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The combination of chemotherapy and immunotherapy motivates a potent immune system by triggering immunogenic cell death (ICD), showing great potential in inhibiting tumor growth and improving the immunosuppressive tumor microenvironment (ITM). However, the therapeutic effectiveness has been restricted by inferior drug bioavailability. Herein, we reported a universal bioresponsive doxorubicin (DOX)-based nanogel to achieve tumor-specific co-delivery of drugs. DOX-based mannose nanogels (DM NGs) was designed and choosed as an example to elucidate the mechanism of combined chemo-immunotherapy. As expected, the DM NGs exhibited prominent micellar stability, selective drug release and prolonged survival time, benefited from the enhanced tumor permeability and prolonged blood circulation. We discovered that the DOX delivered by DM NGs could induce powerful anti-tumor immune response facilitated by promoting ICD. Meanwhile, the released mannose from DM NGs was proved as a powerful and synergetic treatment for breast cancer in vitro and in vivo, via damaging the glucose metabolism in glycolysis and the tricarboxylic acid cycle. Overall, the regulation of tumor microenvironment with DOX-based nanogel is expected to be an effectual candidate strategy to overcome the current limitations of ICD-based immunotherapy, offering a paradigm for the exploitation of immunomodulatory nanomedicines.
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Aberrant activation of oncogenic signaling pathways in tumors can promote resistance to the antitumor immune response. However, single blockade of these pathways is usually ineffective because of the complex crosstalk and feedback among oncogenic signaling pathways. The enhanced toxicity of free small molecule inhibitor combinations is considered an insurmountable barrier to their clinical applications. To circumvent this issue, we rationally designed an effective tumor microenvironment-activatable prodrug nanomicelle (PNM) for cancer therapy. PNM was engineered by integrating the PI3K/mTOR inhibitor PF-04691502 (PF) and the broad spectrum CDK inhibitor flavopiridol (Flav) into a single nanoplatform, which showed tumor-specific accumulation, activation and deep penetration in response to the high glutathione (GSH) tumoral microenvironment. The codelivery of PF and Flav could trigger gasdermin E (GSDME)-based immunogenic pyroptosis of tumor cells to elicit a robust antitumor immune response. Furthermore, the combination of PNM-induced immunogenic pyroptosis with anti-programmed cell death-1 (αPD-1) immunotherapy further boosted the antitumor effect and prolonged the survival time of mice. Collectively, these results indicated that the pyroptosis-induced nanoplatform codelivery of PI3K/mTOR and CDK inhibitors can reprogram the immunosuppressive tumor microenvironment and efficiently improve checkpoint blockade cancer immunotherapy.
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Objective To provide a method to modify accurately the Reverdin osteotomy template for hallux valgus using 3D reconstruction and printing.Methods From June 2015 to June 2016,11 patients (16 feet) with hallux valgus at our departments underwent weight-bearing X-ray examination and continuous spiral CT scanning of the feet.The outer turning angle of hallux averaged 33.50° ± 6.80°,the first intermetatarsal angle 12.20°± 2.90° and the distal metatarsal articular angle 15.20°± 2.60°.Their imaging Dicom data were imported into Materialise Mimics Innovation Suite v16.0 software for generation of 3D models of the pelvis which were then stored in stereolithography format and imported into Imageware 12 software.After optimal templates were reversely rebuilt to have the best angles and range for Reverdin osteotomy in the 3D models,they were manufactured by a rapid prototyping machine.The osteotomy templates were used in surgery to guide the osteotomy of hallux valgus.Correction of hallux valgus,bone union at the osteotomy sites and weight-bearing walk were observed postoperatively.Results Accurate angles of osteotomy were confirmed by postoperative radiography in all the 16 feet.Follow-ups for 6 to 12 months showed in the 16 feet a mean outer turning angle of hallux of 7.31 °±0.33° (from 5° to 11 °) and a mean correction of 21.92°± 4.8° (from 13° to 24°).Bone union was fine at the osteotomy sites and no pain was reported during weight-bearing walk.Conclusion 3D reconstruction and printing can produce a patient-specific template for accurate Reverdin osteotomy for hallux valgus,leading to increased contact area and fine union of the osteotomy ends.
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Objective To analyze and determine the optimal osseous pathway for anterograde screwing in the acetabulum posterior column.Methods Recruited for this study were 40 healthy adult volunteers,20 nales and 20 females,aged from 18 to 56 years (average,34.6 years).Firstly,their abdomen CT scanning images were transformed into Materialise Mimics Innovation Suite 16.0 software to obtain the 3D reconstruction images of the pelvis (.stl file).The Imageware 12.0 software (EDS,USA) was used to produce the optimal osseous pathway for anterograde screwing in the acetabulum posterior column.The diameter and length of the pathway were measured and statistically analyzed.Secondly,after 10 adult fresh pelvic specimens were scanned,the optimal osseous pathway for anterograde screwing in the acetabulum posterior column was determined in the same way as the above.A navigation template for anterograde screwing in the acetabular posterior column was manufactured.The screwing in the posterior column of the acetabulum was conducted using Kirschner wire with the aid of the navigation template.Imaging evaluation was performed after fixation.Results The projection of the safe zone in the acetabular posterior column was irregularly triangle;there were no significant differences regarding the projection size between different ages (P ＞ 0.05).The maximum diameter and the maximum length of the left optimal pathway in males were respectively 22.37 ± 1.42 mm and 131.27 ± 3.63 mm,and those of the right optimal pathway in males respectively 23.16 ± 1.39 mm and 129.23 ± 3.27 mm.The maximum diameter and the maximum length of the left optimal pathway in females were respectively 17.58 ± 1.83 mm and 112.56 ±2.77 mm,and those of the right optimal pathway in females respectively 16.92 ± 1.66 mm and 114.41 ± 2.98 mm.There were no significant differences between the left and right sides for the same item in the same gender (P ＞ 0.05).There were significant differences between males and females for the same item in the same side (P ＜ 0.05).No penetration into the cortex or the hip joint happened.Conclusion The optimal osseous pathway for anterograde screwing in the acetabulum posterior column can be determined by digital techniques,leading to a simple and safe procedure for the treatment of fractures of the acetabular posterior column.
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Objective To study the surgery effect on early application of toe flap to repair thumb severe electric bum.Methods From July 2007 to October 2017,a total of 25 cases of thumb severe electric burn were repaired by thumb toe flap grafting.The function of the finger after operation was evaluated comprehensively,and the effect of 72 hours before and after the injury was compared.Results All the flaps survived and the finger function was excellent.The excellent and good rate of 25 cases was 72％.The excellent and good rate of 72 hours before and after injury were 85.7％ and 54.5％ respectively.5 cases had bad wound complications after operation.1 cases were operated within 72 hours after injury,and 4 cases were operated after 72 hours.Conclusions The early application of toe flap to repair severe electric bum thumb can maximize the recovery of function of the thumb.The earlier the operation,the fewer complications,the better the repair effect.
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Objective To explore the method of pre expanded deltopectoral flap for repairing post burn faciocervical scars.Methods Anterior axillary incisions were made and appropriate expanders were implanted above anterior chest wall at the first stage.After a 4 6 months' expanding,the flaps based on perforating branches of the internal mammary artery,branches from the thoracoacromi al area,or perforating branches from deltoid muscle,were designed and raised according to scars and dominant vessels.The donor sites were closed at same time without skin graft.Results 43 patients with 51 flaps were operated for reconstruction of post burn faciocervical scars.All flaps and donor sites survived well.Conclusions Pre expanded deltopectoral flap is an ideal donor site for repairing post-burn faciocervical scars.
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A reversed phase high performance liquid chromatographic ( RP-HPLC ) method was proposed by using C18 column tandem crown ether chiral column for simultaneous separation of three kinds of aromatic amino acid enantiomers. The chromatographic conditions, including mobile phase proportion, pH, column temperature and flow rate, were optimized. The experimental results showed that the three aromatic amino acid enantiomers could be successfully separated under the optimal conditions such as perchloric acid solution-acetonitrile ( 86:14, V/V, pH = 2 ) as mobile phase, column temperature of 20℃ and flow rate of 0. 4 mL/min. The separation under four HPLC column connection modes was further investigated. The results revealed that different kinds of amino acids could be separated on C18 column, but not for amino acid enantiomers; amino acid enantiomers could be separated on crown ether chiral column, but the chromatographic peaks of each amino acid enantiomers overlapped seriously; baseline separation of three amino acid enantiomers could be obtained under the connection of two columns, but the separation under different column connection sequence almost had no difference except the peak shape.
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Background The situation of zonule is very important for determining the cataract surgery.Ultrasound biomicroscopy (UBM) is an important method to observe the situation of zonule before cataract surgery.Objective This study was to evaluate the accuracy and clinical significance of observing the zonule of cataract patients by UBM.Methods A series cases-observational study was performed.One hundred and thirty eyes of 130 cataract patients who were to receive extracapsular cataract enucleation were enrolled in Tianjin Eye Hospital from January to June 2015,including 59 eyes with cataract associated with primary angle-closure glaucoma (PACG) and 71 eyes with traumatic cataract.UBM examination was carried out before surgery,and the abnormalities of zonule were recorded and compared between UBM and surgery findings.This study was approved by the Ethic Committee of Tianjin Eye Hospital and informed consent was obtained from all subjects.Results A large space between lens and cilliary was exhibited and the echo of zonule was clear on the UBM image in the eyes with traumatic cataract.The typical anatomic findings of the anterior eye segment were displayed,and lens equator came into contact with cilliary on the UBM image,and the echo of zonule was blurry in the eyes with cataract associated with PACG.The eye number of abnormal zonule was consistent between UBM and surgery findings (Kappa=O.952),and no significant difference in the eye number of abnormal zonule between UBM and surgery findings (P =0.250).In 75 zonule abnormal eyes diagnosed by both UBM and surgery findings,zonule abnormal range could not be compared in 1 eye (1/130,0.77％),and exactly consistent in 8 eyes (8/130,6.15％) between the two methods.The difference of zonule abnormal range between the two methods was 1 clock in 35 eyes (35/130,26.92％),and 2 clock in 27 eyes (27/130,20.77％),3 clock in 4 eyes (4/130,3.08％).In 74 zonule abnormal eyes,the mean difference of zonule abnormal meridian between the two methods was (1.36 ± 1.29) clock,an those in 28 traumatic cataract eyes and 36 cataract with PACG eyes were (1.14±1.10) clock and (1.64-± 1.48) clock,respectively.Conclusions UBM is able to observe zonule accurately,the observation effectiveness of UBM for traumatic cataract is better than that of cataract combined with PACG.These results are of clinical valueable for surgical strategy of cataract and prediction of surgical complications.
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Objective To analyze the clinical efficacy of physical vibration lithecbole in treatment of urinary calculi. Methods Ana-lysed the efficacy of 80 patients who underwent physical vibration lithecbole only or combination therapy with surgery in urinary calculi in our hospital from February 2014 to July 2014. Result There were 1 to 4 times calculi discharge among the 80 patients. One month after the sur-gery, the calculi discharge rate was 33. 3% and the calculi clean rate was 22. 2% in the upper ureteral; the calculi discharge rate was 16. 7%and the calculi clean rate was 50. 0% in the distal ureteral; the calculi discharge rate was 40. 0% and the calculi clean rate was 23. 3% in the upper renal calyx;the calculi discharge rate was 27. 7% and the calculi clean rate was 38. 8% in the middle renal calyx;the calculi discharge rate was 60. 0% and the calculi clean rate was 20. 0% in the lower renal calyx. One month after the surgery of physical vi-bration lithecbole combined with Holium laser lithotripsy, the calculi discharge rate was 52. 1% and the calculi clean rate was 39. 1%. Con-clusion Physical vibration lithecbole is a noninvasive treatment for urinary calculi. It has good efficacy in calculi discharge and it can relieve the pain caused by calculi.
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Trimethoprim molecularly imprinted polymer (MIP) was prepared as the coating of stir bar sorptive extraction (SBSE) and applied to the trace analysis of trimethoprim and three sulfonamides in complex samples.The MIP-coating was about 21.5 μm thickness with the relative standard deviations (RSD) of 5.9％ (n=10).It was homogeneous and dense with good thermal and chemical stability.The extraction capability of the MIP-coating was 1.7 times over that of the non imprinted polymer (NIP) coating.The MIP coating exhibited selective adsorption ability to sulfonamides,triazines and methotrexate besides antibacterial synergists.The methods for the determination of trimethoprim and three sulfonamides by MIP-coated stir bar sorptive extraction coupled with HPLC were developed.It was successfully applied to the trace trimethoprim analysis in spiked urine and plasma samples.The linear range was 5 to 200 μg/L and the detection limit was 1.6 μg/L.The recoveries in urine and plasma samples were 84.5％ to 91.7％ with RSDs of 2.9％ -4.4％,71.9％ to 85.1％ with RSDs of 3.0％ -7.3％,respectively.The trimethoprim MIP-coated stir bar was also applied to the trace sulfonamides analysis in spiked milk sample.The linear range was 10-200 μg/L,the detection limit was within the range of 4.5-6.1 μg/L,and the recovery was 83.2％ - 110.2％ with RSDs of 4.1％ -8.0％.
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Objective To explore the effect of TNF-α in intracellular Ca~(2+)-overload associated myocardial injury. Methods Thirty Wistar rats were randomly divided into three groups:control group,Ca~(2+)+-paradox group,and pentoxifylline treatment group. The intracellular Ca~(2+)-overload rat model was established by pre-filling the rats with Langendorff for 20 minutes,isolated rat hearts subjected to Ca~(2+)-depletion for 5 minutes and Ca~(2+)-repletion for 30 minites(Ca~(2+)-paradox). Changes in hemodynamics indexes were monitored continuously. TNF-α in cardiac tissues was tested by ELISA method,and nuclear factor-κB(NF-κB)in cardiac tissues was detected with Western blot. Results Dramatic depression in left ventricle contraction function was found in the Ca~(2+)-paradox hearts:significant decrease in left ventricular diastolic pressure(LVDP),markedly elevated left ventricular end diastolic pressure(LVEDP),decreased dP/dt ratio,increased TNF-α content,decreased cytosolic/homogenate NF-κB ratio. All these changes in Ca~(2+)-paradox group were significantly attenuated upon the treatment with 100 μmol/L pentoxifylline. Conclusions Activation of NF-κB and increased production of TNF-α may play important roles in cardiac injury associated with intracellular Ca~(2+)-overload.
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Objective To explore the effect of melatonin on mitochondria in streptozotocin (STZ)-induced diabetic rats and its potential mechanism. Methods The diabetic rat models were induced by intraperitoneal injection of STZ, and the diabetic rats were randomly divided into two groups: diabetes mellitus group (DM group) and melatonin-treated group (DM± MT group). The normal non-diabetic rats were served as control group. Mitochondrial membrane potential and mitochondrial swelling were measured, the expression of voltage-dependent anion channel (VDAC)was assayed by immunohistochemistry in the heart, liver and kidney among the different groups after 8 weeks. Results (1)Compared with DM group, mitochondrial membrane potential in the heart,liver and kidney were significantly elevated in DM± MT group (553.6± 193.5 vs. 311.4 ± 133.7;745.7±115.8 vs. 358.9±158.7; 951.6±246.1 vs. 425.8±177.9, all P＜0.05). (2)Compared with DM group, mitochondrial swelling in the heart, liver and kidney was reinforced in DM ± MT group. (3)Compared with DM group, the expressions of VDAC in the heart, liver and kidney were significantly up-regulated in DM± MT group (76.93 ± 8.263 vs. 58.59 ± 7.62, 50.69 ± 6.33 vs.40.11±6.30, 77.86±8.59 vs. 61.44± 12.86, all P＜0.05). Conclusions Melatonin has protective effect on the activity of mitochondria in the heart, liver and kidney in diabetic rats possibly by up-regulating the expression of VDAC.
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Gene disruption by homologous recombination is a powerfu l tool for investigating gene function in yeast. Since 1980’s, it has been deve loped a lot. PCR-mediated gene disruption technique makes the manipulation easi er and it can be used to precisely delete genes in yeast. Multi-gene disruption technique can delete several genes successively in the same yeast strain. After the completion of the yeast Saccharomyces cerevisiae genome sequencing, the gene disruption technique for systematic analysis meets the need of the functio nal genomics in yeast. It also enlighten the study on human functional genomics.