Search

Benefices de l'usage combine des medications et de la psychotherapie. Discussion des articles de Rodenhauser, Zaslav, Kalb

A number of traditional Chinese medicines (TCMs) are widely used in prostate cancer treatment in China. The aim of this study was to test the efficacy of a TCM, Zhoushi Qiling Decoction (ZQD), in combination with androgen deprivation therapy (ADT) and explore its underlying mechanism. A total of 151 patients were recruited to receive ADT treatment or ADT+ZQD treatment. The survival of patients who received ADT+ZQD treatment was significantly higher than those who received ADT therapy only. DU145 prostate cancer cells were treated with ZQD (50 mg/mL) for 24 h in vitro and expression levels of an array of miRNAs were examined. Our results suggested that miR-143 demonstrated prominent upregulation in DU145 cells after treatment with ZQD. In patient serum samples, miR-143 expression was also significantly upregulated after ADT+ZQE treatment, which was however absent in patients treated with ADT only. In DU145 cells, ZQD treatment led to a dose-dependent increase in apoptosis, which could be reduced by anti-miR-143 treatment. There was a binding site between miR-143 and B cell CLL/lymphoma-2 (Bcl-2) and ZQD treatment reduced Bcl-2 expression. ZQD treatment led to increased caspase-3 and Bax expression. ZQD treatment could promote apoptosis of prostate cancer cells by promoting miR-143 upregulation, which could be a possible mechanism underlying the inhibitory effect of ZQD in prostate cancer in patient.

Rationale: Development of nanosystems that can be integrated with macrophages (MAs), an emerging carrier system, for effective tumor therapy remains to be challenging. We report here the development of MAs specifically loaded with hyaluronic acid (HA) nanogels (NGs) encapsulated with a photothermal agent of polypyrrole (PPy) and anticancer drug doxorubicin (DOX) (HA/DOX@PPy NGs) for tumor homing and combination photothermo-chemotherapy. Methods: Cystamine dihydrochloride-crosslinked HA NGs were first prepared through a double emulsification method, then loaded with PPy via an in-situ oxidization polymerization and physically encapsulated with DOX. The created HA/DOX@PPy NGs were well characterized and subjected to be endocytosed by MAs (MAs-NGs). The MAs-mediated tumor-homing property, phenotype changes and photothermal performance of MAs-NGs were investigated in vitro, and a subcutaneous tumor model was also established to confirm their targeting capability and enhanced antitumor therapy effect in vivo. Results: The generated hybrid NGs possess a size around 77 nm and good colloidal stability, and can be specifically endocytosed by MAs without appreciably affecting their normal biofunctionalities. In particular, NG-loaded MAs display excellent in-vitro cancer cell and in-vivo tumor homing property. Systemic administration of the MAs-NGs leads to the significant inhibition of a subcutaneous tumor model through combination photothermo-chemotherapy under laser irradiation. Conclusions: The developed hybrid HA-based NG nanosystem incorporated with PPy and DOX fully integrates the coordination and heating property of PPy to regulate the optimized DOX release in the tumor region with the assistance of MA-mediated tumor homing, providing a promising cell therapy strategy for enhanced antitumor therapy.

Background: Immunotherapy has profoundly changed the landscape of cancer management and represented the most significant breakthrough. Yet, it is a formidable challenge that the majority of cancers - the so-called "cold" tumors - poorly respond to immunotherapy. To find a general immunoregulatory modality that can be applied to a broad spectrum of cancers is an urgent need. Methods: Magnetic hyperthermia (MHT) possesses promise in cancer therapy. We develop a safe and effective therapeutic strategy by using magnetism-mediated targeting MHT-immunotherapy in "cold" colon cancer. A magnetic liposomal system modified with cell-penetrating TAT peptide was developed for targeted delivery of a CSF1R inhibitor (BLZ945), which can block the CSF1-CSF1R pathway and reduce M2 macrophages. The targeted delivery strategy is characterized by its magnetic navigation and TAT-promoting intratumoral penetration. Results: The liposomes (termed TAT-BLZmlips) can induce ICD and cause excessive CRT exposure on the cell surface, which transmits an "eat-me" signal to DCs to elicit immunity. The combination of MHT and BLZ945 can repolarize M2 macrophages in the tumor microenvironment to relieve immunosuppression, normalize the tumor blood vessels, and promote T-lymphocyte infiltration. The antitumor effector CD8+ T cells were increased after treatment. Conclusion: This work demonstrated that TAT-BLZmlips with magnetic navigation and MHT can remodel tumor microenvironment and activate immune responses and memory, thus inhibiting tumor growth and recurrence.

Background: Glucocorticoid (GC) administration prior to exposure-based cognitive-behavioural therapy (CBT) has emerged as a promising approach to facilitate treatment outcome in anxiety disorders. Further components relevant for improved CBT efficacy include raised endogenous GCs and reductions in information-processing biases to threat. Aims: To investigate hydrocortisone as an adjunct to CBT for spider fear and the modulating role of threat bias change and endogenous short-term and long-term GCs for treatment response. Methods: Spider-fearful individuals were randomized to receiving either 20 mg of hydrocortisone ( n = 17) or placebo ( n = 16) one hour prior to single-session predominantly computerised exposure-based CBT. Spider fear was assessed using self-report and behavioural approach measures at baseline, 1-day and 1-month follow-up. Threat processing was assessed at baseline and 1-day follow-up. Cortisol and cortisone were analysed from hair and saliva samples at baseline. Results/outcomes: Self-report, behavioural and threat processing indices improved following CBT. Hydrocortisone augmentation resulted in greater improvement of self-report spider fear and stronger increase in speed when approaching a spider, but not on threat bias. Neither threat bias nor endogenous GCs predicted symptom change, and no interactive effects with hydrocortisone emerged. Preliminary evidence indicated higher hair cortisone as predictor of a stronger threat bias reduction. Conclusions/interpretation: Our data extend earlier findings by suggesting that GC administration boosts the success of exposure therapy for specific fear even with a low-level therapist involvement. Future studies corroborating our result of a predictive hair GC relationship with threat bias change in larger clinical samples are needed.

Background: Mindfulness-meditation has a variety of benefits on well-being. However, individuals with primary attentional impairments (e.g. attention deficit disorder) or attentional symptoms secondary to anxiety, depression or addiction, may be less likely to benefit, and require additional mindfulness-augmenting strategies. Aims: To determine whether a single dose of the cognitive enhancer, modafinil, acutely increases subjective and behavioural indices of mindfulness, and augments brief mindfulness training. Methods: A randomised, double-blind, placebo-controlled, 2 (drug: placebo, modafinil) × 2 (strategy: mindfulness, relaxation control) experiment was conducted. Seventy-nine meditation-naïve participants were assigned to: placebo–relaxation, placebo–mindfulness, modafinil–relaxation or modafinil–mindfulness. Pre-drug, post-drug and post-strategy state mindfulness, affect and autonomic activity, along with post-strategy sustained attention and mind-wandering were assessed within a single lab session. After the session, participants were instructed to practice their assigned behavioural strategy daily for one week, with no further drug administration, after which, follow-up measures were taken. Results: As predicted, modafinil acutely increased state mindfulness and improved sustained attention. Differential acute strategy effects were found following mindfulness on autonomic activity but not state mindfulness. There were no strategy or drug effects on mind-wandering. However, exploratory analyses indicated that participants receiving modafinil engaged in more strategy practice across strategy conditions during follow-up. Conclusions: Modafinil acutely mimicked the effects of brief mindfulness training on state mindfulness but did not enhance the effects of this training. Limitations of the current study, and recommendations for future research examining modafinil as an adjunct to mindfulness- (or relaxation-) based treatments are discussed.

Multimodal therapies comprising spa applications are widely used as non-pharmaceutical treatment options for musculoskeletal diseases. The purpose of this randomized, controlled, open pilot study was to elucidate the involvement of the endocannabinoid system in a multimodal therapy approach. Twenty-five elderly patients with knee osteoarthritis (OA) received a 2-week spa therapy with or without combination of low-dose radon therapy in the Bad Gastein radon gallery. A 10-point numerical rating scale (pain in motion and at rest), WOMAC questionnaire, and the EuroQol-5D (EQ-5D) questionnaire were recorded at baseline, and during treatment period at weeks one and two, and at 3-month and 6-month follow-ups. Plasma levels of the endocannabinoid anandamide (AEA) were determined at baseline and at 2 weeks, and serum levels of several cartilage metabolism markers at all five time-points. A significant and sustained reduction of self-reported knee pain was observed in the study population, but no further significant effect of the additional radon therapy up and above base therapy. This pain reduction was accompanied by a significant reduction of AEA plasma levels during treatment in both groups. No significant differences were seen in serum marker concentrations between the groups treated with or without radon, but a small reduction of serum cartilage degradation markers was observed during treatment in both groups. This is the first study investigating AEA levels in the context of a non-pharmacological OA treatment. Since the endocannabinoid system represents a potential target for the development of new therapeutics, further studies will have to elucidate its involvement in OA pain.

Rationale: Hypoxia is one of the crucial restrictions in cancer radiotherapy (RT), which leads to the hypoxia-associated radioresistance of tumor cells and may result in the sharp decline in therapeutic efficacy. Methods: Herein, living photosynthetic microalgae (Chlorella vulgaris, C. vulgaris), were used as oxygenators, for in situ oxygen generation to relieve tumor hypoxia. We engineered the surface of C. vulgaris (CV) cells with calcium phosphate (CaP) shell by biomineralization, to form a biomimetic system (CV@CaP) for efficient tumor delivery and in-situ active photosynthetic oxygenation reaction in tumor. Results: After intravenous injection into tumor-bearing mice, CV@CaP could remarkably alleviate tumor hypoxia by continuous oxygen generation, thereby achieving enhanced radiotherapeutic effect. Furthermore, a cascade phototherapy could be fulfilled by the chlorophyll released from photosynthetic microalgae combined thermal effects under 650 nm laser irradiation. The feasibility of CV@CaP-mediated combinational treatment was finally validated in an orthotropic breast cancer mouse model, revealing its prominent anti-tumor and anti-metastasis efficacy in hypoxic-tumor management. More importantly, the engineered photosynthetic microalgae exhibited excellent fluorescence and photoacoustic imaging properties, allowing the self-monitoring of tumor therapy and tumor microenvironment. Conclusions: Our studies of this photosynthetic microsystem open up a new dimension for solving the radioresistance issue of hypoxic tumors.

How renal function influences post-acute myocardial infarction (AMI) cardiac remodeling and outcomes remains unclear. This study evaluated the impact of levels of renal impairment on drug therapy, echocardiographic parameters, and outcomes in patients with AMI undergoing percutaneous coronary intervention (PCI). A total of 611 patients diagnosed with AMI underwent successful PCI, and two echocardiographic examinations were performed within 1 year after AMI. Patients were categorized according to Group 1: severely impaired estimated glomerular filtration rate (eGFR)

Rationale: Clinical interest in combining targeted radionuclide therapies (TRT) with immunotherapies is growing. External beam radiation therapy (EBRT) activates a type 1 interferon (IFN1) response mediated via stimulator of interferon genes (STING), and this is critical to its therapeutic interaction with immune checkpoint blockade. However, little is known about the time course of IFN1 activation after EBRT or whether this may be induced by decay of a TRT source. Methods: We examined the IFN1 response and expression of immune susceptibility markers in B78 and B16 melanomas and MOC2 head and neck cancer murine models using qPCR and western blot. For TRT, we used 90Y chelated to NM600, an alkylphosphocholine analog that exhibits selective uptake and retention in tumor cells including B78 and MOC2. Results: We observed significant IFN1 activation in all cell lines, with peak activation in B78, B16, and MOC2 cell lines occurring 7, 7, and 1 days, respectively, following RT for all doses. This effect was STING-dependent. Select IFN response genes remained upregulated at 14 days following RT. IFN1 activation following STING agonist treatment in vitro was identical to RT suggesting time course differences between cell lines were mediated by STING pathway kinetics and not DNA damage susceptibility. In vivo delivery of EBRT and TRT to B78 and MOC2 tumors resulted in a comparable time course and magnitude of IFN1 activation. In the MOC2 model, the combination of 90Y-NM600 and dual checkpoint blockade therapy reduced tumor growth and prolonged survival compared to single agent therapy and cumulative dose equivalent combination EBRT and dual checkpoint blockade therapy. Conclusions: We report the time course of the STING-dependent IFN1 response following radiation in multiple murine tumor models. We show the potential of TRT to stimulate IFN1 activation that is comparable to that observed with EBRT and this may be critical to the therapeutic integration of TRT with immunotherapies.

In this study, we construct a subcutaneous tumor mice model of U14 cells, observe the tumor growth, and detect the expression of Foxp3 and VISTA in cervical cancer tissues and adjacent tissues during CMNa-enhancing radiotherapy.From the 15th day, compared with the control group, the tumor volume changes in each treatment group were significant (P

Background: Clinical characteristics and prognosis among combined hepatocellular carcinoma (HCC) and cholangiocarcinoma (cHCC-CC) with HCC and intrahepatic cholangiocarcinoma (ICC) were inconsistent in previous studies. The aim of this study was to compare postoperative prognosis among cHCC-CC, HCC and ICC, and investigated the prognostic risk factor of cHCC-CC after surgical resection. Methods: A total of 1041 eligible patients with pathological diagnosis of cHCC-CC (n=135), HCC (n=698) and ICC (n=208) were enrolled in this study. Univariate and multivariate Cox analysis were applied for assessing important risk factors. cHCC-CC were further 1:1 matched with HCC and ICC on important clinical risk factors. Survival curves of matched and unmatched cohorts were depicted by Kaplan-Meier method with log-rank test. Results: Patients with cHCC-CC had similar rate of sex, age and cirrhosis with HCC (p

Rationale: Integration of several monotherapies into a single nanosystem can produce remarkable synergistic antitumor effects compared with separate delivery of combination therapies. We developed near-infrared (NIR) light-triggered nanoparticles that induce a domino effect for multimodal tumor therapy. Methods: The designed intelligent phototriggered nanoparticles (IPNs) were composed of a copper sulfide-loaded upconversion nanoparticle core, a thermosensitive and photosensitive enaminitrile molecule (EM) organogel shell loaded with anticancer drugs, and a cancer cell membrane coating. Irradiation with an NIR laser activated a domino effect beginning with photothermal generation by copper sulfide for photothermal therapy that also resulted in phase transformation of the EM gel to release the anticancer drug. Meanwhile, the NIR light energy was converted to ultraviolet light by the upconversion core to excite the EM, which generated reactive oxygen species for photodynamic therapy. Results: IPNs achieved excellent antitumor effects in vitro and in vivo with little systemic toxicity, indicating that IPNs could serve as a safe and high-performance instrument for synergetic antitumor therapy. Conclusion: This intelligent drug delivery system induced a chain reaction generating multiple antitumor therapies after a single stimulus.

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer death, which accounts for approximately 10% of all new cancer cases worldwide. Surgery is the main method for treatment of early-stage CRC. However, it is not effective for most metastatic tumors, and new treatment and diagnosis strategies need to be developed. Photosensitizers (PSs) play an important role in the treatment of CRC. Phototherapy also has a broad prospect in the treatment of CRC because of its low invasiveness and low toxicity. However, most PSs are associated with limitations including poor solubility, poor selectivity and high toxicity. The application of nanomaterials in PSs has added many advantages, including increased solubility, bioavailability, targeting, stability and low toxicity. In this review, based on phototherapy, we discuss the characteristics and development progress of PSs, the targeting of PSs at organ, cell and molecular levels, and the current methods of optimizing PSs, especially the application of nanoparticles as carriers in CRC. We introduce the photosensitizer (PS) targeting process in photodynamic therapy (PDT), the damage mechanism of PDT, and the application of classic PS in CRC. The action process and damage mechanism of photothermal therapy (PTT) and the types of ablation agents. In addition, we present the imaging examination and the application of PDT / PTT in tumor, including (fluorescence imaging, photoacoustic imaging, nuclear magnetic resonance imaging, nuclear imaging) to provide the basis for the early diagnosis of CRC. Notably, single phototherapy has several limitations in vivo, especially for deep tumors. Here, we discuss the advantages of the combination therapy of PDT and PTT compared with the single therapy. At the same time, this review summarizes the clinical application of PS in CRC. Although a variety of nanomaterials are in the research and development stage, few of them are actually on the market, they will show great advantages in the treatment of CRC in the near future.

Purpose: Non-Small-Cell Lung Cancer (NSCLC) has gained resistance to common chemo- and radiotherapy due to the oncogenic K-RAS mutations. In this work, lactonic sophorolipids (LSL), a constituent of natural sophorolipids known to inhibit histone deacetylase (HDAC) activity, is used to evaluate its potential anticancer property for the treatment of NSCLC. In addition, ganetespib (GT), a Hsp90 inhibitor, is used for its known antitumor activity in several K-RAS mutant NSCLC cells. We propose, a functional anti-oxidant nanomedicine composed of nanoceria (NC) encapsulated with two-drug cocktail LSL and GT for the assessment of therapeutic efficacy of LSL and targeted combination therapy of NSCLC. NC is an excellent redox platform specifically used to supplement the therapeutic potency of these drugs to target both HDAC inhibition and Hsp90 signaling pathways in NSCLC. Methods: Polyacrylic acid-coated nanoceria (PNC) was formulated and folic acid was conjugated on the surface of PNC using “click” chemistry to target NSCLC and to minimize adverse side effects. Solvent diffusion method was used for the encapsulation of individual drugs and co-encapsulation of drug-cocktail along with an optical dye DiI for diagnosis. We hypothesized that the therapeutic efficacy of LSL will be synergistically accelerated by the inhibition of Hsp90 mechanism of GT and redox activity of NC. Results: For the targeted therapy of NSCLC, A549 cells were used and Chinese hamster ovary (CHO) cells were used as healthy control cells. Results showed more than 40% cells were dead within 24 h when treated with LSL nanodrug. When combined with GT, enhanced ROS signals were detected and more than 80% reduction in cell viability was recorded within 24 h of incubation. Treatments with NC without any drug showed minimal toxicity. Migration assays indicate that the highly metastatic nature of NSCLC is successfully restricted by this combination approach. To validate the effectiveness of this combination therapy various cell-based assays including detection of apoptosis, necrosis and HDAC inhibition of LSL were performed. Conclusion: Functional nanoceria with drug-cocktail LSL and GT is successfully developed for the targeted treatment of undruggable NSCLC. The fluorescence modality helps monitoring the drugs delivery. Results demonstrate the potential therapeutic efficacy of LSL, which is synergistically accelerated by the Hsp90 inhibition mechanism of GT and redox activity of NC.

Combination therapies based on photodynamic therapy (PDT) have received much attention in various cancers due to their strong therapeutic effects. Here, we aimed to explore the safety and effectiveness of a new mitochondria-targeting photodynamic material, TPE-IQ-2O, in combination therapies (combined with surgery or immunotherapy). The safety and effectiveness of TPE-IQ-2O PDT were verified with cytotoxicity evaluation in vitro and a zebrafish xenograft model in vivo, respectively. The effectiveness of TPE-IQ-2O PDT combined with surgery or immune checkpoint inhibitors (ICIs) was verified in tumor-bearing mice. Small animal in vivo imaging, immunohistochemistry, and flow cytometry were used to determine the underlying mechanism. TPE-IQ-2O PDT can not only reduce tumor recurrence in surgical treatment but also effectively improve the response to ICIs in immunotherapy without obvious toxicity. It was also found to ameliorate the immunosuppressive tumor microenvironment and promote the antitumor immunity induced by ICIs by increasing CD8+ tumor-infiltrating lymphocyte accumulation. Thus, TPE-IQ-2O PDT is a safe and effective antitumor therapy that can be combined with surgery or immunotherapy.

Microwave ablation (MWA) has been widely used in the treatment of solid tumors. Studies have been less conducted on the efficacy of MWA used with cell immunotherapy in treating hepatocellular carcinoma (HCC). The current study aimed at exploring the efficacy of MWA in combination with cell immunotherapy in treating HCC. Hepa1-6 HCC mice were treated by MWA, blockade, or the combined therapy (MWA used with blockade), or left untreated. Survival rates of the mice were plotted by Kaplan-Meier Curve, followed by log-rank test. 25 days after the operation, surviving mice were monitored for tumor recurrence, and tumor volumes were calculated every 5 days. Immunohistochemistry and flow cytometry were performed to detect the numbers of CD4(+) and CD8(+) cells in the tumors and spleens of mice. The expressions of related cytokines were detected and measured by ELISPOT and ELISA. The results showed that MWA combined with anti-PD-1/anti-CTLA-4 not only increased the survival time, protected the mice against tumor recurrence, but also enhanced the intratumoral infiltration of cytotoxic T lymphocyte and systemic T-cell immune responses induced by MWA through activation of synergistically specific antitumor immunity. In addition, the combined therapy increased T-helper 1 cell (Th1-type) cytokines, but reduced Th2-type cytokines, resulting in the polarization of Th1 cells. T-cell immune responses of HCC cells were activated by MWA. In addition, the combined therapy of MWA and anti-PD-1/anti-CTLA-4 induced Th1-type immune response, and showed specific antitumor immunity.

Severe pneumonia caused by COVID-19 has resulted in many deaths worldwide. Here, we analyzed the clinical characteristics of the first 17 reported cases of death due to COVID-19 pneumonia in Wuhan, China. Demographics, initial symptoms, complications, chest computerized tomography (CT) images, treatments, and prognoses were collected and analyzed from the National Health Committee of China data. The first 17 reported deaths from COVID-19 were predominately in older men; 82.35% of patients were older than 65 years, and 76.47% were males. The most common initial symptoms were fever or fatigue (14 cases, 82.35%), respiratory symptoms, such as cough (12 cases, 70.59%), and neurological symptoms, such as headache (3 cases, 17.65%). The most common finding of chest CT was viral pneumonia (5 cases, 29.41%). Anti-infectives (11 cases, 64.71%) and mechanical ventilation (9 cases, 52.94%) were commonly used for treatment. Most of the patients (16 cases, 94.12%) died of acute respiratory distress syndrome (ARDS). Our findings show that advanced age and male gender are effective predictors of COVID-19 mortality, and suggest that early interventions to reduce the incidence of ARDS may improve prognosis of COVID-19 pneumonia patients.

Purpose To summarize current knowledge on intracorporeal laser lithotripsy in flexible ureterorenoscopy (fURS), regarding basics of laser lithotripsy, technical aspects, stone clearance, lithotripsy strategies, laser technologies, endoscopes, and safety. Methods A scoping review approach was applied to search literature in PubMed, EMBASE, and Web of Science. Consensus was reached through discussions at the Consultation on Kidney Stones held in September 2019 in Copenhagen, Denmark. Results and conclusions Lasers are widely used for lithotripsy during fURS. The Holmium laser is still the predominant technology, and specific settings for dusting and fragmenting have evolved, which has expanded the role of fURS in stone management. Pulse modulation can increase stone ablation efficacy, possibly by minimizing stone retropulsion. Thulium fibre laser was recently introduced, and this technology may improve laser lithotripsy efficiency. Small fibres give better irrigation, accessibility, and efficiency. To achieve optimal results, laser settings should be adjusted for the individual stone. There is no consensus whether the fragmentation and basketing strategy is preferable to the dusting strategy for increasing stone-free rate. On the contrary, different stone scenarios call for different lithotripsy approaches. Furthermore, for large stone burdens, all laser settings and lithotripsy strategies must be applied to achieve optimal results. Technology for removing dust from the kidney should be in focus in future research and development. Safety concerns about fURS laser lithotripsy include high intrarenal pressures and temperatures, and measures to reduce both those aspects must be taken to avoid complications. Technology to control these parameters should be targeted in further studies.

Purpose Radiotherapy (RT), as part of trimodal therapy, is an attractive alternative treatment in patients with urothelial muscle-invasive bladder cancer (MIBC). There is accumulating evidence suggesting the immunomodulatory effects of RT and its potential synergy when combined with immunotherapy. The aim of this review was to report on the most recent advances on this combination, including the mechanisms of RT immunomodulation, practical approach to combining RT and immunotherapy, and ongoing clinical trials in bladder cancer. Methods Using the PubMed database, we identified articles published between March 2004 and April 2020 on the combination of RT with immunotherapy in localized or metastatic MIBC. A search of the Clinicaltrials.gov and Clinicaltrialsregister.eu/ retrieved ongoing clinical trials on the topic as well. Results Combination of RT with immunotherapy leads to immunogenic cell death and an increase in immune markers thus leading to improved tumor control. For localized MIBC, there are safety concerns related to the use of concurrent immunotherapy with hypofractionated RT, thus neoadjuvant or adjuvant immunotherapy is preferred. In the metastatic setting, the combination of multi-site RT with SBRT-like doses (≥ 6 Gy per fraction) and concurrent immunotherapy seems most efficacious at harnessing the abscopal effect. At least 25 clinical trials combining immunotherapy and RT in MIBC are currently ongoing and will answer pending questions on safety, efficacy, and practical considerations on RT scheduling, fractionation, and targets volumes. Conclusion RT has the potential to synergize with immunotherapy to improve oncological outcomes in patient with localized or metastatic MIBC. Clinical trials results are eagerly awaited.

Electroconvulsive therapy (ECT) has known beneficial effects on the core motor symptoms of Parkinson's disease (PD), likely through induction of dopamine release and sensitivity of dopamine receptors. Mesenchymal stem cells (MSCs) can salvage loss of dopamine in PD through their differentiation into dopaminergic neurons. However, it is not known if combined ECT and MSC transplantation may have a synergistic effect against PD. Here, we showed that ECT significantly increased the differentiation of the transplanted MSCs into dopaminergic neurons in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. On the other hand, transplantation of MSCs significantly increased dopamine levels after ECT. Co-application of ECT and MSC transplantation generated a synergistic effect through increases in dopamine and decreases in pro-inflammatory cytokines, resulting in significantly attenuated defect in stepping test and rotational behavior in MPTP-mice. Together, our data suggest that combined ECT and MSC transplantation can be a valuable treatment of PD.

Contains fulltext : 225496.pdf (Publisher’s version ) (Open Access) Rituximab-containing induction followed by autologous stem cell transplantation (ASCT) is the standard first-line treatment for young mantle cell lymphoma patients. However, most patients relapse after ASCT. We investigated in a randomised phase II study the outcome of a chemo-immuno regimen and ASCT with or without maintenance therapy with bortezomib. Induction consisted of three cycles R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), two cycles high-dose cytarabine, BEAM (carmustine, etoposide, cytarabine, melphalan) and ASCT. Patients responding were randomised between bortezomib maintenance (1·3 mg/m(2) intravenously once every 2 weeks, for 2 years) and observation. Of 135 eligible patients, 115 (85%) proceeded to ASCT, 60 (44%) were randomised. With a median follow-up of 77·5 months for patients still alive, 5-year event-free survival (EFS) was 51% (95% CI 42-59%); 5-year overall survival (OS) was 73% (95% CI 65-80%). The median follow-up of randomised patients still alive was 71·5 months. Patients with bortezomib maintenance had a 5-year EFS of 63% (95% CI 44-78%) and 5-year OS of 90% (95% CI 72-97%). The patients randomised to observation had 5-year PFS of 60% (95% CI, 40-75%) and OS of 90% (95% CI 72-97%). In conclusion, in this phase II study we found no indication of a positive effect of bortezomib maintenance after ASCT.

Ovarian cancer (OC) is associated with poor survival because there are a limited number of effective therapies. Two processes key to OC progression, angiogenesis and immune evasion, act synergistically to promote tumor progression. Tumor-associated angiogenesis promotes immune evasion, and tumor-related immune responses in the peritoneal cavity and tumor microenvironment (TME) affect neovascular formation. Therefore, suppressing the angiogenic pathways could facilitate the arrival of immune effector cells and reduce the presence of myeloid cells involved in immune suppression. To date, clinical studies have shown significant benefits with antiangiogenic therapy as first-line therapy in OC, as well as in recurrent disease, and the vascular endothelial growth factor (VEGF) inhibitor bevacizumab is now an established therapy. Clinical data with immunomodulators in OC are more limited, but suggest that they could benefit some patients with recurrent disease. The preliminary results of two phase III trials have shown that the addition of immunomodulators to chemotherapy does not improve progression-free survival. For this reason, it could be interesting to look for synergistic effects between immunomodulators and other active drugs in OC. Since bevacizumab is approved for use in OC, and is tolerable when used in combination with immunotherapy in other indications, a number of clinical studies are underway to investigate the use of bevacizumab in combination with immunotherapeutic agents in OC. This strategy seeks to normalize the TME via the anti-VEGF actions of bevacizumab, while simultaneously stimulating the immune response via the immunotherapy. Results of these studies are awaited with interest.

Preferable treatments for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) with brain metastasis are elusive. The study intended to estimate the relative efficacy and safety of systemic therapies. Clinical trials about therapies for EGFR-mutant, brain-metastatic NSCLC were identified. Progression-free survival (PFS) and overall survival (OS) were analysed using random effects Bayesian network meta-analyses (NMAs) on the hazard ratio (HR)-scale. Nomogram and Kaplan-Meier plots based on clinical or individual factors are displayed using data obtained from the Surveillance Epidemiology and End Results (SEER) database. Third-generation EGFR- tyrosine kinase inhibitors (EGFR-TKI) (osimertinib), EGFR-TKIs + stereotactic radiosurgery (SRS)/whole brain radiotherapy (WBRT) (gefitinib/erlotinib + SRS/WBRT), and EGFR-TKIs (erlotinib) + anti-vascular endothelial growth factor receptor (anti-VEGFR) (bevacizumab) achieved superior PFS (HR: 0.30 (0.15-0.59); HR: 0.47 (0.31-0.72); HR: 0.50 (0.21-1.21) vs. deferring SRS/WBRT) and acceptability; EGFR-TKIs + SRS/WBRT was top ranking (vs. others) for OS followed by third-generation EGFR-TKI. In the dataset cohort of 1173 brain-metastatic NSCLC patients, the 6-month, 1-year, and 3-year survival rates were 59.8%, 41.3%, and 5.6%, respectively. Race and origin, and year of diagnosis were independent predictors of OS. Survival curves showed that the OS of patients varied significantly by histology and race. Third-generation EGFR-TKI and EGFR-TKIs + SRS/WBRT are more effective and potentially acceptable for EGFR-mutant NSCLC with brain metastases balancing OS and PFS. Surgeries without adjuvant therapies cannot significantly improve the OS of brain-metastatic NSCLC patients. The study highlights importance of osimertinib in these patients and provide a reference for clinical treatments.

This study aimed to determine the maximum tolerance dose (MTD) and to estimate the recommended dose (RD) of concomitant S-1 with carbon-ion radiotherapy (RT) for sinonasal squamous cell carcinoma (SCC). Nine patients with sinonasal SCC received carbon-ion RT with escalating doses of S-1 according to phase I methods. Doses of 40, 60 and 80 mg/m2/day were administered twice daily in dose levels 1, 2 and 3, respectively, from days 1 to 14 and 22 to 35. Carbon-ion RT was administered at a dose of 70.4 Gy (relative biological effectiveness) in 32 fractions, 5 days a week. Two patients developed grade 3 acute dermatitis. However, none developed dose-limiting toxicities. Therefore, the MTD of S-1 could not be determined; the RD was estimated to be 80 mg/m2/day with concurrent carbon-ion RT. Partial response and stable disease were noted in 5 and 4 patients, respectively. The 2-year overall survival and local control rates were 56 and 74%, respectively. Overall, 2 patients developed ≥grade 3 late toxicities; among them, 1 patient developed grade 3 cataract and the other developed grade 4 cataract, optic nerve disorder and hearing impairment. To the best of our knowledge, this phase I study is the first clinical trial to evaluate concomitant S-1 with carbon-ion RT for sinonasal SCC. The MTD of S-1 could not be determined, and the RD was estimated to be 80 mg/m2/day. This study demonstrated a manageable safety profile for this combination. The observed outcomes may facilitate further evaluation of this novel therapy.

Background: Platelets play important roles in tumorigenesis, angiogenesis and metastatic dissemination of tumor cells. Radiofrequency ablation (RFA) could increase the circulating tumor cells in patients with primary or metastatic lung tumors. Whether platelet lysates in hepatocellular carcinoma (HCC) after RFA promote tumor progression has not been elaborated. Methods: HCC patients within Milan Criteria and without taking anti-platelet drugs were selected in the study. MTT assay, colony formation assay, transwell assay, tube formation and western blot were used to evaluate the effect of platelet lysates on HCC cells in vitro. Lung metastatic assay was performed in vivo. Results: Platelet lysates from patients after RFA promoted cell proliferation, colony formation, migration, invasion and vasculogenic mimicry in Hep3B and HCCLM3 cells compared with those from patients before RFA. Platelet lysates after RFA significantly increased the expression of p-Akt, p-Smad3 and snail, and decreased the expression of E-cadherin compared with those before RFA in Hep3B and HCCLM3 cells. Hep3B-Luc2-tdT cells incubation with platelet lysates from patients after RFA displayed enhanced lung metastasis compared with those before RFA. Conclusions: Platelet lysates from HCC patients after RFA promoted the proliferation, migration, invasion and vasculogenic mimicry of HCC cells, which indicated that RFA in combination with anti-platelet drug may be used to improve the prognosis of HCC.

Although phase III trials have been published comparing whole breast irradiation (WBI) with accelerated partial breast irradiation (APBI) using intraoperative radiotherapy (IORT), long-term follow-up results are lacking. We report the 10-year follow-up results of a prospective phase I/II clinical trial of IORT. The inclusion criteria were as follows: (i) tumor size 50 years, (iv) negative margins after resection and (v) sentinel lymph node-negative disease. A single dose of IORT (19–21 Gy) was delivered to the tumor bed in the operation room just after wide local excision of the primary breast cancer using a 6–12 MeV electron beam. Local recurrence was defined as recurrence or new disease within the treated breast and was evaluated annually using mammography and ultrasonography. A total of 32 patients were eligible for evaluation. The median patient age was 65 years and the median follow-up time was 10 years. Two patients experienced local recurrence just under the nipple, out of the irradiated field, after 8 years of follow-up. Three patients had contralateral breast cancer and one patient experienced bone metastasis after 10 years of follow-up. No patient experienced in-field recurrence nor breast cancer death. Eight patients had hypertrophic scarring at the last follow-up. There were no lung or heart adverse effects. This is the first report of 10-year follow-up results of IORT as APBI. The findings suggest that breast cancer with extended intraductal components should be treated with great caution.

Rationale: Developing an effective nanoplatform to realize 'multi-in-one' is essential to broaden the therapeutic potential of combination therapy. Exosomes are ideal candidates since their intrinsic abilities of integrating multiple contents and functions. However, only limited efforts have been devoted to engineering exosomes to integrate the needed properties, also considering the safety and yield, for tumor-targeted and efficient gene/chemo combination therapy. Methods: Herein, by manipulating the exosome membrane, blood exosomes with high abundance and safety are engineered as a versatile combinatorial delivery system, where the doxorubicin (Dox) and cholesterol-modified miRNA21 inhibitor (miR-21i) are co-embedded into the lipid bilayer of exosomes, and the magnetic molecules and endosomolytic peptides L17E are bind to the exosome membrane through ligand-receptor coupling and electrostatic interactions, respectively. Results: It is proved that such engineering strategy not only preserves their intrinsic features, but also readily integrates multiple properties of tumor targeting, efficient transfection and gene/chemo combination therapy into blood exosomes. The lipid bilayer structure of exosomes allows them to co-load Dox and miR-21i with high-payloads. Moreover, profiting from the integration of magnetic molecules and L17E peptides, the engineered exosomes exhibit an enhanced tumor accumulation and an improved endosome escape ability, thereby specifically and efficiently delivering encapsulated cargos to tumor cells. As a result, a remarkable inhibition of tumor growth is observed in the tumor-bearing mice, and without noticeable side effects. Conclusions: This study demonstrates the potential of engineered blood exosomes as feasible co-delivery nanosystem for tumor-targeted and efficient combination therapy. Further development by replacing the drugs combined regimens can potentially make this engineered exosome become a general platform for the design of safe and effective combination therapy modality.

Bone-modifying agents (BMAs) are frequently used for the treatment of bone metastases. Both BMA and radiation therapy (RT) are effective; however, there are few studies that have evaluated the efficacy of the combination treatment. We evaluated the effectiveness of RT + BMA in breast cancer-induced osteolytic bone metastasis as compared to BMA alone. A total of 43 lesions in 25 patients were evaluated. The median follow-up period was 18 (range, 2–90) months. None of the lesions was treated with chemotherapy or molecular targeted drugs during the follow-up period for evaluating the local response. Patients with complete or partial response were considered as responders, while those with stable or progressive disease were considered as non-responders. The rate of response with RT + BMA was significantly higher than that with BMA alone (P = 0.001). The cumulative incidence rate of response at 6 months was 54.4% in the RT + BMA group and 27.5% in the BMA alone group. The median time to response was 4 (range, 2–11) months in the RT + BMA group and 6 (range, 4–16) months in the BMA alone group. The overall survival rate in the responder group (83.1% at 1 year) was significantly higher than that in the non-responder group (37.5% at 1 year) (P = 0.029). In conclusion, RT combined with BMA was found to be more effective than BMA alone for the treatment of osteolytic bone metastasis, which thereby improves the prognosis.

The most favorable treatments for advanced EGFR-mutant NSCLC are less indicated. Forty-one studies were eligible for this Bayesian network secondary analysis. For PFS, erlotinib (Erlo)+bevacizumab (Bev) (HR 0.26, 95% CrI: 0.08-0.75 vs placebo), osimertinib (Osi) (HR 0.29, 0.11-0.70 vs placebo), and afatinib (Afa) were top-ranking individual treatments, while immunotherapy (IT)+anti-VEGFR (aVEGFR)+platinum-based therapy (Plat) (HR 0.42, 0.06-2.63 vs placebo), EGFR-TKI (ET)+aVEGFR (HR 0.35, 0.14-0.85 vs placebo), and ET+aVEGFR+Plat were top-ranking medication classes. For OS, Osi (HR 0.52, 0.10-2.00 vs placebo), cetuximab (Cet)+Bev+Plat (HR 0.51, 0.06-3.38 vs placebo), and cilengitide (Cil)+Cet+Plat were top-ranking individual treatments, while ET+aVEGFR+Plat, ET+Plat, and third-generation EGFR-TKI (3rd ET) were top-ranking medication classes. For PFS regarding the EGFR genomic aberration status, Erlo+Bev, Osi, and Afa were superior for exon 19 deletion status, whereas ET+Bev, Osi, and gefitinib (Gef)+pemetrexed (Peme) were excellent for exon 21 L858Arg mutation status. The results were consistent in terms of the ORR and DoR and remained robust across sensitivity analyses. However, Erlo + Bev had the most grade 3 or higher adverse events. Osi, Erlo+Bev, and Erlo+Bev+Plat are reasonably recommended to balance PFS and OS, but adverse events should be considered. IT+aVEGFR+Plat shows potential superiority, but more clinical evidence is needed.

Introduction: Regenerative capacity of the heart is limited, and the post-infarct left ventricle (LV) dysfunction is associated with poor prognosis. Administration of stem/progenitor cells (SPCs) is a promising approach for cardiac regeneration. Objectives: In the study, we assessed LV function and post-infarcted remodeling in patients with ST-elevated myocardial infarct (STEMI) who received autologous lineage-negative (LIN-) SPCs. Patients and methods: Patients with STEMI and one-vessel coronary artery disease treated with percutaneous revascularisation were divided into study group (LIN- group, 15 patients) that received standard therapy and autologous BM-derived LIN- SPCs and control group (standard therapy group, 19 patients). The cells were administered intracoronary 24 hours after STEMI. The follow-up was 12 months with subsequent non-invasive tests and laboratory parameter evaluation on days 1st, 3rd, and 7th as well as at 1st, 3rd, 6th and 12th month after STEMI. Results: All procedures related to SPCs administration were well tolerated by the patients. In 12-month follow-up, there were no major adverse cardiac events connected with LIN- SPCs administration. During 12-month follow-up, 9 patients from LIN- group (Responders) achieved an improvement in LV ejection fraction (>10% after 12 months) with no signs of unfavorable LV remodeling. Laboratory parameters analysis showed that Troponin T levels were significantly lower until day 7th in the Responders group, while brain natriuretic peptide (BNP) level remained significantly lower from day 3rd to 12th month respectively. Conclusions: Intracoronary infusion of autologous BM-derived LIN- stem/progenitor cells is feasible and safe for patient. Improvement in LV function and prevention of unfavorable remodeling in the 60% of study group seems relatively promising. Stem cell-based therapy for cardiac regeneration still needs more accurate and extensive investigations to estimate and improve their efficacy.

As known, radiation therapy (RT) can exacerbate the degree of hypoxia of tumor cells, which induces serious resistance to RT and in turn, is the greatest obstacle to RT. Reoxygenation can restore the hypoxic state of tumor cells, which plays an important role in reshaping tumor microenviroment for achieving optimal therapeutic efficacy. Herein, we report for the first time that microwave (MW)-triggered IL-Quercetin-CuO-SiO2@ZrO2-PEG nanosuperparticles (IQuCS@Zr-PEG NSPs) have been used to achieve an optimal RT therapeutic outcomes by the strategy of upregulating tumor reoxygenation, i.e. hypoxic cells acquire oxygen and return to normal state. Methods: We prepared a promising multifunctional nanosuperparticle to upregulate tumor reoxygenation by utilizing CuO nanoparticle to generate oxygen under MW irradiation in the tumor microenvironment. The IQuCS@Zr-PEG NSPs were obtained by introducing CuO nanoparticles, MW sensitizer of 1-butyl-3-methylimidazolium hexafluorophosphate (IL), radiosensitizer of Quercetin (Qu) and surface modifier of monomethoxy polyethylene glycol sulfhyl (mPEG-SH, 5k Da) into mesoporous sandwich SiO2@ZrO2 nanosuperparticles (SiO2@ZrO2 NSPs). The release oxygen by IQuCS@Zr-PEG NSPs under MW irradiation was investigated by a microcomputer dissolved oxygen-biochemical oxygen demand detector (DO-BOD) test. Finally, we used the 99mTc-HL91 labeled reoxygenation imaging, Cellular immunofluorescence, immunohistochemistry, and TUNEL experiments to verify that this unique MW-responsive reoxygenation enhancer can be used to stimulate reshaping of the tumor microenvironment. Results: Through experiments we found that the IQuCS@Zr-PEG NSPs can persistently release oxygen under the MW irradiation, which upregulates tumor reoxygenation and improve the combined tumor treatment effect of RT and microwave thermal therapy (MWTT). Cellular immunofluorescence and immunohistochemistry experiments demonstrated that the IQuCS@Zr-PEG NSPs can downregulate the expression of hypoxia-inducible factor 1α (HIF-1α) under MW irradiation. The 99mTc-HL91 labeled reoxygenation imaging experiment also showed that the oxygen generated by IQuCS@Zr-PEG NSPs under MW irradiation can significantly increase the reoxygenation capacity of tumor cells, thus reshaping the tumor microenvironment. The high inhibition rate of 98.62% was achieved in the antitumor experiments in vivo. In addition, the IQuCS@Zr-PEG NSPs also had good computed tomography (CT) imaging effects, which can be used to monitor the treatment of tumors in real-time. Conclusions: The proof-of-concept strategy of upregulating tumor reoxygenation is achieved by MW triggered IQuCS@Zr-PEG NSPs, which has exhibited optimal therapeutic outcomes of combination of RT and MWTT tumor. Such unique MW-responsive reoxygenation enhancer may stimulate the research of reshaping tumor microenvironment for enhancing versatile tumor treatment.

The production of nitric oxide (NO) is a key feature of immunosuppressive myeloid cells, which impair T cell activation and proliferation via reversibly blocking interleukin-2 receptor signaling. NO is mainly produced from L-arginine by inducible NO synthase (iNOS). Moreover, L-arginine is an essential element for T cell proliferation and behaviors. Impaired T cell function further inhibits anti-tumor immunity and promotes tumor progression. Previous studies indicated that radiotherapy activated anti-tumor immune responses in multiple tumors. However, myeloid-derived cells in the tumor microenvironment may neutralize these responses. We hypothesized that iNOS, as an important regulator of the immunosuppressive effects in myeloid-derived cells, mediated radiation resistance of cancer cells. In this study, we used 1400W dihydrochloride, a potent small-molecule inhibitor of iNOS, to explore the regulatory roles of NO in anti-tumor immunity. Radiotherapy and iNOS inhibition by 1400W collaboratively suppressed tumor growth and increased survival time, as well as increased tumor-infiltrating CD8+ T cells and specific inflammatory cytokine levels, in both lung and breast cancer cells in vivo. Our results also suggested that myeloid cell-mediated inhibition of T cell proliferation was effectively counteracted by radiation and 1400W-mediated NO blockade in vitro. Thus, these results demonstrated that iNOS was an important regulator of radiotherapy-induced antitumor immune responses. The combination of radiotherapy with iNOS blockade might be an effective therapy to improve the response of tumors to clinical radiation.

A retrospective study investigated and compared the results of lamina with spinous process (LSP), transverse process strut (TPS) and iliac graft (IG) as bone graft in thoracic single-segment spinal tuberculosis(TB) with the one-stage posterior approach of debridement, fusion and internal instrumentation. 99 patients treated from January 2012 to December 2015 were reviewed. LSP was performed in 35 patients (group A), TPS was undertaken in 33 patients (group B), and IG was carried out in 31 patients (group C). Surgical time, blood loss, hospitalization time, drainage volume, and follow-up (FU) duration were recorded. The visual analog scale (VAS), Oswestry Disability Index (ODI), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), American Spinal Injury Association (ASIA) grade, segmental angle, intervertebral height and bone fusion time were compared between preoperative and final FU. All the patients were followed up for a mean 43.90±10.39 months in group A, 45.30±6.20 months in group B, 44.32±7.17 months in group C without difference(P>0.05). The mean age was younger, the blood loss was less, the hospitalization time and the surgical time were shorter in group A than those in group B and C (P0.05). In conclusion, the LSP and TPS as bone graft are reliable, safe, and effective for single-segment stability reconstruction for surgical management of thoracic TB and TPS could be new bone graft methods.

Rationale: Some studies have shown that the local activation of immunogenic cell death (ICD) by upregulating calreticulin (CRT) expression in solid tumors can improve antitumor effects. Although a promising approach, a key current challenge in ICD tumor therapy is the absence of a clinically translatable method for reproducibly inducing the CRT expression. Herein, we report a novel calreticulin-nanoparticle (CRT-NP) that enhances ICD and synergizes with focused ultrasound (FUS) to achieve local and systemic antitumor effects. Methods: Full-length clone DNA of calreticulin was encapsulated in NPs made from DOTAP and cholesterol. Three CRT-NP intratumoral injections of 20 µg each were given 2 days apart, and FUS heating (42-45°C, ~15min) was applied sequentially 24h after each injection to induce ICD. To investigate ICD specific immune effect, the splenocytes of mice vaccinated with CRT-NP (± FUS) treated B16F10 cells were evaluated ex-vivo for TRP-2 antigen specific immunity. Additionally, the long-term protection was evaluated by re-challenging with the melanoma cells in the flank regions of tumor bearing mice. Results: CRT-NP plus FUS (CFUS) upregulated CRT expression, expanded the population of melanoma TRP-2 specific functional CD4+ and CD8+ T cells and tumor-suppressing M1 phenotype, and increased PD-1 and PD-L1 marker expression in the T cells. Therapeutically, CFUS suppressed B16 melanoma growth by >85% vs. that seen in untreated controls, and >~50% vs. CRT-NP or FUS alone, and prevented tumor growth in distal untreated sites. Conclusions: CRT-NP amplifies the FUS and ICD therapeutic outcomes against melanoma, suggesting that the proposed combinatorial methodology may be clinically translatable.

Rationale: Tuberculosis (TB) remains the leading cause of death among infectious diseases worldwide. Poor compliance of TB patients to the lengthy treatment increases the risk of relapse and leads to the emergence of multidrug-resistant and extensively drug-resistant TB (MDR-TB and XDR-TB). More effective therapies for TB are urgently needed. We hypothesized that granulysin-mediated clearance of M. tuberculosis parasited inside and outside of alveolar macrophages in presumptive infected hosts might enhance the chemotherapeutic efficacy on TB. Methods: Recombinant adenovirus type 5 (rAd5) based therapeutic vaccines rAdhGLi and rAdhGLs (rAds) were respectively developed to express intracellular and extracellular granulysin. The ex vivo bactericidal effects of rAdhGLi and rAdhGLs were evaluated on U937 and RAW264.7 cells. The efficacy of immunotherapy with both rAdhGLi and rAdhGLs on TB SCID mice, or immunotherapy combined with chemotherapy on drug-susceptible TB or MDR-TB mouse models were further evaluated. Results: rAdhGLs, as well as rAdhGLi, showed a direct bactericidal effect on extracellular or intracellular M. tuberculosis H37Rv and MDR-TB clinical strains, respectively. Immunotherapy with a dose of 109 PFU of rAdhGLi and 109 PFU of rAdhGLs demonstrated a more significant bactericidal effect on M. tuberculosis H37Rv infected SCID mice and prolonged their survival periods than rAdhGLi or rAdhGLs alone. More importantly, chemotherapy combined with rAds immunotherapy shortened the chemotherapeutic duration to 4 months on M. tuberculosis H37Rv infected mice and prevented the relapse. Combination of rAds with chemotherapy on MDR-TB mice also more significantly decreased organ bacterial load than their single use. Conclusions: Delivery of granulysin by recombinant adenovirus to the infected lung could enhance the clearance of TB in vivo and might be a promising adjunct therapeutic vaccine for TB and MDR-TB.

Autophagy allows cancer cells to respond changes in nutrient status by degrading and recycling non-essential intracellular contents. Inhibition of autophagy combined with nutrient deprivation is an effective strategy to treat cancer. Pain is a primary determinant of poor quality of life in advanced cancer patients, but there is currently no satisfactory treatment. In addition, effective treatment of cancer does not efficiently relieve cancer pain, but may increase pain in many cases. Hence, few studies focus on simultaneous cancer therapy and pain relief, and made this situation even worse. Method: Ropivacaine was loaded into tumor-active targeted liposomes. The cytotoxicity of ropivacaine-based combination therapy in B16 and HeLa cells were tested. Moreover, a mice model of cancer pain which was induced by inoculation of melanoma near the sciatic nerve was constructed to assess the cancer suppression and pain relief effects of ropivacaine-based combination therapy. Results: Ropivacaine and ropivacaine-loaded liposomes (Rop-DPRL) were novelly found to damage autophagic degradation. Replicated administration of Rop-DPRL and calorie restriction (CR) could efficiently repress the development of tumor. In addition, administration of Rop-DPRL could relieve cancer pain with its own analgestic ability in a short duration, while repeated administration of Rop-DPRL and CR resulted in continuous alleviation of cancer pain through reduction of VEGF-A levels in advanced cancer mice. Further, dual inhibition of phosphorylation of STAT3 at Tyr705 and Ser727 by Rop-DPRL and CR contribute to the reduction of VEGF-A. Conclusion: Combination therapy with Rop-DPRL and nutrient deprivation simultaneously suppresses cancer growth and relieves cancer pain.

The hypoxia of the tumor microenvironment (TME) often hinders the effectiveness of cancer treatments, especially O2-dependent photodynamic therapy (PDT). Methods: An integrated iridium oxide (IrO2)-manganese dioxide (MnO2) nanotheranostic agent was fabricated through bovine serum albumin (BSA)-based biomineralization of Ir3+ and Mn2+. BSA was first covalently modified with chlorin e6 (Ce6), and used to fabricate multifunctional BSA-Ce6@IrO2/MnO2 nanoparticles (NPs) for computed X-ray tomography (CT) and photoacoustic (PA) imaging-guided PDT and photothermal (PTT) therapy of cancer. Extensive in vitro and in vivo studies were performed. Results: The theranostic agent produced can relieve tumor hypoxia by the decomposition of endogenous H2O2 in cancer cells to oxygen. The oxygen generated can be exploited for improved PDT. Paramagnetic Mn2+ released from the NPs in the acidic TME permits magnetic resonance imaging (MRI) to be performed. The exceptional photothermal conversion efficiency (65.3%) and high X-ray absorption coefficient of IrO2 further endow the NPs with the ability to be used in computed CT and PA imaging. Extensive antitumor studies demonstrated that the BSA-Ce6@IrO2/MnO2 nanoplatform inhibits cancer cell growth, particularly after combined PTT and PDT. Systematic in vivo biosafety evaluations confirmed the high biocompatibility of the nanoplatform. Conclusion: This work not only provides a novel strategy for designing albumin-based nanohybrids for theranostic applications but also provides a facile approach for extending the biomedical applications of iridium-based materials.

Neoadjuvant chemotherapy has been used increasingly in patients with early-stage or locally advanced breast carcinoma, and has been recommended as a general approach in locally advanced-stage diseases. Assessing therapy response could offer prognostic information to help determine subsequent nursing plan; particularly it is essential to identify responders and non-responders for the sake of helping develop follow-up treatment strategies. However, at present, diagnostic accuracy of preoperative clinical examination are still not satisfactory. Here we presented an alternate approach to monitor tumor and stroma changes associated with neoadjuvant therapy responses in breast carcinoma, with a great potential for becoming a new diagnostic tool—multiphoton microscopy. Imaging results showed that multiphoton imaging techniques have the ability to label-freely visualize tumor response such as tumor necrosis, and stromal response including fibrosis, mucinous response, inflammatory response as well as vascular hyperplasia in situ at cellular and subcellular levels. Moreover, using automated image analysis and a set of scoring methods, we found significant differences in the area of cell nucleus and in the content of collagen fibers between the pre-treatment and post-treatment breast carcinoma tissues. In summary, this study was conducted to pathologically evaluate the response of breast carcinoma to preoperative chemotherapy as well as to assess the efficacy of multiphoton microscopy in detecting these pathological changes, and experimental results demonstrated that this microscope may be a promising tool for label-free, real-time assessment of treatment response without the use of any exogenous contrast agents.

Multifunctional supramolecular nanoplatforms that integrate the advantages of different therapeutic techniques can trigger multimodal synergistic treatment of tumors, thus representing an emerging powerful tool for cancer therapeutics. Methods: In this work, we design and fabricate a multifunctional supramolecular drug delivery platform, namely Fa-mPEG@CP5-CuS@HMSN-Py nanoparticles (FaPCH NPs), consisting of a pyridinium (Py)-modified hollow mesoporous silica nanoparticles-based drug reservoir (HMSN-Py) with high loading capacity, a layer of NIR-operable carboxylatopillar[5]arene (CP5)-functionalized CuS nanoparticles (CP5-CuS) on the surface of HMSN-Py connected through supramolecular host-guest interactions between CP5 rings and Py stalks, and another layer of folic acid (Fa)-conjugated polyethylene glycol (Fa-PEG) antennas by electrostatic interactions capable of active targeting at tumor lesions, in a controlled, highly integrated fashion for synergistic chemo-photothermal therapy. Results: Fa-mPEG antennas endowed the enhanced active targeting effect toward cancer cells, and CP5-CuS served as not only a quadruple-stimuli responsive nanogate for controllable drug release but also a special agent for NIR-guided photothermal therapy. Meanwhile, anticancer drug doxorubicin (DOX) could be released from the HMSN-Py reservoirs under tumor microenvironments for chemotherapy, thus realizing multimodal synergistic therapeutics. Such a supramolecular drug delivery platform showed effective synergistic chemo-photothermal therapy both in vitro and in vivo. Conclusion: This novel supramolecular nanoplatform possesses great potential in controlled drug delivery and tumor cellular internalization for synergistic chemo-photothermal therapy, providing a promising approach for multimodal synergistic cancer treatment.

Rationale: Corneal transplantation is an effective treatment to corneal blindness. However, the immune rejection imperils corneal allograft survival. An interventional modality is urgently needed to inhibit immune rejection and promote allograft survival. In our previous study, subconjunctival injections of bone marrow-derived mesenchymal stem cells (BM-MSCs) into a rat model of corneal allograft rejection extended allograft survival for 2 d. In this study, we sought to generate IL-10-overexpressing BM-MSCs, aiming to boost the survival-promoting effects of BM-MSCs on corneal allografts and explore the molecular and cellular mechanisms underlying augmented protection. Methods: A population of IL-10-overexpressing BM-MSCs (designated as IL-10-BM-MSCs) were generated by lentivirus transduction and FACS purification. The self-renewal, multi-differentiation, and immunoinhibitory capabilities of IL-10-BM-MSCs were examined by conventional assays. The IL-10-BM-MSCs were subconjunctivally injected into the model of corneal allograft rejection, and the allografts were monitored on a daily basis. The expression profiling of long noncoding RNA (lncRNA) in the allografts was revealed by RNA sequencing and verified by quantitative real-time PCR. The infiltrating immune cell type predominantly upregulating the lncRNA expression was identified by RNAscope in situ hybridization. The function of the upregulated lncRNA was proved by loss- and gain-of-function experiments both in vivo and in vitro. Results: The IL-10-BM-MSCs possessed an enhanced immunoinhibitory capability and unabated self-renewal and multi-differentiation potentials as compared to plain BM-MSCs. The subconjunctivally injected IL-10-BM-MSCs reduced immune cell infiltration and doubled allograft survival time (20 d) as compared to IL-10 protein or plain BM-MSCs in the corneal allograft rejection model. Further, IL-10-BM-MSCs significantly upregulated lncRNA 003946 expression in CD68+ macrophages infiltrating corneal allografts. Silencing and overexpressing lncRNA 003946 in macrophage cultures abolished and mimicked the IL-10-BM-MSCs' suppressing effects on the macrophages' antigen presentation, respectively. In parallel, knocking down and overexpressing the lncRNA in vivo abrogated and simulated the survival-promoting effects of IL-10-BM-MSCs on corneal allografts, respectively. Conclusion: The remarkable protective effects of IL-10-BM-MSCs support further developing them into an effective interventional modality against corneal allograft rejection. IL-10-BM-MSCs promote corneal allograft survival mainly through upregulating a novel lncRNA expression in graft-infiltrating CD68+ macrophages. LncRNA, for the first time, is integrated into an IL-10-BM-MSC-driven immunomodulatory axis against the immune rejection to corneal allograft.

Purpose To investigate men’s experiences of receiving external-beam radiotherapy (EBRT) with neoadjuvant Androgen Deprivation Therapy (ADT) for localized prostate cancer (LPCa) in the ProtecT trial. Methods A longitudinal qualitative interview study was embedded in the ProtecT RCT. Sixteen men with clinically LPCa who underwent EBRT in ProtecT were purposively sampled to include a range of socio-demographic and clinical characteristics. They participated in serial in-depth qualitative interviews for up to 8 years post-treatment, exploring experiences of treatment and its side effects over time. Results Men experienced bowel, sexual, and urinary side effects, mostly in the short term but some persisted and were bothersome. Most men downplayed the impacts, voicing expectations of age-related decline, and normalizing these changes. There was some reticence to seek help, with men prioritizing their relationships and overall health and well-being over returning to pretreatment levels of function. Some unmet needs with regard to information about treatment schedules and side effects were reported, particularly among men with continuing functional symptoms. Conclusions These findings reinforce the importance of providing universal clear, concise, and timely information and supportive resources in the short term, and more targeted and detailed information and care in the longer term to maintain and improve treatment experiences for men undergoing EBRT.

There is an increasing emphasis on cost-effectiveness for all forms of treatment, occurring in parallel with constraints on research dollars. It would therefore seem useful for investigators to try to use ongoing research data as a basis for demonstrating a positive economic impact when outcome data are available. Some thoughts and figures are presented from a large alcoholism project, for which there were also some treatment outcomes. These data permitted dollar estimates, in terms of community impact, which are offered as a basis for further discussion. Although crude, these types of estimates are seen as vital in making the economic arguments, which parallel those for the human misery side of substance abuse.“Cost/benefit ratio” has become a term heard often these days in reference to hospital clinical programs. No longer is it only important to have a successful program in terms of favorable clinical outcomes; now the question heard is “at what cost?” The formulas used in calculating the cost/benefit ...