Inhibiting HER3 Hyperphosphorylation in HER2-Overexpressing Breast Cancer through Multimodal Therapy with Branched Gold Nanoshells.

Treatment failure in breast cancers overexpressing human epidermal growth factor receptor 2 (HER2) is associated mainly to the upregulation of human epidermal growth factor receptor 3 (HER3) oncoprotein linked to chemoresitence. Therefore, to increase patient survival, here a multimodal theranostic nanoplatform targeting both HER2 and HER3 is developed. This consists of doxorubicin-loaded branched gold nanoshells functionalized with the near-infrared (NIR) fluorescent dye indocyanine green, a small interfering RNA (siRNA) against HER3, and the HER2-specific antibody Transtuzumab, able to provide a combined therapeutic outcome (chemo- and photothermal activities, RNA silencing, and immune response). In vitro assays in HER2+ /HER3+ SKBR-3 breast cancer cells have shown an effective silencing of HER3 by the released siRNA and an inhibition of HER2 oncoproteins provided by Trastuzumab, along with a decrease of the serine/threonine protein kinase Akt (p-AKT) typically associated with cell survival and proliferation, which helps to overcome doxorubicin chemoresistance. Conversely, adding the NIR light therapy, an increment in p-AKT concentration is observed, although HER2/HER3 inhibitions are maintained for 72 h. Finally, in vivo studies in a tumor-bearing mice model display a significant progressively decrease of the tumor volume after nanoparticle administration and subsequent NIR light irradiation, confirming the potential efficacy of the hybrid nanocarrier.

Curative islet and hematopoietic cell transplantation in diabetic mice without toxic bone marrow conditioning.

Mixed hematopoietic chimerism can promote immune tolerance of donor-matched transplanted tissues, like pancreatic islets. However, adoption of this strategy is limited by the toxicity of standard treatments that enable donor hematopoietic cell engraftment. Here, we address these concerns with a non-myeloablative conditioning regimen that enables hematopoietic chimerism and allograft tolerance across fully mismatched major histocompatibility complex (MHC) barriers. Treatment with an αCD117 antibody, targeting c-Kit, administered with T cell-depleting antibodies and low-dose radiation permits durable multi-lineage chimerism in immunocompetent mice following hematopoietic cell transplant. In diabetic mice, co-transplantation of donor-matched islets and hematopoietic cells durably corrects diabetes without chronic immunosuppression and no appreciable evidence of graft-versus-host disease (GVHD). Donor-derived thymic antigen-presenting cells and host-derived peripheral regulatory T cells are likely mediators of allotolerance. These findings provide the foundation for safer bone marrow conditioning and cell transplantation regimens to establish hematopoietic chimerism and islet allograft tolerance.

5-Azacytidine depletes HSCs and synergizes with an anti-CD117 antibody to augment donor engraftment in immunocompetent mice.

Depletion of hematopoietic stem cells (HSCs) is used therapeutically in many malignant and nonmalignant blood disorders in the setting of a hematopoietic cell transplantation (HCT) to eradicate diseased HSCs, thus allowing donor HSCs to engraft. Current treatments to eliminate HSCs rely on modalities that cause DNA strand breakage (ie, alkylators, radiation) resulting in multiple short-term and long-term toxicities and sometimes even death. These risks have severely limited the use of HCT to patients with few to no comorbidities and excluded many others with diseases that could be cured with an HCT. 5-Azacytidine (AZA) is a widely used hypomethylating agent that is thought to preferentially target leukemic cells in myeloid malignancies. Here, we reveal a previously unknown effect of AZA on HSCs. We show that AZA induces early HSC proliferation in vivo and exerts a direct cytotoxic effect on proliferating HSCs in vitro. When used to pretreat recipient mice for transplantation, AZA permitted low-level donor HSC engraftment. Moreover, by combining AZA with a monoclonal antibody (mAb) targeting CD117 (c-Kit) (a molecule expressed on HSCs), more robust HSC depletion and substantially higher levels of multilineage donor cell engraftment were achieved in immunocompetent mice. The enhanced effectiveness of this combined regimen correlated with increased apoptotic cell death in hematopoietic stem and progenitor cells. Together, these findings highlight a previously unknown therapeutic mechanism for AZA which may broaden its use in clinical practice. Moreover, the synergy we show between AZA and anti-CD117 mAb is a novel strategy to eradicate abnormal HSCs that can be rapidly tested in the clinical setting.

Antibody Conditioning Enables MHC-Mismatched Hematopoietic Stem Cell Transplants and Organ Graft Tolerance.

Hematopoietic cell transplantation can correct hematological and immunological disorders by replacing a diseased blood system with a healthy one, but this currently requires depleting a patient's existing hematopoietic system with toxic and non-specific chemotherapy, radiation, or both. Here we report an antibody-based conditioning protocol with reduced toxicity and enhanced specificity for robust hematopoietic stem cell (HSC) transplantation and engraftment in recipient mice. Host pre-treatment with six monoclonal antibodies targeting CD47, T cells, NK cells, and HSCs followed by donor HSC transplantation enabled stable hematopoietic system reconstitution in recipients with mismatches at half (haploidentical) or all major histocompatibility complex (MHC) genes. This approach allowed tolerance to heart tissue from HSC donor strains in haploidentical recipients, showing potential applications for solid organ transplantation without immune suppression. Fully mismatched chimeric mice developed antibody responses to nominal antigens, showing preserved functional immunity. These findings suggest approaches for transplanting immunologically mismatched HSCs and solid organs with limited toxicity.

El poder cardíaco un instrumento del pasado, posiblemente una herramienta moderna en la valoración: clínica, terapéutica y pronóstica del choque cardiogénico por síndrome isquémico coronario agudo / The cardiac power output an old tool, possibly a modern tool for assessing cardiac pumping capability, as well as for a short-term prognosis in cardiogenic shock due to acute myocardial infarction

Hemodynamic monitoring has been used extensively during the last decades for risk stratification and guiding treatment of patients with cardiovascular destabilization, especially in the scenario of acute heart failure and cardiac shock. Every cardiac pump has its own maximum performance, which denotes its pumping capability. The heart is a muscular mechanical pump with an ability to generate both flow (cardiac output) and pressure. The product of flow output and systemic arterial pressure is the rate of useful work done, [quot ]or the cardiac power[quot ] (CP). Cardiac pumping capability can be defined as the cardiac power output achieved by the heart during maximal stimulation, and cardiac reserve is the increase in power output as the cardiac performance is increased from the resting to the maximally stimulated state (CPR). Resting CP for a hemodynamically stable average sized adult is approximately 1 W. However, during stress or exercise, CPR can be recruited to increase the heart's pumping ability up to 6 W. In acute heart failure, the patient becomes hemodynamically unstable, and most of the cardiac pumping potential is recruited in order to sustain life. Hence, cardiac power measurements in patients with acute heart failure or with cardiogenic shock at rest represent most of the recruitable reserve available during the acute event, and their measurement reflects the severity of the patient's condition. It has been found that a cutoff value for CP of 0.53 W accurately predict in-hospital mortality for cardiogenic shock patients. Others investigators observed cutoff for increased mortality of CP < 1 W, data that were obtained at doses of maximal pharmacologic support yielding the individual maximal CP. In our experience, the cutoff value for CP that accurately predicts in-hospital mortality for cardiogenic shock patients is 0.7 W, but its impact on short-term prognosis is clearer if the patient achieves a CP equal or higher than 1 W after an optimal myocardial revascularization with interventional cardiac procedures. According to the data collected from the literature, CP deserves a place in the evaluation of the patient with cardiogenic shock due to an acute myocardial infarction, but a more profound analysis of this parameter an further evaluation are required in order to better understand its prognostic meaning in this acute cardiac syndrome.