Abstract Background Tumor-infiltrating lymphocyte (TIL) therapy has been restricted by intensive lymphodepletion and high-dose intravenous interleukin-2 (IL-2) administration. To address these limitations, we conducted preclinical and clinical studies to evaluate the safety, antitumor activity, and pharmacokinetics of an innovative modified regimen in patients with advanced gynecologic cancer. Methods Patient-derived xenografts (PDX) were established from a local recurrent cervical cancer patient. TILs were expanded ex vivo from minced tumors without feeder cells in the modified TIL therapy regimen. Patients underwent low-dose cyclophosphamide lymphodepletion followed by TIL infusion without intravenous IL-2. The primary endpoint was safety; the secondary endpoints included objective response rate, duration of response, and T cell persistence. Results In matched patient-derived xenografts (PDX) models, homologous TILs efficiently reduced tumor size ( p < 0.0001) and underwent IL-2 absence in vivo. In the clinical section, all enrolled patients received TIL infusion using a modified TIL therapy regimen successfully with a manageable safety profile. Five (36%, 95% CI 16.3–61.2) out of 14 evaluable patients experienced objective responses, and three complete responses were ongoing at 19.5, 15.4, and 5.2 months, respectively. Responders had longer overall survival (OS) than non-responders ( p = 0.036). Infused TILs showed continuous proliferation and long-term persistence in all patients and showed greater proliferation in responders which was indicated by the Morisita overlap index (MOI) of TCR clonotypes between infused TILs and peripheral T cells on day 14 ( p = 0.004) and day 30 ( p = 0.004). Higher alteration of the CD8 + /CD4 + ratio on day 14 indicated a longer OS ( p = 0.010). Conclusions Our modified TIL therapy regimen demonstrated manageable safety, and TILs could survive and proliferate without IL-2 intravenous administration, showing potent efficacy in patients with advanced gynecologic cancer. Trial registration NCT04766320, Jan 04, 2021.
Many advanced cancers are characterized by metabolic disorders. A dietary therapeutic strategy was proposed to inhibit tumor growth through administration of low-carbohydrate, average-protein, and high-fat diet, which is also known as ketogenic diet (KD). In vivo antitumor efficacy of KD on transplanted CT26+ tumor cells in BALB/c mice was investigated. The results showed that the KD group had significantly higher blood β-hydroxybutyrate and lower blood glucose levels when compared with the normal diet group. Meanwhile, KD increased intratumor oxidative stress, and TUNEL staining showed KD-induced apoptosis against tumor cells. Interestingly, the distribution of CD16/32+ and iNOS+ M1 tumor-associated macrophages (TAMs) increased in the KD-treated group, with concomitantly less arginase-1+ M2 TAMs. Moreover, KD treatment downregulated the protein expression of matrix metalloproteinase-9 in CT26+ tumor-bearing mice. Western blot analysis demonstrated that the expression levels of HDAC3/PKM2/NF-κB 65/p-Stat3 proteins were reduced in the KD-treated group. Taken together, our results indicated that KD can prevent the progression of colon tumor via inducing intratumor oxidative stress, inhibiting the expression of the MMP-9, and enhancing M2 to M1 TAM polarization. A novel potential mechanism was identified that KD can prevent the progression of colon cancer by regulating the expression of HDAC3/PKM2/NF-κB65/p-Stat3 axis.
Abstract Background Propofol-based sedations are widely used in elderly patients for endoscopic retrograde cholangiopancreatography (ERCP) procedure, but respiratory depression and cardiovascular adverse events commonly occur. Magnesium administered intravenously can alleviate pain and decrease propofol requirements during surgery. We hypothesized that intravenous magnesium was used as adjuvant to propofol might be beneficial in elderly patients undergoing ERCP procedures. Methods Eighty patients aged from 65 to 79 years who were scheduled for ERCP were enrolled. All patients were intravenously administered 0.1 µg/kg sufentanil as premedication. The patients were randomized to receive either intravenous magnesium sulfate 40 mg/kg (group M, n = 40) or the same volume of normal saline (group N, n = 40) over 15 min before the start of sedation. Intraoperative sedation was provided by propofol. Total propofol requirement during ERCP was the primary outcome. Results The total propofol consumption were reduced by 21.4% in the group M compared with the group N (151.2 ± 53.3 mg vs. 192.3 ± 72.1 mg, P = 0.001). The incidences of respiratory depression episodes and involuntary movement were less in the group M than those in the group N (0/40 vs. 6/40, P = 0.011; 4/40 vs. 11/40, P = 0.045; respectively). In the group M, the patients experienced less pain than those in the group N at 30 min after the procedure (1 [0–1] vs. 2 [1–2], P < 0.001). Correspondingly, the patients’ satisfaction was clearly higher in the group M ( P = 0.005). There was a tendency towards lower intraoperative heart rate and mean arterial pressure in group M. Conclusions A single bolus of 40 mg/kg of intravenous magnesium can significantly reduce propofol consumption during ERCP, with higher sedation success and lower adverse events. Trial Registration ID UMIN000044737. Registered 02/07/2021.
Objective:To discuss the application value about the complete care in the knee osteoarthritis nursing in the elder.Methods:40 cases elder patients were randomly divided into observation group and control group,every group for 20 cases,the patients in the observation group were accepted the complete care(included mental regulation,manipulation nursing,physic therapeutics nursing,taking the traditional Chinese medicine nursing,washing with the traditional Chinese medicine,exercise functional and health education),the control group was used the routine nursing.Nursing before and after,two groups were accepted the evaluating of the medical outcomes study.Results:In the end of the nursing,the index PF,RE,SF,MH,RP,VT,BP,GH in the observation group's grade was higher than the control group(P0.05).Conclusion:The complete care can improve the knee osteoarthritis patient's treatment effect.
Purpose: To review the microbiological spectrum and antibiotic sensitivities of the pathogens that cause culture-proven endophthalmitis and to understand the status and trends of antibiotic susceptibility at a public hospital over a 10-year period.Methods: The data of 577 culture-proven endophthalmitis isolates collected between April 2004 and April 2014 were reviewed retrospectively. The antibiotic sensitivities were determined according to the criteria of the Clinical and Laboratory Standards Institute. The changes in antibiotic susceptibility over the 10 years were subjected to χ2 tests for trends.Results: Among these isolates, 65% were gram-positive organisms (375), 16.6% were gram-negative organisms (96), and 18.4% were fungi (106).The predominant pathogens were Staphylococcal species (Staphylococcus epidermidis in 175, other coagulase-negative Staphylococci in 41, and Staphylococcus aureus in 54 cases), followed by Bacillus cereus isolates. The Aspergillus species was the most frequently isolated fungus, and Pseudomonas aeruginosa was the most frequently isolated gram-negative bacteria. The antibiotic susceptibilities of gram-positive bacteria were as follows: vancomycin, 97.6%; levofloxacin, 85.1%; gentamicin, 78.7%; rifampin, 77.2%; ofloxacin, 77.2%; chloramphenicol, 76.4%; and ciprofloxacin, 73.7%. The antibiotic susceptibilities of gram-negative isolates were as follows: ceftazidime, 50.5%; ciprofloxacin, 82.2%; amikacin, 81.3%; tobramycin, 80.2%; imipenem, 79.7%; and gentamicin, 78%. Over the 10-year study, there were significant changes in the antibiotic susceptibilities to the following five antibiotics: vancomycin, imipenem, penicillin G, amikacin, and trimethoprim-sulfamethoxazole (TMP-SMX).Conclusions: Vancomycin remains the most appropriate empirical antibiotic for gram-positive bacteria. The susceptibilities of the gram-negative organisms to ciprofloxacin and amikacin were greater than that to ceftazidime. Trends toward increases in the susceptibilities to the following five antibiotics were observed: vancomycin, imipenem, penicillin G, amikacin, and TMP-SMX.
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