Resistance to Antimalarial Monotherapy Is Cyclic.

Malaria is a prevalent parasitic disease that is estimated to kill between one and two million people-mostly children-every year. Here, we query PubMed for malaria drug resistance and plot the yearly citations of 14 common antimalarials. Remarkably, most antimalarial drugs display cyclic resistance patterns, rising and falling over four decades. The antimalarial drugs that exhibit cyclic resistance are quinine, chloroquine, mefloquine, amodiaquine, artesunate, artemether, sulfadoxine, doxycycline, halofantrine, piperaquine, pyrimethamine, atovaquone, artemisinin, and dihydroartemisinin. Exceptionally, the resistance of the two latter drugs can also correlate with a linear rise. Our predicted antimalarial drug resistance is consistent with clinical data reported by the Worldwide Antimalarial Resistance Network (WWARN) and validates our methodology. Notably, the cyclical resistance suggests that most antimalarial drugs are sustainable in the end. Furthermore, cyclic resistance is clinically relevant and discourages routine monotherapy, in particular, while resistance is on the rise. Finally, cyclic resistance encourages the combination of antimalarial drugs at distinct phases of resistance.

Measuring Cell-Edge Protrusion Dynamics during Spreading using Live-Cell Microscopy.

The development and homeostasis of multicellular organisms rely on coordinated regulation of cell migration. Cell migration is an essential event in the construction and regeneration of tissues, and is critical in embryonic development, immunological responses, and wound healing. Dysregulation of cell motility contributes to pathological disorders, such as chronic inflammation and cancer metastasis. Cell migration, tissue invasion, axon, and dendrite outgrowth all initiate with actin polymerization-mediated cell-edge protrusions. Here, we describe a simple, efficient, time-saving method for the imaging and quantitative analysis of cell-edge protrusion dynamics during spreading. This method measures discrete features of cell-edge membrane dynamics, such as protrusions, retractions, and ruffles, and can be used to assess how manipulations of key actin regulators impact cell-edge protrusions in diverse contexts.

Towards a Consensus on Alzheimer's Disease Comorbidity?

Alzheimer's disease (AD) is often comorbid with other pathologies. First, we review shortly the diseases most associated with AD in the clinic. Then we query PubMed citations for the co-occurrence of AD with other diseases, using a list of 400 common pathologies. Significantly, AD is found to be associated with schizophrenia and psychosis, sleep insomnia and apnea, type 2 diabetes, atherosclerosis, hypertension, cardiovascular diseases, obesity, fibrillation, osteoporosis, arthritis, glaucoma, metabolic syndrome, pain, herpes, HIV, alcoholism, heart failure, migraine, pneumonia, dyslipidemia, COPD and asthma, hearing loss, and tobacco smoking. Trivially, AD is also found to be associated with several neurodegenerative diseases, which are disregarded. Notably, our predicted results are consistent with the previously published clinical data and correlate nicely with individual publications. Our results emphasize risk factors and promulgate diseases often associated with AD. Interestingly, the comorbid diseases are often degenerative diseases exacerbated by reactive oxygen species, thus underlining the potential role of antioxidants in the treatment of AD and comorbid diseases.

Invadopodia, a Kingdom of Non-Receptor Tyrosine Kinases.

Non-receptor tyrosine kinases (NRTKs) are crucial mediators of intracellular signaling and control a wide variety of processes such as cell division, morphogenesis, and motility. Aberrant NRTK-mediated tyrosine phosphorylation has been linked to various human disorders and diseases, among them cancer metastasis, to which no treatment presently exists. Invasive cancer cells leaving the primary tumor use invadopodia, feet-like structures which facilitate extracellular matrix (ECM) degradation and intravasation, to escape the primary tumor and disseminate into distant tissues and organs during metastasis. A major challenge in metastasis research is to elucidate the molecular mechanisms and signaling pathways underlying invadopodia regulation, as the general belief is that targeting these structures can potentially lead to the eradication of cancer metastasis. Non-receptor tyrosine kinases (NRTKs) play a central role in regulating invadopodia formation and function, but how they coordinate the signaling leading to these processes was not clear until recently. Here, we describe the major NRTKs that rule invadopodia and how they work in concert while keeping an accurate hierarchy to control tumor cell invasiveness and dissemination.

Invasion and Metastasis as a Central Hallmark of Breast Cancer.

Hanahan and Weinberg introduced the "hallmarks of cancer" and typified essential biological abilities acquired by human cancer. Since then, a growing understanding of hallmark principles associated with breast cancer has assisted knowledge-based therapeutics development; however, despite the rapidly increasing number of targeted therapeutics, enduring disease-free responses for most forms of breast cancer is rare. Invasion and metastasis are the most defining feature of breast cancer malignancy and the leading cause of patient mortality. Hence, we propose a modified hallmarks model adapted to breast cancer, in which invasion and metastasis are shifted to the center of attention, thereby emphasizing it as a potentially superior therapeutic target. Although the scientific community highly appreciates the importance of the invasion and metastasis hallmark, as can be demonstrated by the growing number of publications on breast cancer metastasis, very few clinical trials concentrate on testing anti-metastasis inhibitors and even fewer trials focus on inhibitors for breast cancer metastasis. Here, we discuss the obstacles of applying research on invasion and metastasis therapeutics into the clinic and present current developments that could provide a potential solution to this dilemma.