Levofloxacin-induced Psychosis in a Young Healthy Patient.

Levofloxacin is a fluoroquinolone antibiotic commonly used to treat a wide range of bacterial infections. It is normally well tolerated with the most common side effect being gastrointestinal distress. Severe side effects including neuropsychiatric symptoms are rare but have been observed even in patients who lack risk factors or are otherwise healthy. Healthcare providers should be aware of these effects and consider transitioning to other antibiotics in patients who develop psychosis or other neuropsychiatric symptoms after initiating this medication. Symptoms rapidly improve after discontinuation of the drug, so prompt recognition can reduce morbidity and mortality. We report a case of levofloxacin-induced psychosis in a young healthy female patient.

Using MKK4's metastasis suppressor function to identify and dissect cancer cell-microenvironment interactions during metastatic colonization.

Host tissue microenvironment plays key roles in cancer progression and colonization of secondary organs. One example is ovarian cancer, which colonizes the peritoneal cavity and especially the omentum. Our research indicates that the interaction of ovarian cancer cells with the omental microenvironment can activate a stress-kinase pathway involving the mitogen-activated protein kinase kinase 4 (MKK4). A combination of clinical correlative and functional data suggests that MKK4 activation suppresses growth of ovarian cancer cells lodged in omentum. These findings prompted us to turn our focus to the cellular composition of the omental microenvironment and its role in regulating cancer growth. In this review, in addition to providing an overview of MKK4 function, we highlight a use for metastasis suppressors as a molecular tool to study cancer cell interaction with its microenvironment. We review features of the omentum that makes it a favorable microenvironment for metastatic colonization. In conclusion, a broader, evolutionary biology perspective is presented which we believe needs to be considered when studying the evolution of cancer cells within a defined microenvironment. Taken together, this approach can direct new multi-dimensional lines of research aimed at a mechanistic understanding of host tissue microenvironment, which could be used to realize novel targets for future research.

Building on the foundation of daring hypotheses: using the MKK4 metastasis suppressor to develop models of dormancy and metastatic colonization.

The identification of a novel metastasis suppressor function for the MAP Kinase Kinase 4 protein established a role for the stress-activated kinases in regulating the growth of disseminated cancer cells. In this review, we describe MKK4's biological mechanism of action and how this information is being used to guide the development of new models to study cancer cell dormancy and metastatic colonization. Specifically, we describe the novel application of microvolume structures, which can be modified to represent characteristics similar to those that cancer cells experience at metastatic sites. Although MKK4 is currently one of many known metastasis suppressors, this field of research started with a single daring hypothesis, which revolutionized our understanding of metastasis, and opened up new areas of exploration for basic research. The combination of our increasing knowledge of metastasis suppressors and such novel technologies provide hope for possible clinical interventions to prevent suffering from the burden of metastatic disease.

Disrupting ovarian cancer metastatic colonization: insights from metastasis suppressor studies.

Ovarian cancer affects approximately 25,000 women in the United States each year and remains one of the most lethal female malignancies. A standard approach to therapy is surgical cytoreduction, after which the remaining microscopic residual disease is treated with chemotherapy. The vast majority of patients have disease recurrence, underscoring the crucial need for approaches to control the regrowth, or colonization, of tissues after local treatment. Improved therapies require mechanistic information about the process of metastatic colonization, the final step in metastasis, in which cancer cells undergo progressive growth at secondary sites. Studies of metastasis suppressors are providing insights into events controlling metastatic colonization. This paper reviews our laboratory's approach to the identification, characterization, and functional testing of the JNKK1/MKK4 metastasis suppressor in ovarian cancer metastatic colonization. Specifically, we demonstrate that interaction of ovarian caner cells with the omental microenvironment activates JNKK1/MKK4 resulting in decreased proliferation without affecting apoptosis. The potential role of the omental microenvironment, specifically milky spot structures, is also described. It is our goal to provide this work as a usable paradigm that will enable others to study metastasis suppressors in clinical and experimental ovarian cancer metastases.

In vitro metastatic colonization of human ovarian cancer cells to the omentum.

Despite the potentially crucial contributions of the omentum in the regulation of ovarian cancer metastatic growth, it remains a poorly understood organ. Due to its anatomic location and structural fragility, the omentum presents inherent challenges to mechanism-based in vivo studies. Thus, the availability of an ex vivo omental model would, in part, address some of these difficulties posed. Here we describe a technique for identifying, isolating and maintaining ex vivo cultures of omenta from immune-compromised and -competent mice. Ex vivo culture conditions were developed that maintain tissue viability, architecture, and function for up to 10 days. Further experiments demonstrate that the ex vivo culture conditions allow for the proliferation of ovarian cancer cells in vitro and support a similar pattern of microscopic lesions after either intraperitoneal injection of ovarian cancer cells or co-culture of ovarian cancer cells with the omentum. In agreement with previous studies from our laboratory, histologic evaluation of these specimens found that ovarian cancer cells, as well as other peritoneal cancer cells, preferentially accumulate in, and colonize, omental areas rich in immune cells. We now recognize that these are specific, functional structures referred to as milky spots. In sum, these are foundational studies of a readily accessible model, which is easily manipulated and can be immediately used to study the dynamic process of omental colonization. It is hoped that investigators will use the data herein as a starting point for refinements and modifications which will enable them to tailor the model to the specific needs of the experimental question(s) they wish to pursue.