Selective regulation of chemosensitivity in glioblastoma by phosphatidylinositol 3-kinase beta.

Resistance to chemotherapies such as temozolomide is a major hurdle to effectively treat therapy-resistant glioblastoma. This challenge arises from the activation of phosphatidylinositol 3-kinase (PI3K), which makes it an appealing therapeutic target. However, non-selectively blocking PI3K kinases PI3Kα/ß/δ/γ has yielded undesired clinical outcomes. It is, therefore, imperative to investigate individual kinases in glioblastoma's chemosensitivity. Here, we report that PI3K kinases were unequally expressed in glioblastoma, with levels of PI3Kß being the highest. Patients deficient of O6-methylguanine-DNA-methyltransferase (MGMT) and expressing elevated levels of PI3Kß, defined as MGMT-deficient/PI3Kß-high, were less responsive to temozolomide and experienced poor prognosis. Consistently, MGMT-deficient/PI3Kß-high glioblastoma cells were resistant to temozolomide. Perturbation of PI3Kß, but not other kinases, sensitized MGMT-deficient/PI3Kß-high glioblastoma cells or tumors to temozolomide. Moreover, PI3Kß-selective inhibitors and temozolomide synergistically mitigated the growth of glioblastoma stem cells. Our results have demonstrated an essential role of PI3Kß in chemoresistance, making PI3Kß-selective blockade an effective chemosensitizer for glioblastoma.

Neurotoxic properties of the Zika virus envelope protein.

Prenatal Zika virus (ZIKV) infection is a serious global concern as it can lead to brain injury and many serious birth defects, collectively known as congenital Zika syndrome. Brain injury likely results from viral mediated toxicity in neural progenitor cells. Additionally, postnatal ZIKV infections have been linked to neurological complications, yet the mechanisms driving these manifestations are not well understood. Existing data suggest that the ZIKV envelope protein can persist in the central nervous system for extended periods of time, but it is unknown if this protein can independently contribute to neuronal toxicity. Here we find that the ZIKV envelope protein is neurotoxic, leading to overexpression of poly adenosine diphosphate -ribose polymerase 1, which can induce parthanatos. Together, these data suggest that neuronal toxicity resulting from the envelope protein may contribute to the pathogenesis of post-natal ZIKV-related neurologic complications.

Common Dermatologic Conditions in Returning Travelers.

PURPOSE OF REVIEW: Travel medicine practitioners often are confronted with returning travelers with dermatologic disorders that could be of infectious causes or inflammatory or allergic. Some dermatologic processes are the result of exposure to insects or acquired due to environmental exposures. There is a broad range of dermatosis of infectious and non-infectious etiologies that clinicians need to consider in the differential diagnosis of dermatosis in travelers. RECENT FINDINGS: With increasing international travel to tropical destinations, many individuals may be exposed to rickettsia (i.e., African tick bite fever, scrub typhus, or Mediterranean spotted fever), parasitic infections (i.e., cutaneous larva migrans, cutaneous leishmaniasis, African trypanosomiasis, or American trypanosomiasis), viral infections (i.e., measles or Zika virus infection), bacterial (i.e., Buruli ulcer) or ectoparasites (scabies or tungiasis), and myiasis. Cutaneous lesions provide clinical clues to the diagnosis of specific exposures during travel among returned travelers. SUMMARY: Dermatologic disorders represent the third most common health problem in returned travelers, after gastrointestinal and respiratory illness. Many of these conditions may pose a risk of severe complications if there is any delay in diagnosis. Therefore, clinicians caring for travelers need to become familiar with the most frequent infectious and non-infectious skin disorders in travelers.

Defusing COVID-19: Lessons Learned from a Century of Pandemics.

Amidst the COVID-19 global pandemic of 2020, identifying and applying lessons learned from previous influenza and coronavirus pandemics may offer important insight into its interruption. Herein, we conducted a review of the literature of the influenza pandemics of the 20th century; and of the coronavirus and influenza pandemics of the 21st century. Influenza and coronavirus pandemics are zoonoses that spread rapidly in consistent seasonal patterns during an initial wave of infection and subsequent waves of spread. For all of their differences in the state of available medical technologies, global population changes, and social and geopolitical factors surrounding each pandemic, there are remarkable similarities among them. While vaccination of high-risk groups is advocated as an instrumental mode of interrupting pandemics, non-pharmacological interventions including avoidance of mass gatherings, school closings, case isolation, contact tracing, and the implementation of infection prevention strategies in healthcare settings represent the cornerstone to halting transmission. In conjunction with lessons learned from previous pandemics, the public health response to the COVID-19 pandemic constitutes the basis for delineating best practices to confront future pandemics.

Structural Vulnerability in the U.S. Revealed in Three Waves of COVID-19.

The novel coronavirus disease (COVID-19) pandemic has unveiled underlying health inequities throughout the United States. The pandemic has spread across U.S. states, affecting different vulnerable populations, including both inner-city and rural populations, and those living in congregate settings such as nursing homes and assisted-living facilities. In addition, since early April, there has been an increasing number of outbreaks of COVID-19 in jails and prisons. We describe three overlapping epidemiologic waves of spread of COVID-19 linked to three different kinds of structural vulnerabilities.

Fatal encephalopathy with wild-type JC virus and ruxolitinib therapy.

OBJECTIVE: JC virus (JCV) infection is a lytic infection of oligodendrocytes in progressive multifocal leukoencephalopathy; less common forms of central nervous system manifestations associated with JCV infection include granule cell neuronopathy, encephalopathy, and meningitis. Presented is the first case of fatal JCV encephalopathy after immunosuppressive therapy that included ruxolitinib. METHODS: Postmortem analysis included next generation sequencing, Sanger sequencing, tissue immunohistochemistry, and formalin-fixed hemisphere 7T magnetic resonance imaging. RESULTS: JCV DNA isolated from postmortem tissue samples identified a novel 12bp insertion that altered the transcription site binding pattern in an otherwise "wild-type virus," which has long been thought to be the nonpathogenic form of JCV. Anti-VP1 staining demonstrated infection in cortical neurons, hippocampal neurons, and glial and endothelial cells. INTERPRETATION: This expands the spectrum of identified JCV diseases associated with broad-spectrum immunosuppression, including JAK-STAT inhibitors, and sheds light on an additional neurotropic virus strain of the archetype variety. ANN NEUROL 2019;86:878-884.

Therapeutic Approaches for Zika Virus Infection of the Nervous System.

Zika virus has spread rapidly in the Americas and has caused devastation of human populations affected in these regions. The virus causes teratogenic effects involving the nervous system, and in adults and children can cause a neuropathy similar to Guillain-Barré syndrome, an anterior myelitis, or, rarely, an encephalitis. While major efforts have been undertaken to control mosquito populations that spread the virus and to develop a vaccine, drug development that directly targets the virus in an infected individual to prevent or treat the neurological manifestations is necessary. Rational and targeted drug development is possible since the viral life cycle and the structure of the key viral proteins are now well understood. While several groups have identified therapeutic candidates, their approaches differ in the types of screening processes and viral assays used. Animal studies are available for only a few compounds. Here we provide an exhaustive review and compare each of the classes of drugs discovered, the methods used for drug discovery, and their potential use in humans for the prevention or treatment of neurological complications of Zika virus infection.

Using the electrocorticographic speech network to control a brain-computer interface in humans.

Electrocorticography (ECoG) has emerged as a new signal platform for brain-computer interface (BCI) systems. Classically, the cortical physiology that has been commonly investigated and utilized for device control in humans has been brain signals from the sensorimotor cortex. Hence, it was unknown whether other neurophysiological substrates, such as the speech network, could be used to further improve on or complement existing motor-based control paradigms. We demonstrate here for the first time that ECoG signals associated with different overt and imagined phoneme articulation can enable invasively monitored human patients to control a one-dimensional computer cursor rapidly and accurately. This phonetic content was distinguishable within higher gamma frequency oscillations and enabled users to achieve final target accuracies between 68% and 91% within 15 min. Additionally, one of the patients achieved robust control using recordings from a microarray consisting of 1 mm spaced microwires. These findings suggest that the cortical network associated with speech could provide an additional cognitive and physiologic substrate for BCI operation and that these signals can be acquired from a cortical array that is small and minimally invasive.