Complement regulatory protein CD46 promotes bladder cancer metastasis through activation of MMP9.

CD46, a transmembrane protein known for protecting cells from complement­mediated damage, is frequently dysregulated in various types of cancer. Its overexpression in bladder cancers safeguards the cancer cells against both complement and antibody­mediated cytotoxicity. The present study explored a new role of CD46 in facilitating cancer cell invasion and metastasis, examining its regulatory effect on matrix metalloproteases (MMPs) and their effect on the metastatic capability of bladder cancer cells. Specifically, CD46 alteration positively influenced MMP9 expression, but not MMP2, in several bladder cancer cell lines. Furthermore, CD46 overexpression triggered phosphorylation of p38 MAPK and protein kinase B (AKT), leading to enhanced activator protein 1 (AP­1) activity via c­Jun upregulation. The inhibition of p38 or AKT pathways attenuated the CD46­induced MMP9 and AP­1 upregulation, indicating that the promotion of MMP9 by CD46 involved activating both p38 MAPK and AKT. Functionally, the upregulation of MMP9 by CD46 translated to increased migratory and invasive capabilities of bladder cancer cells, as well as enhanced in vivo metastasis. Overall, the present study revealed a novel role for CD46 as a metastasis promoter through MMP9 activation in bladder cancers and highlighted the regulatory mechanism of CD46­mediated MMP9 promotion via p38 MAPK and AKT activation.

Exploring cellular immunotherapy platforms in multiple myeloma.

Despite major advances in therapeutic platforms, most patients with multiple myeloma (MM) eventually relapse and succumb to the disease. Among the novel therapeutic options developed over the past decade, genetically engineered T cells have a great deal of potential. Cellular immunotherapies, including chimeric antigen receptor (CAR) T cells, are rapidly becoming an effective therapeutic modality for MM. Marrow-infiltrating lymphocytes (MILs) derived from the bone marrow of patients with MM are a novel source of T cells for adoptive T-cell therapy, which robustly and specifically target myeloma cells. In this review, we examine the recent innovations in cellular immunotherapies, including the use of dendritic cells, and cellular tools based on MILs, natural killer (NK) cells, and CAR T cells, which hold promise for improving the efficacy and/or reducing the toxicity of treatment in patients with MM.

Efficacy of natural killer cell therapy combined with chemoradiotherapy in murine models of head and neck squamous cell carcinoma.

BACKGROUND AIMS: Natural killer (NK) cell-based cancer immunotherapy is effective when combined with other treatment modalities such as irradiation and chemotherapy. NK cell's antitumor function to treat solid tumor, including head and neck squamous cell carcinoma (HNSCC), has been targeted recently. This study assessed NK cell recruitment in response to chemoradiation therapy (CRT) in HNSCC. METHODS: Ex vivo expansion of NK cell, flow cytometry, cell viability assay, cytotoxicity assay, immunohistochemistry, and animal model were performed. RESULTS: Mouse NK cells were recruited to the tumor site by CRT in a nude mouse model. Furthermore, expanded and activated human NK cells (eNKs) were recruited to the tumor site in response to CRT, and CRT enhanced the anti-tumor activity of eNK in an NOD/SCID IL-2Rγnull mouse model. Various HNSCC cancer cell lines exhibited different NK cell ligand activation patterns in response to CRT that correlated with NK cell-mediated cytotoxicity. CONCLUSIONS: Identifying the activation patterns of NK cell ligands during CRT might improve patient selection for adjuvant NK cell immunotherapy combined with CRT. This is the first study to investigate the NK cell's antitumor function and recruitment with CRT in HNSCC mouse model.

Long-Term Outcomes of Left Main Bifurcation Double Stenting in Patients with STEMI and Cardiogenic Shock.

The contribution of different left main (LM) bifurcation stenting techniques on long-term CV mortality has been poorly investigated. We evaluated the 3-year outcomes of revascularization of unprotected complex bifurcation LM in patients with cardiogenic shock (CS) with LM bifurcation/distal disease as culprit lesion. We analyzed 752 consecutive patients with STEMI admitted to our centre from 1 January 2014 to 1 March 2018, searching for patients with CS and complex distal/bifurcation LM disease as culprit lesion who received, at operators' discretion, LM double stenting by means of Culotte, T-stenting/TAP or Nano-crush technique. Fifty-seven patients (23 females, mean age 62.3 ±â€¯10.5 years) with CS and STEMI with distal/bifurcation LM as culprit lesion were identified: 20 patients (35.0%) received Culotte, 16 patients (28.0%) received T-stenting/TAP and 20 (35.0%) received Nano-crush technique. At 3-year follow-up, clinical-driven target lesion revascularization, and mortality rate for all-causes were comparable among different stenting techniques. Conversely, considering 3-year CV mortality as outcome, a statistically significant difference was observed favoring Nano-crush when compared to patients treated with T stenting. Nano-crush obtained a larger improvement of ejection fraction on serial echocardiograms. CS with complex distal/bifurcation LM disease can be treated with acceptable rate of complication and short-term mortality using double stenting techniques. Techniques that minimize rewiring and kissing steps and shorten ischemic time should probably be preferred.

Usefulness of the Finet law to guide stent size selection in ostial left main stenting: Comparison with standard angiographic estimation.

BACKGROUNDS: Intravascular ultrasound has been suggested to optimize stent diameter and length in Left Main (LM) procedures, but in the real-world ostial LM stenting is often accomplished with angiography only guidance. The Finet law which regulates the fractal geometry of human bifurcation has the potential to increase the accuracy of stent-sizing. To retrospectively evaluating the impact on outcomes of the addition of Finet Law to standard quantitative coronary angiography (QCA) in guiding stent selection of ostial LM stenting compared to standard angiography estimation. METHODS: We retrospectively evaluated the clinical and instrumental records of patients with isolated ostial LM disease and bypass surgery contraindications or refusal as determined by the local Heart Team who received stenting from 1 January 2012 to 1 January 2017 at Rovigo General Hospital. Patients were discrimined on the basis of the addition to QCA angiographic evaluation of the Finet-law. RESULTS: Seventy-three patients (45 males, mean age 69.9 ±â€¯10.9 years old) ostial LM stenting, 36 patients using QCA and Finet law (QCA-Finet) and 37 using standard QCA angiographic (QCA-angio) evaluation of the vessel diameter. By QCA, vessel size, mean stent diameter at implantation and after post-dilatation were clearly bigger in the QCA+ Finet than QCA-angio (4.4 ±â€¯0.8 and 3.8 ±â€¯0.7, p < 0.001). At a mean follow-up of 5.0 ±â€¯0.4 years, cardiovascular mortality and cardiovascular events incidence were higher in QCA-angio compared to QCA+Finet group of patients. CONCLUSIONS: Our study suggested that adding the Finet law to standard angiography estimation of the LM stent size may improve long-term outcomes.

The mCME Project: A Randomized Controlled Trial of an SMS-Based Continuing Medical Education Intervention for Improving Medical Knowledge among Vietnamese Community Based Physicians' Assistants.

BACKGROUND: Community health workers (CHWs) provide critical services to underserved populations in low and middle-income countries, but maintaining CHW's clinical knowledge through formal continuing medical education (CME) activities is challenging and rarely occurs. We tested whether a Short Message Service (SMS)-based mobile CME (mCME) intervention could improve medical knowledge among a cadre of Vietnamese CHWs (Community Based Physician's Assistants-CBPAs) who are the leading providers of primary medical care for rural underserved populations. METHODS: The mCME Project was a three arm randomized controlled trial. Group 1 served as controls while Groups 2 and 3 experienced two models of the mCME intervention. Group 2 (passive model) participants received a daily SMS bullet point, and were required to reply to the text to acknowledge receipt; Group 3 (interactive model) participants received an SMS in multiple choice question format addressing the same thematic area as Group 2, entering an answer (A, B, C or D) in their response. The server provided feedback immediately informing the participant whether the answer was correct. Effectiveness was based on standardized examination scores measured at baseline and endline (six months later). Secondary outcomes included job satisfaction and self-efficacy. RESULTS: 638 CBPAs were enrolled, randomized, and tested at baseline, with 592 returning at endline (93.7%). Baseline scores were similar across all three groups. Over the next six months, participation of Groups 2 and 3 remained high; they responded to >75% of messages. Group 3 participants answered 43% of the daily SMS questions correctly, but their performance did not improve over time. At endline, the CBPAs reported high satisfaction with the mCME intervention, and deemed the SMS messages highly relevant. However, endline exam scores did not increase over baseline, and did not differ between the three groups. Job satisfaction and self-efficacy scores also did not improve. Average times spent on self-study per week did not increase, and the kinds of knowledge resources used by the CBPAs did not differ between the three groups; textbooks, while widely available, were seldom used. CONCLUSIONS: The SMS-based mCME intervention, while feasible and acceptable, did not result in increased medical knowledge. We hypothesize that this was because the intervention failed to stimulate lateral learning. For an intervention of this kind to be effective, it will be essential to find more effective ways to couple SMS as a stimulus to promote increased self-study behaviors. TRIAL REGISTRATION: ClinicalTrials.gov NCT02381743.