LPO levels in the ACI recurrence group were (7.22 ± 1.35) mmol/L and (11.23 ± 2.58) nmol/mL, respectively, which were significantly higher than those in the no ACI recurrence group [(3.06 ± 0.28) mmol/L, (7.23 ± 0.37) nmol/mL, t = 28.86, 15.04, both P < 0.001]. ACI recurrence in older adult patients was correlated with Tan score and serum LPO and TpP levels (both P < 0.05). The sensitivity of mCTA combined with serum LPO and TpP levels in the diagnosis of ACI in older adults was 93.10%-96.60% and its specificity was 100.00%. The ROC curve analysis showed that the area under the ROC of mCTA, LPO and TpP in the prediction of ACI recurrence in older adults was 0.986 (95% CI = 0.966-1.000), 0.976 (95% CI = 0.930-1.000) and 0.968 (95% CI = 0.905-1.000), respectively. Conclusion:ACI recurrence in older adults is correlated with Tan score and serum LPO and TpP levels. mCTA, Tan score, and serum LPO and TpP levels have high sensitivity and specificity in the diagnosis of ACI recurrence in older adults, and therefore have a high diagnostic value.

Objective To study the prevalence of cigarettes and e-cigarettes, and to analyze its influencing factors among high school students in Wenzhou. Methods:A self-administered questionnaire survey was conducted among a total of 3 785students from senior high schools and vocational high schools in Wenzhou from September to November in 2020, who were selected by stratified cluster sampling. Their demographic information and the use of tobacco [including the use of cigarettes, e-cigarettes (currently smoking and smoking attempt), and the dual use of them] were asked in the questionnaire of “Global Youth Tobacco Survey”(GYTS). Proportion and rate were used to describe their demographic characteristics and smoking prevalence. Chi-square test was used to compare the difference in smoking prevalence of the high school students with selected characteristics. Multinomial logistic regression was used to analyze the influencing factors of tobacco use among the participants.Results:Among the 3 785 questionnaires, 3 740 were completed, and effective rate was 98.80%. The smoking attempt rate, current smoking rate, e-cigarette attempt rate, e-cigarette using rate, and dual using rate of the high school students in Wenzhou were 11.79% (441/3 740), 2.57% (96/3 740), 10.00% (374/3 740), 2.86% (107/3 740), 0.99% (37/3 740), respectively. Male students, vocational high school students, the students whose parents smoking showed higher smoking attempt rate, current smoking rate, e-cigarette attempt rate than female student, senior high school students and those parents who don′t smoke, respectively (all P<0.05). Best friend smoking [6.076 (2.872-12.855); 4.630 (2.656-8.071)], vocational high school [3.226 (1.877-5.546); 2.238 (1.432-3.496)] were risk factors for e-cigarette and the cigarettes use, belief that whether smoking or not does not make any difference in social activities [0.160 (0.077-0.331); 0.193 (0.096-0.387)], or smoking in social activities makes people more uncomfortable [0.037 (0.018-0.077); 0.155 (0.083-0.288)] were protective factors of e-cigarette and the cigarettes use. Additionally, passive smoking in past week [2.194 (1.129-4.262)], free tobacco products received [2.836 (1.018-7.905)], seeing smoking in campus [2.072 (1.111-3.863)] were all risk factors, while belief that smoking makes young people less attractive [0.280 (0.116-0.676)], not having been to tobacco retail outlets and unexposed to tobacco advertising or promotion [0.241 (0.123-0.473)] can protect senior middle school student away from cigarette. As to e-cigarette, boys were the risk factors [1.831 (1.100-3.050)]; as opposed to being a risk factor for cigarette use [1.942 (1.084-3.478)], rural area was a protective factor for e-cigarette use [0.639 (0.410-0.994)] among high school students in Wenzhou. Conclusions:High school students have relatively low rates of smoking cigarettes and e-cigarette in Wenzhou. Vocational students, best friend smoking are risk factors of e-cigarette and the cigarettes, beliefs that whether smoking or not does not make any difference or smoking makes people more uncomfortable in social activities are protective factors.

Objective:To explore the etiology, clinical diagnosis and treatment strategy of Lesch Nyhan syndrome.Methods:We retrospectively analyzed 2 patients with severe dyskinesia, mental retardation and complicated renal calculi who were admitted to the first people's Hospital of Zhengzhou in August 2019. Case 1, male, 9 years old, had multiple urinary calculi for 1 year. The patient came to the local hospital because double multiple kidney stones and bladder stonesa year ago. The patient had been treated with transurethral holmium laser lithotripsy for bladder stones. The results of infrared spectrum showed that the bladder stone was anhydrous uric acid stone. A week ago, color Doppler ultrasound showed multiple kidney stones and bladder stones. The patient was underdeveloped, mentally retarded and had a full-term cesarean section. There was no history of hypoxia, asphyxia and rescue of the patient. He had the following clinical manifestations: In the waking state, he was no language response to any stimulation. The nasolabial fold on the right was shallow and the corner of the mouth was oblique to the left. He lost the large movements such as lifting head, sitting alone, standing. The trunk showed torsion spasticity, limb muscle strength 2-3, limbs showing spastic hypertonia, limb joints stiff, hands showing fist-like, no involuntary movement and muscle fasciculation. The biceps reflex and knee tendon reflex were not elicited, and the pathological reflex was positive. Serum uric acid was 517 μmol/L. The Case 2 came from the same family, male, 6 years old, had the similar symptoms to his elder brother case 1. The family members complained on behalf of the child about intermittent fever for more than 2 years. The imaging examination of case 2 revealed kidney stones. Serum uric acid was 373 μmol/L. Whole Exome Sequencing and Sanger Sequencing were used to find the genetic causes of the two siblings. The NCBI-Homologene database was used to find the homologous sequence of the human HPRT1 gene, and the human HPRT1 gene sequence was compared with other species to analyze the protein conservation. The online website PredictProtein (http: //www.predactprotein) was used to predict the two-dimensional structure of the HPRT1 gene. The reported cases were summarized and same with the treatment plan.Results:A De novo mutation [c.571T>G(p.Tyr191Asp)] was found in the HPRT1 gene of the child, which was inherited from the mother. Lesch Nyhan syndrome can be diagnosed by the results of gene examination combined with clinical manifestations. The amino acid Tyr at the 191 position and the amino acids before and after it were highly conserved. Amino acid 191 was involved in the β-strand of the protein. We treated the patients with the lowest dose of allopurinol and children's conventional dose of potassium sodium bicitrate granules, and low purine diet. After 3 months of treatment, the serum uric acid was decreased, and the urinary calculi did not increase significantly.Conclusions:Combining with the clinical manifestations of children, HPRT1 gene might be the cause of pediatric disease and the two siblings could be diagnosed as Lesch-Nyhan syndrome. For such patients, the lowest dose of allopurinol and children's conventional dose of potassium sodium hydrogen citrate granule combined with diet could be more effective.

Objective To study the application of walking combined with Buerger exercise in the treatment of grade 0 diabetic foot.Methods Eighty patients with grade 0 diabetic foot were randomly divided into observation group and control group.The control group was trained by walking exercise .The observation group was trained by walking combined with Buerger exercise through 12 months of training.The changes of self-sensory symptoms,ABI and DAWV were observed.Results The self-sensory symptoms of the two groups were significantly decreased (observation group: markedly effective 15 cases,effective 19 cases;control group: markedly effective 5 cases,effective 23 cases).The effective rate of the observation group was higher than that of the control group (85% vs.70%,χ2 =7.831,P <0.05).The ABI ratio of the two groups were higher than those before treatment ,and the ABI ratio of the observation group was higher than that of the control group [(0.889 ±0.113) vs.(0.842 ±0.124),t =1.772 P <0.05].The ratio of DAWV in the observation group was higher than that in the control group [(6.772 ±0.435)cm/s vs.(6.543 ±0.552)cm/s,t =2.061,P <0.05].Conclusion Walking combined with Buerger exercise can improve the blood flow velocity and blood flow of the collateral circulation of the lower limbs of patients with grade 0 diabetic foot,and improve the self-sensory symptoms of peripheral neuropathy .

Objective To investigate the application of resistive exercise combined with Buerger exercise in lower extremity vascular disease of type 2 diabetes mellitus .Methods According to the order of admission ,120 type 2 diabetes mellitus patients with lower extremity vascular disease were randomly divided into resistance exercise group ,Buerger exercise group and combined exercise group ,with 40 cases in each group .The resistance exercise group was given resistance exercise ,the Buerger exercise group was given Buerger exercise ,and the combined exercise group was given resistance exercise combined with Buerger movement .The changes of self -inductance ,ABI and DAWV of the three groups were observed .Results The clinical symptoms of the three groups were significantly reduced ( the resistance exercise group:markedly effective in 10 cases,effective in 14 cases;the Burger exercise group:markedly effective in 15 cases,effective in 17 cases;the combined exercise group: markedly effective in 22 cases,effective in 13 cases),the effective rate of the combined exercise group was higher than that of the resistance exercise group and Buerger exercise group ( the resistance exercise group:60.0％;the Burger exercise group:80.0％;the combined exercise group:87.5％,χ2 =11.333,P <0.05).The ABI of the three groups were higher than those before treatment,and the ABI ratio of the combined exercise group [(0.933 ±0.113)]was higher than that of the resistance exercise group[(0.866 ±0.112)] and the Buerger exercise group[(0.888 ±0.111)](t=1.796,2.663,all P<0.05 ) .The DAWV of the three groups increased compared with those before treatment , and the DAWV of the combined exercise group[(7.023 ±0.535)cm/s]was higher than that of the resistance exercise group [(6.633 ± 0.552)cm/s] and the Buerger exercise group [(6.772 ±0.435) cm/s] (t =2.302,3.209,all P <0.05). Conclusion Resistant exercise combined with Buerger exercise is helpful to improve the blood flow velocity and blood flow in the lower extremity vessel of patients with diabetic lower limb vascular disease , and can improve the self-sensitization symptoms of peripheral neuropathy in patients .