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The immunosuppressive characteristics and acquired immune resistance can restrain the therapy-initiated anti-tumor immunity. In this work, an antibody free programmed death receptor ligand 1 (PD-L1) downregulator (designated as CeSe) is fabricated to boost photodynamic activated immunotherapy through cyclin-dependent kinase 5 (CDK5) inhibition. Among which, FDA approved photosensitizer of chlorin e6 (Ce6) and preclinical available CDK5 inhibitor of seliciclib (Se) are utilized to prepare the nanomedicine of CeSe through self-assembly technique without drug excipient. Nanoscale CeSe exhibits an increased stability and drug delivery efficiency, contributing to intracellular production of reactive oxygen species (ROS) for robust photodynamic therapy (PDT). The PDT of CeSe can not only suppress the primary tumor growth, but also induce the immunogenic cell death (ICD) to release tumor associated antigens. More importantly, the CDK5 inhibition by CeSe can downregulate PD-L1 to re-activate the systemic anti-tumor immunity by decreasing the tumor immune escape and therapy-induced acquired immune resistance. This work provides an antibody free strategy to activate systemic immune response for metastatic tumor treatment, which may accelerate the development of translational nanomedicine with sophisticated mechanism.
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Antígeno B7-H1 , Quinase 5 Dependente de Ciclina , Imunoterapia , Fotoquimioterapia , Fotoquimioterapia/métodos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Imunoterapia/métodos , Animais , Quinase 5 Dependente de Ciclina/metabolismo , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Humanos , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Camundongos , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Porfirinas/química , Porfirinas/farmacologia , Porfirinas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , ClorofilídeosRESUMO
Negative therapeutic feedback of inflammation would extensively attenuate the antitumor effect of photodynamic therapy (PDT). In this work, tumor homing chimeric peptide rhomboids (designated as NP-Mel) are fabricated to improve photodynamic performance by inhibiting PDT-upregulated cyclooxygenase-2 (COX-2). The hydrophobic photosensitizer of protoporphyrin IX (PpIX) and palmitic acid are conjugated onto the neuropilin receptors (NRPs) targeting peptide motif (CGNKRTR) to obtain tumor homing chimeric peptide (Palmitic-K(PpIX)CGNKRTR), which can encapsulate the COX-2 inhibitor of meloxicam. The well dispersed NP-Mel not only improves the drug stability and reactive oxygen species (ROS) production ability, but also increase the breast cancer targeted drug delivery to intensify the PDT effect. In vitro and in vivo studies verify that NP-Mel will decrease the secretion of prostaglandin E2 (PGE2) after PDT treatment, inducing the downregulation of IL-6 and TNF-α expressions to suppress PDT induced inflammation. Ultimately, an improved PDT performance of NP-Mel is achieved without inducing obvious systemic toxicity, which might inspire the development of sophisticated nanomedicine in consideration of the feedback induced therapeutic resistance.
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Ciclo-Oxigenase 2 , Peptídeos , Fotoquimioterapia , Fotoquimioterapia/métodos , Ciclo-Oxigenase 2/metabolismo , Peptídeos/química , Peptídeos/farmacologia , Animais , Humanos , Linhagem Celular Tumoral , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio/metabolismo , Feminino , Meloxicam/farmacologia , Meloxicam/uso terapêutico , Camundongos , Protoporfirinas/química , Protoporfirinas/farmacologia , Dinoprostona/metabolismoRESUMO
A systemic treatment strategy is urgently demanded to suppress the rapid growth and easy metastasis characteristics of breast cancer. In this work, a chimeric peptide-engineered self-delivery nanomedicine (designated as ChiP-CeR) for photodynamic-triggered breast cancer immunotherapy by macrophage polarization. Among these, ChiP-CeR is composed of the photosensitizer of chlorine e6 (Ce6) and the TLR7/8 agonist of lmiquimod (R837), which is further modified with tumor matrix targeting peptide (Fmoc-K(Fmoc)-PEG8 -CREKA. ChiP-CeR is preferred to actively accumulate at the tumor site via specific recognition of fibronectin, which can eradicate primary tumor growth through photodynamic therapy (PDT). Meanwhile, the destruction of primary tumors would trigger immunogenic cell death (ICD) effects to release high-mobility group box-1(HMGB1) and expose calreticulin (CRT). Moreover, ChiP-CeR can also polarize M2-type tumor-associated macrophages (TAMs) into M1-type TAMs, which can activate T cell antitumor immunity in combination with ICD. Overall, ChiP-CeR possesses superior antitumor effects against primary and lung metastatic tumors, which provide an applicable nanomedicine and a feasible strategy for the systemic management of metastatic breast cancer.
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BACKGROUND: Limited literature has focused on the use of totally tubeless mini-percutaneous nephrolithotomy (PCNL) for the treatment of large renal stones. We present our findings of treating patients with large and/or complex renal stones using single renal access totally tubeless mini-PCNL. METHODS: From March 2018 to May 2021, 62 consecutive cases in which single tract totally tubeless mini-PCNL was used to treat complex renal stones were enrolled, all with calculi > 2 cm. All procedure of puncture and dilation were guided by fluoroscope. The complexity of stones was assessed according to the Guy's Scoring System (GSS). The surgical duration, length of hospital stay, analgesia requirement, stone-free rate, and perioperative morbidity were assessed. RESULTS: The mean preoperative stone burden was 36.69 ± 19.76 mm (above 2 cm in all cases), mean surgical duration was 61.93 ± 40.84 min (range 15-180 min), and mean hematocrit reduction was 4.67 ± 2.83%. Postoperative Nalbuphine was used in 6 patients. The mean length of stay was 2.46 ± 1.19 days (range 2-8 days), and the postoperative stone-free rate was 83.9% (52/62), and 87.1% (54/62) after auxiliary ESWL. The overall complication rate was 14.5%, the majority of complications being postoperative transient fever. CONCLUSION: For the treatment of large bursen > 2 cm and/or complex renal stones, totally tubeless single tract mini-PCNL ensures a feasible SFR, low morbidity and short hospital stay. According to the low complication rate in our study, the totally tubeless manner was not associated with an increased risk of postoperative morbidity, and patients benefited from decreased postoperative analgesics use.
Assuntos
Cálculos Renais , Litotripsia , Nefrostomia Percutânea , Feminino , Humanos , Cálculos Renais/cirurgia , Masculino , Nefrostomia Percutânea/métodos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: To assess the morbidities of tubeless percutaneous nephrolithotomy (PCNL) using supra-costal access and re-evaluate traditional concept of increased complications with supra-costal access. METHODS: From January 2010 to December 2014, a single surgeon performed 118 consecutive one-stage fluoroscopic guided PCNL's for complex renal and upper ureteral stone. Our definition for complex renal stone is defined as partial or complete staghorn stone, multiple renal stones in more than 2 calyxes, obstructive uretero-pelvic stone > 2 cm, and a renal stone in single functional kidney. Inclusion criteria include: staghorn stones, renal calculi > 2 cm in diameter, upper ureteral stone > 1.5 cm in diameter. Exclusion criteria for tubeless PCNL include: significant bleeding or perforation of the collecting system, large residue stone, multiple PCNL tract and obstructive renal anatomy. Morbidity, operation time, analgesia requirement, length of hospital stay, stone- free rate, were analyzed. RESULTS: Of the 118 consecutive PCNL, eighty-six patients underwent tubeless PCNL (56 supra-costal and 30 sub-costal) and included in our prospective follow-up period. The mean age, operation side, stone locations were similar. The male to female ratio is higher in supra-costal than sub-costal. Large renal stones and staghorn stones makes up for most patients (supra-costal: 75%, sub-costal: 80%). The stone-free rate of supra-costal group was 59% (33/56) and in sub-costal group was 50% (15/30). The operative times, length of stay, post-op analgesic use, hematocrit change was similar in both groups. The overall complication rate is 6% [supra-costal (1/56), sub-costal (4/30)] with the majority being infectious complications. CONCLUSIONS: Supra-costal access above 12th rib during tubeless PCNL is safe and effective procedure and is not associated with higher incidence of post-op complications in experience hands.
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Cálculos Renais/diagnóstico por imagem , Cálculos Renais/cirurgia , Nefrolitotomia Percutânea/métodos , Complicações Pós-Operatórias/diagnóstico por imagem , Costelas/diagnóstico por imagem , Costelas/cirurgia , Feminino , Humanos , Masculino , Nefrolitotomia Percutânea/efeitos adversos , Nefrolitotomia Percutânea/tendências , Duração da Cirurgia , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Resultado do TratamentoRESUMO
Tumor-associated macrophages (TAMs) are the most abundant immune cells in solid tumor tissues, which restrict antitumor immunity by releasing tumor-supporting cytokines and attenuating phagocytosis behaviors. In this work, a chimeric peptide engineered bioregulator (ChiP-RS) is constructed for tumor immunotherapy through macrophage polarization and phagocytosis restoration. ChiP-RS is fabricated by utilizing macrophage-targeting chimeric peptide (ChiP) to load Toll-like receptor agonists (R848) and Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP-2) inhibitor (SHP099). Among which, ChiP-RS prefers to be internalized by TAMs, repolarizing M2 macrophages into M1 macrophages to reverse the immunosuppressive microenvironment. In addition, SHP-2 can be downregulated to promote phagocytotic elimination behaviors of M1 macrophages, which will also activate T cell-based antitumor immunity for metastatic tumor therapy. In vitro and in vivo findings demonstrate a superior suppression effect of ChiP-RS against metastatic tumors without systemic side effects. Such a simple but effective nanoplatform provides sophisticated synergism for immunotherapy, which may facilitate the development of translational nanomedicine for metastatic tumor treatment.
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Neoplasias , Fagocitose , Humanos , Neoplasias/terapia , Macrófagos/metabolismo , Imunoterapia , Citocinas/metabolismo , Microambiente TumoralRESUMO
Although photodynamic therapy (PDT) is a promising antitumor strategy for tumor treatment, the short half-life and the limited diffusion distance of reactive oxygen species (ROS) greatly hamper its antitumor efficacy. Moreover, tumor cells develop antioxidative microenvironments to weaken the oxidative damage caused by PDT. Herein, a plasma membrane-targeted photooxidant (designated as SCPP) is prepared by the self-assembly of a chimeric peptide (Pal-K(PpIX)-R4) and sorafenib. Plasma membrane-targeted SCPP could enhance lipid peroxidation (LPO) through in situ PDT upon light irradiation. Moreover, sorafenib-mediated chemotherapy could block cystine/glutamate antiporter xCT (SLC7A11) to inhibit the syntheses of intracellular GSH and glutathione peroxidase 4 (GPX4), which would destroy the antioxidant defense system of tumors. As a consequence, SCPP achieves a highly efficient tumor inhibition through enhanced PDT and ferroptosis therapy. This study might provide guidance for multisynergistic tumor therapy with a sophisticated mechanism under unfavorable conditions.
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PURPOSE: To compare immediate percutaneous drainage of renal abscess via ultrasonographic guidance to surgical drainage. PROCEDURES: This was a retrospective cross-sectional study of 27 patients (mean age of 59.37 +/- 12.25 years) with renal abscesses. Immediate percutaneous catheter drainage was performed in patients with pus-containing cavities greater than 3 cm who consented in the emergency section (n = 12). Other patients underwent surgical drainage (n = 11). Both groups were also treated with empirical antibiotic therapy. Four patients were treated exclusively with antibiotics and were excluded from the analysis. FINDINGS: Abscess size on computer tomography (CT) was similar between the percutaneous catheter drainage (PCD) patients and open surgical drainage patients (7.47 +/- 1.75 cm vs. 8.67 +/- 1.87 cm; P = 0.13). There was no significant difference in mean duration of hospitalization (PCD, 19.5 +/- 10.5 days; surgical drainage, 14.55 +/- 4.52 days. P = 0.15). Larger abscess size and higher C-reactive protein levels were important prognostic factors in both groups. Microbiological analysis revealed Escherichia coli and Klebsiella pneumoniae in most abscesses. CONCLUSIONS: Patients treated with percutaneous drainage for renal abscess had outcomes comparable to those treated with surgical drainage.
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Abscesso/terapia , Drenagem/métodos , Nefropatias/terapia , Pele/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cateterismo , Estudos Transversais , Infecções por Escherichia coli , Feminino , Hospitalização , Humanos , Nefropatias/microbiologia , Infecções por Klebsiella , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: This is an initial review of the safety and efficacy of anterior preperitoneal modified Kugel (MK) mesh herniorrhaphy application without using optional onlay mesh. METHODS: We retrospectively reviewed patients who underwent herniorrhaphy by a single surgeon from July 1st, 2009 to December 31st, 2010. During these 18 months, a total of 72 patients underwent single-layer MK mesh herniorrhaphy. Anterior preperitoneal approach was used to place the mesh. If the patient's inguinal hernia defect did not exceed the memory ring of MK mesh, the onlay mesh was omitted. Postoperative results (wound infection, recurrence, and chronic pain/discomfort) were recorded and analyzed. RESULTS: A total of 72 patients underwent anterior preperitoneal single layer MK mesh herniorrhaphy. One patient had recurrent hernia after 1 year and was treated with a laparoscopic transabdominal preperitoneal operation. The most common postoperative complaint was mild soreness which was self-resolving after 1 month. Mean total operative time (skin to skin) was 73 minutes. The average hospital stay was 2 days. Most of the postoperative complications including soreness (14%), pain for > 3 months (1.4%), and scrotal hematoma (1.4%) were self-resolving. One patient experienced wound infection, which was treated with oral antibiotics. One patient had recurrence 1 year after the operation. CONCLUSION: The postoperative complication and recurrence rates of single-layer MK mesh herniorrhaphy was comparable with previously reported tension-free repair. Single-layer application is safe and feasible. A longer follow-up period and larger study group with a control group are needed to verify our method.
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Hérnia Inguinal/cirurgia , Herniorrafia/instrumentação , Herniorrafia/métodos , Telas Cirúrgicas , Resistência à Tração , Adulto , Idoso , Estudos de Coortes , Feminino , Seguimentos , Hérnia Inguinal/diagnóstico , Herniorrafia/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Segurança do Paciente , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/fisiopatologia , Recidiva , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Taiwan , Resultado do Tratamento , Cicatrização/fisiologiaRESUMO
Hepatic cancer remains a challenging disease and there is a need to identify new treatments. Sann-Joong-Kuey-Jian-Tang (SJKJT), a traditional medicinal prescription, has been used to treat lymphadenopathy and exhibits cytotoxic activity in many types of human cancer cells. Our previous studies revealed that SJKJT is capable of inhibiting colon cancer colo 205 cells by inducing autophagy and apoptosis. However, the effects and molecular mechanisms of SJKJT in human hepatocellular carcinoma have not been clearly elucidated. In the present study we evaluated the effects of SJKJT in human hepatic cellular carcinoma Hep-G2 cells. The cytotoxicity of SJKJT in Hep-G2 cells was measured by MTT assay. The cell cycles were analyzed by fluorescenceactivated cell sorting (FACS). The protein expression of translationally controlled tumor protein (TCTP), Mcl-1, Fas, TNF-α, Caspase-8, Caspase-3 and Bax in Hep-G2 cells treated with SJKJT was evaluated by western blotting. The protein expression of Caspase-3 was also detected by immunofluorescence staining. The results showed that SJKJT inhibits Hep-G2 cells in a time- and dosedependent manner. During SJKJT treatment for 48 and 72 h, the half-maximum inhibitory concentration (IC50) was 1.48 and 0.94 mg/ml, respectively. The FACS results revealed that increased doses of SJKJT were capable of increasing the percentage of cells in the sub-G1 phase. Immunofluorescence staining showed that Hep-G2 treated with SJKJT had increased expression of Caspase-3. The western blot results showed that the protein expression of Fas, TNF-α, Caspase-8, Caspase- 3 and Bax was upregulated, but that of TCTP and Mcl-1 was downregulated in Hep-G2 cells treated with SJKJT. In conclusion, these findings indicated that SJKJT inhibits Hep-G2 cells. One of the molecular mechanisms responsible for this may be the increased Fas, TNF-α, Caspase-8, Caspase- 3 and Bax expression; another mechanism may be via decreasing TCTP and Mcl-1 expression in order to induce apoptosis.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Caspases/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/enzimologia , Caspase 3/metabolismo , Caspase 8/metabolismo , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas/farmacologia , Proteína de Domínio de Morte Associada a Fas/metabolismo , Células Hep G2 , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides , Proteína Tumoral 1 Controlada por Tradução , Receptor fas/metabolismoRESUMO
Breast cancer is the leading cause of cancer-related deaths in women worldwide. Tanshinone IIA (Tan-IIA) is one of the pure compounds from Salviae miltiorrhizae radix (Danshen). Tan-IIA can inhibit human breast cancer cells but the molecular mechanisms are not well understood. Our previous study showed that Tan-IIA can inhibit hep-J5 human hepatocellular carcinoma cells through the endoplasmic reticulum (ER) stress-induced apoptotic pathway. In the present study, we evaluated the effects of Tan-IIA on BT-20 human breast cancer cells and assessed the involvement of the ER-stress-apoptotic pathway. The cytotoxicity of Tan-IIA in BT-20 cells was measured by the MTT assay. The cell cycles were analyzed by flow cytometry. The expression of ER stress-related proteins in BT-20 cells treated with Tan-IIA were evaluated by western blotting and immunocytochemical staining. These results showed that Tan-IIA can inhibit BT-20 cells and increase the sub-G1 phase in a time- and dose-dependent manner. Tan-IIA could increase the protein expression of caspase 12, GADD153, caspase 3, phospho-JNK, phospho-p38 and Bax, but decreased Bcl-xl and phospho-ERK expression in BT-20 cells. These findings indicate that Tan-IIA possesses therapeutic potential for human breast cancer BT-20 cells; one of the molecular mechanisms may be through inducing ER stress and the MAPK pathway to induce apoptosis and inhibit proliferation.