Metabolic Modulation of the Tumor Microenvironment Leads to Multiple Checkpoint Inhibition and Immune Cell Infiltration.

Cancer cells are known to be glycolytic, driving increased glucose consumption and its conversion to lactate. This process modulates the tumor microenvironment (TME). In the TME, glycolytically activated immune cells often become anergic, leading to an increase in immune checkpoint proteins such as programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). Most glycolytic inhibitors not only inhibit glycolysis of cancer but also of immune cells. Therefore, using a nanoparticle-delivered agent to preferentially inhibit glycolysis in tumor cells, and not in immune cells, has the potential to attenuate the expression of checkpoint proteins. Pyruvate dehydrogenase kinase 1 (PDK1) can be an important target to achieve tumor specific glycolysis inhibition. We report TME modulation by a mitochondrion-targeted nanoparticle (NP) containing a prodrug of dichloroacetate (DCA), a PDK1 inhibitor. We demonstrated that the targeted NP alters the TME which results in increased immunological activation against cancer cells, causing a decrease in mean tumor volume. Here, we also show findings that when Mito-DCA, a prodrug of DCA, was combined with anti-PD-1, a checkpoint inhibitor, results from in vivo syngeneic models showed an upregulation in the number of tumor infiltrating lymphocytes. This work provides a platform to bring therapeutic efficacy by selectively inhibiting glycolysis of cancer cells.

Reduction of Cisplatin-Induced Ototoxicity without Compromising Its Antitumor Activity.

Cisplatin is a major chemotherapeutic that continues to have a significant impact in the treatment of more than 50% of all cancers. Since its Food and Drug Administration approval in 1978 for the treatment of advanced ovarian and bladder cancer, this chemotherapeutic has made significant strides and its application has been extended to a large variety of other cancers. However, the vast majority of patients who receive cisplatin therapy often suffer from nephrotoxicity, neurotoxicity, nausea, and ototoxicity. Numerous methods currently exist for overcoming nephrotoxicity- and nausea-related side effects, but there is no clear prevention to fight ototoxicity and neurotoxicity. In this work, we examined Platin- A, a prodrug of cisplatin and aspirin, using preclinical mouse- and guinea pig-based models and demonstrated its efficacy with reduced ototoxicity. In addition, in vitro studies documented that when Platin- A is used in combination with a clinically relevant dose of radiation, its efficacy can further be improved by attacking cellular bioenergetic profiles, producing multiple modes of DNA damage, and delaying repair of damaged DNA. These studies demonstrated novel properties of the prodrug, Platin- A, highlighting its superior efficacy with reduced toxicity.

Cerebral lesions incidentally detected on 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography images of patients evaluated for body malignancies.

OBJECTIVES: The purpose of this work was done to evaluate the value of including the brain in the field of view of a whole-body 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography (FDG-PET) study of patients referred for the evaluation of body malignancies. METHODS: A total of 1026 consecutive patients were included in this work. The primary diagnoses were the following: lung (n = 253), colorectal (n = 148), head and neck (n = 61), lymphoma (n = 249), melanoma (n = 84), and others (n = 231). Whole-body FDG images including the brain were acquired with a dedicated PET tomograph (GE advance, General Electronic Medical Systems, Milwaukee, WI) one hour after the intravenous administration of 10 mCi of FDG. Two experienced nuclear medicine physicians interpreted the images. Positive findings in the brain or the skull were correlated with other imaging studies and clinical follow-up. RESULTS: Abnormal findings were detected in 3.9% (40/1026) of the patients. Among the 40 abnormal focal lesions, 29 patients had a known history of cerebral disease, cerebrovascular or metastatic disease in most patients. Of the 11 patients without a prior history of cerebral disease, four patients had increased focal FDG uptake suggestive of metastases. Among these, two were proven clinically, one was proven to be a skull base metastasis on MRI, and the other had negative clinical follow-up, but only of two months duration. The other seven patients had a decreased focal FDG uptake most consistent with infarct, one was proven clinically, and the other six had a negative clinical follow-up (mean of 6.3 months, range 1-10), but had multiple risk factors for cerebrovascular disease. CONCLUSIONS: We conclude that FDG-PET screening for cerebral lesions in patients with body malignancy has little clinical impact. Unsuspected cerebral or skull metastases were detected in 0.4% (4/1026) of the patients.

Psicología de las organizaciones: problemas contemporáneos / Organizational psychology: readings on human behavior in organization

Este libro se propone ser fuente de material fundamental de psicología de las organizaciones para quienes estudien, a cualquiera de los tres niveles posibles la administración de empresas. Figuran aquí trabajos de numerosos autores que han contribuido a nuestra comprensión de la conducta humana tanto en grupos como en organizaciones

Psicología de las organizaciones: experiencia / Organizational psichology: an experimental approach

Este libro trata de comunicar ciertos principios generales de psicología y pericia de posible aplicación en sociedades y empresas. La ciencia intenta aclarar una realidad concreta descubriendo las leyes y los principios generales que determinan esa realidad. La generalización da sentido al caso concreto, pero el caso sitúa la generalización en el mundo real; la hace aplicable. El experimentar situaciones sociales para después analizar tal experiencia produce el enlace eficaz de generalización y realidad concreta